Therapy 21 Eberhard Nieschlag and Hermann M. Behre

Contents 21.1 Indications and Preparations: An Overview 21.1 Indications and Preparations: An Overview ...... 437 21.2 Pharmacology of Testosterone All forms of described in the previ- Preparations ...... 439 ous chapters associated with Leydig cell insuffi - 21.2.1 Oral Testosterone Preparations ...... 439 ciency require testosterone therapy. In secondary 21.2.2 ...... 441 hypogonadism long-term testosterone therapy is also 21.2.3 Intramuscular Testosterone Preparations 442 indicated. This is only to be interrupted for GnRH or 21.2.4 Testosterone Preparations .. 444 21.2.5 Testosterone Implants ...... 445 gonadotropin therapy when offspring are desired. 21.3 Monitoring Testosterone Therapy in Hypogonadism ...... 446 Male hypogonadism is the main indication for testos- terone. Table 21.1 provides an overview of other pos- 21.3.1 Psyche and Sexuality ...... 446 21.3.2 Somatic Parameters ...... 447 sible applications. Some of these applications are 21.3.3 Laboratory Parameters ...... 447 dealt with in other chapters of this volume, for example 21.3.4 Prostate and Seminal Vesicles ...... 449 in constitutionally delayed puberty (Chap. 12), in late- 21.3.5 Bone Mass and Muscles ...... 450 onset hypogonadism (LOH) (Chap. 14), in male hor- 21.4 Evaluation of Testosterone monal contraception (Chap. 29) and in idiopathic Substitution Therapy ...... 451 male infertility (Chap. 22). In addition, this chapter 21.5 Excessive Height ...... 451 deals with its use in excessively tall stature (Sect. 21.6 Misuse and Abuse of Anabolic ...... 452 21.5) and with its abuse in doping and body building (Sect. 21.6). Because of its erythropoetic effect testos- References ...... 453 terone is also licensed for the treatment of aplastic and renal anemia, but lost ground to erythropoetin after the

Table 21.1 Use of testosterone in men Clinical applications Hypogonadism Primary hypogonadism Secondary hypogonadism LOH Delayed puberty Aplastic and renal anemia Off-label use Excessive growth Application under discussion Aging male Experimental use Male contraception E. Nieschlag () Obsolete application Idiopathic infertility Centre of Reproductive Medicine and Andrology of the University, Domagkstr. 11, D-48149 Münster/Germany Abuse High-performance athletics e-mail: [email protected] and bodybuilding

E. Nieschlag et al. (eds.), Andrology, 437 DOI: 10.1007/978-3-540-78355-8_21, © Springer-Verlag Berlin Heidelberg 2010 438 E. Nieschlag and H. M. Behre latter was introduced. For treatment of this condition, sexuality of their patients to date (Gooren et al. 2007). the reader is referred to textbooks of internal medicine. The International Recommendations for LOH also Testosterone therapy is indicated when, in cases establish 8 nmol/L as the absolute lower threshold for with defi ciency, serum testosterone concen- testosterone substitution and the range between 8 and trations drop below a certain level (see Chap. 5). 12 nmol/L as relative indications (Nieschlag et al. In Germany 12 nmol/L is considered the lower level 2006; Behre et al. 2004; Wang et al 2008). In unclear of normal. Surprisingly this level is lower in other cases calculated free testosterone below 225 pmol/L countries, e.g., Spain (9.0), Great Britain (7.5–8.0) and can be considered as an indication for testosterone France (7.5 nmol/L) (Nieschlag et al. 2004; Gooren substitution. Additionally the pharmacogenetics of tes- et al. 2007). A study designed to verify these differ- tosterone increasingly play a role and must be taken ences in aging hypogonadal patients concluded that not into consideration together with symptom-specifi c one single threshold level coincided with the occur- threshold levels when substituting hypogonadal rence of symptoms of hypogonadism, but that there are patients (Zitzmann and Nieschlag 2007). symptom-specifi c threshold levels ranging between 15 and 8 nmol/L. Loss of vigor and libido are observed Thus testosterone substitution must become more even below 15 nmol/L, while erectile dysfunction oriented towards patients’ complaints than at present caused by lack of testosterone occurs only below and consider carefully symptom-specifi c threshold 8 nmol/L. The other symptoms occur between these serum levels. 12 nmol/L total serum testosterone two levels (Fig. 21.1) (Zitzmann et al. 2006). A study in continues to be a good indication for low normal lev- younger hypogonadal men came to similar conclusions els. The effectiveness of substitution can be measured (Kelleher et al. 2004). directly by testosterone concentrations in serum. The question at which testosterone levels substitu- tion is initiated has been more determined by the phy- sicians’ perception of hypogonadism than by the Since we are dealing with hormone replacement ther- patients’ complaints. The fact that physicians, when apy, its effectiveness can be measured directly by questioned, mentioned the loss of libido as the most checking serum testosterone concentrations. frequent symptom of testosterone defi ciency shows how little importance physicians have attached to the According to international consensus which remains valid, the major goal of testosterone therapy is to Total testosterone nmol / L replace testosterone levels at as close to physiologi- 20 cal concentrations as is possible (Nieschlag et al. 74 1992). Furthermore, the naturally occurring testos- Normal terone molecule should be used for substitution in order to guarantee the broad spectrum of testosterone 69 effects. Available testosterone preparations should be 15 judged according to these criteria. Loss of libido 84 Loss of vigor 12 Certain target organs are able to use testosterone directly, Obesity 65 while for others it must fi rst be converted to 5a-DHT or 10 in order for them to become effective (Chap. 2). Feeling depressed, disturbed sleep Lacking concentration 67 To achieve a physiological balance between testoster- Diabetes mellitus type 2 (also non-obese men) 8 one and its active metabolites, natural testosterone Hot flushes should be used and not synthetic which are 75 Erectile dysfunction metabolized into other forms (e.g., 19-nortestosterone) 0 or are direct derivatives of the metabolites (e.g., mester- olone). In the same vein there is little purpose in apply- Fig. 21.1 Threshold levels of serum testosterone for various symptoms of late onset hypogonadism (LOH) in 434 patients ing estrogens either directly or exclusively to the (Zitzmann et al. 2006) hypogonadal male. Nor has any rational basis for the 21 Testosterone Therapy 439 use of testosterone precursors such as DHEA or andros- described below, nasal, conjunctival or rectal routes of tendione been established to date. The use of natural application can be chosen; however, at present these testosterone allows all androgen-dependent functions to forms play no role in clinical use. be induced or maintained in the safest way possible and This chapter deals with aspects relevant to andro- side effects to be avoided. gen therapy. For further reading reference is made to Testosterone was fi rst synthesized in 1935 current monographs (Nieschlag and Behre 2004). (Butenandt and Hanisch 1935; Ruzicka and Wettstein Table 21.1 and Fig. 21.3 provide an overview of avail- 1935) and used clinically shortly thereafter; thus it is able preparations and dosages. one of the oldest hormones in clinical use. First testos- terone implants were used, and since the 1950s testos- terone enanthate or cypionate were applied as i.m. injections. In the 1970s orally effective testosterone 21.2.1 Oral Testosterone Preparations undecanoate followed, and in the 1990s the fi rst trans- dermal testosterone substitution appeared in the form It would seem obvious to use natural testosterone in of a testosterone fi lm applied to the scrotum. Further the form it is secreted by the testes for substitution transdermal applications were membranes for non- therapy. In fact, orally applied free testosterone is well scrotal skin and fi nally testosterone gels were intro- absorbed from the intestine, but is completely metabo- duced. Injectable represents lized by the liver in the fi rst pass effect, so that it does a real depot preparation. A mucoadhesive buccal tes- not reach target organs. About 400–600 mg testoster- tosterone tablet completes the spectrum of currently one would have to be given orally, i.e., about 100-fold available preparations (Nieschlag 2006). of the amount normally secreted by the testis daily, in The experienced physician must select the form order to exceed the testosterone-metabolizing capacity most suitable for the patient, considering both his of the liver and to achieve normal peripheral serum symptoms and phase of life. Often several preparations levels. As administering such great amounts of testos- will have to be tried before fi nding an optimal choice terone seems uneconomical and as possible long-term for the individual patient. side effects are diffi cult to evaluate, this form of appli- cation never went beyond the experimental stage (Nieschlag and Behre 2004). 21.2 Pharmacology of Testosterone Preparations 21.2.1.1 Testosterone Undecanoate

In chemical terms, testosterone is derived from the In order to avoid the fi rst pass effect in the liver after basic structure of all androgens, i.e., from . oral application, testosterone was esterifi ed with unde- It owes its specifi c biological activity to the keto-group canoic acid in position 17b. This long aliphatic side in position 3, the double-bond in position 4 and the chain allows resorption of the molecule into the lymph hydroxy-group in position 17 of the basic androstane so that testosterone can enter the circulation through structure (Fig. 21.2 and Chap. 2). the thoracic ducts and via the subclavial vein, thus reaching target organs prior to hepatic metabolism. Principally, three approaches enable testosterone to Resorption is improved if oral testosterone is taken be used in therapy: with a meal containing fats. Testosterone undecanoate is available in 40 mg 1. Chemical modifi cation of the molecule capsule form with the testosterone being dissolved in oil 2. Esterifi cation in position 17 and (Andriol®; Testocaps®). As testosterone represents 63% 3. Various forms of application of the molecular weight, one capsule contains about 25 mg testosterone. For good absorption, ingestion with As routes of application are particularly important for a meal is required (Bagchus et al. 2003). Maximum clinical purposes, testosterone preparations will be dis- serum peaks are attained about 2–6 h after ingestion cussed here in these terms. In addition to the modalities (Schürmeyer et al. 1983; Behre and Nieschlag 1998b). 440 E. Nieschlag and H. M. Behre

Fig. 21.2 Molecular 18 OH structures of testosterone CH3 12 17 and various testosterone 19 11 13 16 CH 15 preparations 3 14 1 9 2 10 8 3 5 7 Testosterone 4 6 O O OCCHCH OH 2 3 CH CH3 3 CH3

CH3 CH3 17α- O O O O C (CH ) CH OH 2 5 3 CH CH3 3 HO CH3

CH3 CH3 F O O O

O C (CH2)2 OH CH3 CH3 CH3 CH3 CH3 O O O

O C (CH2)9CH3 OH CH3 CH3

CH3

Testosterone undecanoate 19-Nortestosterone O O O

OC (CH2)3CH3 OH CH3 CH3

CH3

Testosterone buciclate 7α-Methyl-19-Nortestosterone O O CH3

Fig. 21.3 Historical development of testosterone preparations for clinical use 21 Testosterone Therapy 441

40 however, can lead to elevated liver enzymes, as well

35 as to cholostasis and peliosis (for review see Nieschlag 1981). 30 Fluoxymesterone also contains a methyl group in 25 position 17a in addition to a fl uoride atom and 20 hydroxy group. Although this modifi cation makes fl u- 15 a highly effective oral testosterone

10 preparation, the 17a methyl group makes it liver-toxic Testosterone (nmoI/I) as well. For this reason these substances were taken 5 off the market in Germany, fi rst as monosubstances 0 0 1 2 3 4 5 6 7 8 9 10 and subsequently their use in combined preparations Days was prohibited. As they are still available in other countries, it is necessary to warn against their toxic Fig. 21.4 Serum testosterone concentrations following oral side effects. application of 3 × 40 mg testosterone undecanoate to hypogo- nadal men (pharmacokinetic computer simulation assuming basal testosterone levels of 7 nmol/l). The gray area indicates the range of testosterone in normal men In general, 17a-methylation of all androgens (also of anabolic steroids) may cause liver toxicity and therefore these preparations should be generally This means that two to four capsules spread over the considered obsolete. course of a day are required for substitution. Although relatively high testosterone concentrations are given, no long-term side effects or toxic effects have been observed (Gooren 1998). 21.1.2.3 Mesterolone Testosterone undecanoate is best suited for substi- tution therapy when the patient has a residual capac- Mesterolone (Proviron®, Vistimon®) is derived from the ity to secrete testosterone (e.g., Klinefelter patients in 5a-reduced testosterone metabolite 5a- the early phase of substitution). Another domain of (DHT) and is likewise not subject to hepatic metabolism testosterone undecanoate medication are situations following . As a DHT derivative, when intramuscular injections cannot be given however, it can only compensate for DHT-dependent because of clotting disturbances (e.g., patients on functions and not for the immediate effects of testoster- marcumar medication) or the patient cannot attend a one and those following aromatization to estrogens. physician for the injections (e.g., on holidays) ). The Thus, it does not develop the full spectrum of testoster- disadvantage of this therapy lies primarily in the one effects which are necessary for hormone replace- short-lived peaks and troughs in serum testosterone ment therapy and it is therefore not suitable for which do not mimic physiological conditions and in substitution in hypogonadism. the poor predictability of individual resorption pat- terns (Fig. 21.4).

21.2.2 Buccal Administration 21.2.1.2 Methyl Testosterone and Fluoxymesterone Incorporating testosterone into polyethylene matrices with limited water-solubility represents a new attempt 17a-Methyl testosterone resulted from attempts to develop forms for buccal application: Striant®. The started shortly after testosterone synthesis in 1935 to mucoadhesive tablets adhere to the gingiva above the modify the molecule chemically. The methyl group in incisors for many hours and slowly release testoster- position 17a protects the testosterone molecule from one into the circulation. Twice daily application results being metabolized in the liver so that it can reach tar- in even serum levels (Fig. 21.5) (Korbonits et al 2004; get organs after oral administration. Long-term use, Nieschlag et al 2004; Wang et al 2004). 442 E. Nieschlag and H. M. Behre

21.2.3 Intramuscular Testosterone Table 21.2 Pharmacokinetic data of various testosterone Preparations preparations Preparation Application Mean Terminal residence mean time 21.2.3.1 Testosterone Enanthate time (MRT) (t½) Testosterone p.o. 3.7 h 1.6 h undecanoate When natural testosterone is injected intramuscularly, Testosterone i.m. 1.5 days 0.8 days its half-life is very short. In order to prolong its effec- propionate tiveness, testosterone was esterifi ed in position 17 with Testosterone i.m. 8.5 days 4.5 days aliphatic side chains. The duration of half-life depends enanthate upon the length and structure of the side chain. Testosterone Intramuscular administration of testosterone enan- undecanoate In tea seed oil i.m. 34.9 days 20.9 days thate is the form most widely used in hormone replace- In castor oil i.m. 36.0 days 33.9 days ment therapy and was introduced in 1952. Its terminal Testosterone i.m. 60.0 days 29.5 days half-life is 4.5 days (Table 21.2). The standard dose is buciclate 200–250 mg testosterone enanthate (e.g., Testoviron® Depot 250 mg, Testosterone Depot). As the pharma- cokinetics show, supraphysiological serum testoster- enanthate was the most widely used therapy for many one concentrations are rapidly achieved and are years, as there were no suitable alternatives. maintained for several days (Fig. 21.5) (Behre et al. Testosterone cypionate and testosterone cyclo- 2004). Subsequently serum levels gradually decline, hexanecarboxylate, available in some countries, have passing the lower level of normal on about day 12. the same as testosterone enanthate Repeated injections, such as are necessary for substitu- and, consequently, similar advantages and disadvan- tion therapy, produce a “saw-tooth profi le” with supra- tages as testosterone enanthate. physiological, physiological and infraphysiological levels following one another depending on the injec- tion interval (Fig. 21.6). While this substitution regi- 21.2.3.2 Testosterone Propionate men is adequate to maintain the biological effects of testosterone, the patient fi nds these extremes disturb- Testosterone propionate (Testoviron®) has a short half- ing, as general well-being, moods, and sexual activity life as a consequence of its short side chain (Table 21.2). refl ect these patterns. Nonetheless, testosterone Initial serum concentrations following i.m.

Buccal system (n=29) Fig. 21.5 Serum testosterone Transdermal patch (n=28) concentration (mean ± SD) 40 following 7–8 days therapy with Striant®, one tablet every 35 12 h; times of application marked by thin arrows 30 compared to transdermal therapeutic systems 25 (Androderm® or Andropatch®) 5 mg/day, time of application 20 marked by large arrows). 15 Serum levels over 24 h are shown (0 = 8 o’clock for buccal 10 testosterone, 22 h for transder- mal testosterone). Dotted line 5 indicates normal range Mean (SD) Testosterone nmoI/L (Modifi ed from Korbonits et al. 0 2004. With permission of the 0 2 4 6 8 10 12 14 16 18 20 24 Endocrine Society, USA) Time (hours) 21 Testosterone Therapy 443

1 week 80 a combination of testosterone propionate and testoster- 60 one enanthate offer any advantage (Behre et al. 2004). 40 20 0 21.2.3.3 Testosterone Undecanoate 80 2 weeks 60 Testosterone undecanoate, introduced to Europe in the 40 1970s as an oral preparation (see Sect. 21.2.1.1), was 20 fi rst developed in China as an injectable form (Wang 0 et al. 1991). Testosterone undecanoate was dissolved 80 3 weeks in tea seed oil. When castor oil was used as vehicle, 60 the half life could be extended even further (Behre Testosterone (nmol/l) 40 et al. 1999a, Table 21.3). Along with the longer effec- 20 tiveness, the absence of initial supraphysiological 0 80 peaks made it superior to testosterone enanthate 4 weeks 60 (Fig. 21.7). 40 For substitution 1,000 mg testosterone undecanoate ® 20 (Nebido ) are injected about four times per year. In 0 order to achieve a steady state at the beginning of sub- 0 246810121416 Weeks stitution the second injection is given 6 weeks after the fi rst, further injections follow 10–14 weeks later Fig. 21.6 Testosterone serum levels in hypogonadal men follow- (Fig. 21.8). Individual intervals are determined accord- ing of 250 mg testosterone enanthate ing to serum testosterone levels which are measured given at intervals of 1, 2, 3, or 4 weeks. The gray area indicates the normal range of testosterone immediately before the next injection. These determi- nations are then repeated at yearly intervals. Values that are too high lead to extension of injection inter- vals, those that are too low to a shortening of injection may be as high as with testosterone enanthate, but the intervals. Slow intergluteal injections are recom- injections must be repeated every 2–3 days because of mended. No adverse side effects have been observed, its short half-life to achieve full substitution. Because even after many years of use (Nieschlag et al 1999; of the necessity for frequent injections testosterone von Eckardstein et al 2002; Schubert et al 2004; propionate is not suitable for chronic therapy, nor does Zitzmann and Nieschlag 2007).

Table 21.3 Testosterone preparations used in Germany for substitution of hypogonadism Application Preparation Recommended Annual consump- Single unit cost Annual doses for chronic tion (€)a cost (€)a treatment (in units) Oral Andriol® Testocaps 1–3 Capsules daily 365–1095 0,85 312–935 Buccal Striant™ 2 Tablets/day 730 1,03 749 Intramuscular Nebido® Every 10–14 weeks 4–5 139,56 558–698 Testoviron®-Depot-250 Every 2–3 weeks 17–26 23,98 408–623 Testosteron-Depot Every 2–3 weeks 17–26 19,54 332–508 Jenapharm® Transdermal Androtop® Gel 50 mg 1 Satchel/day 365 2,07 754 Testim® Gel 1 Tube/day 365 2,24 817 Testocur® Gel 2,5 or 5 g 1 Satchel/day 365 2.07 754 Testogel® 50 mg 1 Satchel/day 365 2,07 754 Tostran® Gel 2–4 g/day 730–1460 0,99 726–1451 Testopatch® 2,4 mg/d 2 Patches every 2 days 365 2,06 753 aCosts calculated according to doses recommended by the manufacturers and prices from the “Rote Liste 2008” (list of all medica- tions on the market in Germany) 444 E. Nieschlag and H. M. Behre

Fig. 21.7 Comparative pharmacokinetics 60 following single intramuscular injections of 55 250mg Testosterone enanthate i.m. 250 mg testosterone enanthate, 1,000 mg testosterone undecanoate, and 600 mg 50 testosterone buciclate in hypogonadal men. 45 The dotted lines represent the normal range 40 of testosterone Normal range 35 30 1000mg Testosterone undecanoate i.m. 25 20

Testosterone (nmol/l) 15 600mg Testosterone buciclate i.m. 10 5 0 0 2 4 6 8 10 12 14 16 Time (weeks)

25 system for replacement therapy of hypogonadal men met with diffi culties as in hypogonadism testosterone 20 doses in the range of normal production i.e., about 6 mg per day are required to be transported through the skin, 15 whereas the corresponding dose of estradiol for women lies in the mg-range. Different skin types have differing 10 resorption capacities. Since scrotal skin has high blood circulation extending into the uppermost layers of the

Testosterone (nmoI/I) 5 epithelial layers (because of its role in physiological temperature regulation), this skin type has especially 0 high resorption capacity (about 40 times higher than 0T3T2 T4 T5T6 T7 T8 T9 T10 the skin of the lower arm). This particularity was used Fig. 21.8 Serum testosterone concentrations before and during to advantage in developing a trans-scrotal application long-term therapy with intramuscular testosterone 1,000 mg system. Although currently no longer used, it deserves (Nebido®, injection interval between injections 1 and 2, 6–10 mention as the fi rst transdermal preparation. weeks, thereafter every 10–14 weeks). Serum levels are shown The trans-scrotal therapeutic system (Testoderm®) as box and whiskers plots (red line in box: mean value; black 2 line in box: medium value: 15% of single determinations within consists of a 40 or 60 cm polymere membrane loaded box; 10th and 19th percentile shown by whiskers). 0 = basal with 10 or 15 mg pure natural testosterone. When these testosterone concentrations before therapy; T2 = testosterone membranes are applied to the scrotum they release ® concentration immediately before 2nd Nebido injection etc. enough testosterone into the system to guarantee physi- Dotted line indicates lower level of normal ological serum testosterone levels for one day. When the 21.2.4 Transdermal Testosterone membrane is applied in the morning, physiological daily rhythms of testosterone can be mimicked (Bals-Pratsch Preparations 1986). Daily renewal provides constant serum testoster- one levels in the normal range. Patients treated with this 21.2.4.1 Testosterone Patches form of substitution therapy (for up to 10 years) show very good results (Behre et al. 1999b). Since an Transdermal application of medication has gained “enhancer” need not be used, skin irritations rarely occur. in popularity in recent years because of the many In order to guarantee good skin contact, the scrotum must advantages it has over conventional forms. In the endo- be freed of hair from time to time (scissors or razor). crinological fi eld the transdermal form has become Following transscrotal forms, transdermal testos- widely used for treating menopausal defi ciency symp- terone patches were developed which can be applied to toms with estrogens. Development of a transdermal non-scrotal skin (e.g., abdominal or upper arm skin) 21 Testosterone Therapy 445

Day 90 fi ve minutes. During this time contact with women or children must be avoided, because of the danger of 40 contamination. Thereafter the danger is negligible, especially if the skin is washed after evaporation of the alcohol (Rolf et al. 2002). Physiological levels result 30 when the gel is applied in the morning (Fig. 21.9). Long-term use over several years showed good results (MacNicholas and Ong 2006; Wang et al 2004). 20 The latest development are gels with high concen- Serum T(nmoI/L) trations of testosterone (Tostran® 2% and Testocur® 2.5%) 10 and no risk of skin irritation (McGriff-Lee 2002; Kühnert et al. 2005; Behre et al. 2004). As only small areas of skin are required for resorption, scrotal appli- 0 cation is in clinical testing which would require less gel 0 81624 as scrotal skin has a much higher resorption capacity Time (hours) that the general skin (Kühnert et al. 2005). This would Fig. 21.9 Serum testosterone concentrations (mean ± SEM) make the substitution with testosterone gels more eco- after 90 day therapy with transdermal testosterone gel (Testogel® nomical and ecologically advantageous. or Androtop® Gel) at a dose of 50 mg/d (squares, one package/d) oder 100 mg/d (circles, 2 packages/d) compared to transdermal therapeutic system (Androderm®, triangle, 5 mg/d). Serum lev- els are shown over 24 h (0 = 8 a.m.). Dotted line represents the 21.2.4.3 Transdermal Dihydrotestosterone normal range (Modifi ed from Swerdloff et al. 2000. With per- mission from the Endocrine Society, USA) In France a further transdermal preparation is on the market containing 5a-dihydrotestosterone (Andrac- (e.g., Androderm®). In order to transport the required tim®). At a concentration of 2.5% the DHT is incorpo- amount of testosterone through the skin, these systems rated into a hydroalcoholic gel from which the DHT are equipped with an “enhancer” which may lead to penetrates the skin if it is applied to suffi ciently large skin irritation. Two systems must be applied in the eve- surfaces, e.g., the chest and abdomen. Supraphysiological ning and worn for 24 h for hormone replacement ther- DHT values are measured in serum. Hypogonadal apy. Daily renewal is necessary for chronic substitution patients treated in this matter are rapidly adequately sub- (Fig. 21.5 and 21.9) (Meikle 1998). As in the transscro- stituted (Schaison and Couzinet 1998). However, the tal systems, testosterone values in the normal range and criticism that is applicable to mesterolone is also valid with a physiological circadian profi le can be achieved, here, namely that the full spectrum of direct testosterone with DHT and estradiol remaining in the normal range. effects and those mediated by estradiol are not able to be Although the patches mentioned above are hardly exerted. Moreover, applying a gel over such a large skin used today recently a new testosterone patch was surface seems impractical; contact with skin and under- developed causing little skin irritation and which must wear may cause testosterone uptake and virilization in be changed only every other day; however, two sys- the female partner (Delanoe et al. 1984). tems with either 1.8 or 2.4 mg resorbed per day must be used (Testopatch®). 21.2.5 Testosterone Implants 21.2.4.2 Testosterone Gels Testosterone implants are among the oldest testosterone A further application in transdermal form is the use of preparations. They consist of pure testosterone molded testosterone gels, which are applied to large skin areas under heat into cylindrical forms of 12 mm length and in order to allow suffi cient amounts of the hormone to 4.5 mm diameter. An implant contains 200 mg. They are be resorbed (Androtop®Gel, Testim®, Testogel®). implanted through a 0.5–1 cm incision under the abdom- These gels are applied in the morning to the upper arm, inal skin under sterile conditions using a trocar. The shoulders and abdomen and are left to dry for wound is closed with a bandage or stitches. Patients 446 E. Nieschlag and H. M. Behre with a tendency towards infection are given an antibiotic Table 21.4 Criteria for monitoring testosterone substitution prophylactically. If three to six implants are inserted, Psychic and sexual General well-being slowly declining serum testosterone levels in the normal parameters range are achieved for 4–6 months (Behre et al. 2004). Intellectual and physical activity Despite the long-lasting depot effect and the positive Mood Libido serum testosterone levels these products are only avail- Erections able in the UK, in Australia and South Africa. The minor Sexual activity surgery necessary for implantation, an 8.5% extrusion Somatic parameters Body proportions rate (n = 97.3 in 221 patients over a period of 13 years) Body weight and bleeding (2.3%) and occasionally infection (0.6%) Muscle mass and strength are limiting factors (Kelleher et al. 1999). Fat mass and distribution Hair pattern (beard, pubes, frontal hair line) 21.3 Monitoring Testosterone Therapy Sebum production Voice mutation in Hypogonadism Local side effects at application site Laboratory parameters Serum testosterone All forms of testosterone therapy listed above pursue (SHBG, free testosterone, salivary testosterone) the same goal, namely to provide optimal substitution Gonadotropins (LH, FSH) with testosterone. From its physiological effects and DHT, Estradiol from those resulting from pharmacokinetics and phar- Erythropoiesis (hematocrit, macodynamics various parameters can be measured to erythrocyte count, hemoglobin) determine the effectiveness of testosterone therapy; Possibly liver enzymes, lipid levels, these will be discussed in the following sections (over- HbA1c view in Table 21.4). Prostate/seminal Ejaculate volume vesicles Prostate size/ultrasound results (Palpation and TRUS) PSA in serum 21.3.1 Psyche and Sexuality Urofl ow Bones Bone density A patient’s general well-being and activity are good parameters to check the effectiveness of replacement While loss of libido and sexual appetite are signs therapy. When testosterone levels are adequate, the of reduced testosterone levels, adequate substitution is patient feels active in body and mind, alert and in good accompanied by sexual thoughts and phantasies. spirits, whereas inadequate testosterone levels are Their frequency correlates with testosterone values. accompanied by inactivity, lethargy and depressive Spon taneous nightly or morning erections are signs moods which improve with testosterone substitution of good substitution, but even when testosterone val- (Barratt-Connor et al. 1999; Christiansen 2004; Wang ues are defi cient, erections can still be provoked by et al. 2004). visual stimulation. In the normal to slightly subnormal Elements such as aggressiveness, tension, irritability range serum testosterone correlates with the frequency and anger are also positively infl uenced by testosterone of ejaculations and sexual intercourse; however, substitution (O’Connor et al. 2002). This improvement above the lower limit of normal such a correlation no in aggressiveness among hypogonadal men brought longer exists so that further increase of testosterone about by testosterone substitution must be differentiated will not lead to a further increase in sexual activity. from the unresolved question whether supraphysiologi- This indicates that in-depth conversation and a sexual cal testosterone administration to normal men increases diary – at least from time to time – give useful hints for aggressivity (Christiansen 2004). Moreover, in hypogo- evaluating testosterone therapy. Sexual questionnaires nadal men testosterone improves sociability and adjust- providing information about sexual thoughts and phan- ment. Finally, testosterone supports brain functions such tasies, appetite, satisfaction with sexuality, frequency as spatial cognition by activating the relevant brain areas of erections and ejaculations can make results of ther- (Cherrier et al. 2001; Zitzmann et al. 2001). apy objective (Beutel et al. 2005; Morales et al. 2007). 21 Testosterone Therapy 447

When testosterone values were decreased pharma- about increasing greasiness of skin, especially on the cologically by GnRH antagonists, it appeared that head which makes frequent shampooing necessary. adequate sexual function was still found in the pres- Patients should be informed about these normal symp- ence of relatively low and slightly subnormal testos- toms of masculinity. Acne may occur with the onset of terone values (Behre et al. 1994a), whereas other testosterone substitution in young patients as a sign of functions required higher testosterone values. Thus, triggered puberty, but is also occasionally observed in while the patient’s sexuality provides an important substituted adults. This applies especially when prepa- parameter for monitoring therapy, it cannot be consid- rations such as testosterone enanthate are used which ered the only one. could cause supraphysiological serum testosterone levels, but is rarely seen with testosterone undecanoate i.m. or gels. Switching products and/or dose reduction may be necessary to improve acne. 21.3.2 Somatic Parameters Gynecomastia may occur when doses of testosterone enanthate are too high. This makes dose reduction neces- Muscle mass and strength increase in hypogonadal sary. Pre-existing gynecomastia in Klinefelter patients patients treated with testosterone and they develop a will hardly be infl uenced by testosterone substitution. more virile phenotype (Bhasin et al. 2004). The anabolic Shortly after initiation of testosterone substitution, effect of testosterone causes body weight to increase by patients who have not gone through puberty will expe- about 5%. Thus, body weight, easily monitored, is one rience mutation of the voice (Akcam et al. 2004). This of the parameters to be checked routinely. The relative phenomenon reinforces the patient’s self-confi dence increase of muscle mass concomitant with the loss of fat and social adjustment as the gap between chronological can be measured, but does not yet belong to standard and biological age is closed. Being recognized as a man monitoring of testosterone therapy. Similarly, the distri- on the basis of the voice is of enormous importance for bution of fat over lower abdomen, hips and buttocks, the patient’s self-confi dence; this becomes especially characterized by a feminine pattern in the hypogonadal obvious from telephone conversations. Once mutation patient, assumes a masculine type under testosterone has taken place, the voice provides no further index of treatment (Allan et al. 2008; Isidori et al. 2005). testosterone therapy, as larynx size, vocal cord length The development and maintenance of a male hair and thus vocal register are maintained even without pattern is a good parameter for monitoring testosterone further testosterone substitution. therapy (Randall 2004). Beard growth and the frequency In the course of time patients with prepubertal of shaving are easily checked. Hair growth in the upper hypogonadism develop eunuchoid bodily proportions, pubic triangle especially is an important indicator for as the epiphyseal fi ssures close more slowly than in adequate testosterone replacement. Whereas women, normal growth. Testosterone substitution initiates a prepubertal boys and untreated hypogonadal patients brief growth spurt prior to rapid closure of the fi ssures have a straight hairline, androgenization is accompanied and cessation of growth. In these patients bone age of by the formation of temporal recession and, depending the left hand must be determined before the onset of on genetic disposition, by balding. Some patients con- puberty and periodic determinations of bone age will sider this a negative effect about which they should be show when bone maturity is reached. The ratio of arm- informed prior to therapy. The male hair pattern is of span to height and trunk height to leg length should be greater diagnostic importance than its intensity. A higher followed until defi nite bodily proportions are estab- testosterone dose may be necessary for patients with lished. Further increase of arm span indicates insuffi - long CAG repeats to achieve satisfactory beard growth. cient testosterone therapy. A well-substituted patient will comment on the need for shaving daily or may develop a full beard. Some predisposed patients may not, however, develop beard growth. In these cases the 21.3.3 Laboratory Parameters polymorphism may be of importance. Hypogonadal patients have prepubertal dry skin. When serum testosterone concentrations are used to Testosterone substitution induces sebum production evaluate testosterone substitution therapy, the pharma- and during the early phases some patients complain cokinetic profi le of the various preparations must be 448 E. Nieschlag and H. M. Behre considered. Furthermore, for long-term evaluation of good substitution is established, the patient should be testosterone therapy, methods of determining testoster- checked at 6–12-month intervals with blood samples one serum concentrations must be subjected to strict being taken at the end of a therapy interval. quality control so that reliable values will be available Basically, the determination of total testosterone in over long periods (see too Chap. 7). serum suffi ces and measuring free testosterone i.e., Since for routine evaluation the duration of action that fraction not bound to sex hormone binding globulin of a given preparation is of prime importance, serum (SHBG) is unnecessary, as free and bound testosterone testosterone values should be measured immediately are well correlated in most instances. Hyperthyroidism before the next application of a testosterone prepara- and medication for epilepsy may, however, cause SHBG tion. Especially for oral or transdermal preparations, to increase so that total testosterone also rises. the exact timepoint of the last application must be Conversely, extreme adipositas leads to a drop in total noted in order to interpret the results properly. testosterone (see Chap. 7). In patients developing therapy-induced gynecomas- • For practical purposes, substitution therapy with tia simultaneous determination of estradiol and testos- testosterone enanthate should start with 3-week terone is indicated in order to check for increased intervals between injections of 250 mg. If values are conversion to estradiol. In this event, the dose should below normal 3 weeks after injection of testoster- be reduced or medication should be switched to one one enanthate the injection interval should be producing physiological serum values. reduced. If, however, the values are still in the upper Whereas gonadotropins are of decisive impor- range, the interval may be increased. tance to differentiate between primary and secondary • Six weeks after the fi rst i.m. injection of testoster- hypogonadism, their role in monitoring testosterone one undecanoate (Nebido®) the second follows and therapy for (primary) hypogonadism is less signifi cant. a third follows 12 weeks after the second. After a In some forms of primary hypogonadism e.g., anor- further 12 weeks and immediately before the 4th chia, serum testosterone concentrations and LH but injection serum testosterone is determined. If the also FSH are correlated relatively well. In these cases, value is too high the injection interval should be normalization of gonadotropins may occur. In the most extended to more than 12 weeks, if too low, the frequent form of hypogonadism, the Klinefelter syn- interval is shortened to 10 weeks. These determina- drome, however, under testosterone therapy LH and tions and possible adjustments should be made FSH values do not always correlate with serum testos- annually thereafter. terone values although all other parameters indicate • Low serum testosterone measured 2–4 h after inges- adequate testosterone substitution. Likewise, oral and tion of oral testosterone undecanoate (Andriol®) transdermal testosterone therapy have little infl uence should fi rst serve as a reminder to the patient that on gonadotropins. For these reasons, gonadotropins the capsules should be taken with a meal to insure are not very useful for monitoring testosterone therapy better resorption. Because of the marked intra- and and then only in primary hypogonadism. interindividual varying resorption patterns, how- The slight anemia characteristic of hypogonadal ever, it is diffi cult to monitor testosterone unde- patients disappears under testosterone therapy. Thus, canoate therapy by serum testosterone levels and hemoglobin, erythrocyte count and hematocrit are other parameters must be considered additionally. good parameters for monitoring therapy (Jockenhövel • When transdermal testosterone application by et al. 1997). If testosterone doses are too high, hemo- patches (Testopatch®) produces unsatisfactory serum globin, erythrocytes and hematocrit may move into the values, suffi cient contact between patch and skin supraphysiological range and polycythemia may should be checked (hair growth interfering with the develop. This is particularly true for testosterone enan- contact between patch and skin?). As these patches thate (Calof et al. 2005). In this case, the testosterone are supplied in two sizes (1.8 and 2.4 mg/24 h) dose must be reduced. If hematocrit exceeds 55% bloodlet- adjustment is possible by choosing either a larger or ting may be indicated. Especially older and adipose smaller patch. patients and those with short CAG repeats of the andro- Testosterone may have to be determined repeatedly gen receptor tend to develop polycythemia (Hajjar until the correct form of substitution is found. Once et al. 1997; Zitzmann and Nieschlag 2007) (Fig. 21.10). 21 Testosterone Therapy 449

preparations (Jockenhövel et al. 1999). Testosterone therapy of hypogonadal patients should cause these

60 parameters to move into the normal range for males and it remains unclear whether an increase in LDL and

55 a decrease of HDL within the limits of normal has any biological signifi cance for the cardiovascular system. 50 Taken together, the pro- and anti-atherogenic effects of testosterone appear to be balanced (von Eckardstein 45 and Wu 2004). Patients at risk should be given the

Hematocrit % preparation least likely to cause pathological altera- 40 tions of these parameters.

35 15 30 20 25 20 21.3.4 Prostate and Seminal Vesicles 25 15 AR (CAG) 30 10 5 n 35 Nadir totalnmoI/L testosterone Under the infl uence of testosterone therapy, prostate and seminal vesicles of the hypogonadal patient enlarge Fig. 21.10 Hematocrit in 66 hypogonadal men in relation to and assume normal functions. This can best be docu- serum testosterone nadir values and androgen receptor CAG mented by the increase of ejaculate volume into the repeats. In total, 515 intramuscular injections of testosterone normal range. Normal ejaculate volume (>2 ml) is a undecanoate (1,000 mg Nebido®) were administered in 10–14 week intervals over several years. The green area signifi es the good parameter for measuring the effi cacy of testoster- upper limit of normal, the red area the pathologically elevated one therapy. hematocrit (Zitzmann and Nieschlag 2007). Testosterone treatment does not enlarge prostate volume over the normal range. This is also true of tes- If despite adequate substitution anemia persists, other tosterone enanthate therapy which intermittently reasons, e.g., iron defi ciency must be considered and achieves supraphysiological serum testosterone values must then be treated accordingly. At the beginning of (Fig. 21.6). PSA (prostate specifi c antigen) values testosterone therapy, red blood counts should be per- increase slightly but remain in the normal range and formed every 3 months, later at yearly intervals. urofl ow is not infl uenced negatively. The testosterone preparations recommended here have no negative infl uence on liver function even when used chronically (Gooren 1998; Hajjar et al. 1997; As benign prostate hyperplasia (BPH) and pros- Meikle 1998; Behre et al. 1999b; Zitzmann and tate carcinoma increase with age and thus also the Nieschlag 2007) even though some physicians continue danger of stimulating an existing prostate carci- to believe so (e.g., Gooren et al. 2007). This idea devel- noma, before testosterone therapy, every patient oped from the obsolete administration of 17a-alkylated should be thoroughly examined and, if over 45, the anabolic steroids which are indeed liver toxic. This prostate should be checked at least annually. does not apply to natural testosterone. However, moni- toring liver function is particularly important in patients Rectal examination of the prostate for size, surface and with hepatic disease or with hypogonadism caused by consistency is part of routine monitoring of testoster- general disease (see Chap. 18). In these cases, addi- one therapy. tional medication may infl uence liver function and thus If possible, rectal palpation should be supplemented also testosterone metabolism e.g., by increasing SHBG by transrectal ultrasonography (TRUS) as it allows concentrations. This must be considered when evaluat- non-invasive evaluation of the entire organ. Precisely ing testosterone values. Liver values should be checked measured prostate volume is a parameter for testoster- at yearly follow-up. one substitution, but does not only depend on serum Testosterone infl uences lipid metabolism and the testosterone levels, but also on androgen receptor poly- clotting system. Although is it diffi cult to fi nd bioequiv- morphism (Behre et al. 1994b; Zitzmann et al. 2003) alent doses, the effects vary when comparing different (Fig. 21.11). Measurement of PSA (prostate specifi c 450 E. Nieschlag and H. M. Behre

50 21.3.5 Bone Mass and Muscles

40 Reduced bone mass in hypogonadal man can be nor-

30 malized by testosterone therapy (Behre et al. 1997; Snyder et al. 1999; Zitzmann and Nieschlag 2004) 20 (Fig. 21.12). In good therapeutic adjustment both cor- tical as well as trabecular mass increase while verte-

Prostate volume (ml) 10 bral surfaces (in QCT) remain unaltered (Leifke et al. 1998). If, however, testosterone therapy begins very 0 late, predominantly cortical bone mass will increase 20 30 40 50 60 70 80 (Finkelstein et al. 1989); vertebral bone mass can also Age (years) increase and even normalize in patients in whom tes- Hypogonadal patients Hypogonadal patients Normal prior to testosterone under testosterone men tosterone therapy becomes necessary at an advanced treatment therapy age (Behre et al. 1997; Snyder et al. 1999).

Fig. 21.11 Prostate volume (planimetric determination by trans- rectal ultrasound) in hypogonadal patients prior to testosterone As osteoporosis and risk of fracture compromise therapy, in hypogonadal men receiving long-term effective tes- the quality of patient life, we measure bone den- tosterone substitution, and in age-matched normal men sity before and at 1–2 year intervals in every patient antigen) in serum is part of routine monitoring of the on testosterone therapy. The results are considered prostate. Increases over 4 ng/ml or an increase during when choosing the testosterone dose. the course of long-term therapy of over 0.4 ng/ml per year are cause for alarm for a possible carcinoma. Even if not all patients can be monitored in this man- However, cancer may be present even with low PSA ner, at least those with long untreated hypogonadism values and may be obscured by testosterone substitu- and older patients should be examined at the time of tion. Therefore checkups 3–6 months after initiation of fi rst diagnosis. If bone density values are pathological, testosterone substitution and yearly thereafter are nec- normalization should be documented by further inves- essary (Nieschlag et al. 2006; Wang et al. 2008). tigations. At the very earliest, increases in bone density When a carcinoma is suspected, the patient must be can be observed half a year after inception of testoster- referred for urologic consultation, in the course of one therapy. The various diagnostic procedures are which prostate biopsy may complete the diagnosis. discussed in Chap. 6.

Fig. 21.12 Bone mineral 240 density (BMD), measured by 200 QCT of the lumbar vertebrae 160 ) during long-term testosterone 3 120 substitution therapy up to 16 years in 72 hypogonadal patients. Circles indicate 100 hypogonadal patients with fi rst QCT measurement before initiation of testosterone 80 substitution therapy, squares show those patients already receiving testosterone therapy 60 at the fi rst QCT. The dark pink area indicates the range 40 of high fracture risk, the white Bone mineral density [QCT] (mg/cm area shows the range without signifi cant fracture risk, and the light red area indicates the 20 intermediate range where Before 2 4 6 8 10 12 14 16 therapy fractures may occur Duration of testosterone substitution (years) 21 Testosterone Therapy 451

Muscle mass also increases during testosterone Even if one or another patient must be convinced of the substitution, while fat mass simultaneously decreases usefulness of a suggested therapy because he lacks the (Bhasin et al. 2004; Rolf et al. 2002). Increased muscle imagination to see its advantages, in the long run hardly mass is caused by hyperplasia of existing muscle cells any patient is willing to forego substitution therapy. accompanied by transformation of mesenchymal cells Increased public discussion of the effects of testoster- into new muscle cells. one and suggestions from increasing numbers of self- help groups make it easier for patients to formulate their own ideas concerning adequate therapy. It remains 21.4 Evaluation of Testosterone the physician’s task to guide the patient, to monitor the various parameters and to fi nd optimal therapeutic Substitution Therapy adjustment for the individual patient. Concerning comparison of costs of the various Testosterone defi ciency is not life-threatening, but it licensed modalities for testosterone treatment of hypo- does reduce the quality of life drastically and may gonadal men in Germany (Table 21.3) it must be noted induce various illnesses. The assumption, often that physicians’ fees for injection must be added to the expressed, that testosterone is responsible for shorter costs for the medications, whereas all gels and trans- life expectancy in men can hardly be tested experimen- dermal modalitites are applied by the patient himself. tally. The same long life-span of men castrated prepu- However, the necessary contact between doctor and bertally and of intact men (Nieschlag et al. 1993) patient required by the injections should not be under- supports the theory that factors other than testosterone estimated as advantageous for the patient-physician are responsible for the different life expectancies relationship. In any event, renewal of a prescription between the sexes (see also Sect. 13.1.2, Acquired should be used by patient and physician as an opportu- Anorchia). Low serum testosterone levels were even nity for exchanging information about the quality of described as predictive of shorter life expectancy substitution. Over and beyond this, every hypogonadal (Shores et al. 2006). At the very least there is no reason patient should be monitored yearly in a centre special- to deny a patient testosterone substitution. ized in these diseases. Any cost-effectiveness analysis Testosterone is characterized by high therapeutic should also include additional parameters necessary for safety, supported by the absence of serious long-term therapy supervision as shown in Table 21.4. side effects following high dose administration as used for excessively tall stature (see Sect. 21.5) and its ille- gal use in extremely high doses in athletics and by bodybuilders (see Sect. 21.6). The only real contrain- 21.5 Excessive Height dications are manifest prostate carcinoma or a very rare mamma carcinoma. Testosterone defi ciency at the time of puberty causes It is diffi cult to quantify the actual advantage of testos- eunuchoid skeletal proportions, whereas normally tes- terone substitution therapy. The improved quality of life tosterone induces proportioned body growth by timely of a patient receiving testosterone therapy is undisputed. induction of epiphyseal maturation. Prior to puberty Increased self-confi dence and satisfaction, confi rmed by testosterone can cause closure of the epiphyseal lines sexual activities, are factors not be underestimated con- and cause small stature, as for example in pubertas cerning the patient’s social integration. By supporting praecox. It is possible to take advantage of these facts physical and psychic activity his capacities are increased in order to modify fi nal height in boys predisposed to or maintained; elimination of anemia, strengthening of excessive height (over 2 m). High-dose testosterone the skeleton and musculature and reduction of risk of administered early can stop growth. fracture prevent invalidity and infi rmity. Usually, 250 mg testosterone enanthate every week or 500 mg every 2 weeks are given intramuscularly between the ages of 12–16 years for about 1 year. The Adequate replacement therapy allows the patient to dose to be administered is at least twice that used for be integrated into society and to enjoy satisfactory substitution. Therapeutic phases that are too short cou- quality of life. pled with discontinuance before complete epiphyseal 452 E. Nieschlag and H. M. Behre maturity prevents the therapeutic goal from being cal counselling towards better adjustment is always reached. Before growth ceases, possible therapeutic indicated. Often such care is suffi cient and makes fur- success can be tested by determining bone age. The ther testosterone therapy superfl uous. sooner therapy is begun, the more effective growth reduction will be. If bone age exceeds 14 years, testos- terone is usually without effect (for review see Drop 21.6 Misuse and Abuse et al. 1998). However, very early therapy should be avoided as precocious puberty with its psychosocial of Anabolic Steroids and physical implications would be induced. Even if testosterone is not licensed for this indica- As testosterone has a strong anabolic i.e., protein- tion (as in Germany), for many years such treatment building component and induces muscle growth when was carried out relatively often since the early 1950s. accompanied by relevant physical exercise, in the It is remarkable that no controlled studies have been 1950s and 1960s an attempt was made to dissociate the performed to test the actual therapeutic effect. For this androgenic and anabolic effects by chemically altering reason it is also important to question the results of the testosterone molecule. As a result, a multitude of possible long-term effects. so-called anabolic steroids were synthesized and some During treatment with pharmacological doses of of them were also applied clinically (Kochakian 1976). testosterone, testicular development is suppressed (see They attempt to make clinical use of the positive effects Chap. 29) and the question arises whether this tempo- of testosterone on muscle metabolism, blood formation rary suppression of the testis and the high doses of tes- and bone metabolism, while dispensing with andro- tosterone may have untoward effects in the (pre) genic side effects e.g., virilization in women and chil- pubertal patient. A similar question can be raised con- dren. However, separation of anabolic and androgenic cerning studies on male contraception based on testos- components remained impossible in anabolic steroids. terone, but with the difference that here vertical growth Extreme physical performance carried out over is to be suppressed in an immature patient. After cessa- extended periods causes a drop of testosterone in circu- tion of therapy the endocrine pituitary-gonadal axis lation. Until recently, it was believed that use of andro- quickly returns to normal. Long-term follow-up stud- gens by eugonadal athletes would, at the very outside, ies in treated boys showed no anomalies attributable to have placebo effects. Recent investigations were able to treatment compared to control populations (de Waal show that pharmacological doses of androgens accom- 1995; Lemcke et al. 1996). No alterations in the car- panied by exercise could indeed induce muscle growth diovascular system and in serum lipids or in the pros- (Bhasin 2004; Choong et al. 2008). This, however, does tate (volume, sonographic structure and PSA) were not apply to all androgenic steroids. For the androgen observed. Subnormal semen parameters seen relatively precursor , taken by famous baseball frequently in follow-up examinations were attributable players such as Mark McGwire and freely available in to cryptorchidism and varicocele rather than to testos- the USA as an over-the-counter food supplement, no terone therapy (Lemcke et al. 1996). Concerning ther- anabolic effect could be documented (King et al. 1999). apeutic safety, follow-up investigations to date show Present studies to date failed to confi rm any necessity that the use of relatively high doses of testosterone in for substitution therapy in high-performance athletics. puberty remains without long-term side effects. Nevertheless, the gain in strength and muscle mass Even if long-term follow-up investigations do not induced by testosterone and anabolics led to their abuse argue against such therapy, it should be considered that by high-performance athletes and bodybuilders. The this testosterone therapy accelerates pubertal develop- doses taken are often 10–100 fold higher than those ment with all its psychic and physical consequences. used in replacement therapy (Wilson 1988; Knuth et al. Since psychological reasons for this therapy outweigh 1989; Schänzer 2004). Testosterone itself, followed by any medical considerations, each individual case should (19-nortestosterone), , stana- be carefully considered and therapy should only be zolol, methenolone, mesterolone, 17a-methyltesto- administered in cases of extreme expected height. As sterone and many other substances are used. Often the boys (and their parents!) tend to suffer from extreme sub stances are combined and used in increasing and height predominantly during the growth period, but are decreasing regimens (“stacking”). Special attention later well integrated, adequate medical or psychologi- should be given to this abuse. Because of these high 21 Testosterone Therapy 453 doses androgenic side-effects such as suppression of Akcam T, Bolu E, Merati AL, Durmus C, Gerek M, Ozkaptan hypothalamic-pituitary function and spermatogen- Y (2004) Voice changes after androgen therapy for hypogonadotrophic hypogonadism. Laryngoscope 114: esis up to azoospermia (Knuth et al. 1989), acne, gyne- 1587–1591 comastia and fl uid retention (and virilization with Bagchus WM, Hust R, Maris F, Schnabel PG, Houwing NS irreversible alterations of voice and clitoris in women) (2003) Important effect of food on the of oral are well-known side-effects. Furthermore, if (obsolete) testosterone undecanoate. Pharmacotherapy 23:319–325 Bals-Pratsch M, Knuth UA, Yoon YD, Nieschlag E (1986) 17a-alkylated steroids (stanazolol, 17a-methyltestos- Transdermal testosterone substitution therapy for male terone) are used, liver toxicity with cholostasis, peliosis hypogonadism. Lancet ii:943–946 and even malignant neoplasm may result. Increased Barratt-Connor E, von Mühlen DG, Kritz-Silverstein D (1999) aggressiveness has been repeatedly ascribed to anabolic Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo study. J Clin Endocrinol Metab 84: steroids and single cases are always cited as examples. 573–577 Whether these cases are coincidental, as to be expected Behre HM, Böckers A, Schlingheider A, Nieschlag E (1994a) in widespread abuse of anabolics or whether there is a Sustained suppression of serum LH, FSH testosterone and causal connection, cannot be determined to date because increase of high-density lipoprotein cholesterol by daily injections of the GnRH antagonist cetrorelix over 8 days in convincing studies on long-term effects are lacking normal man. Clin Endocrinol 40:241–248 (Nieschlag 1992). Behre HM, Bohmeyer J, Nieschlag E (1994b) Prostate volume However, reports on young men succumbing to in testosterone-treated and untreated hypogonadal men in sudden death following anabolic abuse are cause for comparison to age-matched normal contrals. Clin Endocrinol 40:341–349 alarm as they show a high incidence of coronary ath- Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E (1997) erosclerosis and acute infarction; it must be noted, Long-term effect of testosterone therapy on bone mineral however, that testosterone and anabolic dosage density in hypogonadal men. J Clin Endocrinol Metab exceeded by far those amounts administered clinically 82:2386–2390 Behre HM, Abshagen K, Oettel M, Hübler D, Nieschlag E and in most cases a series of other drugs were taken, (1999a) Intramuscular injection of testosterone undecanoate thus making a defi nite diagnosis and conclusions dif- for the treatment of male hypogonadism: phase I-studies. fi cult (Kistler 2006). 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J Urol Isidori A, Lenzi A, Fabbri A (2005) Effects of testosterone 157:849–854 on body composition, bone metabolism and serum lipid pro- Nieschlag E (1981) Ist die Anwendung von Methyltestosteron fi le in middle-aged men: A meta-analysis. Clin Endocrinol obsolet? Dtsch Med Wschr 106:1123–1125 63:280–293 Nieschlag E (1992) Testosteron, Anabolika und aggressives Jockenhövel F, Vogel E, Reinhardt W, Reinwein D (1997) Effects Verhalten bei Männern. Dtsch Ärztebl 89:2967–2972 of various modes of androgen substitution therapy on eryth- Nieschlag E (2006) Testosterone treatment comes of age: New ropoiesis. Eur J Med Res 2:293–298 options for hypogonadal men. Clin Endocrinol 65:275–281 Jockenhövel F, Bullmann C, Schubert M, Vogel E, Reinhardt W, Nieschlag E, Behre HM (eds) (2004) Testosterone – action, defi - Reinwein D, Müller-Wieland D, Krone W (1999) Infl uence of ciency, substitution, 3rd edn. Cambridge University Press, various modes of androgen substitution on serum lipids and Cambridge lipoproteins in hypogonadal men. Metabolism 48:590–596 Nieschlag E, Behre HM (2004) Clinical use of testosterone in Kelleher S, Turner, L, Howe C, Conway AJ, Handelsman DJ hypogonadism and other conditions. In: Nieschlag E, (1999) Extrusion of testosterone pellets: A randomized con- Behre HM (eds) Testosterone – action, defi ciency, substitu- trolled clinical study. Clin Endocrinol 51:469–471 tion. 3rd edn. Cambridge University Press, Cambridge, pp Kelleher S, Conway AJ, Handelsman DJ (2004) Blood testoster- 375–404 one threshold for androgen defi ciency symptoms. J Clin Nieschlag E, Wang CH, Handelsman DJ, Swerdloff RS, Endocrinol Metab 89:3813–3817 Wu FCW, Einer-Jensen N, Khanna J, Waites GMH, World King DS, Sharp RL, Vukovich MD, Brown GA, Reifenrath TA, Health Organization (eds) (1992) Guidelines for the use of Uhl NL, Parsons KA (1999) Effect of oral androstenedione androgens. 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Nieschlag E, Nieschlag S, Behre HM (1993) Life expectancy Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, and testosterone. Nature 366:215 Matsumoto AM, Snyder PJ, Weber T, Longstreth J, Berman N Nieschlag E, Büchter D, von Eckardstein S, Abshagen K, (2000) Long-term pharmacokinetics of transdermal testos- Behre HM (1999) Repeated intramuscular injections of tes- terone gel in hypogonadal men. J Clin Endocrinol Metab tosterone undecanoate for substitution therapy of hypogo- 85:4500–4510 nadal men. Clin Endocrinol 51:757–763 von Eckardstein A, Wu FCW (2004) Testosterone and cardiovascu- Nieschlag E, Behre HM, Bouchard P, Corrales JJ, Jones TH, lar diseases. In: Nieschlag E, Behre HM (eds) Testosterone – Stalla GK, Webb SM, Wu FC (2004) Testosterone replace- action, defi ciency, substitution, 3rd edn. Cambridge University ment therapy: Current trends and future directions. 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New Drugs Mark 8:28–32 Testishormons, Testosteron (Androsten 3-on-17-ol). Helv World Health Organization, Nieschlag E, Wang Ch, Handelsman chim Acta 18:1264–1275 DJ, Swerdloff RS, Wu FCW, Einer-Jensen N, Khanna J, Schänzer W (2004) Abuse of androgens and detection of illegal Waites GMH (eds) (1992) Guidelines for the use of andro- use. In: Nieschlag E, Behre HM (eds) Testosterone – Action, gens. WHO, Geneva defi ciency, substitution, 3rd edn. Cambridge University Wilson JD (1988) Androgen abuse by athletes. Endocr Rev Press, Cambridge, pp 715–735 9:181–199 Schaison G, Couzinet B. (1998) Percutaneous dihydrotestoster- Zitzmann M, Nieschlag E (2004) Androgens and bone metabo- one treatment In: Nieschlag E, Behre HM (eds) Testosterone lism. In: Nieschlag E, Behre HM (eds) Testosterone – action, – caction, defi ciency, substitution, 2nd edn. Springer, defi ciency, substitution, 3rd edn. Cambridge University Heidelberg, pp 423–436 Press, Cambridge, pp 233–254 Schubert M, Minnemann T, Hübler D, Rouskova D, Christoph A, Zitzmann M, Nieschlag E (2007) Androgen receptor gene CAG Oettel M, Ernst M, Mellinger U, Krone W, Jockenhövel F repeat length and body mass index modulate the safety of (2004) Intramuscular testosterone undecanoate: Pharma- long-term intramuscular testosterone undecanoate therapy in cokinetic aspects of a novel testosterone formulation during hypogonadal men. J Clin Endocrinol Metab. 92: 3844–3853 long-term treatment of men with hypogonadism. J Clin Zitzmann M, Weckesser M, Schober O, Nieschlag E (2001) Endocrinol Metab 89:5429–5434 Changes in cerebral glucose metabolism and visuospatial Schürmeyer T, Wickings EJ, Freischem CW, Nieschlag E (1983) capability in hypogonadal males under testosterone substi- Saliva and serum testosterone following oral testosterone tution therapy. Exp Clin Endocrinol Diabetes 109: undecanoate administration in normal and hypogonadal 302–304 men. Acta Endocrinol 102:456–462 Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E (2003) Shores MM, Matsumoto AM, Sloan KL, Kivlaha DR (2006) Prostate volume and growth in testosterone-substituted Low serum testosterone and mortality in male veterans. Arch hypogonadal men are dependent on the CAG repeat poly- Intern Med 166:1660–1665 morphism of the androgen receptor gene: a longitudinal Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, pharmacogenetic study. J Clin Endocrinol Metab Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF, 88:2049–2054 Haddad JG Jr, Strom BL (1999) Effect of testosterone treat- Zitzmann M, Faber D, Nieschlag E (2006) Association of spe- ment on bone mineral density in men over 65 years of age. cifi c symptoms and metabolic risks with serum testosterone J Clin Endocrinol Metab 84:1966–1972 in older men. J Clin Endocrinol Metab 91:4335–4343 Empirical Therapies for Idiopathic Male Infertility 22

Eberhard Nieschlag and Axel Kamischke

Contents 22.1 Defi nition and Incidence of Male Idiopathic Infertility 22.1 Defi nition and Incidence of Male Idiopathic Infertility in Men ...... 457 22.2 Empirical Therapy ...... 458 The term “idiopathic infertility” designates diagnosis 22.2.1 hCG/hMG ...... 458 by exclusion. Only after all other possible causes for 22.2.2 Pulsatile GnRH ...... 459 infertility have been eliminated can the diagnosis 22.2.3 Highly Purifi ed of “idiopathic infertility” be established. Seminal and Recombinant FSH ...... 459 para m eters are frequently subnormal and may be 22.2.4 Antiestrogens and Aromatase Inhibitory Agents ...... 459 associated with elevated serum FSH, indicating sper- 22.2.5 Androgens ...... 460 matogenic failure. Testicular biopsies often show 22.2.6 Kallikrein ...... 463 incomplete spermatogenic arrest or focal SCO and 22.2.7 Pentoxiphylline ...... 463 fail to provide further information concerning patho- 22.2.8 a-Receptor Blocking Agents ...... 463 22.2.9 Antioxidants ...... 463 genesis. These patients represent the largest group of 22.2.10 Further Substances ...... 464 men attending fertility clinics. 22.2.11 Physical Procedures ...... 464 22.3 Therapeutic Guidelines ...... 464 The collective diagnosis of “idiopathic infertility” References ...... 465 most likely comprises a multitude of different patho- genic mechanisms. One of andrology’s most important and exciting tasks is to disclose the workings of these mechanisms und ultimately to eliminate their cause by rational therapy. New points of departure are expected from research on molecular genetics and biological regulation of ; the effects of gonado- tropins and sex hormones at the molecular level, and the biology of the gametes. Examples of such accom- plishments of research are the microdeletions of the Y chromosome, the CFTR mutations in congenital bilat- eral aplasia of the vas deferens (CBAVD) and the pathology of the androgen receptor. It should be pointed out that the term idiopathic infertility has different meanings in andrology and  E. Nieschlag ( ) gynecology. In gynecology, the term “female idio- Centre of Reproductive Medicine and Andrology of the University, Domagkstr. 11, D-48149 Münster/Germany pathic infertility” refers to a condition in which clini- e-mail: [email protected] cal examination does not reveal any pathological

E. Nieschlag et al. (eds.), Andrology, 457 DOI: 10.1007/978-3-540-78355-8_22, © Springer-Verlag Berlin Heidelberg 2010 458 E. Nieschlag and A. Kamischke

fi nding which might explain the infertility of the cou- 22.2 Empirical Therapy ple. Here it would be more accurate to speak of unex- plained infertility (see Chap. 20). Although pathological fi ndings may be seen in an idiopathic 22.2.1 hCG/hMG infertile male, there are (as yet) no causal explanations and, consequently, no rational therapy exists. For want of a rational therapeutic approach to idiopathic infertility it seemed reasonable to apply previously suc- cessful endocrine treatment modalities for appropriate Even in the absence of clearcut pathophysiological indications, i.e., in secondary hypogonadism. Because concepts explaining the suitability of a given medi- of the success rate of hCG/hMG treatment in inducing cation for treating idiopathic infertility, numerous pregnancies in partners of patients with hypogonado- pharmacological regimes were and continue to be tropic hypogonadism and on the hypothesis that eleva- applied, often for considerable periods of time, both tion of gonadotropins may lead to stimulation of in combined and sequential form. These are sum- spermatogenesis, this regimen was also applied to marized below as “empirical therapy”. The postu- patients with normogonadotropic fertility disturbances. late of evidence-based medicine following controlled Numerous open studies tried to demonstrate its effec- studies is particularly appropriate for the critical tiveness. It was used for almost 25 years for idiopathic evaluation of these therapeutic regimes. infertility without clear proof of its therapeutic effi cacy, making a controlled clinical study an urgent necessity. A placebo-controlled, prospective and random- Empiric therapeutic procedures were long practiced in ized study then showed that treatment with hCG/hMG andrology until their lack of effectiveness was tested in could not demonstrate any benefi cial effect on randomized controlled studies. As it proves to be con- para meters or pregnancy rates in partners of patients with tinuously tempting to resurrect these therapies, results normal serum concentrations of LH, FSH and testoster- to date are summarized here to prevent the reader from one and sperm concentrations below 106/ml, compared undertaking unnecessary therapeutic attempts. Thus, to the placebo group (Knuth et al. 1987). Each change in older studies are listed here which have disproved pre- the treatment group could be matched with a similar vious therapeutic attempts. change in the double-blind placebo group (Fig. 22.1),

10

8 hCG/hMG

6 Placebo /ml) 6 4

2

0

Motile sperm (10 -2

-4

-6 Couples

Fig. 22.1 Results of a placebo-controlled, double-blind, ran- values. Patients are grouped according to the extent of the change domized study concerning hCG/hMG treatment for male idio- observed. Stars representing patients with no corresponding pathic infertility. Columns represent differences in sperm motility “partner” in the verum group. No differences between verum and after a treatment period of 12 weeks compared to pretreatment placebo group can be observed (Knuth et al. 1987) 22 Empirical Therapies for Idiopathic Male Infertility 459 emphasizing the importance of placebo for the evalua- FSH or recombinant FSH (Foresta et al. 1998, 2002, tion of therapeutic benefi ts in clinical studies. In conclu- 2005; Baccetti et al. 2004; Comodo et al. 1996; Matorras sion, there is no evidence for benefi ts of hCG/hMG et al. 1997; Kamischke et al. 1998; Paradisi et al. 2006). treatment in normogonadotropic idiopathic infertility. Two studies lacked analysis of pregnancy (Foresta et al. 1998, 2002) and only three were randomized and pla- cebo-controlled (Comodo et al. 1996; Kamischke et al. 22.2.2 Pulsatile GnRH 1998; Paradisi et al. 2006). With the exception of a sig- nifi cant increase in sperm motility and concentration in the study by Paradisi et al. (2006), none of the placebo- In preliminary studies it was suggested that oligoasthe- controlled studies showed any increase in sperm para- noteratozoospermia in men with elevated serum FSH meters compared to baseline values or to the placebo might be caused by too infrequent GnRH pulses. Thus group. A meta-analysis of all randomized studies with the term “slow pulsing oligospermia” was introduced pregnancy rates provided an odds ratio of 1.52 for preg- into andrology (Wagner and Warsch 1984). A further nancy rates (Fig. 22.2) so that 14 patients would have to carefully done study reported slower LH-pulsatility be treated in order to achieve one additional pregnancy. but normal FSH-pulsatility in men with oligozoo- In view of the high costs and moderate chances of suc- spermia compared to controls (Reyes-Fuentes et al. cess, in its present form FSH therapy for idiopathic 1996). In addition, the amplifi ed mass of LH and FSH infertility does not seem justifi ed (Kamischke and secreted basally as well as after GnRH-injection was Nieschlag 1999) and a current Cochran Review (Attia higher in infertile men than in controls in this study. It et al. 2007) recommends further studies prior to a gen- was claimed that GnRH injections administered at a eral recommendation of FSH in idiopathic infertility. physiologic pulse frequency would improve sperm However, in several studies, unfortunately uncon- parameters in these patients. An uncontrolled study trolled, improvements of sperm morphology evidenced was then able to show that such therapy indeed nor- by electronic imaging (Bartoov et al. 1994) were regis- malized FSH values, but neither improvements in tered, as were signifi cant increases of testicular vol- sperm parameters nor in pregnancy rates were proved ume and DNA condensation of sperm (Kamischke et (Bals-Pratsch et al. 1989). The hypothesis that elevated al. 1998). Just what mechanisms are involved remains FSH values are the cause and not the effect of disturbed unclear. Suggestions from a further uncontrolled study spermatogenesis could not be confi rmed. The lack of a indicate that especially patients with moderate hypo- pathophysiological concept and therapeutic success spermatogenesis as seen in testicular histology, as made a controlled study with this design superfl uous. opposed to those with spermatogenic arrest, may profi t from FSH therapy (Foresta et al. 2000). Here too con- 22.2.3 Highly Purifi ed trolled studies should be carried out to confi rm these results. However, results provide hints that further and Recombinant FSH investigations into the mechanism of action are worth- while and would help to identify patients who might Once highly purifi ed FSH became available for clini- react positively. cal use it was also applied to male infertility. An increase in fertilization and pregnancy rates was reported in men treated with highly purifi ed FSH who 22.2.4 Antiestrogens and Aromatase had failed to fertilize an oocyte in vitro prior to treat- ment (Acosta et al. 1992). Inhibitory Agents Although the evidence revealed by these studies is weak because of their uncontrolled design, they gave Antiestrogens (e.g., clomiphene, ) antagonize rise to a series of studies, which were, however, again estrogenic activity by competitively blocking the estro- largely uncontrolled. To date a total of eight random- gen receptor at target sites. Aromatase inhibitors (e.g., ized studies without cross-over design, and with preg- testolactone) exert similar effects by inhibiting aro- nancy rates as end parameter, were carried out in men matase enzyme activity which normally converts andro- with idiopathic infertility who received highly purifi ed gens to estrogens. Since estrogens suppress pituitary 460 E. Nieschlag and A. Kamischke

Fig. 22.2 Individual (squares) and combined (COR: diamonds) odds ratio Comodo et al., 1996; n=26 for pregnancies in random- ized controlled studies with highly purifi ed or recombi- Matorras et al., 1997; n=136 nant human FSH (95% confi dence interval). The Kamischke et al., 1998; n=61 broken line shows the COR

Baccetti et al., 2004; n=44

Foresta et al., 2005; n=128

Paradisi et al., 2006; n=30 1.52 (0.95 – 2.44) FSH COR n=430 0.01 0.10 0.50 12 510 5075 Odds Ratio gonadotropin secretion via a negative feedback, both with testosterone undecanoate plus tamoxifen, although blockade as well as lowering endog- the rationale of such combined therapy seems unclear. enous estrogen levels will lead to an increase in circu- In view of the proven ineffectiveness of prescribing lating LH and FSH. On the hypothesis that such an androgen alone for male infertility and in view of the increase would result in an improvement of spermato- low androgen dose, it can be assumed that the effects genic activity and sperm concentration, antiestrogens observed are due to tamoxifen. Whether such increased and aromatase inhibiting agents were widely used to motility also leads to increased pregnancy rates was treat male idiopathic infertility. not investigated at fi rst (Adamopoulos et al. 1997). The ineffi cacy of the incomplete aromatase inhibi- Using the same regime, the same group was then able tor testolactone in the treatment of male infertility has to demonstrate a signifi cant improvement of pregnancy been shown by a placebo-controlled, double-blind, rates, along with a signifi cant improvement of sperm randomized trial (Clark and Sherins 1989). motility, concentration and morphology (Adamopoulos Since then a series of studies with the antiestro- et al. 2003) (Fig. 22.3). gens clomiphene and tamoxifen for male infertility When this study is included in the odds ratio of the have been performed. In fi ve double-blind, placebo- double-blind placebo-controlled studies or all placebo- controlled studies (Ainmelk et al. 1987; Ronnberg controlled studies, a signifi cant effect of antiestrogens 1980; Sokol et al. 1988; Torök 1985; WHO 1992) car- on pregnancy rates in partners of men with idiopathic ried out up to 1992 including a large-scale WHO infertility (Fig. 22.4) becomes apparent. Twelve men study with clomiphene (WHO 1992), neither a single must be treated to achieve one additional pregnancy study nor the combined odds ratio of all studies were which, considering the low costs of antiestrogens, rep- able to show any effect on pregnancy rates (Kamischke resents an interesting option. According to the present and Nieschlag 1999). Even when the fi ve placebo- state of knowledge, a careful recommendation of anti- controlled not-blinded studies were also included in estrogens for men with moderately disturbed fertility the analysis (Fig. 22.4), no signifi cant effect could be can be justifi ed. shown and 24 patients would have had to be treated in order for one additional pregnancy to be achieved. Also in view of potential side-effects (Rolf et al. 1996), antiestrogens should not be applied outside 22.2.5 Androgens clinical studies (Vandekerckhove et al. 1998). A further placebo-controlled double-blind study The requirement of testosterone for normal spermato- found an increase of sperm motility under treatment genesis under physiological conditions led to the use 22 Empirical Therapies for Idiopathic Male Infertility 461

Ronnberg, 1980; n=29 Török et al., 1984; n=54 Ainmelk et al., 1987; n=36 Sokol et al.,1989; n=20 WHO, 1992; n=141 Antiestrogens combined odds ratio Double-blind studies n=280 NNT = 35

SIG, 1982; n=179 Wang, 1983; n=40 Micic, 1985; n=105 Hargraeve, 1986; n=70 Krause, 1992; n=84

Antiestrogens combined odds ratio n=758 NNT = 24

0.01 0.10 0.50 1 2 5 10 50 Odds ratio

Fig. 22.3 Individual (squares) and combined (diamonds; COR) odds ratios for pregnancy rates in randomized controlled studies with antiestrogens (95% confi dence intervals). The dotted line shows the COR

Adamopoulos et al., 2003 WMD Sperm concentration n= 212 6.7 (3.77 – 9.63) WMD Progressive sperm motilityt n=212 10.8 (7 – 14.6) WMD Sperm morphology n=61 5.3 (3.87 – 6.87)

OR Adamopoulos et al. and Antiestrogens 1997 OR Pregnancies Adamopoulos et al. n= 175 4.78 (2.23 – 10.25)

OR Antiestrogen Adamopoulos et al. n=455 2.37 (1.44 – 3.89) Double-blind placebo studies

OR Antiestrogen Adamopoulos et al. n=933 1.95 (1.34 – 2.81) Placebo controlled studies NNT = 12

0.01 0.10 0.50 12 510 50 Odds ratios / WMD

Fig. 22.4 Individual (squares) and combined (diamonds; COR) randomized controlled studies with antiestrogens and testoster- weighted mean differences (WMD) for sperm motility, concen- one undecanoate (95% confi dence intervals). The dotted line tration and morphology and odds ratios for pregnancy rates in shows the COR of androgens in the therapy of idiopathic infertility in testosterone derivative Ð was used for almost 2 decades men, although this cannot be justifi ed rationally, since in andrological practice, until a multi-centered, pla- androgen defi ciency could not be demonstrated in cebo-controlled, double-blind and randomized WHO these patients. Mesterolone especially Ð a 5a-reduced study with 246 couples proved its ineffectiveness, as no 462 E. Nieschlag and A. Kamischke

Mauss, 1974 n = 209

Afjes et al., 1983 n = 59

SIG, 1984 n = 328

WHO, 1989 n = 117

Pusch, 1989 n = 58

Comhaire et al., 1991 n = 24

Gerris et al., 1991 n = 52

Gregoriou et al., 1993 n = 54

Comhaire et al., 1995 n = 64

Androgene n = 1025 COR

0,01 0,100,50 1 2 510 50 75

Odds Ratio

Fig. 22.5 Individual (squares) and combined (COR: diamonds) odds ratio for pregnancies in randomized controlled studies with androgens (95% confi dence interval). The dotted line shows the COR (From Kamischke and Nieschlag 1999) statistically signifi cant increase in pregnancy rates was activity would be increased following treatment with seen (WHO 1989). Further publications followed, so testosterone, resulting in elevated sperm concentrations that nine randomized, placebo-controlled, double- compared to pretreatment values (so-called rebound blind studies could be evaluated in a meta-analysis. effect). This initial speculation, however, could not be With respect to pregnancy rates, in 1,025 couples a confi rmed by later clinical studies, neither in patients combined odds ratio of only 1.02 (Fig. 22.5) resulted. with idiopathic infertility nor in normal volunteers. All In other words, 359 patients would have to be treated studies were uncontrolled and the pregnancy rates for one additional pregnancy to occur (Kamischke and reported were widely scattered. For these reasons this Nieschlag 1999). Hence, administration of androgens therapy cannot be recommended. However, the initial is not warranted in cases of idiopathic male infertility. fear that rebound therapy might lead to hyalinization of This statement is supported by the fact that despite an the seminiferous tubules was not confi rmed. Likewise, almost exponential increase in placebo-controlled complete reversibility of suppressed spermatogenesis andrological studies, no new studies with androgens was observed in volunteers treated with testosterone for have been performed. contraceptive purposes (see Chap. 29). Testosterone and its synthetic derivatives suppress To date there is no proof for the effectiveness of oral pituitary gonadotropin secretion, thus leading to inhibi- testosterone undecanoate and thus no rationale for its tion of spermatogenesis. A large proportion of patients use. One attempt failed to justify the use of androgens treated with androgens become azoospermic. This effect for idiopathic infertility by giving testosterone unde- of exogenously administered androgens is used for con- canoate prior to in-vitro fertilization (Abdelmassih traceptive trials in males (see Chap. 29). It was believed et al. 1992). Here again, the observational data were that in men with idiopathic infertility, spermatogenic uncontrolled and could not be confi rmed in a subsequent 22 Empirical Therapies for Idiopathic Male Infertility 463 controlled study (Comhaire et al. 1995). A placebo- repeatedly tried. However, there is neither evidence for controlled, double-blind study described an increase in circulatory disturbances in idiopathic infertility nor is sperm motility when men with idiopathic infertility there proof for any clear therapeutic effects of pen- were treated with testosterone undecanoate as a sup- toxyphylline as an infertility regimen (Wang et al. plementary agent to tamoxifen treatment (Adamopoulos 1983; Shen et al. 1991). et al. 1997) and a further controlled study was able to Apart from oral application, pentoxyphylline was report a three-fold increase of pregnancy rates in the used as an in-vitro additive in IVF in order to improve verum group (Adamopoulos et al. 2003). This high fertilization rates. However, an improvement in fertil- success rate has not been confi rmed by further studies, ization rates in asthenozoospermia, after IVF-failure and since the manufacturer has not applied for licens- or in the presence of anti-sperm antibodies could not ing for this indication so far, its use in male infertility been clearly demonstrated (for review see Tournaye remains experimental and must be classifi ed as an indi- et al. 1995). vidual attempt at therapy.

22.2.8 a -Receptor Blocking Agents 22.2.6 Kallikrein Although no clear pathophysiological concept exists There is no clear pathophysiological or pharmacologi- for the use of a-receptor blocking agents in the treat- cal concept for kallikrein as a treatment regimen in idio- ment of male infertility, placebo-controlled studies have pathic male infertility. Nevertheless, it was applied in been performed using such substances and reported andrological practice since the 1980s. Originally, increases in ejaculate volume, sperm concentration and improvement of sperm motility was claimed after kal- total number of motile sperm (Yamamoto et al. 1995; likrein application. A controlled, randomized, placebo- Gregoriou et al. 1997). However, effi cacy in terms of controlled, double-blind trial including 91 couples improved pregnancy rates has not been demonstrated. (Keck et al. 1994) was unable to demonstrate that kal- In addition, most of the studies revealed only weak sta- likrein effected any signifi cant improvement of seminal tistical evidence for the observed effects. Further con- parameters and pregnancy rates. Similar negative results trolled clinical studies are necessary before the effi cacy were reported in Japan (Yamamoto et al. 1996). The of such treatment can be appropriately evaluated. results were in line with a prospective, placebo-con- trolled, randomized study done in Israel including 114 couples which showed no improvement in seminal parameters (Glezermann et al. 1993). Both properly 22.2.9 Antioxidants designed studies lead to the conclusion that kallikrein Ð given orally at the doses tested – has no benefi cial effect In almost all fi elds of medicine oxidative damage of on male idiopathic infertility (Vandekerckhove 2000a). proteins and nucleic acids is being discussed as a major contributing factor in pathology such as aging, degen- erative diseases, cancer and arteriosclerosis. The role of oxidative stress and especially the therapeutic use of 22.2.7 Pentoxyphylline antioxidative vitamins has been widely considered for fertility disturbances (Tremellen 2008). Although oxi- Pentoxyphylline belongs to the family of methylxan- dative stress could be damaging to reproduction by thines. One pharmacological effect is the relaxation affecting spermatogenesis, sperm maturation or stor- of vascular smooth muscles. It is therefore prescribed age, reactive oxygen species (ROS) in physiological in vasculatory diseases associated with circulatory dis- amounts are required for normal sperm function (Aitken turbances (e.g., intermittent claudication). It has been 1995). For instance, an inverse correlation has been speculated that in men with idiopathic infertility tes- shown between fertilization rates in vitro and the ROS ticular circulation might be disturbed and would be scavenging properties of sperm involved (Yeung et al. improved by pentoxyphylline (Heite 1979) which was 1996). In placebo-controlled studies, administration of 464 E. Nieschlag and A. Kamischke

200Ð1,000 mg ascorbic acid given to patients with of increased ejaculate volume (possibly via increased increased sperm agglutination (but without anti-sperm testosterone) had no effect (Carani et al. 1999). When antibodies) or to heavy smokers (Dawson et al. 1992) applying this hormone in men with no pituitary dis- led to improved sperm quality. In addition, controlled ease, it must be considered that increased growth hor- studies have been performed for other antioxidants. mone may lead to prostate hypertrophy, as observed in After a 2-month course of glutathione application, acromegalic patients (Colao et al. 1999). improvement in sperm motility was reported (Lenzi On the theory that oxytocin increases the contractility et al. 1993); carnitin (Lenzi et al. 2003) or carnitin of the epididymis and may promote higher sperm num- combined with L-acetyl carnitin (Lenzi et al. 2004) bers by increased emptying of the sperm reserves, oxyto- led to increased sperm motility and vitamin E, when cin was given i.v. or intranasally immediately before given orally for 3 months, seems to enhance zona pel- ejaculation, but failed to improve ejaculate parameters or lucida binding of sperm as seen in the hemi-zona-assay pregnancy rates (Byrne et al. 2003; Walch et al. 2001). (Kessopoulou et al. 1995). A positive effect of carnitin, Despite the lack of any convincing data, substances however, could not be confi rmed (Sigman et al. 2006). used empirically also include interferon-a, mast cell One study found an increased pregnancy rate after vita- blockers and antihistamines (ketotifen), angiotensin- min E administration (Suleiman et al. 1996). However, converting enzyme (ACE) inhibitors (Captopril), and combined vitamin C and E in a randomized placebo- salts. controlled study failed to show a positive effect on sperm parameters or pregnancy rates (Rolf et al. 1999), while a further study found a positive effect of the combination prior to ICSI treatment with respect to 22.2.11 Physical Procedures pregnancy rates (Greco et al. 2005). In view of the highly contradictory results and the small numbers of Overheating the genital organs is considered a means patients in mostly uncontrolled studies to date, a recent to reduce fertility (see Chap. 19) and cooling of the overview concludes that attempts with antioxidants scrotal organs has been variously tried as therapy. No continue to be considered experimental and have no convincing theory for increasing pregnancy rates has place in clinical routine (Patel and Sigman 2008). Still yet been developed (Jung and Schuppe 2007). various antioxidants continue to be used for male infer- Acupuncture has also been considered for treat- tility treatment. A particularly clever fi rm combines all ment of male infertility. No positive effects on preg- substances in question such as vitamin C, E, B6 and nancy rates have been reported (Ng et al. 2008).

B12, folic acid, L-carnitin, Coenzyme Q10, selenium, zinc, carotinoids and omega-3 fatty acids and sells them with suggestive names without proof of the effec- tiveness of the single or combined substances. It is the 22.3 Therapeutic Guidelines physician’s task to enlighten the patient and shield him from unnecessary expense. Notwithstanding, the fi eld In summary, pharmacological approaches to the ther- deserves further research to fi nd out which patients apy of male idiopathic infertility have been highly dis- may indeed profi t from antioxidative therapy. appointing. Although a variety of drug regimens has been offered for clinical practice, no single regimen mentioned above turned out to have any signifi cant effect on pregnancy rates in controlled clinical stud- 22.2.10 Further Substances ies. This overview emphasizes the importance of well- designed, randomized controlled clinical studies for Several other substances have been used to treat idio- the evaluation of therapeutics in andrology (Kamischke pathic male infertility. Bromocriptine, successfully and Nieschlag 1999). Until a given therapeutic regi- used in hyperprolactinemia, was tried without success men has proven its benefi ts in controlled clinical stud- in infertility (Vandekerckhove et al. 2000b). ies, it should not be prescribed for general practice Though lacking any clear concept, recombinant and physicians should be guided by the following growth hormone was also tried, but with the exception principle: 22 Empirical Therapies for Idiopathic Male Infertility 465

Any therapy in male infertility is to be considered with optimization of female reproductive functions are experimental as long as it has not proven its effi cacy the measures most likely to achieve success. in randomized controlled clinical studies. Therapeutic regimens without evidence for their effi cacy should only be applied in clinical studies. References

Abdelmassih R, Dhont M, Comhaire F (1992) Pilot study with This principle demands great discipline from the phy- 120 mg Andriol treatment for couples with a low fertilization sician who may be urged towards therapeutic interven- rate during in-vitro fertilization. Hum Reprod 7:267Ð268 tion by the patient’s suffering and expectations. In Acosta A, Khalifa E, Oehninger S (1992) Pure human follicle addition, consensus among the medical profession is stimulating hormone has a role in the treatment of severe male infertility by assisted reproduction: Norfolk’s total necessary to prevent untimely use of unproven thera- experience. Hum Reprod 7:1067Ð1072 pies so that spontaneous pregnancies are not ascribed Adamopoulos DA, Nicopoulou S, Kapolla N, Karamertzanis M, to these therapies by grateful patients. Andreou E (1997) The combination of testosterone unde- At present attention previously given to empirical canoate with tamoxifen citrate enhances the effects of each agent given independently on seminal parameters in men forms of therapy is waning in the face of clinical suc- with idiopathic oligozoospermia. Fertil Steril 67:756Ð762 cess enjoyed by techniques of assisted fertilization. Adamopoulos DA, Pappa A, Billa E, Nicopoulou S, Koukkou E, Pharmacological approaches to male idiopathic infer- Michopoulos J (2003) Effectiveness of combined tamoxifen tility are becoming less important. In particular, ICSI citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia. Fertil Steril 80:914Ð920 is proving to be benefi cial in cases of severe oligoas- Afjes JH, van der Vijver JC, Brugman FW, Schenck PE (1983) thenoteratozoospermia and even in azoospermia (see Double-blind cross over treatment with mesterolone and pla- Chap. 23). Especially assisted fertilization is proving cebo of subfertile oligozoospermic men value of testicular anew the adage that intensive therapy of female repro- biopsy. Andrologia 15:531Ð535 Ainmelk Y, Belisle S, Carmel M, JP Tetrault (1987) Tamoxifen ductive functions is the best treatment for male infertil- citrate therapy in male infertility. Fertil Steril 48:113Ð127 ity, summarized in the following principle: Aitken RJ (1995) Free radicals, lipid peroxidation and sperm function. Reprod Fertil Dev 7:659Ð668 Attia AM, Al-Inany HG, Proctor ML (2007) Gonadotrophins for Every therapy for male infertility must be accompa- idiopathic male factor subfertility. Cochrane Database Syst nied by optimization of female reproductive func- Rev 2007 CD00 5071 tions. This is especially valid when no effective Baccetti B, Piomboni P, Bruni E, Capitani S, Gambera L, Moretti E, Sterzik K, Strehler E (2004) Effect of follicle- treatment is available for disturbed male fertility. stimulating hormone on sperm quality and pregnancy rate. Asian J Androl 6:133Ð137 Bals-Pratsch M, Knuth UA, Hönigl W, Klein HM, Bergmann M, Empirical therapies which have remained without suc- Nieschlag E (1989) Pulsatile GnRH-therapy in oligozoo- cess so far must not prevent the search for effective treat- spermic men does not improve seminal parameters despite ments of male infertility. The success of assisted decreased FSH levels. Clin Endocrinol 30:549Ð560 Bartoov B, Har-Even D, Eltes F, Lederman H, Lunenfeld E, reproduction notwithstanding, most patients would pre- Lunenfeld B (1994) Sperm quality of subfertile males before fer to conceive their children in privacy and not in the and after treatment with human follicle-stimulating hor- laboratory and would prefer a cause-related therapy for mone. Fertil Steril 61:727Ð734 their illness. In addition, especially when the costs for Byrne MM, Rolf C, Depenbusch M, Cooper TG, Nieschlag E (2003) Lack of effect of a single i.v. dose of oxytocin on assisted reproduction are not assumed by insurers, there sperm output in severely oligozoospermic men. Hum Reprod is much demand for medication which is reimbursable or 18:2098Ð2102 at least less costly than assisted reproduction. This pres- Carani C, Granata AR, De Rosa M, Garau C, Zarrilli S, Paesano L, sure must not give rise to hasty prescribing but should Colao A, Marrama P, Lombardi G (1999) The effect of chronic treatment with GH on gonadal function in men with motivate researchers to carry out more intensive research. isolated GH defi ciency. Eur J Endocrinol 140:224Ð230 It is the time-consuming and responsible task of the treat- Clark R, Sherins RJ (1989) Treatment of men with idiopathic ing physician to enlighten the patient and the couple and oligozoospermic infertility using the aromatase inhibitor to provide counsel while guiding them through the jungle testolactone. Results of a double-blinded, randomized, pla- cebo-controlled trial with crossover. J Androl 10:240Ð347 of medications and procedures offered. In view of the Colao A, Marzullo P, Piezia S, Ferone D, Giaccio A, Cerbone G, lack of rational therapies, intensive counseling along Pivonello R, Di Somma C, Lombardi G (1999) Effect of 466 E. 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Hum Reprod 9:325Ð329 tosterone undecanoate improve the in-vitro fertilizing capacity Kessopoulou E, Russel JM, Powers HJ, Cooke ID, Sharma KK, of spermatozoa in patients with idiopathic testicular failure Barratt CLR, Pearson MJ (1995) A double-blind random- (results of a double-blind study). Hum Reprod 10:2600Ð2602 ized placebo cross-over controlled trial using the antioxidant Comodo F, Vargiu N, Farina M (1996) Double-blind FSH-HP/ vitamin E to treat reactive oxygen species associated male Placebo treatment of severe male factor related infertility: infertility. Fertil Steril 64:825Ð831 Effect on sperm parameters and IVF/ICSI outcome. ESHRE Knuth UA, Hönigl W, Bals-Pratsch M, Schleicher G, Nieschlag Abstract Book S41 E (1987) Treatment of severe ologozoospermia with hCG/ Dawson EB, Harris WA, Teter MC, Powell LC (1992) Effect of hMG. A placebo-controlled double-blind trial. J Clin ascorbic acid supplementation on the sperm quality of smok- Endocrinol Metab 65:1081Ð1087 ers. 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Arch Steril 20(Suppl. 1):38Ð42 Androl 2:479Ð486 Jung A, Schuppe HC (2007) Infl uence of genital heat stress on Reyes-Fuentes A, Chavarria ME, Carrera A, Aguilera G, Rosado in humans. Andrologia 39:203Ð215 A, Samojlik E, Iranmanesh A, Veldhuis JD (1996) Alterations Kamischke A, Nieschlag E (1999) Analysis of medical treat- in pulsatile and follicle-stimulating hor- ment of male infertility. Hum Reprod 14(Suppl 1):1Ð23 mone secretion in idiopathic oligoasthenospermic men: 22 Empirical Therapies for Idiopathic Male Infertility 467

Assessment by deconvolution analysis Ð a clinical research Cochrane Library. The Cochrane Collaboration, Issue 2. center study. J Clin Endocrinol Metab 81:524Ð529 Update Software, Oxford Rolf C, Behre HM, Nieschlag E (1996) Tamoxifen bei männli- Vandekerckhove P, Lilford R, Vail A, Hughes E (2000a) Kinin cher Infertilität. Analyse einer fragwürdigen Therapie. Dtsch enhancing drugs for unexplained subinfertility. The Cochrane med Wschr 121:33Ð39 Collaboration, Database Syst Rev 2000 CD 153 Rolf C, Cooper TG, Yeung CH, Nieschlag E (1999) Antioxidant Vandekerckhove P, Lilford R, Vail A, Hughes E (2000b) treatment of patients with asthenozoospermia or moderate Bromocriptine for idiopathic oligo/asthenospermia. Cochrane oligoasthenozoospermia with high-dose vitamin C and vita- Database Syst Rev CD 152 min E: A randomized, placebo-controlled, double-blind Vandekerckhove P, Lilford R, Vail A, Hughes E (2007) Clomiphene study. Hum Reprod 14:1028Ð1033 or tamoxifen for idiopathic oligo/asthenospermia. Cochrane Ronnberg, L (1980) The effect of clomiphene citrate on different Database Syst Rev CD 151 sperm parameters and serum hormone levels in preselected Wagner ROF, Warsch F (1984) Pulsatile LHRH therapy of “slow infertile men: A controlled double-blind cross-over study. pulsing oligospermia”: Indirect evidence for a hypothalamic Int J Androl 3:479Ð486 origin of the disorder. Acta Endocrinol (Copenh) 105(Suppl Shen M-R, Chiang P-H, Yang R-C, Hong C-Y, Chen S-S (1991) 264):142Ð145 Pentoxifylline stimulates human sperm motility both in vitro Walch K, Eder R, Schindler A, Feichtinger W (2001) The effect and after oral therapy. Br J Clin Pharmacol 31:711Ð714 of single-dose oxytocin application on time to ejaculation SIG Scottish Infertility Group (1984) Randomized trial of mes- and seminal parameters in men. J Assist Reprod Genet terolone versus vitamin C for male infertility. Br J Urol 18:655Ð659 56:740Ð744 Wang C, Chan CW, Wong KK, Yeung KK (1983) Comparison of Sigman M, Glass S, Campagnone J, Pryor JL (2006) Carnitine the effectiveness of placebo, clomiphene citrate, mesterolone, for the treatment of idiopathic asthenospermia: A random- pentoxyfylline and testosterone rebound therapy for the treat- ized, double-blind, placebo-controlled trial. Fertil Steril 85: ment of idiopathic oligospermia. Fertil Steril 40:358Ð365 1409Ð1414 WHO Task Force on the Diagnosis and Treatment of Infertility Sokol RZ, Steiner BS, Bustillo M, Petersen G, Swerdloff RS (1989) Mesterolone and idiopathic male infertility: A dou- (1988) A controlled comparison of the effi cacy of clomi- ble-blind study. Int J Androl 12:254Ð264 phene citrate in male infertility. Fertil Steril 49:865Ð870 WHO Task Force on the Prevention and Management of Suleiman SA, Ali M, Zaki ZME, el-Malik EM, Nasir MA (1996) Infertility (1992) A double-blind trial of clomiphene citrate Lipid peroxidation and human sperm motility: Protective for the treatment of idiopathic male infertility. Int J Androl role of vitamin E. J Androl 17:530Ð537 15:299Ð307 Török L (1985) Treatment of oligozoospermia with tamoxifen Yamamoto M, Hibi H, Mijake K (1995) Comparison of the (open and controlled studies). Andrologia 17:497Ð501 effectiveness of placebo and a-blocker therapy for treatment Tournaye H, Devroey P, Camus M, Van der Linden M, Janssens of idiopathic oligozoospermia. Fertil Steril 63:396Ð340 R, Van Steirteghem A (1995) Use of pentoxifylline in assisted Yamamoto M, Katsuno S, Hibi H, Miyake K (1996) The lack of reproductive technology. Hum Reprod 10(Suppl. 1):72Ð79 effectiveness of kallikrein in the treatment of idiopathic oli- Tremellen K (2008) Oxidative stress and male infertility Ð a gozoospermia: A double-blind, randomized, placebo-con- clinical perspective. Hum Reprod Update 14:243Ð258 trolled study. Jap J Fertil Steril 41:1Ð6 Vandekerckhove P, Lilford R, Hughes E (1998) The medical Yeung CH, De Geyter C, De Geyter M, Nieschlag E (1996) treatment of idiopathic oligo/asthenospermia: anti- oestrogens Production of reactive oxygen species by and hydrogen per- (clomiphene or tamoxifen) versus placebo or no treatment. oxide scavenging activity of spermatozoa in an IVF pro- In: Lilford R, Hughes E, Vandekerckhove P (eds) Subfertility gram. J Assist Reprod Genet 13:495Ð500 Module of the Cochrane Database of Systematic Reviews. Assisted Reproduction 23 Christian De Geyter, Maria De Geyter, and Hermann M. Behre

Contents 23.7.1 Collection of Semen for Assisted Reproduction ...... 483 23.7.2 Preparation of Sperm for Assisted 23.1 Assisted Reproduction as a Treatment Reproduction ...... 485 of Infertility ...... 470 23.7.3 Filtration ...... 485 23.2 Methods of Assisted reproduction Available 23.7.4 Swim-up ...... 485 for Treatment of Male Infertility ...... 470 23.7.5 Density Gradient Centrifugation ...... 486 23.7.6 Sorting of Spermatozoa Based 23.3 Insemination ...... 471 on Defi ned Characteristics ...... 487 23.3.1 Spontaneous Conception Rate 23.7.7 Removal of Contaminant in the Infertile Couple ...... 471 Infectious Particles ...... 487 23.3.2 Intravaginal and Intracervical 23.7.8 Processing of Sperm for Insemination (ICI) ...... 471 ICSI in Diffi cult Cases ...... 488 23.3.3 Intrauterine Insemination (IUI) ...... 472 23.7.9 Treatment of Spermatozoa In vitro ...... 488 23.3.4 Intratubal Insemination (ITI) ...... 473 23.8 Ovarian Follicular Development, 23.3.5 Direct Intraperitoneal Ovarian Stimulation, Ovulation Insemination (DIPI) ...... 473 Induction and Oocyte Collection ...... 488 23.3.6 Intrafollicular Insemination ...... 473 23.8.1 Monitoring of Ovarian Follicular 23.4 In vitro Fertilization and Related Development and Ovarian Techniques ...... 474 Stimulation for Insemination ...... 488 23.4.1 In vitro Fertilization (IVF) ...... 474 23.8.2 Ovarian Stimulationfor 23.4.2 Gamete Intra-Fallopian IVF and ICSI ...... 489 Transfer (GIFT) ...... 476 23.9 Methods of Oocyte Collection ...... 490 23.4.3 Intra-Fallopian Transfer of Zygotes 23.10 Assisted Hatching ...... 491 (ZIFT) or Pronucleate-Stage Oocyte Transfer (PROST) ...... 477 23.11 Embryo Transfer ...... 492 23.4.4 Tubal Embryo Transfer (TET) ...... 477 23.12 Cryopreservation of Oocytes 23.5 Micro-assisted Fertilization ...... 477 in the Pronucleate Stage ...... 492 23.5.1 Previously Used Techniques 23.13 Complications of Assisted Reproduction ...... 493 of Micro-assisted Fertilization ...... 478 23.13.1 Ovarian Hyperstimulation Syndrome 23.5.2 Intracytoplasmic Sperm (OHSS) ...... 493 Injection (ICSI) ...... 478 23.13.2 Ovarian Torsion...... 494 23.6 Semen Donation ...... 482 23.13.3 The Risk of Multiple Pregnancies ...... 494 23.13.4 Cancer Risk in the Mother 23.7 Collection and Preparation of Sperm After Assisted Reproduction ...... 494 for Assisted Reproduction ...... 483 23.14 Genetic Counselling in Assisted Reproduction ...... 495 23.15 Health of the Offspring After Ch. De Geyter (*) Assisted Fertilization ...... 496 Universitätsspital Basel, Spitalstr. 21, CH-4031 Basel, Switzerland References ...... 497 e-mail: [email protected]

E. Nieschlag et al. (eds.), Andrology, 469 DOI: 10.1007/978-3-540-78355-8_23, © Springer-Verlag Berlin Heidelberg 2010 470 Ch. De Geyter et al.

23.1 Assisted Reproduction the many techniques of assisted reproduction currently as a Treatment of Infertility available. Nowadays, virtually all cases of male infer- tility can be potentially treated by some method of assisted fertilization. The broad array of treatment Ideally, medicine should deal with the childlessness of options together with an increasing demand due to the each infertile couple in two subsequent steps. First, all present-day demographic trend towards delaying the factors interfering with natural conception should be time of childbirth later in life has caused an impressive identifi ed (see Chap. 20). Secondly, the targeted treat- uprise in the number of treatments with assisted repro- ment of each factor contributing to the infertility duction in Europe and elsewhere (Fig. 23.1). A signifi - should be identifi ed and initiated. Unfortunately, nei- cant proportion of newborns – varying between 1.5% ther in gynecology nor in andrology can many of the and 4.5% in various countries – now originate from identifi ed causes of infertility be overcome by a tar- assisted reproduction. geted treatment, so that instead a number of thera- peutic strategies have been developed to deal with childlessness exclusively as a symptom without removing the cause of infertility itself. Most of these 23.2 Methods of Assisted Reproduction strategies can be summarized by the term “assisted Available for Treatment reproduction”. The major disadvantage of any form of assisted reproduction is its short-term effi cacy, of Male Infertility because the therapeutic effect of assisted reproduction is active only during the treatment cycle itself. If this Assisted reproduction comprises various treatment treatment cycle proves to be unsuccessful or if infertil- modalities, which can be differentiated by more or less ity recurs after delivery of a healthy baby, the entire stringent control over the processes of fertilization and treatment must be repeated. by the degree of invasiveness. For the purpose of this Notwithstanding this major disadvantage, today the chapter the various forms of assisted reproduction are majority of infertile couples can be treated with one of subdivided into four major groups:

4.5 1997 1998 4.0 1999 3.5 2000 2001 3.0 2002 2003 2.5 2004 2.0

1.5

total no. of children born (%) 1.0 no. children born after IVF or ICSI / 0.5

0.0 Denmark Finland Iceland Norway Sweden Switzerland* Germany* Austria*

Fig. 23.1 The use of assisted reproduction in various countries newborns conceived with IVF or ICSI is noted in most countries in Europe, in which all treatments with IVF and ICSI were reg- (Nygren et al. 2001a and b; Andersen et al. 2005, 2006). istered. The number of births of neonates conceived with assisted *Whereas in Switzerland in 2004 only incomplete delivery data reproduction is set in relation to the overall births of neonates were available, Germany and Austria were able to provide com- (in %). Over the years a steady increase in the relative number of plete delivery data only in 2004 (Andersen et al. 2008) 23 Assisted Reproduction 471

determined by various factors, the most important being • Insemination denotes a group of techniques in the duration of infertility (Léridon and Spira 1984). It is which the sperm are transferred into the female during the fi rst three ovulatory cycles after inception of partner by various methods. Insemination aims unprotected sexual intercourse that the highest concep- at increasing the concentration of fertile sperma- tion rates per cycle are observed: 20–25% (Spira 1986; tozoa in the vicinity of the oocyte within the Hull 1992). In subsequent cycles the rate of naturally Fallopian tube around the time of ovulation. occurring pregnancies steadily decreases, so that after • In in vitro fertilization (IVF) fertilization does 12 months the pregnancy rate may vary between 0.75% not take place in the Fallopian tube of the female and 3.97% per cycle (Crosignani et al. 1991). partner. Before ovulation the oocyte is removed Prognostically favorable fi ndings in the patient’s from the mature follicle and cultured in an artifi - history are previous intact pregnancies with the same cial environment in which fertilization and early partner, the age of the female partner and the duration embryonic development can take place. With of infertility (Collins et al. 1983). Conversely, endo- this technology variable numbers of motile sper- metriosis, tubal factors and male infertility all are matozoa can be added to selected oocytes, obser- prognostically unfavorable for future childbearing vation of the result of fertilization, selection of (Collins et al. 1995). Although the parameters of con- fertilized oocytes and transfer of a defi ned num- ventional semen analysis bear hardly any relationship ber of embryos into the uterine cavity. to the physiology of sperm capacitation and fertiliza- • In intracytoplasmic sperm injection (ICSI) a tion and despite the limited number of studies, they are single vital is placed into the oocyte correlated with the likelihood of natural conception by penetrating it, through all its investments, with and can therefore be used to delineate male infertility a micropipette. ICSI enables successful fertiliza- to some extent. The probability of natural conception tions not only despite severe abnormalities in is severely reduced in the presence of reduced ejacu- motility, morphology and capacitation process of late volume (Bostofte et al. 1982), a low percentage of the injected spermatozoa, but also despite func- normal sperm morphology (Ombelet et al. 1997; tional and anatomical anomalies of the testes, the Bonde et al. 1998), reduced concentration of sperm in epididymis and the efferent ducts. the seminal plasma (Bostofte et al. 1982; Ombelet • In semen donation spermatozoa from a fertile et al. 1997; Bonde et al. 1998) and in the presence of donor are used in order to substitute the absence high numbers of immotile spermatozoa (Bostofte et al. of functional gametes in the partner. In theory, all 1983). Another factor determining the degree of infer- available techniques of assisted fertilization can be tility and the effi cacy of assisted reproduction is the used in semen donation. However, the practice combination of multiple infertility factors in both part- of semen donation is usually regulated by country- ners. For example, the therapeutic effi cacy of heterolo- specifi c legislation, requiring maximal safety of gous insemination in male infertility is higher in male both the recipient and the offspring through optimal patients suffering from azoospermia than in patients diagnostic screening of the donor and through cry- with only abnormal semen quality (Emperaire et al. ostorage of donated semen before use. Semen dona- 1982). This difference can only be explained by differ- tion can be either anonymous or non-anonymous. ences in the fertility status of the female partner. Natural conceptions in previously infertile couples are commonly observed, particularly when the diagnostic 23.3 Insemination and therapeutic interventions are of prolonged duration.

23.3.1 Spontaneous Conception Rate in the Infertile Couple 23.3.2 Intravaginal and Intracervical Insemination (ICI) Any treatment of infertility is effective only if its preg- nancy rate exceeds the conception rate in the untreated This form of assisted fertilization represents the earli- infertile couple. The spontaneous conception rate is est method of insemination. With these techniques 472 Ch. De Geyter et al. some anatomical barriers in the vagina and in the cer- intratubal vix of the female partner (cervical infertility) and dis- turbances of sperm deposition in the male partner IUI (hypospadias, retrograde ejaculation, impotentia coe- undi) can be overcome. During intravaginal or intracervical insemination ICI 1–2 ml of freshly collected or cryopreserved and thawed semen is deposited in the vagina or in the cervical canal DIPI by the use of a catheter connected to a syringe. Besides intrafollicular the liquefaction of the semen, which occurs spontane- ously after 30 min of incubation at room temperature, no particular manipulation or preparation of the semen is necessary, so that this treatment does not require any Fig. 23.2 Graphic presentation of the different techniques of laboratory equipment. Special care should be taken not insemination: intracervical (ICI), intrauterine (IUI), intratubal, direct intraperitoneal (DIPI), intrafollicular to introduce any semen into the uterine cavity, because the prostaglandins contained in the seminal plasma may cause painful contractions of the myometrium. To pre- probability of fertilization. One particular modifi cation vent contact of the semen with the vaginal milieu, which of intrauterine insemination involves the perfusion of a owing to its acidity is hostile to sperm, the semen sam- larger volume of a prepared sperm sample (4 ml) over a ple can be separated from the vagina with a cap fi tted period of 4 min into the uterine cavity, to ensure the on the portio of the cervix immediately after the cervi- attachment of a larger number of spermatozoa to the cal insemination. After about 6 h this cap can be mucosa of the Fallopian tube (Kahn et al. 1993). Later removed by the patient herself. prospective studies and a single meta-analysis showed In recent times intravaginal and intracervical insem- higher pregnancy rates in couples with unexplained inations have been replaced largely by intrauterine infertility only (Trout and Kemmann 1999). As Fallopian insemination (IUI) because of the higher effi cacy of tube perfusion combines both closure of the cervix the latter. In several controlled studies, the therapeutic either with a clamp or with an infl ated balloon and the effi cacy of IUI was compared with intracervical and fl ushing of the Fallopian tubes with a signifi cant vol- intravaginal insemination and the former was found to ume, the initial higher pregnancy rates achieved with the be signifi cantly superior in prospective studies using perfusion method in some studies may also be explained frozen/thawed donor semen. The latter was used to by the fl ushing of debris out off the tubal lumen. reduce the number of variables possibly infl uencing Apart from being less invasive and costly than IVF the results of the comparison (Cruz et al. 1986; Byrd or ICSI, the therapeutic effi cacy of IUI as an isolated et al. 1990; Patton et al. 1992; Hurd et al. 1993; procedure has been questioned recently (Fig. 23.3). Williams et al. 1995; Fig. 23.2). With intrauterine Although IUI is frequently used as a fi rst-line therapy insemination higher sperm numbers can be brought in male infertility, insuffi cient data have been collected into the uterine cavity and into the Fallopian tubes to substantiate the effi cacy of IUI as an isolated method (Ripps et al. 1994). as compared with timed intercourse (Bensdorp et al. 2007). On the other hand, when comparing with IVF, the cost effectiveness of IUI may be considered benefi - cial, particularly if the cumulative pregnancy rate of up 23.3.3 Intrauterine Insemination (IUI) to six treatment trials are taken in account (Goverde et al. 2000). Therefore, it is important to explain to the In intrauterine insemination 0.2–0.5 ml of a washed patients that IUI must not be considered as one single sperm sample is introduced with a fi ne catheter con- treatment, but rather as a series of successive trials. nected to a syringe into the uterine cavity of a periovula- Although in cases with male immunological infertility tory patient. The aim of this technique is to achieve a IUI has been offi cially approved in many countries, the higher concentration of motile spermatozoa within the pregnancy rates have been found to be low (Francavilla lumen of the Fallopian tube in order to increase the et al. 1992). 23 Assisted Reproduction 473

unstimulated Unstimulated menstrual cycle + Menstrual cycle timed intercourse or + intracervical insemination intrauterine insemination 3.1 (1.5-6.3)1

1.8 (1.0-3.9)2 1.4 (0.9-2.4)1 1.7 (1.2-2.6)2 3.2 (2.0-5.3)2

ovarian stimulation ovarian stimulation with gonadotropis + with gonadotropins timed intercourse or + intracervical insemination intrauterine insemination 2.1 (1.3-3.5)1

Fig. 23.3 Odds ratio and the corresponding 95% confi dence leads to a better outcome (odds ratio > 1). The best results intervals of the pregnancy rates after IUI as compared to natu- were consistently achieved after ovarian stimulation with ral conception at the predicted moment of ovulation (metaanal- gonadotropins followed by ovulation induction. For the con- ysis by Cohlen et al. 2004 [1]) or compared with intracervical struction of this fi gure only data dealing with male infertility insemination (Guzick et al. 1999 [2]). In most studies IUI were included

IUI is performed easily, requires minimal equip- and 0.2–2 ml of this is injected into the peritoneal cav- ment and remains practically without complications. ity (Forrler et al. 1986). The spermatozoa can be trans- Infections after IUI, such as endometritis or pelvic ported into the lumen of the Fallopian tube by the infl ammatory disease, are observed extremely rarely. ciliary movement of the mucosal cells covering the abdominal infundibulum of the oviduct. With DIPI, not only the cervix but also the isthmic part of the 23.3.4 Intratubal Insemination (ITI) Fallopian tube is circumvented, as both are considered to be obstacles for defective spermatozoa. This method can be applied only to patients with In several animal species it was shown that, in addition intact Fallopian tubes and was fi rst used predomi- to the cervix, a second sperm reservoir exists in the nantly in couples suffering from unexplained and cervi- isthmic part of the Fallopian tube (see also Chap. 3). cal infertility, later also in male infertility. Using Based on these fi ndings, the technique of intratubal controlled randomized settings, the pregnancy rate of insemination was invented to transfer washed sperma- direct intraperitoneal insemination was not better than tozoa beyond the isthmic portion of the Fallopian tube the pregnancy rate of timed natural intercourse (Campos- in order to achieve a higher sperm concentration within Liete et al. 1992) or of IUI (Hovatta et al. 1990). This the ampulla, where fertilization normally occurs technique may still be used in women with a severe cer- (Jansen and Anderson 1987). However, controlled vical stenosis which cannot be passed without damage studies demonstrated that with intratubal insemination to the endometrium. No induction of antisperm antibod- the pregnancy rate is no better than with IUI (Oei et al. ies could be demonstrated as a consequence of this 1992; Hurd et al. 1993). method of insemination.

23.3.5 Direct Intraperitoneal Insemination (DIPI) 23.3.6 Intrafollicular Insemination

In direct intraperitoneal insemination the posterior In intrafollicular insemination several mature vaginal pouch is punctured with a needle connected to cumulus-oocyte complexes are recovered by transvaginal a syringe containing the prepared sperm , ultrasound-guided puncture of all but one preovulatory 474 Ch. De Geyter et al. ovarian follicle. After selection of the most mature ovaries, more oocytes can be inseminated and possibly cumulus-oocyte complexes, these are mixed with fertilized within the frame of one treatment cycle, 0.03–0.5 ml of the previously prepared sperm suspen- thereby offering the opportunity to select fertilized sion and are then inserted during the same transvaginal oocytes for further embryo culture. ultrasound-guided puncture into one mature ovarian Unfortunately, the early high expectations of con- follicle. The rationale of intrafollicular insemination ventional IVF for the treatment of severe male infertil- is based on the fi nding of some factors present in fol- ity were not fulfi lled for several reasons. First, the licular fl uid (e.g. progesterone) which may physiologi- prolonged coincubation of sperm and oocytes is asso- cally stimulate both capacitation and the acrosome ciated with a signifi cantly reduced pregnancy rate reaction of spermatozoa. In a prospective cohort study compared with a coincubation time of 4–5 h (Dirnfeld involving 50 couples only one pregnancy could be et al. 1999) and the presence of an excessive concen- achieved (Nuojua-Huttonen et al. 1995), so this tech- tration of spermatozoa around the oocyte may in some nique does not seem to be of any benefi t compared to cases compromise the pregnancy rates (Kastrop et al. other forms of insemination. 1999; Benoff et al. 1999). In observational cohort stud- ies involving couples treated because of male infertil- ity only the success rates of IVF were the lowest of all (Tournaye et al. 1992; Tan et al. 1992) and were not 23.4 In vitro Fertilization and Related better than the spontaneous conception rate during a Techniques 6-month waiting period (Soliman et al. 1993). The advent of ICSI has now replaced conventional IVF in the treatment of severe male infertility. IVF is 23.4.1 In vitro Fertilization (IVF) still used for the treatment of female infertility, such as tubal infertility or unexplained infertility. The basic hallmark of IVF, distinguishing it from other Although IVF can be performed with some success procedures of assisted fertilization, is that the physio- in the unstimulated menstrual cycle, it has become logical process of fertilization takes place outside the widespread practice to carry out this treatment in body of the patient in an artifi cially constructed envi- combination with hormonal stimulation of the ova- ronment. For this purpose, one or more oocytes are ries, so that multiple oocytes become available for recovered from preovulatory ovarian follicles and sub- IVF. The improved pregnancy rate of IVF after sequently coincubated in a complex culture medium, hormonal stimulation of ovarian follicular develop- designed to mimic the tubal fl uidic milieu. Motile ment results mainly from the selection of several fer- spermatozoa are then separated from immotile sper- tilized oocytes and their in vitro culture up to the matozoa, non-spermatozoal cells and seminal plasma. embryonic stage. Ovarian stimulation also provides a Subsequently, a defi ned number of motile spermatozoa better assessment of the events controlling follicular are then co-incubated with an oocyte. After identifi ca- maturation, in turn leading to the collection of more tion of successful fertilization, either at the pronuclear mature oocytes with high developmental capacity. stage, at an earlier cleavage stage or at the later blasto- Furthermore, ovarian stimulation compensates for cyst stage, the embryos are placed in the uterine cavity clinical and subclinical defects in the follicular devel- for nidation in the endometrium and pregnancy. opment of some patients. On the other hand, ovarian IVF was originally introduced for the treatment of hyperstimulation and the transfer of more than one tubal infertility caused either by occlusion of the embryo at the time entail a high incidence of multiple Fallopian tubes or by impairment of their function pregnancies. Multiple pregnancies, particularly in (Edwards 1981). However, soon after its successful previously infertile women, are associated with con- introduction, its potential value for the treatment of siderable obstetric and neonatal risks, which in turn male infertility became an issue of intensive debate. In entail high additional fi nancial costs (Callahan et al. contrast to all existing forms of artifi cial insemination, 1994; Schieve 2006). The rapidly increasing number IVF offers the possibility of inseminating the oocytes of treatments with assisted reproduction leading to with a predetermined number of motile sperm. In more deliveries of multiples has caused an upsurge addition, as a result of the hormonal stimulation of the in the numbers of prematurely born neonates. 23 Assisted Reproduction 475

Consequently, there is a multinational trend to replace deliveries is prohibited. The legal and ethical discus- only one single embryo per cycle selected from a sions about the possibility of surplus embryos have cohort of growing embryos based on morphological not been solved yet. assessment. It has been demonstrated that the selection and transfer of a single embryo (often denominated elective SET) can be performed successfully without ICSI has now replaced conventional IVF for the lowering the overall pregnancy rates (Vilska et al. treatment of couples suffering from idiopathic male 1999; Gerris et al. 1999, 2002; Papanikolaou et al. infertility. 2006), even in women older than 35 years (Veleva et al. 2006). In addition, in some countries, such as Sweden, where elective SET was introduced nation- Whereas the decision to perform ICSI rather than IVF wide, the incidence of multiple deliveries was reduced is obvious in severe male infertility, the choice may (Karlström and Bergh 2007). Finally, as neonatal birth become diffi cult in many borderline cases. Although weight is signifi cantly lower after IVF (De Geyter today many treatment units perform ICSI indifferently et al. 2006), for reasons that are still unknown, this dif- in all cases (Jain and Gupta 2007), the fertilization ference seems not to be present in neonates originating rates obtained with IVF have been shown to be similar from single embryo transfer (De Sutter et al. 2006). to those observed after ICSI in couples with normal However, in some countries – among them Germany seminal parameters (Table 23.1). On the other hand, and Switzerland – the selection of single embryos out some studies have demonstrated that the frequency of of a cohort of several available embryos as a strategy complete failure of fertilization of all oocytes is higher to improve pregnancy rates while preventing multiple after IVF than after ICSI (Table 23.1). The dilemma of

Table 23.1 Results of various prospective studies performed on couples or on sibling oocytes randomized to either conventional IVF or ICSI. In IVF the fertilization rate (%) refers to all inseminated oocytes, whereas in ICSI to all oocytes retrieved. The failed fertilization (%) denotes those cycles with complete failure of fertilization Authors IVF ICSI Study design Fertilization rate Failed fertilization Fertilization rate Failed fertilization Aboulghar et al. 18 49 60 0 Sibling oocytes, (1996) male infertility Ruiz et al. (1997) 48.1 11.4 52.5 0 Sibling oocytes, unexplained inf. Moreno et al. 77.7 33.3 70.2 18.9 Couples, low (1998) ovarian response Pisarska et al. 52.8 7.9 63.5 2.6 Sibling oocytes, (1999) male infertility Staessen et al. 60.3 12.5 63.8 3.6 Sibling oocytes, (1999) tubal & unexplained inf. Verheyen et al. 22.9 50 63.4 0 Sibling oocytes, (1999) male infertility Bukulmez et al. 64.8 10.5 53.5 2.6 Couples, tubal (2000) infertility Bhattacharya et al. 58 5 47 2 Couples, non-male (2001) infertility Hershlag et al. 52 10.9 61.8 0.9 Sibling oocytes, (2002) male and unexplained inf. Van der 51.3 24.5 50.8 0.9 Sibling oocytes, Westerlaken male infertility et al. (2006) 476 Ch. De Geyter et al. performing conventional IVF or, alternatively, ICSI, Originally, GIFT was developed for the treatment still largely relies on conventional semen analysis. of couples suffering from unexplained infertility, but The predictive accuracy of conventional semen anal- soon it was used in male infertility as well. However, ysis for the results of IVF was determined prospec- in prospective-controlled studies, GIFT did not prove tively and reached 77% for the prediction of an to be more successful than conventional IVF in the inadequate fertilization rate and 95% for the prediction treatment of unexplained and male infertility (Leeton of a suffi cient fertilization rate (Duncan et al. 1993). et al. 1987; Fig. 23.5). Nowadays, this technique has Confronted with the inability to predict the fertilizing been largely abandoned and replaced by IVF and capacity of semen with borderline characteristics, ICSI. some authors advise treating sibling oocytes with IVF and ICSI separately (Van der Westerlaken et al. 2006). However, for this strategy a suffi cient number of oocytes is required. The use of sperm function tests, based on the physi- ology of capacitation, such as hyperactivated motility using computer-assisted sperm motion analysis (De TET Geyter et al. 1998), and binding of capacitated sperm to the zona pellucida (Mahutte and Arici 2003) have also been evaluated to predict the lack of fertilization. However, none of the available sperm function tests can reliably predict the absence of fertilization ability in IVF. GIFT IVF / ET ZIFT

Fig. 23.4 Graphic presentation of the different methods of 23.4.2 Gamete Intra-Fallopian replacement of gametes or embryos: in vitro fertilization (IVF) Transfer (GIFT) and replacement of the embryos into the uterine cavity, gamete intra-Fallopian transfer (GIFT), zygote intra-Fallopian transfer (ZIFT), tubal embryo transfer (TET) The culture media used for IVF were originally based on buffered salt solutions conceived for the growth of mouse embryos. Although with time the composition of the culture media became more elaborate, it was originally thought that the tubal environment was bet- Leeton et al. 1987 ter suited for supporting the processes of sperm capac- Tanbo et al. 1990 itation, fertilization and early embryonic development. Therefore, the technique of intra-Fallopian transfer Tournaye et al. 1992 of gametes (GIFT) was developed as an alternative to Fluker et al. 1993 both IVF and IUI (Fig. 23.4). In GIFT, ovarian stimulation is performed using Scholtes et al. 1994 protocols similar to IVF, but mature oocytes are col- all studies lected by laparoscopy only. Based on the morphologi- cal assessment of the cumulus oophorus and the corona 0 1 2 3 4 5 6 7 8 9 Odds ratio (± 95 % confidence interval) radiata or, if possible, by the visualization of the fi rst polar body, two to four mature oocytes are selected Fig. 23.5 The odds ratio (and the 95% confi dence interval, and mixed with prepared semen. During the same lap- based on the chi-squared test according to Pearson, Mantel and aroscopy, these selected cumulus-oocyte complexes Haenszel) of IVF compared with GIFT, ZIFT and TET was cal- culated using the data from several prospective studies. In most are then inserted by a catheter through the abdominal studies the pregnancy rate of IVF was superior to those of other infundibulum into the ampulla of one intact Fallopian treatment modalities (odds ratio > 1), especially when the data tube, where fertilization can take place. of all studies are compiled 23 Assisted Reproduction 477

23.4.3 Intra-Fallopian Transfer of the endometrium caused by diffi cult catheteriza- of Zygotes (ZIFT) or Pronucleate- tion in some patients. This technique has now been Stage Oocyte Transfer (PROST) abandoned.

In order to combine the advantage of GIFT, permitting 23.5 Micro-assisted Fertilization early embryonic development within the physiological environment of the Fallopian tube, with the advantage of IVF, in which information about the fertilization Among the various methods of micro-assisted fer- process is acquired, intra-Fallopian transfer of tilization, intracytoplasmic sperm injection was the zygotes (ZIFT) was developed. Simultaneously, and last to be developed. Its introduction has rapidly based on the same reasoning as for ZIFT, an analogous revolutionized the treatment of male infertility. method, the transfer of pronucleate-stage oocytes into the Fallopian tube (PROST), was introduced into assisted reproduction. In both methods two operations Historically, the development of the various methods had to be performed on the same patient on two con- of micro-assisted fertilization was characterized by the secutive days. Oocytes are collected by ultrasound- stepwise circumvention of all processes involving guided vaginal puncture of the preovulatory follicles sperm capacitation and fertilization (Fig. 23.6). The after ovarian stimulation and are then coincubated results achieved by the different methods of micro- overnight with motile spermatozoa. The next morning assisted fertilization clearly demonstrated that only pronuclei are identifi ed as a sign of successful sperm those techniques in which the physiological sequences penetration. Two to three oocytes in the pronucleate of fertilization were most effectively bypassed achieved stage or zygotes may then be replaced during laparos- the highest pregnancy rates. copy through the abdominal infundibulum into the Micro-assisted fertilization developed out of con- lumen of the Fallopian tube. ventional IVF. Therefore, the various techniques jointly Although very high pregnancy rates were achieved, denominated micro-assisted fertilization require hor- the therapeutic advantage of these complex treatments, monal stimulation of the ovaries, the collection of compared with conventional IVF, could not be proven mature oocytes from preovulatory follicles and the in prospective settings. Both techniques have now been replacement of fertilized oocytes into the uterine cav- abandoned. ity of the patient. All techniques of micro-assisted fer- tilization differ from conventional IVF by the necessity of preparing the oocytes from the surrounding cells of cumulus oophorus corona radiata 23.4.4 Tubal Embryo Transfer (TET) the and of the

Transvaginal/transuterine transfer of embryos into the Fallopian tube was introduced to reduce the physi- zona drilling cal burden on the patient caused by ZIFT. Using spe- cially designed fl exible catheters, the isthmo-ampullar lumen of the oviduct can be reached via the vagina ICSI and the uterine cavity (Jansen and Anderson 1987), avoiding both laparoscopy and general anesthesia. This type of catheterization can be performed as an SUZI outpatient procedure in most patients without any need of narcotics or analgesia. However, in a pro- PZD spective randomized study, this treatment did not result in signifi cantly better pregnancy rates than con- Fig. 23.6 Graphic presentation of the different methods of micro-assisted fertilization: zona drilling, partial zona dissection ventional IVF (Scholtes et al. 1994). The pregnancy (PZD), subzonal sperm injection (SUZI), intracytoplasmic rate may be occasionally compromised by damage sperm injection (ICSI) 478 Ch. De Geyter et al.

the application of an acid solution to the zona pellu- cida with a micropipette or the use of a laser beam. Although higher fertilization rates were achieved than with conventional IVF, the pregnancy rate with zona drilling remained extremely low. The technique used was later adopted for improvement of the implantation rate by opening the zona pellucida prior to embryo replacement: “assisted hatching” (see Sect. 23.10). In order to enhance further the penetration of motile spermatozoa into the perivitelline area, larger openings in the zona pellucida than those made in 100 µm zona drilling were produced by the partial dissection of the zona pellucida (PZD) from the vitelline mem- brane. This is achieved by fi rst slightly aspirating the Fig. 23.7 Mature oocyte surrounded by the cells of the corona oocyte onto a holding pipette. Then the zona is punc- radiata and of the cumulus oophorus tured tangentially with a microneedle. By removing the microneedle at a right angle to the oocyte, the (Fig. 23.7). This is achieved in part enzymatically with zona is torn and dissected from the membrane of the hyaluronidase, in part mechanically using a fi ne bore oocyte. micropipette. Preparation of the freshly collected In subzonal sperm injection (SUZI) one or more oocytes prior to insemination allows better identifi ca- motile spermatozoa are inserted with a micropipette tion of the maturity stage of the oocyte (by visualiza- into the perivitelline space between the zona pellucida tion of the polar body, metaphase II) and improves the and the membrane of the oocyte. Until the develop- selection of high quality oocytes. The likelihood of ment of ICSI the subzonal injection of multiple sper- successful fertilization and pregnancy are impaired by matozoa was regarded as the most effective method of the following dysmorphic characteristics of the oocyte: micro-assisted sperm injection in severe male infertil- broad perivitelline space, inhomogeneous texture of ity. In patients suffering from abnormal sperm quality the egg’s cytoplasm and abnormal structures in the not only the binding of capacitated sperm to the zona perivitelline space. pellucida is hampered, but also the acrosome reaction and fusion with the vitelline membrane of the oocyte are disturbed. Thus, subzonal sperm injection was 23.5.1 Previously Used Techniques more successful when several motile spermatozoa were injected into the perivitelline space. Experience of Micro-assisted Fertilization with the subzonal injection of several motile spermato- zoa demonstrated that in the human system not only The earliest technique of micro-assisted fertiliza- the zona pellucida, but also the vitelline membrane uti- tion, zona drilling, was originally developed because lizes a protective mechanism against the penetration of the zona pellucida was at that time considered the excess spermatozoa, so that the rate of polyspermy most diffi cult obstacle to successful fertilization in remains low. Nowadays, this technique has been com- patients with abnormal sperm quality. Fertilization was pletely replaced by ICSI. facilitated by boring a small hole into the zona pellu- cida. After insemination of these pretreated oocytes with high concentrations of motile spermatozoa, indi- 23.5.2 Intracytoplasmic Sperm vidual spermatozoa were able to slip through the hole, to complete the acrosome reaction in the perivitelline Injection (ICSI) space and to fuse with the membrane of the oocyte. Various techniques of boring a hole in the zona The fi rst report of a pregnancy with ICSI (Palermo pellucida of human oocytes were developed, such as et al. 1992) was soon followed by the application of 23 Assisted Reproduction 479

Fig. 23.8 Injection of one a motile spermatozoon into the b cytoplasm of an oocyte (ICSI). a: The spermatozoon is captured by the injection micropipette, which is then directed to the oocyte fi xed on a holding pipette. b: Penetration of the zona pellucida. c: Penetration of the vitelline membrane of the oocyte. d: Aspiration of some cytoplasm into the injection pipette before the spermato- c d zoon is transmitted into the oocyte

this technique in routine assisted reproduction world- ascertain the rupture of the oocyte’s membrane prior to wide, clearly demonstrating the high therapeutic effi - placement of the spermatozoon into the cytoplasm and cacy of ICSI in the treatment of couples suffering from to activate the oocyte, the vitelline membrane together severe male infertility. with some cytoplasm is aspirated into the micropipette. After withdrawal of the micropipette the vitelline mem- brane closes rapidly and no trace of the process is seen In this procedure a single vital spermatozoon is within minutes after the procedure. inserted with a micropipette both through the zona To facilitate drawing of the sometimes highly motile pellucida and the vitelline membrane into the cyto- spermatozoa into the micropipette, the prepared sper- plasm of a mature oocyte. matozoa may be incubated in culture medium supple- mented with the macromolecule polyvinylpyrrolidone For ICSI the spermatozoon is fi rst immobilized (PVP). Owing to the viscosity of the medium, the veloc- mechanically and then aspirated with its head towards ity of the capacitating sperm becomes lower. Individual the tip of the micropipette. The vitality of sperm is usu- spermatozoa are immobilized by touching them with ally identifi ed by observation of its movement. Some the micropipette, thereby opening their membrane. The selection of the better spermatozoon can be performed oocyte can only be activated if one or more cytoplasmic based on morphology and progressive motility, but not factors are liberated from the spermatozoon’s equato- on genotypic properties. rial segment into the injected oocyte. Indeed, whereas The oocyte is aspirated onto the tip of a holding in older forms of micro-assisted fertilization non- pipette and will be held fi xed in a position, in which the fertilization mainly resulted from non-penetration of polar body is visible at its upper or lower pole. As such, spermatozoa, failure of fertilization in ICSI seems to be damage of the meiotic spindle is thought to be avoided caused chiefl y by lack of activation of the oocyte despite during the microinjection, because the latter usually successful injection of a spermatozoon into the cyto- resides close to the polar body (Fig. 23.8). During the plasm (Flaherty et al. 1998). injection process fi rst the zona pellucida and then the One of the most important requirements for suc- vitelline membrane are penetrated subsequently with a cessful fertilization in ICSI is the meiotic status of the beveled micropipette holding a single spermatozoon. To oocyte, e.g. metaphase II. Before ICSI the oocytes 480 Ch. De Geyter et al. have to be freed of the surrounding cells of the corona collection (De Vos et al. 1999; Balakier et al. 2004). In radiata and the cumulus oophorus using enzymatic many of the metaphase I oocytes the fi rst polar body digestion with hyaluronidase and mechanical means. will become extruded during incubation in-vitro and This denudation of the oocytes allows assessment of can be used subsequently for ICSI. However, the fertil- the maturity status of the oocyte. Maturity is defi ned as ization of those oocytes matured in-vitro is signifi - the metaphase II stage of meiosis. At the metaphase II cantly lower and both the quality of embryo development stage of meiosis the oocyte’s chromosomes have and their implantation rates have been demonstrated to become arranged at the metaphase plate at the equato- be lower (De Vos et al. 1999). Increasing the delay rial plane of the oocyte. The chromosomes are fi rmly between polar body extrusion and ICSI to at least 4 h attached to the meiotic spindle. In light microscopy allows completion of nuclear maturation and improves this stage is identifi ed by the observation of the fi rst the outcome (Balakier et al. 2004; Hyun et al. 2007). In extruded polar body, which then resides between the many cases extending interval between the administra- vitelline membrane and the zona pellucida (Fig. 23.9). tion of hCG and the collection of the oocytes from The timing between denudation of the freshly collected the conventional 35 h to 39 to 40 h may be benefi - oocytes and their injection does not affect their devel- cial to reduce the number of immature oocytes (Raziel opmental potential (Van de Velde et al. 1998). Under et al. 2006). normal conditions approximately 85% of all oocytes After intracytoplasmic sperm injection the exact collected after ovarian hyperstimulation and ovulation timing of the various steps of fertilization has been induction are at the metaphase II stage and can be used determined (Payne et al. 1997): for ICSI. Metaphase I oocytes are identifi ed by light micro- • Extrusion of the second polar body after approxi- scopy by the absence of an extruded polar body (Fig. mately 2.5 h 23.9). A signifi cant number of oocytes, approximately • Appearance of the female pronucleus after approxi- 12%, are still in the metaphase I stage at the moment of mately 5 h

germinal vesicle metaphase I

metaphase II first & second polar body

Fig. 23.9 Using an inverted microscope the maturity of oocytes can be identifi ed together with their activation first polar body zygote during fertilization 23 Assisted Reproduction 481

• Appearance of the male pronucleus a few minutes ICSI has been applied successfully in a high diver- later sity of conditions with abnormal sperm function: • Collateral approximation of both pronuclei after • Severe forms of idiopathic male infertility in which approximately 7 h capacitation and fertilization are highly unlikely to The probability of activation and further development occur: such as severe hypergonadotropic oligoas- of the injected oocyte depends on its quality, which thenoteratozoospermia, in which only few motile can be partially estimated by assessing its morphology. spermatozoa can be recovered from the ejaculate. Other important factors in the success rate of ICSI are • Organic causes of male infertility in which the the experience of the embryologist involved. Approx- absence or loss of function of various anatomic imately 10% of all injected oocytes become atretic parts of the male genital tract causes infertility: after the procedure (Nagy et al. 1995). It must be obstructive azoospermia with sperm recovered assumed that the meiotic spindle is not located in the from the epididymis or from a testicular biopsy. vicinity of the polar body in approximately 20% of all • In men suffering from severe infertility and hyper- oocytes (Konc et al. 2004) and that in some oocytes it gonadotropic azoospermia, spermatozoa can be may be damaged during the intracytoplasmic injection recovered from testicular tissue. Usually more than (Hewitson et al. 1999). Although the meiotic spindle one biopsy is needed in order to retrieve a suffi cient can potentially be visualized using computerized imag- number of spermatozoa. ing analysis, this technique has not yet been shown to • The presence of anti-sperm antibodies in male immu- be benefi cial. nological infertility is an indication for ICSI, particu- In 2.5–6.5% of all injections the oocyte fails to larly if those antibodies are bound to the surface of become activated, thereby not extruding the second the spermatozoa’s head (Lombardi et al. 2001). polar body, leading to digynic triploidy (Sultan et al. • Rare and sporadic forms of male infertility which 1995; Grossmann et al. 1997; Flaherty et al. 1998). A are probably caused by mutations, such as globo- triploidic embryo cannot lead to a healthy pregnancy zoospermia (Lundin et al. 1994; Bourne et al. 1995; and should not be transferred to the recipient’s uterus. Liu et al. 1995; Catt et al. 1996; Battaglia et al. 1997; Rybouchkin et al. 1997; Tejera et al. 2008, Fig. 23.10) and total sperm immotility (Nijs et al. Intracytoplasmic sperm injection by far exceeds 1996; Casper et al. 1996; Liu et al. 1997; Kahraman all other forms of micro-assisted fertilization in the et al. 1997; Peeraer 2004). In these rare occasions limited number of motile sperm needed for success- the fertilization rate after ICSI seemed to be lower ful fertilization and in the apparent absence of any than the usual, which varies between 60–70%. In correlation between sperm (dys)function and the men with complete immobile spermatozoa, such as fertilization rate.

The high effi cacy of ICSI has widely extended the spectrum of treatable abnormalities in male fertility. The success rate of ICSI in male infertile couples is not limited by conventional semen characteristics such as concentration, progressive motility or percentage nor- mal morphology, nor by the degree of physiological maturation in the testis and the epididymis, nor by the exhibition of capacitation by the spermatozoa. Even the presence of motion in spermatozoa as a sign of vitality is not required for the success of ICSI, as in patients with complete absence of sperm motility, vitality can be demonstrated either by the swelling of sperm in a hypotonic solution or by treating previously immobile spermatozoa with pentoxifyllin. Fig. 23.10 Electrone microscopic image of globo zoospermia 482 Ch. De Geyter et al.

in the Karthagener syndrome the vitality of the process or in semen samples displaying much apop- spermatozoa can be identifi ed by using the swelling tosis leading to DNA damage, ICSI is not successful test (Casper et al. 1995; Liu et al. 1995; Peeraer with ejaculated spermatozoa (Tournaye et al. 1996; 2004). With this method the intactness of the mem- Greco et al. 2005). However, the collection of sper- brane of a spermatozoon is used to determine its matozoa from the testicular tissue (TESE) may be vitality. helpful under these circumstances. • Successful pregnancies after ICSI with round sper- ICSI can be performed successfully with frozen- matids collected from testicular tissue biopsies have thawed spermatozoa from tumor patients in whom been have been reported by few authors (Tesarik sperm quality was often already impaired in the origi- and Mendosa 1996; Antinori et al. 1997), but not by nal ejaculate and who could not be treated successfully others (Levran et al. 2000; Urman et al. 2002). with earlier treatment modalities. It must however be Because of the risk of imcomplete or abnormal noted that spermatogenesis may recur, as spermatozoa genomic imprinting of the male gamete, the risk of could be recovered from the semen of as many as 28% this method to the offspring can at present not be of men who previously underwent high-dose chemo- predicted (Urman et al. 2002). therapy followed by bone marrow transplantation (Rovó et al. 2006). Because in contrast to conventional IVF, no sper- Whereas in most spermatological situations ICSI matozoa are bound to the zona pellucida in oocytes presents as a highly effective method to induce suc- treated with ICSI, the latter method is commonly used cessful fertilizations, the probability of pregnancy in preimplantation genetic diagnosis (PGD) or in polar largely depends on factors determined by the female body biopsy in order to avoid any interference of the partner. DNA of residual spermatozoa with the diagnostic process. Intracytoplasmic sperm injection as a treatment for The overall results of ICSI are mainly infl uenced by male infertility reaches its limitation in at least four the age of the female partner (Abdelmassih et al. 1996), different clinical entities: by the ovarian response to the hormonal stimulation • Signifi cantly lower fertilization and implantation and by the quality of the oocytes. Although the oocytes rates were reported in couples treated because of can indeed be successfully penetrated with ICSI, many hypergonadotropic azoospermia and in whom oocytes do not become activated (Flaherty et al. 1998). sperm has to be retrieved from testicular tissue The probability of pregnancy remains dependent on (Tournaye 1999). Although the role of the maternal the quality of the replaced embryos and on the hor- genome is by far more important for subsequent monal environment in the recipient. Therefore, if the embryonic development, the paternal genome also desired pregnancy does not occur despite successful plays a role, particularly after some cleavage stages fertilization induced by ICSI, the female partner, of embryonic development. Particularly in cases of already carrying most of the therapeutic burden, might severely reduced semen quality, embryonic devel- easily be placed in the position of being blamed for the opment appears to be disturbed (Sakkas et al. 2004), failure of treatment. possibly because of apoptosis in the spermatozoa with DNA damage (Irvine et al. 2000). • In some cases of globozoospermia surprisingly low fertilization rates were reported (Liu et al. 1995; Battaglia et al. 1997). The low fertilization rates in 23.6 Semen Donation globozoospermia are caused by failure of oocyte acti- vation (Rybouchkin et al. 1997) and can be overcome In semen donation spermatozoa from a fertile donor by artifi cial activation of the oocyte (Rybouchkin instead of spermatozoa collected from the infertile et al. 1997; Tejera et al. 2008). partner are used in order to achieve a pregnancy. • In necrozoospermia, in which all seminal spermatozoa Although the widespread use of semen donation in have lost their vitality because of some degenerative earlier decades has been largely supplanted by ICSI 23 Assisted Reproduction 483

(Katzorke 2008), semen donation may still be used in adults arising from semen donation can enquire about various clinical conditions: the identity of the donor through offi cial instances. The introduction of non-anonymity has led to fewer men • The male partner has no spermatozoa in his ejacu- willing to donate their semen, although local legisla- late nor in the biopsies taken from his . tion protects both the donors and the offspring from • Because of a malignant disease, which was treated fi nancial litigation. successfully with chemotherapeutics and/or irradia- tion or bilateral orchidectomy. Semen donation is used in those cases only when no spermatozoa had been stored frozen for fertility preservation. 23.7 Collection and Preparation • The male partner suffers from a genetic condition of Sperm for Assisted which carries a high risk of transmission to his off- Reproduction spring, thereby jeopardizing the health of his poten- tial children. 23.7.1 Collection of Semen for Assisted In many countries the selection of fertile semen donors is regulated by law and often the prerequisites of this Reproduction selection is similar to those used for organ donation in transplantation surgery (Katzorke 2008). Apart from Usually, semen can be collected for assisted fertiliza- fertility, the absence of transmittable viruses, such as tion by masturbation after a period of abstinence of hepatitis B, hepatitis C and HIV must be assured, but 2–7 days, as recommended by the World Health also the absence of genetic disease, such as structural Organization (WHO 1999, see also Chap. 9). In patients chromosomal abnormalities, mutations of the CFTR with few spermatozoa the number of spermatozoa col- gene and others. In order to fulfi l these criteria, semen lected can be increased by prolonging the period of samples of selected donors are now stored frozen, abstinence and/or by the production of more than one which has contributed to a signifi cant reduction of ejaculate prior to semen preparation (Tur-Kaspa et al. present-day effi cacy of semen donation for IUI 1990; Cooper et al. 1993; De Jonge et al. 2004). (Botchan et al. 2001). The success rates per cycle are Sometimes, owing to a pathological or psycho- much lower than ICSI and vary between 7% and 16%. logical blockade, semen cannot be collected by mas- Therefore, in many institutions, instead of IUI with turbation. In those cases, semen may be stored frozen donated semen, assisted reproduction is being per- prior to the treatment and be thawed. In patients suffer- formed using donated frozen/thawed spermatozoa in ing from impotence caused by paralysis in the seg- order to achieve higher pregnancy rates. However, in ments ThXI-LII, ejaculation can also be induced by some countries only IUI, but not IVF or ICSI is permit- vibration or by electroejaculation. Although these ted with donated semen. procedures are effective in 90% of the patients, in some Furthermore, in many countries, the number of patients viable spermatozoa may also be collected children to be produced by one single semen donor is through aspiration from the epididymis (MESA) or restricted. The number of children after semen dona- through a testicular biopsy (TESE). tion from one donor is limited to 5 in France, to 8 in In some cases with severe agglutinating male Switzerland, Belgium and in the U.S., to 10 in the UK immunological infertility or in patients with viscous and in Austria and to 25 in the Netherlands (Sawyier semen, special care must be taken for appropriate col- and McDonald 2008). lection of the semen sample. Sperm preparation can be Although most semen donations worldwide remain facilitated by collecting the semen into 2 ml of equili- anonymous, there is a trend towards non-anonymous brated culture medium in order to reduce not only the semen donations, because the children’s right to know agglutination of sperm, but also to limit the binding of their biological roots has been acknowledged in vari- antibodies to the sperm surface during liquefaction. In ous countries, such as Sweden, Norway, Austria, the some cases, dissociation of agglutinated sperm can United Kingdom, The Netherlands, Switzerland, also be achieved by the addition of proteolytic Australia and New Zealand (Daniels 2007). In coun- enzymes, e.g. trypsin. These enzymes can be added to tries with non-anonymous semen donation young the sperm suspension in an albumin-free culture 484 Ch. De Geyter et al. medium for up to 20 min without damage (Pattinson sought for ICSI (“testicular sperm extraction”, et al. 1990). The medium containing the enzyme should TESE). Even in severe testicular atrophy with be washed away before insemination to prevent any highly elevated serum FSH levels some of the semi- interference of the proteolytic enzyme with the inter- nal tubules may contain localized spermatogenesis, action between the gametes. from which viable spermatozoa can be collected for In patients suffering from retrograde ejaculation, ICSI in approximately 50% of all cases (Tournaye three different methods can be used for sperm collec- et al. 1999). Viable spermatozoa can be identifi ed tion for assisted fertilization. by slight or more intensive motility at 200- to 400- fold magnifi cation with an inverted microscope and • First, antegrade ejaculation may be achieved by isolated from the tissue with a micropipette. For the administration of specifi c drugs, such as alpha- better planning, the testicular biopsy may be per- adrenergic substances (phenylpropanolamine, oxe- formed some time before oocyte collection and drine) or anticholinergics (bromopheniramine) stored frozen until thawing (Fisher et al. 1996). The (Kamischke and Nieschlag 1999, see also Chap. 23). thawing of the tissue and its culture overnight in • An alternative consists of collecting the freshly ejac- medium supplemented with recombinant FSH ulated sperm from the bladder through a catheter. (25 IU/L) signifi cantly improves the fertilization Because of the acidity and the high osmolarity of the rate, the implantation rate and even the pregnancy urine, adequate preparation of the patient is neces- rate (Balaban et al. 1999). Preincubation of the tes- sary to protect the sperm before and after ejaculation. ticular tissue up to 48 h has been shown to be benefi - Before ejaculation the bladder should be emptied cial in some cases (Morris et al. 2007). Pentoxifylline and rinsed with 10 ml of the culture medium. Before has been used to activate immotile spermatozoa col- ejaculation the urine may be alkalinized by oral lected from testicular biopsies for ICSI (Terriou intake of a high-dose sodium bicarbonate (1–4 g). et al. 2000; Kovacˇic˘ et al. 2006). • A third method consists of the extraction of sperma- tozoa from the testicular tissue (TESE). At present, there is a trend towards collecting the sper- • In some forms of azoospermia spermatozoa can be matozoa from the testis rather than from the epididymis, collected from the epididymis through the micro- because the former is much less time-consuming and surgically incised tubule and by aspiration into a costly than the latter. capillary (“microsurgical epididymal sperm aspi- The prediction of fi nding spermatozoa in frozen- ration”, MESA). Usually motile spermatozoa are thawed biopsies based on the histological proof of foci not found immediately and several incisions into the with active spermatogenesis in single testicular tubules epididymis have to be made, fi rst in the distal por- was incorrect in only 2.9% of all cases. In 0.7% of all tion of the cauda epididymidis, and then more prox- biopsies testicular cancer or carcinoma in situ was imally, until motile spermatozoa can be recovered. detected (Schulze et al. 1999). The fertilization rate, In most patients suffering from long-standing the implantation rate and the pregnancy rate did not obstructive azoospermia motile spermatozoa are not differ after ICSI performed with sperm retrieved from recovered from the cauda epidydimidis, but rather freshly collected testis biopsies or from previously from the more proximal portion of the epididymis. cryopreserved biopsies (Ben-Yosef et al. 1999; The concentration of the spermatozoa recovered Verheyen et al. 2004), although there is an ongoing from an obstructed epididymis may vary, but motil- controversy on the benefi ts of cryopreserving testicu- ity is usually below 20%. This time-consuming pro- lar tissue in men with severely impaired spermatogen- cedure can also be performed 1 day before oocyte esis (Nicopoullos et al. 2004). collection. Alternatively, sperm can be recovered for Alternative methods for the collection of spermato- ICSI not only from the vas deferens and the zoa from testicular or epididymal tissue have been epididymis, but also from the testis itself. For this described. Viable spermatozoa can be retrieved by sim- purpose one (in obstructive azoospermia) or up to ple percutaneous puncture of the epididymal tubule nine tissue samples (in hypergonadotropic azoo- (“percutaneous epididymal sperm aspiration”, spermia, Devroey et al. 1994) can be removed from PESA, Craft et al. 1995) or from the testis (“testicular the testis, in which viable spermatozoa can be fi ne needle sperm aspiration”, TEFNA, Lewin et al. 23 Assisted Reproduction 485

1999) and subsequent aspiration with a syringe has 23.7.3 Filtration also been described. The advantage of these techniques is that sperm collection for ICSI can be performed not Filtration of spermatozoa on a column preloaded only faster but also without the costly equipment with glasswool (Paulson and Polakoski 1977) or with needed for MESA or TESE. The number of aspirated glass beads (Daya et al. 1987) has found some accep- spermatozoa seems to be lower with PESA and with tance. The suspension containing the spermatozoa TEFNA than with alternative, more invasive techniques freed from the seminal plasma is loaded onto a verti- (Tournaye et al. 1999). At the moment, no prospective cally positioned column, which is prefi lled with either randomized study has been performed to compare the 15 mg of glass wool (microfi bercode 112) or with 1 g clinical benefi ts of the available methods. of glass beads (each of 75 to 150 mm diameter). Before adding the sperm suspension the column is rinsed 23.7.2 Preparation of Sperm with culture medium to remove potential toxic sub- stances and to equilibrate the content of the column. for Assisted Reproduction The sperm suspension is then added on top of the col- umn, fl ows downward and a highly motile fraction of Before the actual processing of the semen sample can spermatozoa can be gathered dropwise from the col- be started, the semen must be liquefi ed by simple incu- umn and used for assisted fertilization. Immotile bation at room temperature for 30 min. spermatozoa, leucocytes and round cells tend to A subsequent washing procedure of the semen is adhere to the glass or remain trapped in the mesh, in required, because seminal plasma – even at low con- contrast to the motile spermatozoa, which readily centration (10%) – can exert toxic effects both on the pass through the column. sperm itself, as well as on the oocytes. Furthermore, The fi ltration of sperm has the advantage of rapidly bacteria may be present in the semen, which, after achieving a high yield of progressively motile sperma- insemination into the genital tract of the female partner tozoa. In this regard sperm fi ltration with columns or after insemination in vitro, may proliferate and cause loaded with glass wool seems to be as effective as the damage. Seminal plasma also contains high concentra- swim-up-method (Van der Ven et al. 1988; Katayama tions of prostaglandins, which, after their introduction et al. 1989) or as density gradient centrifugation (Van into the uterine cavity, may induce paroxysmal and den Bergh et al. 1997). The loss of spermatozoa during painful contractions of the myometrium. The prepara- the fi ltration process seems to be low and the duration tion of the semen not only separates the spermatozoa of the processing is particularly short (10 min). The from the surrounding seminal plasma, but the propor- results of IVF with fi ltered sperm are comparable to tion of highly motile and normally formed spermato- those achieved with swim-up sperm (Van der Ven et al. zoa is increased and the process of capacitation is also 1988; Katayama et al. 1989). Recently, there has been induced through the removal of blocking factors from renewed interest in fi ltration of spermatozoa, because the surface of the ejaculated spermatozoa. Recently, the glass wool loaded in the fi ltration columns can be new aspects of semen preparation, other than just covered with binding proteins, so that spermatozoa can removing the seminal plasma, have received attention, be retained in the column based on specifi c properties. such as selecting those spermatozoa bearing an X- or Columns loaded with glass wool and coated with Y-chromosome or removing apoptotic spermatozoa Annexin V have been used for the fi ltration of samples from the sample. of spermatozoa free of apoptotic cells (Grunewald Based on the different physical principles the vari- et al. 2007). ous methods of sperm preparation are divided into fi ve groups: • Filtration 23.7.4 Swim-up • Swim-up • Density grade centrifugation Swim-up is a widely used method for sperm prepara- • Sorting tion in assisted fertilization (originally described by • Removal of contaminant infectious particles Lopata et al. 1976). It is based on the principle that 486 Ch. De Geyter et al. the most motile and capable spermatozoa can swim centrifuged. For this purpose Percoll® can be used, vigorously upwards against gravity into a layer of cul- which contains colloidal particles made of silicone ture medium positioned on top of the sperm pellet. A with diameters between 15 and 30 nm. These particles fraction of highly motile sperm free of seminal plasma are coated with the biologically inert polyvinylpy- and leucocytes can be collected after 60–90 min of rollidone. incubation. The signifi cance of swim-up for sperm In the column containing various layers of different preparation is further enhanced by the fi nding that those density colloidal particles not only vital and dead sper- properties needed for the penetration of motile sperm matozoa but also leucocytes and spermatozoa can be into the supernatant are the same required for the pen- separated during centrifugation. Various modifi cations etration into cervical mucus and for the actual fertil- and compositions of the solutions containing the col- ization of oocytes (De Geyter et al. 1988). Thus the loidal particles have been designed: continuous den- concentration of sperm after swim-up is also correlated sity gradients (Berger et al. 1985), discontinuous with the results of assisted fertilization. In contrast to density gradients (Guérin et al. 1989) and discontinu- earlier reports, no selection of Y-chromosome bearing ous density gradients in small volume (mini-Percoll®, spermatozoa can be achieved with the swim-up- Ord et al. 1990). For the establishment of continuous procedure (Han et al. 1993). density gradients ultracentrifugation must be per- The main disadvantage of the swim-up-method is formed (>100,000 g) which is more suitable for the the low recovery rate of motile spermatozoa, espe- separation of small-sized particles such as viruses cially in cases with severe abnormalities of the origi- and mitochondria. Therefore, for the separation of nal semen sample, and by the lengthy time interval the relatively larger sized spermatozoa, discontinuous needed for sperm preparation. Furthermore, the cen- density gradients are predominantly used. The enriched trifugation of the semen diluted with culture medium fraction containing motile spermatozoa can be recog- and the subsequent concentration of capacitating nized easily as a discrete turbid band in the area spermatozoa and oxygen radical-secreting leuko- between 85% and 100% of the Percoll® suspension. cytes into a densely packaged pellet, are potentially Density gradient centrifugation based on Percoll® has damaging both to the membrane and the DNA of the been shown to be detrimental in many cases due to spermatozoa. contamination with endotoxins and has been forbidden Nevertheless, in comparison to other methods of for clinical use (Henkel and Schill 2003). Since then, sperm preparation such as density gradient centrifuga- various alternative solutions have been made available tion and fi ltration, swim-up is characterized by better for use in reproductive medicine (such as PureSperm®, motility and relatively higher numbers of normally Ixaprep®, Isolate® and SilSelect®), all leading to accept- formed spermatozoa (Englert et al. 1992). The swim- able results during clinical application. up method is highly reproducible when performed by Although density gradient centrifugation yields different technicians. more motile spermatozoa than the swim-up-method, the impact of both methods on the results of conven- tional IVF remains controversial. A recent meta-analysis has not been able to detect differences in the pregnancy 23.7.5 Density Gradient Centrifugation rates after IUI with respect to various techniques of semen preparation (Boomsma et al. 2007). With density gradient centrifugation, motile and nor- Compared with the swim-up method (at least mally formed spermatozoa are separated not only by 60 min), sperm preparation with density gradient cen- centrifugal force, but also by differences in the density trifugation (20 min) is less time-consuming. Density of individual cells. The density of living spermatozoa is gradient centrifugation is not associated with any known to differ from that of degenerated or dead sper- enrichment of Y-chromosome-carrying spermatozoa matozoa. To achieve a separation with density gradient (Vidal et al. 1993). Furthermore, the risk of infl amma- centrifugation, the washed sperm suspension is layered tion caused by colloidal silicone particles in the genital onto a column comprising several layers of a col- tract of the patients after insemination was ruled out loid suspension of different density and subsequently experimentally (Pickering et al. 1989). 23 Assisted Reproduction 487

23.7.6 Sorting of Spermatozoa Based fertilization (Said et al. 2006; Grunewald et al. 2007). on Defi ned Characteristics Removal of apoptotic spermatozoa by utilizing their binding affi nity to annexin V resulted in higher fertil- ization rates in the surrogate hamster zona-free pene- Recently, more experimental work has been carried out tration test and in an experimental ICSI model (Said to promote the sorting of fertilizing spermatozoa based et al. 2006). on defi ned biological properties considered to be ben- A third example for the successful selection of efi cial for the process of assisted fertilization. The ear- functional spermatozoa is given by the electrophoresis liest example was the sorting of spermatozoa based on of spermatozoa based on the negative electric charge the higher DNA content of spermatozoa carrying the X of the surface of the membrane in intact spermatozoa. chromosome to separate those from Y-chromosome This property is used to separate high quality sperma- bearing spermatozoa using fl ow cytometry (FACS). tozoa in a magnetic fi eld (Ainsworth et al. 2005). Viable spermatozoa with predefi ned properties were At present, only one successful pregnancy has been sorted using either fl ow cytometry or sorting was based achieved with ICSI after having selected spermatozoa on minute differences in DNA content or magnetic using this novel method (Ainsworth et al. 2007). All beads covered with antibodies against certain surface centrifugation of spermatozoa is avoided. The major markers. Flow cytometry is used for the separation of disadvantage of this method is its failure to improve spermatozoa containing the Y chromosome from those the number of motile spermatozoa in the prepared carrying the X chromosome in order to achieve a higher sample to be used for assisted fertilization. yield of embryos with female genotype. For this purpose spermatozoa have to be marked with a fl uores- cent dye, which allows the distinction of spermatozoa 23.7.7 Removal of Contaminant based on the quantity of DNA in their genome. Spermatozoa with an X chromosome contain approxi- Infectious Particles mately 3% more DNA than spermatozoa carrying a Y chromosome. In recent years an increasing number of infertile men With fl ow cytometry a suffi cient number of motile present with concomitant infections, such as hepatitis spermatozoa can be selected rapidly enough to be used B, hepatitis C and HIV. Those infections present a seri- in assisted fertilization (Johnson et al. 1993). Several ous risk for contamination of the partner, the personnel pregnancies were achieved using this method in IUI, in and the laboratory environment. Except for hepatitis conventional IVF and in ICSI, mainly for the preven- B, which has the potential to become integrated into tion of X chromosome-linked genetic diseases (Fugger the spermatozoon’s genome, all those contaminants et al. 1998). Although this method of sperm selection reside in the seminal plasma at variable concentrations can be abused to manipulate the sex of the newborn, it and can be separated from the capacitating spermato- has achieved some importance for the prevention of zoa using conventional washing methods. X-bound genetic illnesses. The risk of alterations in The fi rst infectious agent, demonstrated to be the DNA structure induced by the fl uorescent dyes has removable from the capacitating spermatozoa, was been excluded in extensive animal research. HIV (Semprini et al. 1992). For this purpose various Sorting of fertilizing spermatozoa can also be modifi cations of the density gradient centrifugation achieved by using magnetic bead sorting (MACS). method have been used and the safety of the method Semen contains a sizeable subpopulation of damaged has been established in a large multicentric trial spermatozoa undergoing apoptosis. Apoptosis or pro- (Bujan et al. 2007) and can be used in all existing grammed cell death entails damage both to the cell’s methods of assisted reproduction (Savasi et al. 2007). integrity and to its DNA. Using magnetic beads loaded In HIV infected infertile men it is still recommended with annexin V, a phospholipid-binding protein with to determine the viral load in the sample used for high affi nity for transmembrane surface markers which assisted reproduction. In addition, the swim-up become externalized during apoptosis, damaged sper- method has also been used in a smaller cohort of men matozoa destined to undergo cell death can be sorted infected with HIV and shown to be effective (Tschudin and removed from the sample to be used for assisted et al. 2008). 488 Ch. De Geyter et al.

23.7.8 Processing of Sperm for ICSI 2-deoxyadenosine (Aitken et al. 1986), pentoxifylline in Diffi cult Cases (Yovich et al. 1990) and caffeine (Imoedemhe et al. 1992). These substances act as inhibitors of phospho- diesterase, which is associated with an increase of the In some patients treated with ICSI, often only isolated intracellular concentration of cAMP. It has been dem- motile spermatozoa are available and no adequate sep- onstrated that after addition of each of these substances aration can be performed. In these cases one simple to the seminal plasma or to the culture medium, the washing of the sample consisting of centrifugation and motility, velocity and extent of hyperactivation can be discharge of the supernatant fl uid and resuspension of increased signifi cantly (Imoedemhe et al. 1992; Kay the pellet of spermatozoa, can suffi ciently clean the et al. 1993). Pentoxifylline is widely used in cases sample of debris. with complete immobility of the spermatozoa and in To facilitate catching single motile spermatozoa TESE (Terriou et al. 2000; Kovacˇic˘ et al. 2006). with the micropipette, the viscosity of the culture medium may be increased by the addition of a high concentration of the biologically inert polyvinylpyrol- lidone (8 g/100 ml culture medium), a macromolecule 23.8 Ovarian Follicular Development, with a molecular weight of 360,000 kDa. Any alleged Ovarian Stimulation, Ovulation mutagenic action of polyvinylpyrrolidone possibly Induction and Oocyte Collection entering the oocyte during the intracytoplasmic injec- tion has been ruled out experimentally (Ray et al. 1995). Nowadays, the accumulated manual expertise in many 23.8.1 Monitoring of Ovarian Follicular centres has led to complete avoidance of those sub- Development and Ovarian stances. Pentoxifylline has also been used to enhance Stimulation for Insemination the motility of spermatozoa and thereby their visibility for catching, particularly in testicular biopsies. The therapeutic effi cacy of insemination may not only ICSI can also be performed successfully with result from an increased number of motile spermato- immotile but vital spermatozoa (Nijs et al. 1996; zoa in the lumen of the Fallopian tube, but also from Casper et al. 1996; Liu et al. 1997). Because vitality of the exact timing of ovulation, with which insemination the sperm cannot be recognized by cellular move- is usually synchronized. Watchful management con- ments, the integrity of the spermatozoon’s membrane sisting of the close observation of the endogenous is used to prove its vitality. This can be achieved with changes occurring during a natural menstrual cycle the hypoosmotic swelling test. For this purpose the leading to ovulation can be chosen for optimal timing sperm are incubated in culture medium previously of insemination and has been demonstrated to be ben- diluted 1:1 (v/v) with distilled water. A typical swell- efi cial in cases with severe reduction of semen quality ing of the tail of the sperm indicates its vitality. The (Cohlen et al. 1998). sperm will recover when transferred with the micropi- Insemination in the natural cycle stands in contrast pette into the native culture medium before ICSI. to a active management of all events during the follicu- lar phase of the menstrual cycle, such as stimulation of ovarian follicular development and by induction of ovulation. Originally, the adoption of this strategy in 23.7.9 Treatment of Spermatozoa In vitro supporting IUI was motivated by the early successes of ovarian hyperstimulation used in IVF and ICSI. As well as the selection of fertile spermatozoa by dif- Ovarian function can be stimulated with clomiphene ferent methods of sperm preparation, changing the citrate, with gonadotropins and, more recently, with composition of the culture medium surrounding the aromatase inhibitors. Although some studies have spermatozoa has been used to improve the results of demonstrated higher pregnancy rates with ovarian assisted fertilization. stimulation and ovulation induction with gonadotro- For this purpose various chemical substances are pins (Guzick et al. 1999, Fig. 23.3), there is still insuf- added to the culture in order to stimulate sperm motility: fi cient evidence concerning the effi cacy of an expectant, 23 Assisted Reproduction 489 watchful versus active management followed by IUI different treatment protocols for the stimulation of (Cantineau et al. 2007), and particularly in couples suf- ovarian follicular development were developed over fering from male infertility (Bensdorp et al. 2007). time and were correlated with the results of assisted The effi cacy of the concomitant management of the fertilization. menstrual cycle may also depend on the characteristics Initially, follicular development was stimulated with of semen quality. Whereas in the presence of a moder- clomiphene citrate with or without human urinary ate reduction of semen parameters a benefi cial effect gonadotropins, but 25–30% of the treatment cycles of an active management of follicular development had to be abandoned because of premature luteiniza- was observed, this was not the case in cases with more tion and/or premature ovulation. severe reduction of seminal parameters (Cohlen et al. Premature ovulation is now effectively avoided 1998). This seemingly paradoxical fi nding illustrates either by the combination of ovarian hyperstimulation the relative contribution of female infecundity in cou- with long-acting GnRH-agonists, which are used to ples primarily diagnosed with mild male infertility and inhibit the preovulatory rise of LH and thereby prema- explains how an exogenous management of the men- ture ovulation, or with GnRH-antagonists, which are strual cycle may contribute to the outcome of IUI. given during the later stages of follicular development. However, the most important disadvantage of Although various combinatory protocols with gonado- gonadotropin stimulation is the higher rate of multiple tropins and GnRH-agonists have been described over pregancies. Any insemination should be cancelled in time, it was demonstrated in several large cohort stud- the presence of more than three follicles with a diam- ies that a preceding down-regulation with long-acting eter of at least 14 mm. The risk of multiple pregnancies GnRH-agonists consistently leads to signifi cantly can be reduced signifi cantly by low-dosed gonadotro- higher pregnancy rates in IVF and ICSI. The following pin administration. Cancellation of cycles can be protocols for the combination of gonadotropins with avoided by the aspiration of supernumerary follicles GnRH-agonists have been described: immediately before IUI (De Geyter et al. 1996). • Long protocol: before ovarian hyperstimulation is Gonadotropin stimulation of the ovaries may also be initiated, the endogenous secretion of gonadotropins complicated by the ovarian hyperstimulation syn- is down-regulated with long-acting GnRH-agonists, drome, which is a potentially life-threatening compli- applied during the preceding menstrual cycle, either cation. The severe form of the ovarian hyperstimulation during the luteal phase or at the very early beginning syndrome is rare in patients treated with insemination, of the menstrual cycle or during intake of a birth compared with treatment cycles for IVF or ICSI, control pill. because of the generally lower doses of gonadotropins • Short protocol: treatment with the GnRH-agonist is used in the former group. initiated together with ovarian hyperstimulation with gonadotropins, thereby using the fl are-up effect of the GnRH-agonist on the endogenous gonadotro- 23.8.2 Ovarian Stimulation pin secretion for ovarian hyperstimulation. In the for IVF and ICSI short protocol the GnRH-agonist is given until the end of the follicular phase. • Ultrashort protocol: similar as in the short protocol, Although IVF and ICSI can be performed with some but the GnRH-agonist is given for only a few days. degree of success in the untreated, natural menstrual cycle or with minimal ovarian stimulation (Pellinck However, the major disadvantage of using long-acting et al. 2006), the reported pregnancy rates are generally GnRH-agonists, as compared to GnRH-antagonists, low, approximately 8–9% per treatment cycle. Despite resides in the higher consumption of gonadotropins, the low intensity of the method, the dropout rate thereby considerably increasing treatment costs, and exceeded the pregnancy rate even after three unsuccess- the higher risk of the ovarian hyperstimulation syn- ful treatment trials (Pellinck et al. 2007). It has been drome due to the unopposed recruitment of growing long-standing experience that the pregnancy rates in ovarian follicles (Al-Inany et al. 2007). IVF and ICSI can be raised signifi cantly by the presence The recent trend to milder stimulation regimens in of higher numbers of available oocytes. A multitude of younger women treated with IVF and ICSI, the need to 490 Ch. De Geyter et al. reduce consumption of the more costly recombinant In cases not leading to successful pregnancy, sup- gonadotropins and the widespread desire to limit the port of the luteal phase with progesterone only often complexity of the treatment protocols has led to the leads to early menstruation. The addition of a single development of protocols involving the use of GnRH- midluteal administration of hCG (for example a single antagonists to prevent premature ovulation. dose of 2,500 international units) is helpful to prevent Two protocols based on the use of GnRH-antagonists early bleeding, but does not lead to higher pregnancy have been developed: rates (Herman et al. 1996). Premature menstruation can also be prevented by additional administration of • Single or dual administration of a high dose of a estrogens. However, the current tendency to use vari- GnRH-antagonist, initially given at approximately ous estrogenic preparations in addition to progester- 14 mm follicular diameter (Olivennes et al. 1994). one remains without any confi rmed scientifi c basis • Multiple-dose GnRH-antagonist: starting at approx- (Gelbaya et al. 2008). imately 12 mm follicular diameter the GnRH- The widespread support of the luteal phase with antagonist is given daily until ovulation induction progesterone or analogues beyond the initial confi rma- (Diedrich et al. 1994). tion of pregnancy has been demonstrated to have no Whereas population-based, observational studies have benefi cial effect on the prevention of miscarriages initially suggested a lower effi cacy of ovarian hyper- (Schmidt et al. 2001; Nyboe Andersen et al. 2002). stimulation using GnRH-antagonists (Pouly et al. 2004), probably due to selective use of this protocol in women with low response to gonadotropin treatment (Griesinger et al. 2005), comparable pregnancy and delivery rates 23.9 Methods of Oocyte Collection were achieved with GnRH-antagonist-supported proto- cols as compared to those using GnRH-agonists Originally, laparoscopy was the only technique avail- (Al-Inany et al. 2007). The use of GnRH-antagonists able for low-invasive oocyte collection, originally con- during ovarian hyperstimulation with gonadotropins tributing to the fi rst successful introduction of IVF entails three advantages: (1) consumption of less gonad- during the 1970s (Steptoe 1970), because it gave the otropin preparations as the result of a slightly shorter physician easier and less traumatic access to the ovaries duration of the stimulation; (2) reduced complexity of to collect oocytes than laparotomy. Instead of the earlier the stimulation protocol; (3) reduced risk of the ovarian laparoscopical method, oocytes are now most almost hyperstimulation syndrome. universally collected by ultrasound-guided transvagi- Ovarian hyperstimulation, particularly if either nal puncture of the follicles, which can be performed GnRH-agonists or GnRH-antagonists are used, leads without general anaesthetics. Ultrasound-guided trans- to a signifi cant shortening of secretion of progesterone vaginal puncture of preovulatory follicles with a hollow of the luteal body and inevitably requires a hormonal needle has become an outpatient procedure, thereby support of the luteal phase (Hutchinson-Williams et al. contributing to the widespread availability of assisted 1989). Support of the luteal phase has been performed reproduction. Three main properties of the ovary with human chorionic gonadotropin (hCG) or with enabled development of this procedure: fi rst, the ovaries some gestagenic preparation, mainly progesterone. are usually located directly behind the vagina. Sec- Although support of the luteal phase with hCG is more ondly, the ovaries are hardly sensitive to pain. Thirdly, effective, the risk of the ovarian hyperstimulation syn- owing to the plasticity of the organ, the follicles can be drome is much higher than with a gestagenic prepara- emptied one by one by slight movement of the needle, tion (Daya and Gunby 2004). Therefore, support of the thereby avoiding repeated transvaginal punctures luteal phase with progesterone, either given transvagi- (Fig. 23.11). Most follicles must not be fl ushed with a nally or parenterally, has become the method of choice. rinsing fl uid in order to collect the oocytes. The vaginal administration of progesterone results in The complication rate of this procedure is very low. an accumulation of progesterone in the uterus, thereby Vaginal or intra-abdominal bleedings may rarely occur. enhancing the endometrial secretory function in the Infections may occur after incidental puncture of endo- presence of low circulating levels of progesterone and metrial cysts or other intestinal structures, such as the thus avoiding side effects (Cicinelli et al. 2000). appendix. 23 Assisted Reproduction 491

a b

Fig. 23.11 For ultrasound-guided collection of oocytes a hol- of the aspiration needle is visualized with a white arrow. In the low needle is fi rst inserted transvaginally towards the antrum of aspirated follicular fl uid the cumulus oophorus-oocyte complex a mature ovarian follicle (a). Then the needle is inserted into the can be identifi ed rapidly under a stereomicroscope follicle (b) and its content is aspirated into a culture tube. The tip

a b

assisted hatching

Fig. 23.12 Assisted hatching may be effective in improving the applied acid solution. This technique was modifi ed from two implantation rate in embryos surrounded by an abnormally thick micro-assisted fertilization methods, “zona drilling” and “partial zona pellucida (a). For “assisted hatching”, performed immedi- zona dissection” and aims at improving the implantation rate of ately before embryo replacement into the uterine cavity, the zona the embryos (b) pellucida is opened (arrow) with a laser beam or with locally

23.10 Assisted Hatching remarkably thickened zona pellucida (Fig. 23.12), which is thought to be a barrier during the hatching of The capacity of non-selected embryos to implant after blastocyst embryos. IVF or ICSI is generally as low as 20%. This low The techniques developed for “zona drilling” and embryonic implantation rate is caused by genetic “partial zona dissection”, originally conceived to abnormalities in more than half of the replaced embryos. improve fertilization rates in couples suffering from Implantation may also be impaired by mechanical male infertility, were modifi ed to improve the implan- obstacles such as the zona pellucida, which is known tation rate. The method essentially consists of making to become hardened during in vitro culture and may a hole in the zona pellucida of approximately the same interfere with the hatching process, in which the blas- diameter as the thickness of the zona pellucida itself. tocyst escapes from the zona pellucida. Additionally, Assisted hatching was fi rst performed with a locally the development of some embryos generated with IVF applied acid solution, later also with a laser beam. or ICSI may lag behind normal embryo development Assisted hatching was considered helpful in women in the Fallopian tube, also causing diffi culties during with an abnormally thick zona pellucida (>13 mm) and the hatching process. Finally, some embryos possess a in embryos with fragmented blastomeres (Cohen et al. 492 Ch. De Geyter et al.

1992). However, randomized prospective studies have uterine cavity may lead to higher pregnancy rates not been able to demonstrate any benefi cial effect of (Abou-Setta et al. 2007). After a few minutes the patient assisted hatching, neither in patients with unfavorable is allowed to stand up and to leave the unit. prognosis (Primi et al. 2004) not in those with a favor- The complication rate of intrauterine embryo transfer is able prognosis (Sagoskin et al. 2007). A signifi cantly higher prevalence of monozygotic twinning was The optimal technique of embryo transfer is one of observed after assisted hatching (Hershlag et al. 1999). the most important factors contributing to consis- However, this technique has been shown to accelerate tently high pregnancy rates in IVF and ICSI. the hatching process in blastocysts. very low. In rare cases endometritis may occur. The replaced embryos may slip into the Fallopian tube, 23.11 Embryo Transfer causing ectopic pregnancies especially in patients with widened tubal diameters (sactosalpinx). The surgical removal of unilateral or bilateral hydrosalpinges visible The embryos resulting from successful IVF are placed in ultrasound, prior to assisted reproduction (Strandell in the genital tract of the patient for later implantation, et al. 1999) has considerably contributed to reduce the usually in the uterine cavity. Uterine placement of risk of ectopic pregnancies after IVF or ICSI. embryos is a procedure causing no or little pain and is Occasionally, stenosis of the cervical canal may con- nowadays performed within a few minutes as part of a stitute an insurmountable obstacle to the replacing of routine gynecological investigation. embryos. However, earlier reports describing success- After visualization of the cervix with a speculum, ful transmyometrial injection of embryos through the the anterior portion of the cervix is clamped with a for- anterior wall of the uterus into the endometrium (Kato ceps. Under slight traction a catheter is introduced into et al. 1993) have not been confi rmed by others. the cervical canal. Then the embryos are aspirated, along with a small drop of cultured medium (approxi- mately 10 ml), into a fi ne catheter (Fig. 23.13). This fi ne 23.12 Cryopreservation of Oocytes catheter is then inserted carefully through the previ- ously positioned broader catheter into the uterine cavity in the Pronucleate Stage (about 6 cm depth). Not only the low volume of fl uid introduced along with the embryos is important, but The German Embryo Protection Act but also legisla- also carrying out the procedure in an absolutely atrau- tion in some other countries, among them Switzerland, matic fashion. After the transfer, the presence of all stipulate that in each treatment cycle with IVF or embryos adhering to the catheter should be checked ICSI not more than three oocytes may be fertilized and under the microscope. Although embryo transfers are replaced after development into the embryo stage. If still being performed blindly in many institutions, the more than three oocytes are fertilized with IVF or ultrasound-guided insertion of the catheter into the ICSI, they can be cryopreserved in the pronucleate

a b c

Fig. 23.13 Sonographic presentation of the transfer of an cavity. The embryos are situated in a droplet of culture medium embryo into the uterine cavity. (a) Tip of the replacement cath- surrounded by two air bubbles and by two additional droplets of eter guided through the cervical canal into the uterine cavity. (b) culture medium (c) The tip of the catheter is situated in the upper part of the uterine 23 Assisted Reproduction 493 stage prior to completion of the fertilization process. no crystallization takes place, thereby reducing the When pregnancy does not occur in the treatment cycle risk of damage to the biological material. In order to with fresh oocytes, the cryopreserved oocytes may be achieve maximal rapidity, only single oocytes can be thawed and replaced, thereby avoiding repeated ovar- stored frozen. Higher success rates can be achieved ian stimulation and oocyte collection. with open systems, which allow greater speed in the Cryopreservation of oocytes in the pronucleate stage freezing process. However, at present the safety of vit- must be carried out prior to the approximation of both rifi cation remains to be documented scientifi cally. pronuclei, about 20 h after in vitro insemination in IVF or after the ICSI procedure. The pronucleate oocytes are fi rst dehydrated at room temperature in a series of 23.13 Complications of Assisted solutions in order to prevent crystallization of water within the oocyte during the freezing process, which Reproduction may cause extensive damage. Before starting the freez- ing protocol of the pronucleate oocytes, they have to be The widespread use of assisted reproduction for the treated with stepwise increasing concentrations of one alleviation of infertility, the rising age of the infertile of more cryoprotectants. Then, surrounded by the high- partners and the broadening of conditions that can be est concentration of the cryoprotectant solution, the treated with assisted reproduction have all raised con- zygotes are inserted into plastic tubes, often called cerns about the possible short-term and long-term straws. After sealing and coding of the straws, cryo- health risks, not only to the women treated but also to preservation is performed in liquid nitrogen, usually in their offspring. Disecting the risks of the various thera- an automated system, which controls the freezing pro- peutic components of assisted reproduction from those cess at a predetermined pace. At −6°C to −7°C seeding resulting from infertility has been diffi cult and is still is induced, after which crystallization occurs, avoiding ongoing. As infertility itself leads to a higher incidence possible damage to the oocytes. Long-term cryopreser- of complications during pregnancy and delivery (De vation follows by transferring the straws into tanks Geyter 1994) appropriate conclusions can only be fi lled with liquid nitrogen (below −140°C). drawn from pregnancies achieved in previously infer- Replacement of the thawed pronucleate oocytes tile couples conceiving naturally. Uterine bleeding takes place after their development into the early during early pregnancy, pre-eclampsia, abnormal pla- embryonic stage. This is usually performed in the nat- centation including placenta praevia and premature ural menstrual cycle, after treatment with clomiphene rupture of the membranes have all been demonstrated citrate or after preparation of the endometrium with to occur more frequently after assisted fertilization exogenous estrogen preparations followed by micron- (Källén et al. 2005). However, much of our present ized progesterone or other gestagenic preparations. knowledge has been compiled from nationwide regis- With conventional slow-freezing protocols, the sur- tries, in which data of both fertile and infertile couples vival rate of the thawed oocytes varies between were gathered jointly. In addition, data about the poten- 75–90%. With unselected oocytes the results of embryo tial long-term consequences of assisted reproduction, transfer with frozen/thawed oocytes at the pronucleate such as the incidence of cancer in previously infertile stage seems to be comparable to freezing and thawing women or metabolic and/or fertility hazards in their of cleavage stage embryos (Senn et al. 2000). Neither offspring, will only be available in future decades. increased prevalence of malformations nor of develop- Nevertheless, the occurrence of some of the notable mental abnormaties have been observed among chil- complications is known and will be discussed here. dren conceived after replacement of frozen-thawed pronucleate oocytes (Ludwig et al. 1999). Recently, alternative protocols for the cryopreser- 23.13.1 Ovarian Hyperstimulation vation of oocytes at the pronucleate stage, other than the conventional slow freezing protocols, have been Syndrome (OHSS) proposed. Vitrifi cation has the promise of achieving much higher success rates. Vitrifi cation defi nes an OHSS is a common complication of all forms of ultra-rapid freezing method (less 1/10,000 s), in which medical stimulation of ovarian function, affecting up 494 Ch. De Geyter et al. to 2% of all treatments with assisted reproduction, 23.13.3 The Risk of Multiple Pregnancies particularly IVF and ICSI (Delvigne and Rosenberg 2002). The presence of hCG in the patient’s blood Although the fi rst pregnancies arising after IVF were circulation is essential for the development of OHSS, achieved in the unstimulated, natural menstrual cycle, which usually develops about 12 days after ovula- various forms of ovarian stimulation were soon intro- tion induction, occasionally earlier. It is associated duced to raise the pregnancy rates of IVF. This strategy with a massive swelling of the abdomen due to an envisages the transfer of more than one embryo per enlargement of the ovaries accompanied by ascites cycle, which was benefi cial for improving the pregnancy (Delvigne and Rosenberg 2003). The latter often rates. The drawback of this strategy consists of high leads to hemoconcentration (as measured by hemat- numbers of multiple pregnancies, not only twins, but ocrit) thereby causing physical distress (with high also high order multiple pregnancies, such as triplets leukocyte numbers in the peripheral blood count), and quadruplets. In many countries multiple pregnancy and an increased risk of intravascular blood clotting. rates were as high as 40%, so that more children were The hypovolemia may lead to anuria. OHSS is charac- born from multiple pregnancies than from singletons. terized by low sodium, high potassium and low albu- The high numbers of multiple pregnancies induced by min levels in the serum. If not managed properly, assisted reproduction have installed a heavy burden on OHSS is a potentially life-threatening condition. obstetric and neonatal institutions, but also on the long- Women with an otherwise subclinical diaphragmic term physical and social wellbeing of the previously hernia may also develop unilateral or bilateral pleural infertile couples and their children. In order to reduce effusions, which are characterized by dyspnoe and fre- the number of multiple pregnancies induced by assisted quent coughing. fertilization, many countries have issued a restrictive The treatment of OHSS consists of correction of the legislation with regard to the number of embryos to be composition of circulating blood through infusion replaced per cycle (often limited to three). Currently, therapy and aspiration of ascites and/or pleural effu- there is a widespread trend to replace only one single sion. Nowadays, OHSS can be prevented in many embryo per treatment. Unfortunately, the restrictive leg- patients by using milder stimulation regimens, through islation in various countries, such as Germany and prolonged coasting (Sher et al. 1995) and by avoiding Switzerland, is counterproductive for the adoption of the administration of hCG during the luteal phase this policy, as this necessitates the selection of one (Delvigne and Rosenberg 2003). embryo out of a cohort of several embryos, thereby pro- ducing surplus embryos (Van den Bergh et al. 2005). Whereas by far most multiple pregnancies arising 23.13.2 Ovarian Torsion from assisted reproduction are multizygotic, the rate of monozygotic multiple pregnancies is also higher. Although the mechanism of monozygotic twinning is Ovarian hyperstimulation leads to an enlargement of not known, it seems to be related to the hardening of the ovaries, particularly during the luteal phase and zona pellucida during prolonged culture in vitro. during early pregnancy. After the 9th week of gesta- Transfer of embryos at the blastocyst stage is not con- tion, the placenta resumes its function and the size sidered to lead to a higher incidence of monozygotic of the ovaries will gradually become normal again. twinning by some authors (Papanikolaou et al. 2006), Particularly in slender women treated with ICSI but not by others (Jain et al. 2004). because of male infertility and in whom intraperito- neal adhesions are not prevalent, these enlarged ova- ries may undergo torsion. In ovarian torsion blood 23.13.4 Cancer Risk in the Mother circulation from and to the organs may become compromised leading to the organ’s infarction. It After Assisted Reproduction occurs in 0.1–0.3% of all cases and is observed more often in women with multiple pregnancies (Kallén There is some uncertainty whether there is any assoca- et al. 2005). tion between hormonal stimulation of ovarian function 23 Assisted Reproduction 495 for assisted fertilization and a higher incidence of vari- in the cystic-fi brosis transductance regulator-gene ous malignant diseases, such as breast cancer, ovarian (CFTR) and microdeletions of the Y-chromosome. cancer and others. The possibility of such an associa- tion must be differentiated from known correlations between the failure to conceive and the occurrence of All patients who consider assisted reproduction and malignant disease (such as ovarian cancer) and delayed whose fertility problem has a genetic basis should conception and the occurrence of malignant disease undergo formal genetic counselling. The same rec- (such as breast cancer). In addition, various conditions ommendation is made when the patients’ medical causing infertility have also been associated with a history or the family history suggest specifi c genetic higher risk of malignancy, such as the association of risk factors. endometriosis with ovarian cancer and the association of polycystic ovary disease and endometrial cancer. Particularly those couples whose infertility requires Furthermore, the time interval between the widespread treatment with ICSI are at risk of some genetic use of ovarian hyperstimulation and the occurrence of abnormality: various forms of cancer, such as ovarian cancer, which is a disease affl icting women at a very advanced age, is • Four to 5% of men and 6–7% of women enrolled in still insuffi cient to detect a meaningful association. ICSI programs have an abnormal karyotype, either Various large-scale studies have been performed, but at numerical or structural. present there is no evidence delineating a consistent • Severe oligozoospermia (less than 1 million/ml) association between assisted reproduction and a higher and non-obstructive azoospermia represent the most incidence of breast cancer, ovarian cancer, endometrial clearcut indications for ICSI. Whereas a deletion in cancer and cervical cancer (Venn et al. 1999; Dor et al. the AZFc-region of the Y-chromosome may be 2002; Lerner-Geva et al. 2003; Gauthier et al. 2004; associated with the presence of few spermatozoa in Kristiansson et al. 2007). the ejaculate, deletions of the AZFa- and of the AZFb-regions lead to complete azoospermia (Simoni et al. 2008). • MESA/TESE with consecutive ICSI are the treat- 23.14 Genetic Counselling in Assisted ment modality of choice for congenital bilateral Reproduction absence of the vas deferens (CBAVD) and bilateral ejaculatory duct obstruction. Approximately 85% of men presenting with either of these variants of Concern with the genetic causes of male infertility fol- obstructive azoospermia carry mutations in the cys- lowed the fi rst introduction of ICSI (Palermo et al. tic fi brosis (CFTR) gene. 1992) and has resulted in the detection of an array of • In about 1% of men treated with ICSI, the fertility different genotypes associated with male infertility. problem is one facet of a syndrome type of disorder. The condition of infertility by itself has been demon- • Two percent of patients enrolled for ICSI are strated to entail a higher risk of malformations in the affected with non-reproductive, potentially herita- offspring, but ICSI by itself seems to add to the inher- ble disorders, such as congenital heart disease, cleft ent risk of malformations in infertile couples (Katalinic lip and palate and others. This rate slightly exceeds et al. 2004; Gjerris et al. 2008). The risk of neonatal the baseline prevalence (1%) of such disorders malformations seems not to be directly related to the among fertile controls. source of the spermatozoa (ejaculated, epididymal or testicular) nor to the concentration of spermatozoa in In general, careful documentation of the personal, med- the seminal plasma (Ludwig et al. 2003). Although a ical and family history (if necessary including the con- defi ned genetic syndrome causing infertility cannot be struction of a pedigree) should be performed. In cases identifi ed in most couples, a few cases are clearly the of recurrent miscarriage (including those in close rela- sequel of a genetic problem. Particularly male infertility tives), of unexplained azoospermia or severe oligozoo- has been associated with genetic abnormalities, such spermia, both partners should be karyotyped and testing as structural chromosomal abnormalities, mutations the male partner for Y chromosomal microdeletions is 496 Ch. De Geyter et al.

Table 23.2 List of information to be taken from the history of • In couples, treated with ICSI because of severe the infertile couple and special indications chromosomal analysis male infertility, a higher risk of de novo chromo- prior to assisted reproduction somal abnormalities in the offspring, particularly of Important questions with regard to genetic risks in the the sex chromosomes, has been observed (Meschede presence of male infertility: and Horst 1997; Meschede et al. 2000). Recurrent intrauterine fetal demise in consanguineous couples • The neonatal birth weight of children, conceived History of neonatal malformation or hereditary diseases after assisted reproduction, particularly IVF and among relatives ICSI, but lesser so after IUI and after the replace- Infertility among close relatives ment of frozen/thawed oocytes or embryos, has Consanguinity among both partners been demonstrated to be signifi cantly lower (De Indication for chromosomal analysis, in addition to routine indications: Geyter et al. 2006) and this difference becomes Recurrent miscarriage in the female partner (three or more pronounced in singleton deliveries, which more) were characterized by the presence of a vanishing Intrauterine fetal demise, particularly when the fetus multiple during early pregnancy (De Geyter et al. presented with malformation 2006; Pinborg et al. 2007). Although the cause of Malformations in the female partner or in her kinship this phenomenon is unknown, it may be related to Infertility among close relatives the current policy of replacing more than one embryo per cycle (De Sutter et al. 2006). • The occurrence of rare imprinting disorders causing advisable (see Chap. 8). Other tests, such as muta- the Angelman syndrome, Prader-Labhard-Willi tion screening in the CFTR gene in patients with syndrome, Beckwith-Wiedemann syndrome and CBAVD are performed when suggested by the clinical the Silver-Russell syndrome (Sutcliffe et al. 2006; situation. Kagami et al. 2007) in children conceived with The physician in charge of therapy should at least assisted reproduction (both IVF and ICSI) has check the points listed in Table 23.2 and organize the raised some concern, although the conclusions appropriate genetic laboratory tests. remain controversially discussed (Doornbos et al. 2007; Bowdin et al. 2007). The utterly low inci- dence of these syndromes requires very large cohort 23.15 Health of the Offspring studies to verify such a relationship. Retrospective cohort studies in patients suffering from the After Assisted Fertilization Beckwith-Wiedemann syndrome indicated a high prevalence of previous treatments with assisted From its early beginnings the introduction of ICSI for reproduction (Gosden et al. 2003). In contrast, an the treatment of male infertility has raised much con- Australian study estimated the incidence risk at one cern with regard to safety of the technique as to the risk diseased child out of 4,000 newborns after assisted of malformations in the offspring (Niemitz and Feinberg reproduction (Halliday et al. 2004). Although ani- 2004). However, since then, the large-scale experience mal research has established a link between culture has demonstrated that, apart from those cases in which of embryos in vitro with imprinting disorders in the male infertility has a defi nite genetic background as offspring (Maher 2005), more long-term follow-up depicted above, this treatment is not associated with a studies are necessary to quantify such an associa- major risk of malformation in the offspring. The inci- tion in clinical assisted reproduction. dence of neonatal malformations must be seen with respect to the condition of infertility, which by itself Various studies have examined the intellectual and pertains to a higher health risk to the offspring, and the psychomotoric development of children conceived current trend to delaying childbearing to later in life. with assisted reproduction and compared their perfor- Despite these comforting fi ndings, close observa- mances with those of children conceived naturally. tion of the outcome of assisted reproduction, of ICSI in Although single studies have reported signfi cant dif- particular, have revealed some risks, which must be ferences (Bowen et al. 1998), most other studies have communicated: not been able to confi rm these, particularly those 23 Assisted Reproduction 497 focussing on children at various ages of development monitoring (EIM) Consortium, European Society of Human (at 2 years: Bonduelle et al. 1998; at 5 years: Ponjaert- Reproduction and Embryology (ESHRE) (2008) Assisted reproductive technology in Europe, 2004: results generated Kristoffersen et al. 2005; at 8 years: Leunens et al. from European registers by ESHRE. 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pregnancy rate and eliminates the risk of multiple birth. advantage to cervical cap insemination in a donor insemina- Hum Reprod 14:2392–2395 tion program? Fertil Steril 63:295–298 WHO (1999) Laborhandbuch zur Untersuchung des menschli- Yovich JM, Edirisinghe WR, Cummins JM, Yovich JL (1990) chen Ejakulates und der Spermien-Zervikalschleim- Infl uence of pentoxiphylline in severe male factor infertility. Interaktion. 4. Aufl age, Springer, Berlin Heidelberg Fertil Steril 53:715–722 Williams DB, Moley KH, Cholewa C, Odem RR, Willand J, Gast MJ (1995) Does intrauterine insemination offer an Cryopreservation of Human Spermatozoa 24 Sabine Kliesch, Axel Kamischke, Trevor G Cooper, and Eberhard Nieschlag

Contents 24.6 Use and Quality of Stored Cryopreserved Semen Samples ...... 515 24.1 Introduction ...... 506 24.6.1 Use of Cryopreserved Samples ...... 515 24.6.2 Quality of Stored Cryopreserved 24.2 History of Cryopreservation Semen Samples ...... 516 of Human Semen ...... 506 24.7 Problems and Limitations 24.3 Indications for Cryopreservation of Semen ...... 506 of Cryopreservation ...... 517 24.3.1 Fertility Preservation ...... 506 24.7.1 Genetic Risks ...... 517 24.3.2 Infertility Treatment ...... 509 24.7.2 Psychological Aspects ...... 517 24.3.3 Donor Semen ...... 511 24.7.3 Methodological Considerations ...... 517 24.3.4 Quarantine of Potentially Infected Samples ...... 511 References ...... 518 24.3.5 Quality Control of Semen Analysis ...... 511 24.4 Requirements and Risk Assessment for Cryoconservation of Human Semen ...... 511 24.4.1 Required Resources ...... 511 24.4.2 Risk of Cross-contamination ...... 512 24.4.3 Staff Safety and Protection ...... 512 24.4.4 Labelling of Straws and Records ...... 512 24.5 Preparation of Semen Samples for Cryopreservation ...... 512 24.5.1 Preparing the Sample ...... 512 24.5.2 Routine Sample Freezing and Cryoprotectants ...... 512 24.5.3 Relative Resistance of Spermatozoa to the Freezing Process ...... 513 24.5.4 Standard Cryoprotectants ...... 513 24.5.5 Adding the Cryoprotectant ...... 514 24.5.6 Closing the Straws ...... 514 24.5.7 Freezing the Samples ...... 514 24.5.8 Storing the Samples ...... 515 24.5.9 Thawing the Samples ...... 515 24.5.10 Frozen Semen Transport ...... 515

S. Kliesch () Centre of Reproductive Medicine and Andrology of the University, Domagkstrasse 11, 48149 Münster, Germany e-mail: [email protected]

E. Nieschlag et al. (eds.), Andrology, 505 DOI: 10.1007/978-3-540-78355-8_24, © Springer-Verlag Berlin Heidelberg 2010 506 S. Kliesch et al.

24.1 Introduction of the intracytoplasmic sperm injection (ICSI) tech- nique the cryopreservation of spermatozoa was extended to testicular and epididymal tissue with sin- This chapter provides a review of the present state of gle spermatozoa extracted by operative techniques technology, practicability and limits of cryopreserva- (surgical incision or microsurgical procedure). tion of human spermatozoa. Its aim is to encourage physicians and health care providers to consider the needs of a patient’s quality of life with respect to his family planning and fertility on a long-term basis and 24.3 Indications for Cryopreservation to include these topics when counselling the patient of Semen and planning therapy. Sperm cryopreservation is an important part of the work of many semen analysis laboratories, particularly those associated with infertil- 24.3.1 Fertility Preservation ity clinics. Spermatozoa may be stored for a variety of reasons and some of these may require modifi cations Men may store semen before undergoing a procedure of the cryopreservation procedure. or exposure that might prevent or impair fertility, such as multimodality oncology treatment with especially Cryopreservation of semen represents a preventive cytotoxic alkylating agents, radiotherapy and/or surgi- therapeutic option for normal men, infertile and cal procedures, which is likely to impair spermatogen- oncological patients and offers the chance of main- esis or semen deposition permanently, and vasectomy taining potential parenthood. (as insurance against a change in marital situation or desire) (Meseguer et al. 2006; Schmidt et al. 2004). For patients about to undergo chemo- and radio-therapy, the 24.2 History of Cryopreservation semen should be collected before the patient com- mences any therapy because of the potential risk of of Human Semen mutagenesis in the spermatozoa (Krause 2007). Patients undergoing organ transplantation or treatment for rheu- The fi rst observation that the motility of human sper- matic arthritis, Morbus Crohn or colitis ulcerosa should matozoa could be preserved after freezing and thawing also be offered semen sampling prior to therapy. In cer- was made by Lazzaro Spallanzani in 1776. In the mid- tain countries, men on active duty in a dangerous occu- dle of the nineteenth century the idea arose to establish pation; e.g., in military defence forces, may provide a sperm bank for cattle breeding. Around the same samples when posthumous procreation is acceptable. time the possibility of freezing soldiers’ semen before Prophylactic cryopreservation of semen offers the they went to war was considered, with the purpose, chance of preventing the hazardous effects of disease should they die, of enabling their wives to bear their and therapy on fertility and may contribute to the per- children. Serious attempts to improve the technical sonal stabilization of the mainly young patients in this requirements of the cryopreservation of semen were critical and acute situation. Most patients deciding in performed in the fi rst half of the twentieth century favor of cryopreservation of semen are those with malig- (Trottmann et al. 2007). Great improvements were nant diseases. Others seek cryopreservation because the achieved by introducing the fi rst cryoprotective sub- extent of their disease is not yet clear, or potentially stance, glycerol, into the cryopreservation process to toxic treatments have to be performed because of benign protect spermatozoa during freezing. This led to the diseases that may damage testicular function. use of human spermatozoa stored on dry ice at −79°C (Polge et al. 1949). Subsequently liquid nitrogen (−196°C) was used and shortly thereafter the fi rst suc- 24.3.1.1 Vasectomy and After Vasovasostomy cessful fertilization and pregnancy with cryopreserved semen was reported. Since then thousands of births Cryopreservation of spermatozoa may be seriously worldwide have resulted from the use of cryopreserved considered for patients who will undergo vasectomy donor semen (Leibo et al. 2002). With the introduction because no hormonal, reversible contraceptive device 24 Cryopreservation of Human Spermatozoa 507 comparable to the female pill is available for men depend on the therapeutic modalities, the substances (Djerassi and Leibo 1994). Vasectomy is an invasive and dosages chosen. and often irreversible contraceptive method (see Chap. Malignant diseases strike many patients at a time 28) and the patient and his female partner have to when family planning has not started or is not yet fi n- make a defi nite decision on their family planning. ished. At this critical point of time, individual repro- Daily clinical work, however, demonstrates that sud- ductive function may have a high impact on quality of denly changed circumstances of the patients’ lives life. Of the 1,132 oncological patients at our center (the death of a child or the female partner; a new part- (mean age 28 years) presenting for cryopreservation of nership) give rise to the wish to reverse vasectomy their semen between 1989 and 2008, only 24% were and to perform microsurgical vasovasostomy or already married and only 10% had already fathered at vasoepididymostomy (vasotubulostomy). For these least one child before they became ill. patients cryopreserved semen might offer the chance The extent of impairment of gonadal function by to father a child by means of assisted fertilization in chemo- and/or radiotherapy cannot be predicted defi - case of unsuccessful or impossible refertilization. nitely and the possibility of testicular recovery depends After successful vasovasostomy or vasoepididymos- on the therapeutic intervention itself, the dosages tomy there is a risk that patency of the ducts may not applied and the susceptibility of the patient (Kliesch et be permanent, resulting in re-obstruction. Therefore al. 1996; Palmieri et al. 1996). Until now it has not been patients could be offered the possibility to cryopre- possible to protect testicular function from the toxic serve either intraoperatively aspirated spermatozoa or effects of chemo- and/or radiotherapy (Kamischke et al. ejaculated semen after successful refertilization. In 2003). Retrograde ejaculation after retroperitoneal about one third of patients intraoperative sperm aspi- lymphadenectomy can be treated empirically with some ration is successful in collecting motile spermatozoa medical effort, but impotentia generandi resulting from that may be used for later microinjection therapy if radical surgery (e.g., radical prostatectomy, cystopros- refertilization fails (Belker and Bergamini 1997). tatectomy or rectal exenteration) can be treated only Alternatively, testicular sperm extraction (TESE) may with TESE (Kamischke and Nieschlag 1999). also be combined with a microsurgical refertilization In patients with testicular tumors or other malignan- procedure, if vasal or epididymal sperm retrieval is cies (e.g., Hodgkin disease, leukemia) impairment of not suffi cient. However, the additional costs must be testicular function is known. However, the underlying critically discussed with the patient, especially when causes of reduced fertility in relation to the malignant considering the overall low frequency of patients disease are not understood (Hansen et al. 1991; Viviani using these intraoperatively cryopreserved depots et al. 1991). Data from our own patients revealed reduced after successful microsurgery (Practice Committee of semen parameter values with oligozoospermia in 63% of the American Society for Reproductive Medicine men with testicular tumors, 43% of men with lymphatic 2006; Kolettis et al. 2005). or leukemic diseases and 45% of patients with different solid tumors (Fig. 24.1) prior to cryopreservation. Prior to radio- and/or chemotherapy a total of 89 patients were 24.3.1.2 Oncological Diseases in Adults azoospermic; 90 patients had sperm concentrations between 0.1 × 106/ml, but 433 patients had normal sperm Malignant diseases in adolescents and adults can be concentrations (modifi ed from Kamischke et al. 2004). cured by surgery, chemo- and/or radio-therapy in a However, reduced sperm concentrations do not play the high percentage of cases, resulting in increased sur- most important role in predicting the success of assisted vival rates. In those patients where this is not possible, fertilization procedures (Palermo et al. 1992). an increase of disease-free intervals may be achieved Sperm motility is particularly impaired by the cryo- by adequate therapeutic strategies. Therefore the impli- preservation process (Fig. 24.2). While the mean pro- cations for long-term toxicity and delayed results of gressive motility of sperm in oncological patients is therapeutic intervention become more and more impor- about 40%, a signifi cant drop of sperm motility to a tant. Chemo- and/or radiotherapy, as well as surgical mean of 21% is noticed immediately after freezing and intervention, have a negative infl uence on male repro- thawing an aliquot, independent of the underlying dis- ductive functions; the effects can be irreversible and ease and the patients’ age (Keck and Nieschlag 1993; 508 S. Kliesch et al.

Fig. 24.1 Age and sperm 1000 concentrations in semen of 683 patients with malignan- cies at the time of cryopreser- vation. Note logarithmic 100 scale. The lower normal limit

for sperm concentration is 20 /ml) [log-scale] million spermatozoa/ml 6 lower normal limit semen (broken line) (Updated 1.0 and modifi ed from 14–17 y (n = 29) Kamischke et al. 2004) >17–20 y (n = 50) > 20 y (n = 604) 0.1 Sperm concentration (10

0.0 12 14 16 18 20 22 30 40 50 60 70 Age (years)

Kliesch et al. 1996). The better the pre-freeze sperm 24.3.1.3 Oncological Diseases in Childhood motility is (Fig. 24.2), the better post-thaw motility tends to be. As sperm motility is regarded as one of the The survival rates of oncological patients who become important parameters for increasing success rates in ill at a young age, e.g., with testicular tumors, Hodgkin insemination and in vitro fertilization (IVF) therapies disease, leukemia or Ewings sarcoma, have increased, (De Geyter et al. 1992), this decrease of sperm motility owing to early detection and improved therapeutic con- due to the cryopreservation itself, may explain the often cepts. Cryopreservation cannot only be offered success- unsuccessfully performed insemination or IVF cycles. fully to adults but also to juvenile patients with However, with respect to ICSI, the percentage of motile malignancies. Prior to and after cryopreservation ado- sperm is not as relevant. In ICSI treatment sperm lescent boys show semen parameters comparable to motility is used as an indicator of vitality of the sper- those of adults, independent of the underlying oncologi- matozoon selected for microinjection (see Chap. 23). cal disease (Kliesch et al. 1996; Kamischke et al. 2004).

80 Testicular tumors (n = 450) Lymphomas, Leukemias (n = 245) 70 Other malignancies (n = 103)

60

50

40

30 Fig. 24.2 Sperm motility

prior to (abscissa) and after Sperm motility after thawing (%) 20 (ordinate) freezing and thawing of semen from patients with different 10 oncological diseases at the time of cryopreservation of 0 semen. The lower normal limit 0102030 40 50 60 70 80 90 for the pre-freeze progressive Sperm motility before freezing (%) sperm motility is 50% 24 Cryopreservation of Human Spermatozoa 509

All our adolescent oncological patients showed age- pituitary hypogonadism. Under special circumstances, adjusted normal or above normal testicular volumes in such as assisted ejaculation for anejaculation, spermato- the lower or subnormal adult range, irrespective of zoa may be prepared from urine after retrograde ejacula- sperm count. As in our department only one of the ado- tion or collected surgically from the genital tract (TESE; lescent patients showed azoospermia, one might specu- microsurgical epididymal sperm aspiration, MESA). It is late that an age-adjusted normal testicular volume in the used rarely for patients unable to provide fresh semen on lower to subnormal adult range is a positive predictor the day of a therapeutic procedure. for successful spermarche and subsequent cryopreser- vation (Kamischke et al. 2004). Although chemotherapy protocols used in childhood have become less harmful, the prognosis concerning gonadal toxicity and impair- 24.3.2.1 Assisted Fertilization ment of gonadal function on a long-term basis remains diffi cult and depends on the chemotherapeutic combi- The cryopreservation of surgically sampled spermatozoa nations and the necessity of multimodal treatment for use in assisted fertilization techniques has become options used. Up to 16% of patients exposed to thera- increasingly important in recent years. Epididymal sperm pies not using alkylating substances (e.g., adriamycin, aspiration and testicular extraction of spermatozoa, in vincristine, methotrexat) show persistent azoospermia combination with cryopreservation, have become routine during adulthood after childhood treatment. procedures in reproductive centers for cases with both When cisplatin-based chemotherapies are used, a reconstructable and non-reconstructable obstruction and mean of 37% of cured patients remains azoospermic primary testicular failure (non-obstructive azoospermia). during adulthood. If alkylating substances (e.g., Information on the quality of cryopreserved sperm cyclophosphamide or ) are used during samples used for assisted fertilization is variable. No childhood cancer treatment, infertility may result in systematic information on the number of treatment 68% of the treated patients during adulthood (for cycles, methods of gynecological therapy and the total review see Kliesch et al. 1996). Whether the possibil- number of treated andrological patients is available. ity of sampling gonadal tissue in oncologically ill (pre- Between 1983 and 1992 a total of 117 pregnancies and pubertal) boys prior to toxic treatment will offer a real 115 births after insemination or IVF with cryopreserved chance for later re-transplantation to regain fertility semen samples of oncological patients was published depends on future research developments. So far, fi rst (Sanger et al. 1992). In Germany two centers provided experimental attempts have been made to establish data on cryopreserved semen samples of oncological transplantation techniques (for review see patients. They reported on 136 cryopreserved speci- Bahadur and Ralph 1999; Schlatt et al. 1999). mens collected between 1974 and 1988, including those from eight patients who used their cryopreserved spermatozoa for assisted fertilization after a period of The preventive aspect of cryopreservation of sperma- up to 5 years (Köhn and Schill 1988; Holland-Moritz tozoa in respect to long-term life quality, including and Krause 1990). In our centre patients with long-term potential paternity, should be considered when coun- depots use their cryopreserved semen samples for selling the very young patient and his parents prior to assisted reproduction in up to 14% of cases. treatment which may prove toxic to the gonads. Simultaneous with the further development of the techniques of assisted reproduction (insemination, IVF, microinjection), chances of inducing a pregnancy 24.3.2 Infertility Treatment increased because of the improvement in sperm quality by better freezing techniques and improved preservation Men may store spermatozoa for treatment of their partner of sperm function. Therefore the “minimal criteria” for by intra-uterine insemination (IUI), IVF or ICSI in cases spermatozoa to be cryopreserved (e.g., post-thaw- of severe oligozoospermia, intermittent presence of motility of at least 10%, sperm concentration >10 × 106/ motile spermatozoa in the semen or partially successful ml) (Köhn and Schill 1988; Keck and Nieschlag 1993) treatment of infertility, such as surgery for genital tract that were generally accepted several years ago have obstruction or gonadotropin treatment for hypothalamo- become irrelevant in view of microinjection therapy. 510 S. Kliesch et al.

24.3.2.2 MESA and TESE Samples Including shown that percutaneous sperm aspiration resulted in Onco-TESE successful sperm extraction in only 61%. With the sur- gical technology of MESA or TESE, sperm recovery In the context of andrologically relevant microsurgery, rates were 93% and 100%, respectively. The MESA MESA offers the chance of obtaining spermatozoa from aspirates obtained during one operation may be used patients with obstructive azoospermia who cannot be for altogether seven ICSI-treatment cycles, if neces- successfully treated by reconstructive microsurgery. sary. Moreover, the trauma by fi ne needle punctures is Patients with post-infectious obstructive azoospermia, even worse than that induced by open surgical sperm as well as those with congenital bilateral agenesis of the retrievement (Shufaro et al. 2002). vas deferens or abnormalities of the epididymides, Especially in severely infertile men, namely those belong to this treatment group (Craft and Tsirigotis with non-obstructive azoospermia, open surgical testicu- 1995). Aspirated spermatozoa not used for fertility treat- lar sperm extraction results in better sperm retrieval rates ment can be cryopreserved and may be used for further compared to fi ne needle aspiration. In 452 azoospermic treatment cycles in assisted fertilization. Cryopreser- men, altogether 63 were found to have positive sperm vation of surgically obtained sperm specimens may pre- results with TESA (14%) compared to 228 men with vent more invasive surgery. Experience with the quality TESE (50%) (Friedler et al. 1997; Mercan et al. 2000). of these cryopreserved samples has shown that microin- Whether microsurgical TESE procedures result in further jection therapy may be performed successfully with improvement of sperm cryopreservation remains to be fresh, as well as with cryopreserved, epididymal sper- elucidated in further studies (Colpi et al. 2009). In addi- matozoa. However, it is also known that both post-thaw tion, testicular histology is useful in hypergonadotropic motility of epididymal spermatozoa and pregnancy rates infertile men, being at higher risk for TIN or testicular are lower compared with those from microinjection tumor compared to normal males (see Chap. 13). therapy with fresh spermatozoa (Palermo et al. 1999). In addition, onco-TESE may play a special role in In addition to epididymal spermatozoa, testicular patients with bilateral testicular tumor, with single spermatozoa can be frozen from patients with severe tumor bearing testicles and azoospermia after gonado- oligoasthenozoospermia or hypergonadotrophic azoo- toxic treatment without suffi cient pre-treatment cryo- spermia with testicular dysfunction due to focal preservation depots. This severely impaired subgroup Sertoli-cell-only syndrome or incomplete arrest of of oncological patients needs special attention. Bilateral spermato genesis. For this, TESE from surgically (synchronous or metachronous) testicular tumor may obtained testicular tissue is used in combination with occur in 2–3% of testis cancer patients and contralat- ICSI (Devroey et al. 1995; Silber et al. 1995). Patients eral TIN in another 5% of men. If treatment options should be offered the possibility of cryopreserving are discussed and semen analysis reveals azoospermia, unused testicular tissue for later preparation in further tumor enucleation or inguinal orchiectomy should be treatment cycles. Experience in recent years with combined with TESE for cryopreservation in special- TESE itself, as well as with that of cryopreserved tes- ized centers. Long-term survivors of oncological dis- ticular tissue, has proved it to be an effective treatment eases revealing azoospermia may be offered testicular option for infertile azoospermic men. Overall, in up to biopsy for diagnosis and TESE options to determine 70% of azoospermic men, spermatozoa may be fertilization potential (Schrader et al. 2003). extracted from testicular tissue (Jezek et al. 1998). However, pregnancy rates vary – depending on the center and especially on the severity of spermatogenic 24.3.2.3 Patients with Anejaculation impairment – between 10% and 30% (Friedler et al. 1997). The chances for fertilization and pregnancy A minor, less extensively considered patient group is achieved with testicular spermatozoa are much higher that with lesions of the spinal cord. Up to 95% of these when single spermatozoa are found in the sediment of patients lose their ability to ejaculate. By electrovibra- the patient’s ejaculate (Palermo et al. 1999). tion or rectal electric stimulation ejaculations may be Comparing the different methodologies for sperm produced and semen may be successfully used for extraction in men with obstructive azoospermia, the assisted fertilization (Kamischke and Nieschlag 1999). puncture procedure does not allow any control con- The penile electrovibrator offers a simple, and rectal cerning the punctured area and, in addition, it was electrostimulation a more complex and inconvenient 24 Cryopreservation of Human Spermatozoa 511 method for the treatment of anejaculation and much 24.3.5 Quality Control of Semen Analysis depends on interdisciplinary and logistic cooperation between patient and physicians. Cryopreservation offers Cryopreservation of spermatozoa can play a role in the advantage of collecting semen samples for later use establishing internal and external quality control sys- in artifi cial fertilization treatment (Chung et al. 1995). tems in andrology (Cooper et al. 1992; Neuwinger et al. 1990). However, the costs of transport of such samples and the quality of the post-thaw specimens 24.3.3 Donor Semen severely limits such application and since these pio- neering studies no others have been reported. Semen is stored from healthy donors known or pre- sumed to be fertile. These donors may be recruited by the clinic or sperm bank and used anonymously or as donors known to the recipients. The use of donor gam- 24.4 Requirements and Risk Assessment etes is accepted in some countries but not in others. for Cryoconservation of Human Where accepted, there are relatively uniform guide- Semen lines for the selection and screening of donors. However, legal regulation varies widely. For example, anonymity of donors is required in some countries, Running a cryolaboratory successfully involves ensur- whereas elsewhere donor children will be told the ing the physical security and scrupulous labelling of identity of the donor upon request when they have the frozen specimens. Comprehensive risk assessment attained legal age. The use of cryopreserved donor is recommended. semen for heterologous assisted fertilization is prac- The cryopreservation and subsequent storage of ticed in various countries and depends on applicable human spermatozoa is a highly complex process pos- laws (ESHRE 2004). ing a special responsibility for, and potential liability Donor spermatozoa may be used for IUI, IVF or ICSI of, the laboratory staff. All procedures involving the to treat the partner of an infertile man who has no live identity of donor or patient samples, including receipt spermatozoa or elongated spermatids suitable for ICSI, of samples, preparation and labelling of straws, place- or where treatment has failed or is too costly; to prevent ment in tanks and thawing of straws for use or discard- transmission of an inherited disorder or to prevent fetal ing, should be double-checked by two people and hemolytic anaemia from blood group incompatibility. evidence of this checking witnessed in laboratory Additional uses are for recurrent abortion – donor records (Tedder et al. 1995; Mortimer 2004; Gilling- insemination may result in a successful pregnancy and, Smith et al. 2005; Tomlinson 2005). Ideally one per- for single or lesbian women wishing to conceive. son should only process one semen sample at any given time. It is necessary to comply with local legis- lation regarding genetic and infection screening (see guidelines in American Fertility Society (1990); 24.3.4 Quarantine of Potentially British Andrology Society (1999); Canadian Fertility Infected Samples and Andrology Society (1992); Fertility Society of Australia; Jalbert et al. 1989; EU Regulations 2006). The advent of acquired immunodefi ciency syndrome human immunodefi ciency virus (HIV – AIDS) in the early 1980s required the introduction of a quarantine period and further testing of the donor before use of his 24.4.1 Required Resources stored semen in order to minimize infectious disease transmission. Men with HIV controlled by anti-retroviral Running a cryolaboratory also involves ensuring the therapy may store samples with undetectable viral load physical security of the vessels, specimens and storage for IUI, IVF or ICSI to attempt conception while reduc- room to reduce risk of loss by theft or fi re and to guard ing the risk of transmission of HIV to the female part- against the failure of cryopreservation straws, ampoules ner (Gilling-Smith et al. 2005). and vessels. Splitting of samples and storage at different 512 S. Kliesch et al. sites may be considered to reduce risk of total loss of It is important to have a unique code for each donor or samples. As well as ensuring a constant liquid nitrogen storage client and to use a code in laboratory data sheets supply, detectors to indicate low liquid nitrogen levels and computer databases to maintain anonymity. The key in the freezers and low atmospheric oxygen alarm sys- to the code identifying the donor should be kept sepa- tems in the rooms are necessary. rately and securely.

24.4.2 Risk of Cross-contamination 24.5 Preparation of Semen Samples for Cryopreservation There is a risk of cross-contamination with infectious agents between samples via a cryopreservation vessel 24.5.1 Preparing the Sample in storage. This will depend on the protocol used and the location and method of storage of high risk sam- ples (known to contain or possibly containing viruses The liquefi ed ejaculate is analyzed according to the such as HIV and HCV), including the type of storage guidelines of the World Health Organization (WHO container (whether vials or straws), the method of 2009) (see Chap. 9). The standard parameters of sperm sealing the straws (whether heat or polymer) and the concentration, total number of spermatozoa, sperm nature of storage (whether in liquid nitrogen or its morphology and sperm motility prior to cryopreserva- vapor). Storage in the vapor phase rather than in the tion give important information for later use of the liquid nitrogen itself may reduce the chances of semen in assisted fertilization procedures. Additional cross-contamination. However, large temperature sperm function tests can be performed, such as the gradients can exist in vapor storage vessels depending hypo-osmotic swelling (HOS) test to investigate on the shape, sample load and type of sample contain- whether the sperm’s fl agellar membrane remains intact. ers. In extreme cases, a temperature of less than However, no correlation between hypo-osmotic swell- −100°C cannot be achieved (Tomlinson 2005). If ing and sperm quality after cryopreservation is evident vapor phase storage is used, care must be taken to (Chan et al. 1993). The eosin test (of sperm head mem- avoid the samples warming to greater than −130°C branes) may be useful to demonstrate the percentage of (the glassy transformation temperature), as this may vital sperm after cryopreservation. damage the spermatozoa (see Clarke 1999). Selection of motile spermatozoa by a swim-up pro- cedure prior to cryopreservation improves the mor- phology and motility of spermatozoa obtained after freezing and thawing (Péréz-Sanchez et al. 1994). 24.4.3 Staff Safety and Protection However, the swum-up spermatozoa are damaged to the same extent as spermatozoa in the original sample For protection of the staff working in the unit, there so the improvement refl ects merely the better quality should be provision of personal protective equipment of the initial sample. (insulated gloves, goggles), and the room should be fi t- ted with an oxygen sensor with alarm. 24.5.2 Routine Sample Freezing and Cryoprotectants 24.4.4 Labelling of Straws and Records Intracellular ice crystals lead to cellular lesions and To ensure patient samples, there should be double death during thawing, whereas extracellular ice crystal checking of the identity of samples at each step vul- formation raises extracellular tonicity and damages nerable to error; a robust labelling and identifying cell membranes by the cell shrinkage invoked. To min- code, a procedure and mechanism of regular audit of imize this, cryoprotective media are added to the ejac- the use of material and samples remaining in storage. ulate prior to the freezing process. These are based 24 Cryopreservation of Human Spermatozoa 513 either on egg yolk mixed with low molecular weight spermatozoa survive freezing and thawing (Keel and (penetrating) compounds such as glycerol or consist of Webster 1993). Optimizing the cryopreservation process culture media with macromolecular, non-penetrating should minimize this damage and increase pregnancy compounds such as human serum albumin together rates (Woods et al. 2004). with or without glycerol. Cryoprotective substances that do not penetrate the sperm membrane (e.g., human serum albumin and additions based on egg yolk) are protective by binding to and stabilizing the cell mem- 24.5.4 Standard Cryoprotectants brane (Watson et al. 1992). Several cryopreservation protocols are now used with variations in composition of the cryoprotectant 24.5.4.1 For Normal Samples and complexity of the freezing procedure. Cell sur- vival with freezing and thawing depends largely on A commonly used cryoprotectant is glycerol-egg yolk- minimizing intracellular ice crystal formation by the citrate (GEYC). Cryoprotectants similar to GEYC can use of appropriate cryoprotectants and appropriate also be obtained commercially (see Table 24.1) but rates of cooling and warming to control the amount of other cryoprotectants, freezing and sperm bank man- intracellular water subject to ice formation (Sherman agement protocols are available (Mortimer 2004; Wolf 1990; Keel and Webster 1993; Watson 1995). 1995). Improvements to the basic cryoprotectant Temperatures above −130°C, the glassy transition include the addition of antioxidants (e.g., vitamin E), 2 + temperature, are important because if the spermatozoa Ca -chelating agents (e.g., EDTA) or derivatives of spend signifi cant periods of time above this tempera- phosphatidylcholine (platelet-activating factor) and ture, recrystallization can occur with growth of poten- derivatives of methylxanthine (pentoxyphylline) to the tially damaging intracellular ice crystals, particularly cryopreservatives (Alvarez and Storey 1993; Wang during the thawing process. et al. 1993) that may be benefi cial in certain cases but are not adopted routinely.

24.5.3 Relative Resistance Table 24.1 Indications and frequency of cryopreservation (of 1,136 consecutive patients of the Centre of Reproductive of Spermatozoa Medicine and Andrology of the University, Münster, Germany) to the Freezing Process Diagnosis Number of patients (%) Testicular tumors 573 (50) During the process of freezing, spermatozoa are exposed Hodgkin disease/non-Hodgkin 201 (18) disease to extreme temperature changes that alter sperm mor- Leukemias 99 (9) phology and damage sperm function at many levels. Bone tumors 74 (7) Spermatozoa may be more resistant than other cells to Other malignancies 61 (5) cryopreservation damage because of their lower water Benign diseases 128 (11) content. Human spermatozoa tolerate a range of cooling and warming rates and samples do not need seeding to induce ice crystal formation. They are not very sensitive to rapid initial cooling (cold shock), possibly because of 24.5.4.2 For Samples with Low Sperm Numbers high membrane fl uidity from the unsaturated fatty acids in the lipid bilayer (Clarke et al. 2003). Nevertheless, Epididymal fl uid, testicular extracts or other sperm osmotic effl ux of water by hypertonic cryoprotectants suspensions processed by swim-up or centrifugation and raised osmolality as a result of extracellular ice for- on density gradients and resuspended in a sperm prep- mation leads to dehydration, changes in intracellular aration medium with Hepes buffer and human serum electrolyte concentrations and disruption of sperm mem- albumin 4 mg/ml can be cryopreserved with Tyrode- brane permeability (Hammerstedt et al. 1990; Watson et glucose-glycerol cryoprotectant or a commercial cryo- al. 1992). On average only about 50% of the motile protectant containing human albumin. 514 S. Kliesch et al.

24.5.4.3 Improvements in Cryopreservation equipment, usually a maximum of 12 straws can be Techniques stored in one cryo-cassette.

Novel techniques aimed at improving post-thaw sperm motility by non-linear temperature changes of extra- 24.5.5.2 For Samples with Low Sperm Numbers cellular solute concentration (Morris et al. 1999) have shown promise and vitrifi cation (the very rapid freez- For semen samples containing only a few motile sper- ing of cells without ice crystal formation) achieved by matozoa (from oligozoospermic ejaculates) and sperm plunging a very small (~20 ml) sample in a cryo-loop suspensions obtained from the genital tract stored for directly into liquid nitrogen, with or without cryopro- subsequent ICSI, it is necessary to centrifuge the semen tectants, produces good results (Isashenko et al. at 1,500 g for 10 min to concentrate the spermatozoa to a 2004a, b, 2005), but neither technique has been adopted minimum volume of 0.4 ml before treating the same as into routine practice. Further, not broadly distributed above. Surgically retrieved spermatozoa (either epididy- methods for cryopreservation of single spermatozoa mal or testicular) are placed in a special medium for include the use of empty zona pellucida as a sperm transportation and further preparation, mixed with cryo- storage container, freezing in micro-droplets, the protectives, cryopreserved and stored in liquid nitrogen. microencapsulation of spermatozoa and the use of The ampoules for storage vary from laboratory to labo- mini-straws. ratory. Usually for epididymal probes “straws” are used, whereas for testicular probes small tubes suitable for sterile cryopreservation are employed. 24.5.5 Adding the Cryoprotectant

24.5.5.1 For Normal Samples 24.5.6 Closing the Straws

After liquefaction at 37°C the sterile ejaculate is care- To avoid cross-contamination, total closure of the straw fully mixed with the same volume of a cryoprotective is necessary: straws with an upper plug of dry polyvinyl medium (CPA). This can be done in several steps in alcohol powder held between two sections of cotton order to prevent excessive volume changes during CPA wool automatically seal when the semen contracts and additions (Gao et al. 1997). Several cryoprotectants polymerizes the powder. Secure straws made from heat- are commercially available (Table 24.2). sealable ionomeric resin are available for storage in liq- For fertility preservation or infertility treatments, uid nitrogen (CBS High Security Straws). These are suffi cient normal specimens should be stored to pro- leak-, bacteria- and virus-proof and mechanically resis- vide ten or more inseminations, in order to ensure a tant at −196°C (Mortimer 2004; Gilling-Smith et al. good chance of pregnancy. The diluted semen sample 2005; Tomlinson 2005). in the vial is transferred to “straws” under sterile labo- ratory conditions. Each straw has a maximum volume of 300 ml and consists of a plastic material that offers optimal temperature distribution during cooling. Great 24.5.7 Freezing the Samples care should be taken to prevent the admission of air bubbles into the straw, as they can expand upon warm- Most groups work with stepwise freezing. Shortly after ing and cause the straw to explode. Depending on the reaching the freezing point of water, extracellular ice

Table 24.2 Cryoprotectants (CPA) used for human spermatozoa Name Supplier Macromolecule Lipid CPA Freezing medium Irvine Scientifi c No albumin Egg yolk Glycerol SpermCryo™ Provitro No albumin No egg yolk Glycerol SpermCryo™ All-round Cryosinternational No albumin No egg yolk Glycerol SteriTec® Steripharm Albumin No egg yolk Glycerol 24 Cryopreservation of Human Spermatozoa 515 crystal formation begins at about −5°C, and at about −15°C should be well adjusted (Leibo et al. 2002). When to −80°C intracellular ice crystal formation occurs. semen samples are thawed, thawing speed should be There are no uniform guidelines for the optimal freez- adapted to the freezing speed (Leibo et al. 2002). ing time to be chosen between 0°C to −80°C. In prin- Programmed cryo-machines can thaw as in the freezing ciple, cooling leads to increased cell shrinkage by process, but in reverse, and thawing at room tempera- dehydration if it is performed too rapidly, while it pro- ture or in a water bath at 37°C can be acceptable. More motes ice crystal formation if it is performed too slowly. rapid thawing may be better if the freezing process is A freezing speed of 8–21°C per min is used by most rapid (Verheyen et al. 1993). After cryopreservation is groups working with cryopreservation of human semen. performed, a small aliquot of the sample should be After −196°C is reached, the cryopreserved semen thawed and analyzed for sperm motility. This informa- samples are stored in liquid nitrogen. tion may be helpful for later use of the sperm during With programmable freezers, e.g., Planer Kryo assisted fertilization techniques. Removing cryopro- 10-Serie II (Planer) and ICEcube 1,810 (tec-lab), in which tectant by sequential dilution in small volume steps the programme controls injection of liquid nitrogen vapor avoids undue osmotic stresses (Gao et al. 1997) and into the freezing chamber, the cryo-cassettes are cooled may improve pregnancy results. by a computerized, automated process that offers stan- dardized and reproducible cryopreservation conditions. Manual methods are naturally less controllable than those from programmable freezers but can give adequate 24.5.10 Frozen Semen Transport results. Here the straws are fi rst placed in a refrigerator freezer (−20°C) for 30 min, then on dry ice (−79°C) for Once frozen, spermatozoa can be transported in com- 30 min before placing in liquid nitrogen (−196°C). mercially available dry shipper tanks which are cooled with liquid nitrogen; during its evaporation suitably low temperatures are maintained for several days to several weeks, depending on the size of the tank. 24.5.8 Storing the Samples Compliance with local, national or international regu- lations on shipping liquid nitrogen should be observed. Long-term storage of semen samples may be under- Shipping samples on dry ice requires the notifi cation taken in the institution performing cryopreservation. code UN-1845 and shipment of liquid nitrogen requires Constant storage temperatures must be guaranteed and UN-1977. should not be endangered by repeated opening of the liquid nitrogen containers. Long-term storage may also be performed in a commercial cryobank. Patients who decide on long-term storage sign a contract with the 24.6 Use and Quality of Stored institution performing long-term storage that may be continued or cancelled on a yearly basis. The costs are Cryopreserved Semen Samples usually paid by the patient, but in very exceptional cases costs may be borne by the health insurance. If the 24.6.1 Use of Cryopreserved Samples semen sample is needed for assisted fertilization, it can be sent to the doctor on the patient’s authorization. Up to now, existing cryo-depots have only rarely been used. Altogether 69% of the patients of the Department of Clinical Andrology of the Center of Reproductive Medicine and Andrology (former Institute of Repro- 24.5.9 Thawing the Samples ductive Medicine) initially store their semen samples on a long-term basis. In a retrospective analysis, 455 Inadequate freezing and thawing conditions may lead patients who opted initially for long-term storage of to cell shrinkage, osmotic cell lesions and ice crystal their semen samples were asked about their cryo- formation. Therefore the freezing and thawing times depots by a questionnaire. Two hundred and one 516 S. Kliesch et al.

Fig. 24.3 Fate of the Terminated unused Existing unused Used cryo-depots with respect to the initial oncological Total n=201 49.6% 8% diagnoses of 201 patients 42.3% who were referred for cryopreservation between 1984 until July 1999 and who opted initially for long-term cryopreservation of their semen and responded to a questionnaire Other cancers n=24 33.3% 66.7%

Leukemia n=12 8.3% 83.4% 8.3%

Lymphoma n=52 40.4% 48.1% 11.6%

Testicular cancer n=113 48.7% 49.6% 7.9%

questionnaires were completed and during a mean of modern cryo-techniques leads to a decrease of sperm 4.1 years (range 0–12 years) 8% of patients used their quality. Smith and Steinberger (1973) were able to show cryopreserved samples for artifi cial reproduction tech- that storage for longer than 36 months resulted in a niques (Fig. 24.3). Twenty-nine of these patients decrease of sperm motility. However, no systematic or achieved a spontaneous pregnancy after cessation of prospective studies exist that investigate the infl uence of the oncological therapy without further medical help. modern standardized cryopreservation techniques on Cryopreserved spermatozoa were used in 39 treatment the maintenance of sperm quality during long-term stor- cycles. A total of 14 pregnancies resulted, of which age. So far, results and experience with cryopreserved fi ve failed to carry to term. A triplet pregnancy was semen are based on investigations with sperm of normal achieved, resulting in a live birth of twins. One third of healthy donors. However, these results may not be treatment cycles was performed after ICSI was offered applicable to oncological patients because these patients at the end of 1994. Twenty-seven cycles with ICSI already show limitations of sperm concentration, motil- resulted in fertilization and 12 pregnancies, of which ity and morphology prior to anti-tumor therapies. four were aborted. Reports concerning the use of cryo- On the assumption that most oncological patients preserved semen from oncological patients for ICSI will undergo aggressive chemo- and/or radiotherapy therapy are still rare, possibly due to the short period of after cryopreservation of their ejaculates, there will be time since introduction of the technique (Lass et al. a certain period of time following treatment before 1998; Naysmith et al. 1998). The introduction of samples are used for family planning. Our youngest microinjection therapy will defi nitely contribute to the patient to use cryopreservation was 13 years old (Kliesch more successful use of cryopreserved semen samples et al. 1996) and it is probable that at least a 5-year of oncological patients. period may pass before these patients use their cryopre- served semen for assisted fertilization. Adequate coun- selling in respect to the chances of inducing a pregnancy 24.6.2 Quality of Stored Cryopreserved by means of assisted reproduction using cryopreserved semen samples remains diffi cult. Semen stored under Semen Samples appropriate conditions shows no obvious deterioration of sperm quality with time, and children have been Only little information is available about whether long- born from semen stored for over 28 years (Clarke et al. term storage of cryopreserved semen samples using 2006; Feldschuh et al. 2005). 24 Cryopreservation of Human Spermatozoa 517

The best pregnancy rates by artifi cial insemination The documented data of IVF centres and the data with cryopreserved donor semen are not different from obtained from offspring of oncological patients indi- those achieved with fresh semen and range from 15% cate that no increased genetic risk and no increased to 25% per month or cycle of treatment. However, risk for malformation exists that could result from pregnancy rates of 7–12% per month are more usual, the underlying oncological disease or the applied often related to post-thaw sperm quality, timing of assisted fertilization technique with cryopreserved insemination and particularly, recipient factors such as spermatozoa (Sanger et al. 1992; Dodds et al. 1993; older age, previous pregnancy with donor insemination Rufat et al. 1994; Schenker and Ezra 1994). and ovulatory and uterine tubal disorders (Le Lannou and Lansac 1993). The evidence suggests that there is no increase in abnormal pregnancy outcomes after the use of frozen spermatozoa by artifi cial insemination: 24.7.2 Psychological Aspects the rates of spontaneous abortion (13%), major birth defects (about 1%) and sex ratio (51:49, male:female) Counselling of patients in respect to cryopreservation are similar to those of natural pregnancies (Sherman takes place when the physical and psychological integ- 1986). rity of the patient is disturbed. In view of the acute and stressful situation (confrontation with diagnosis and treatment), it seems diffi cult for both patient and doc- 24.7 Problems and Limitations tor to consider the relative importance of cryopreserva- tion to preserve potential parenthood with respect to of Cryopreservation the long-term quality of life. Semen storage before a potentially sterilizing procedure often has signifi cant 24.7.1 Genetic Risks psychological value because of the hope of future paternity. However, for juvenile patients this counsel- ling requires a high degree of involvement and willing- The question whether an increased genetic risk exists ness to break taboos and to discuss problems of for the offspring of patients suffering from malignancies sexuality and fertility. Notwithstanding, cryopreserva- or treated by oncological chemo- and/or radiotherapy tion may contribute to the patient’s personal stability remains diffi cult to answer. In principle, two different in an acute and oppressive situation. In adolescents aspects are to be considered. One refers to the risk aris- (aged 12–21 years at diagnosis) it was shown that suc- ing from the malignant disease itself and possibly muta- cessful cryopreservation in 67% of males leads to sig- genic effects of chemo- and/or radiotherapy. The other nifi cant release in terms of anxiety concerning fertility involves the possible risk of a genetically determined aspects. Moreover, discussion of fertility aspects is disease in the offspring when using assisted fertilization much easier after successful cryopreservation (Edge techniques with cryopreserved spermatozoa. et al. 2006). Saito et al. (2005) could show that cryo- The available cytogenetic investigations in sperma- preservation also leads to some relief in dealing with tozoa from patients after chemo- and/or radiotherapy the life-threatening illness. However, up to date only a show a signifi cantly increased proportion of structural maximum of 67% of adult patients at risk for gonado- chromosomal anomalies in comparison with controls toxic treatment are informed about and only 51% are (Genescà et al. 1990; Rousseaux et al. 1993). However, offered the possibility of cryopreservation of semen these in vitro results are not supported by clinical data (Saito et al. 2005). that suggest increased rates of anomalies in children born. With respect to the clinical aspect of a poten- tially increased genetic risk, no case-control studies exist that provide reliable answers to these questions. In addition, the problem of familial cancer risk exists 24.7.3 Methodological Considerations and should lead to the recommendation to offer any cancer patient genetic counselling prior to fertilizing One methodological problem of cryopreservation is therapies. insuffi cient preparation of the ejaculate with reduced 518 S. Kliesch et al. quality, contributing to further decrease of sperm qual- http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic- ity and function by the process of freezing. These meth- demande/guides/semen-sperme-acces/semen-sperme_ directive_e.html odological shortcomings render the later use of Chan SYW, Pearlstone A, Uhler M, et al (1993) Human sperma- cryopreserved spermatozoa for assisted fertilization tozoal tail hypo-osmotic swelling test, motility characteris- diffi cult. 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Schenker JG, Ezra Y (1994) Complications of assisted reproduc- Tomlinson M. (2005) Managing risk associated with cryopreser- tive techniques. Fertil Steril 61:411–422 vation. Hum Reprod 20:1751–1756 Schlatt S, Rosiepen G, Weinbauer GF, et al (1999) Germ cell Trottmann M, Becker AJ, Stadler T, et al (2007) Semen quality transfer into rat, bovine, monkey and human testes. Hum in men with malignant diseases before and after therapy and Reprod 14:144–150 the role of cryopreservation. Eur Urol 52:355–367 Schmidt KL, Larsen E, Bangsboll S, et al (2004) Assisted repro- Verheyen G, Pletincx I, Van Steirteghem A (1993) Effect of freez- duction in male cancer survivors: fertility treatment and out- ing method, thawing temperature and post-thaw dilution/ come in 67 couples. Hum Reprod 19:2806–2810 washing on motility (CASA) and morphology characteristics Schrader M, Müller M, Sofi kitis N, Straub B, Miller K (2003) of high-quality human sperm. Hum Reprod 8:1678–1684 “Onco-tese”: Testicular sperm extraction in azoospermic can- Viviani S, Ragni G, Santoro A, et al (1991) Testicular dysfunc- cer patients before chemotherapy – new guidelines? Urology tion in Hodgkin’s disease before and after treatment. Eur 61: 421–425 J Cancer 27:1389–1392 Sherman JK (1986) Current status of clinical cryobanking of Wang R, Sikka SC, Veeraragavan K, et al (1993) Platelet activat- human semen. In: Paulson JD et^Sal (eds) Andrology. ing factor and pentoxifylline as human sperm cryopro- Academic, Orlando, pp 517–547 tectants. Fertil Steril 60:711–715 Sherman, JK (1990) Cryopreservation of human semen. In: Keel Watson PF (1995) Recent developments and concepts in the BA, Webster BW (eds) CRC handbook of the laboratory cryopreservation of spermatozoa and the assessment of their diagnosis and treatment of infertility. CRC Press, Boca post-thawing function. Reprod Fertil Develop 7:871–91 Raton, FL, pp 229–259 Watson PF, Critser JK, Mazur P (1992) Sperm preservation: fun- Shufaro Y, Prus D, Laufer N, Simon A (2002) Impact of repeated damental cryobiology and practical implications. In: testicular fi ne needles aspirations (TEFNA) and testicular Templeton AA, Drife JO (eds) Infertility. Springer Verlag, sperm extraction (TESE) on the microscopic morphology of New York/London/Heidelberg, pp 101–114 the testis: An animal model. Hum Reprod 17:1795–1799 WHO (2009) Laboratory manual for the examination and pro- Silber SJ, Van Steirteghem AC, Liu J, et al (1995) High fertiliza- cessing of human semen. WHO, Geneva, (in press) tion and pregnancy rate after intracytoplasmic sperm injec- Wolf DP (1995) Semen cryopreservation. In: Keye WR, Chang tion with spermatozoa obtained from biopsy. Hum RJ, Rebar RW et al (eds) Infertility evaluation and treatment. Reprod 10:148–152 W.B. Saunders, Philadelphia, PA, pp 686–695 Smith KD, Steinberger E (1973) Survival of spermatozoa in a Woods EJ, Benson JD, Agca Y, et al (2004) Fundamental cryobi- human sperm bank. J Am Med Ass 223:774 ology of reproductive cells and tissues. Cryobiology 48: Tedder RS, Zuckerman MA, Goldstone AH, et al (1995) 146–156 Hepatitis B transmission from contaminated cryopreserva- tion tank. Lancet 346:137–140 Psychology of Fertility Disorders 25 R. Oberpenning, F. A. Muthny, and F. Oberpenning

Contents 25.1 Introduction and Overview

25.1 Introduction and Overview ...... 521 The World Health Organisation (WHO), which, as 25.2 Psychological Conditions of Unwanted early as 1967, recognized unwanted childlessness as a Childlessness ...... 522 disease, anticipates an approximate increase of two 25.3 Psychological Effects of Unwanted million new infertile couples. Many couples try to Childlessness ...... 523 overcome this diffi cult crisis with the help of reproduc- 25.4 The Psychology of Male Fertility tive medicine. The medical and psychological oppor- Disorders ...... 524 tunities regarding treatment, consultation and therapy 25.5 Psychological Aspects of the Desire available to the couple to overcome this crisis are for Children ...... 525 extremely important. 25.5.1 Acceptance of Multiple The present-day techniques of assisted reproduc- Pregnancies ...... 526 tion (ART) belong to the areas of modern high-tech 25.6 The Role of Clinical and Psychosocial medicine. In addition to traditional methods such as Factors in the Indication and Contraindication surgery, hormone treatment and insemination, these of Therapeutic Procedures ...... 526 include in-vitro fertilization (IVF), intracytoplasmic 25.6.1 Psychosocial Consultation Within sperm injection (ICSI), including cryotransfer, testicu- an ART Team for Persons Seeking lar sperm extraction (TESE), microsurgical sperm Parenthood ...... 527 aspiration from the epidydimis (MESA), as well as the 25.6.2 Aims of Psychotherapeutic Intervention ...... 528 donation of gametes (Chap. 23). 25.6.3 Effects of Psychotherapeutic In 2006 almost 60,000 IVF, respectively ICSI treat- Intervention ...... 529 ments were carried out. The success rate of IVF and 25.6.4 Further Psychosocial Developments the ICSI treatments measured by the baby-take-home Following Infertility Treatment with Special Reference to Family rate was between 16.9 and 22.3% in 2005 (Deutsches Constellations ...... 529 IVF-Register 2006). 25.6.5 Outlook and Future Psychological The decision for invasive infertility therapy can be Research ...... 533 seen as the expression of a conscious decision to References ...... 534 become parents. On the other hand, developments in reproductive medicine could also give the couples desiring a child the impression that they can put off realizing this wish until they are older, thus causing a postponed wish to have a child to become an unful- fi lled wish for a child (Wischmann 2006b).  R. Oberpenning ( ) At the beginning of infertility treatment, the major- Clinic for Urology and Paedriatic Urology, St.-Agnes Hospital Bocholt, Germany ity of unintentionally childless couples have unrealisti- e-mail: [email protected] cally high expectations regarding its success. Thus the

E. Nieschlag et al. (eds.), Andrology, 521 DOI: 10.1007/978-3-540-78355-8_25, © Springer-Verlag Berlin Heidelberg 2010 522 R. Oberpenning et al. general public assess the birth rate as 40% of each More recent results of a prospective study on 1,088 embryo transfer (Stöbel-Richter et al. 2006). A rela- women before and during their fi rst IVF or ICSI tively large number of couples discontinue therapy treatment support the above-mentioned reservations because of psychological stress, others fi nd it very hard since there is no connection between the variables of to cope with their unfulfi lled wish for parenthood and “fearfulness” or “depression”, on the one hand, and the are hard put to fi nd any alternative life prospects. fertilization or pregnancy rates, on the other hand In the course of this chapter, the following psycho- (Lintsen et al. 2006). logical themes will be treated: In a study on the psychosocial aspects of unwanted childlessness Wischmann and Stammer (2001) plead for ¥ Former and current psychological research on the depathol ogizing childless couples because no psycho- unfulfi lled desire for a child with particular consid- social predictors for the start of a pregnancy could be eration of the psychological conditions and effects determined. There were merely some indications that of infertility men’s being unburdened was a predictor for pregnancy ¥ Psychological aspects of the desire for a child initiation. Thus psychological traits as a predictor for ¥ The role of psychosocial factors in the indication/ infertility proved to be of no use. contraindication for therapeutic procedures Further investigations on the psychological charac- ¥ Effects of psychosocial/psychotherapeutic inter- teristics of couples’ involuntary childlessness should ventions rather pursue prevention of infertility since knowledge ¥ Further psychosocial developments following infer- about the complexities of conception is often insuffi - tility treatment with particular consideration of cient among the general public. Forty percent of the selected family constellations (e.g., families with persons questioned in a representative study in 2007 twins or other multiple births, starting a family by (Institute for Demoscopy Allensbach 2007) presumed, donor insemination, donor eggs, donor embryos or for example, that it only becomes more diffi cult for a adoption) woman to conceive from the age of 40 onwards. ¥ Prospects and future psychological research Approximately 20% of couples report to their physi- cian that they do not have sexual intercourse during the time which is optimal for conception. Moreover, many 25.2 Psychological Conditions unintentionally childless couples are not aware that the consumption of nicotine can limit the man’s ejacula- of Unwanted Childlessness tion parameters. For example, the success rates of ICSI treatment are signifi cantly lower if the male partner When categorizing the psychological studies on the smokes (Zitzmann et al. 2003). Smokers who are igno- conditions of unwanted childlessness, personality- rant of this could be offered a withdrawal-from-nicotine psychological, psycho-dynamic, stress-theoretical and program aimed at conveying appropriate coping strate- psychobiological approaches can be distinguished. gies in order to improve chances of successful treat- At the end of the fi fties and the middle of the sixties, ment in the future. personality-psychological approaches, which saw infer- The stress theory of infertility formerly assumed that tility in relation to certain personality traits of those persisting stress caused various reduced organic func- concerned, were dominant among psychological inves- tions and that a subjectively experienced stress situation tigations on unwanted childlessness (Sturgis et al. can lead to infertility resulting from disturbed endocrine 1957). Thus, a great number of psycho-vegetative com- functions. Schuermann in 1948 and Stieve in 1952 sus- plaints were attributed to infertile couples, and childless pected that extreme stress impulses such as, for exam- couples were seen as mainly depressive, fearful and ple, death sentences, wartime events, imprisonment inhibited personalities. Comparative psychological and internment in a concentration camp are accompa- investigations on fertile and infertile couples in the sev- nied by anatomically recognizable alterations in enties and eighties expressed reservations towards the gonads and can reduce sperm production. This theory concept of “psychogenic infertility” or refused to attri- stimulated research into male infertility based on stress bute male/female infertility to certain personality traits theory. The following studies further differentiated or emotional disorders (Seibel and Taymor 1982). connections between stress and infertility according to 25 Psychology of Fertility Disorders 523 the kind of stress (e.g., stress burdens in the private/ Psychodynamic investigations in the 1950s were based professional area) and ejaculation parameters (Stauber on psychoanalytic theory and regarded the repression 1979; Poland et al. 1986). of psychological confl icts as the central factor in the Psychobiological investigations pursued stress the- conditional connection with infertility (Jacobsen 1946; ory and attempted to determine those psychological Langer 1953). With particular consideration of the factors which are a part of the organism’s stress reac- couple’s relationship, which was described as clinging tion. In the mid 1980s Hellhammer et al. 1985 investi- and symbiotic (Stauber 1979, 1989), involuntary child- gated the possible connection between personality and lessness appeared as a common symptom of a couple infertility. The surprising result of these investigations to fend off other psychic problems (Goldschmidt and was that infertile men displayed personality character- De Boor 1976). Even if these and similar investigations istics such as self-confi dence, extroversion and social contained stimulating ideas on psychological confl icts competence, whereas persons with a tendency to as possible conditions for infertility, they could not depression, introversion and social fear showed higher adequately and, in fact, rather only speculatively fertility parameters (Hubert et al. 1985). explain the reciprocal relationship between psyche and Stress-induced infertility is seen in connection with soma (Bents 1985; Ulrich 1988). More recent studies specifi c forms of coping and specifi c personality traits. conclude that it is now time to put the concept of “psy- Men with idiopathic infertility compared to a fertile chogenic sterility, as psychoanalysis sees it” to rest male control group showed no signifi cantly greater since, when all is said and done, women with serious tendency to active coping (Deipenwisch et al. 1994). psychological problems can also become pregnant In active coping, individuals do not avoid stress situa- without any diffi culties (Apfel and Keylor 2002). tions and rather tackle them actively, thus possibly According to the current guidelines for psychoso- changing them in such a way that the burden may be matically oriented diagnosis and therapy of fertility dis- reduced. It appears worth noting that men with idio- turbances, a fertility disturbance of psychological origin pathic infertility, compared to the control group were (Strau§ et al. 2004) can be said to exist if a couple characterized by a greater regularity in the rhythm of ¥ In spite of medical counselling, behaves in a manner daily activities as well as in the pattern of sleep quality detrimental to achieving fertility (e.g., substance (Matzen et al. 1999). abuse, high-performance sports, extreme professional In a current study with 157 test persons, a general stress, eating disorders, etc.) connection between psychological stress factors (job ¥ Do not have sexual intercourse on fertile days, or if stress/life-event stress) and semen parameters could there are no organically caused disturbances of sexual not be proven. However, in one case, the death of a function close relative correlated signifi cantly with a temporary ¥ Agree to medically indicated fertility treatment, but reduction of sperm motility (Fenster et al. 1997). fail to initiate it after a long period of consideration Although lower stress levels promote natural fertil- (e.g., checking tubal patency or recording semen ity, stress reduction in infertile couples has not been parameters, etc.) proven to lead to successful fertility treatment (Campagne 2006). Nevertheless it is conceivable that At present the prevalence of infertility of psychological an initial therapy for stress reduction can reduce the origin may be assessed at 5% (Wischmann 2006a). In number of treatment cycles required, prepare the cou- contrast, idiopathic sterility, a medically unexplained fer- ple for possible unsuccessful treatment, or can make tility disturbance, has a frequency of approximately 10%. further invasive measures unnecessary.

25.3 Psychological Effects Even after 40 years of research, the connections of Unwanted Childlessness between psychological stress (as cause or reaction) and infertility have still not been fully explained Investigators’ statements vary considerably according and doubts about the concept remain (Sanders and to their psychological orientation (e.g., psychoanaly- Bruce 1997; Wischmann 2006a). sis, behavioral or cognitive psychology), according to 524 R. Oberpenning et al. the cause of infertility (on the part of the woman, the (Beutel et al. 1999) showed that women, regardless of man or both partners) or according to the strength of the kind of treatment, had signifi cantly more depres- their desire to have a child. The fact that infertility rep- sions than the reference population and their male resents a very stressful life happening is, however, partners. The men of the ICSI/MESA/TESE group mainly confi rmed. In most of the studies, women were felt considerably more responsible for the infertility, more fearful, depressive and had less self-confi dence and less content with their daily life, as a result of the than those in the control groups throughout infertility partly stressful kind of treatment. All in all, the inves- treatment. Moreover, the longer the treatment period, tigation considered the following groups at risk for the lower the level of contentment regarding partner- depression: ship and sexuality, the latter of which was caused by ¥ Unsuccessfully, or repeatedly treated couples the necessity to have sexual intercourse at the time pre- ¥ Couples with lower social status scribed (Eckert et al. 1998; Strau§ et al. 2004). ¥ Couples of foreign nationality and In the study by Hölzle et al. (2000), the connection ¥ Couples in which the male partner does not provide was clearly evident between women’s sense of how adequate support to his partner in a properly sympa- impossible it would be for them to conceive of a life thetic manner without a child and the low rate of pregnancies. Strau§, on the other hand, found a higher rate of pregnancies An important and psychologically infl uential compo- among women who idealized pregnancy. nent of IVF/ICSI treatment is the uncertainty during A model for the process of coping with a diagnosis ovarian stimulation, fertilization, embryo transfer and of infertility suggests eight phases, comprising: shock, while waiting for the result of the pregnancy test. This denial, annoyance-anger related to not becoming preg- uncertainty is accompanied by ambivalent feelings, nant, a sense of guilt and shame, isolation, depression, emotional stress and positive feelings such as hope and grief and, in the end, acceptance of the diagnosis confi dence. Accordingly, conveying the results of the (Guttormsen 1992). Skipping over the acceptance examination to the couple as quickly and realistically phase of the diagnosis of infertility can result in a con- as possible can greatly reduce their sense of stress siderably higher level of stress during medical treat- (Boivin et al. 1998). ment of these couples (Onnen-Isemann 2000). Nowadays there is agreement that unwanted child- Studies concerned with the emotional preconditions lessness or limited fertility of couples can be under- and long-term results of childlessness indicate that, in stood as a bio-psycho-social occurrence. The results of the case of some couples, their regrets about childless- psychological examinations which were reached with ness increase with age and that these negative thoughts standard measuring instruments and control groups affect their subjective well-being (Wirtberg et al. 2007). mostly reveal no or unessential differences between Women generally feel more burdened by not having fertile couples and those with disturbed fertility. children than men, both in the short and the long-term (Hjelmstedt et al. 1999). Partners who were both respon- Couples desiring children do not show any psycho- sible for not having children generally remain together pathological peculiarities. There are only higher more often than couples in whom only one of the part- levels of depression, fear and psychosomatic com- ners was the cause of childlessness (Snarey et al. 1987). plaints among the women, which can, however, be In a followup-examination of couples with heterolo- regarded as the result of infertility treatment/therapy gous treatment by insemination, the highest rate of (Strau§ et al. 2004). separation occurred among those who had not managed to have children either by means of the treatment or by adoption or by spontaneous pregnancy (Goebel and Lübke 1987): on the other hand, an investigation of IVF 25.4 The Psychology of Male Fertility couples ascertained that the couples on average assessed their marital contentment as greater after conclusion of Disorders treatment than beforehand, regardless of whether the treatment was successful or not (Leiblum et al. 1987). There are also disorders among the males in almost The fi rst retrospective study which dealt with the half of the couples with an unfulfi lled desire for off- different coping styles of 281 IVF or ICSI couples spring. Only after methods such as MESA/TESE/ICSI/ 25 Psychology of Fertility Disorders 525 became available, was treatment of serious fertility Table 25.1 Reasons for desire for a child according to (Lalos disturbances in males possible. et al. 1985) When an andrological factor is involved, there are Philosophical motives indications of mildly raised levels of fearfulness and Hopes for immortality through one’s own children increased psychosomatic complaints among the men Ensuring human survival Meaning of life affl icted (Kedem et al. 1990; Glover et al. 1996). God’s will Research into the treatment of serious male fertility Socio-cultural motives disorders indicate that during this treatment the man Satisfying social needs feels more seriously responsible for childlessness than Improving the woman’s or the man’s status before, and perceives the therapy, especially MESA/ Interpersonal motives TESE, as a stressful experience (Beutel et al. 1999). Confi rmation of relationship by pregnancy During the counselling sessions infertile men often A child as the expression of a couple’s love Intrapsychological motives report a sense of guilt towards their partner, who nor- Confi rmation of one’s own sexual identity mally bears the main burden of the treatment. Studies Replacement for another lost person in which the cause of infertility lies with the man indi- Understanding and identifi cation with one’s own parents cate greater emotional stress on the man (Nachtigall Revival of one’s own childhood 1992; Beutel et al. 1999), especially among those who Sign of independence are vulnerable for stress situations in general and rather deal with them in a passive manner or avoid coping (e.g., resignation). Thus, a longitudinal section study own desire for children. At the same time, there was a on 120 men who were involuntarily without offspring stronger wish for a child among persons with negative found that raised stress levels correlated with reduced recollections of their parents’ manner of upbringing in semen parameters (Pook et al. 2004). Moreover, men expectation of satisfying desire for social recognition. less often seek social support to help them cope better There were, however, no relevant connections found with their unfulfi lled desire to have a child (Band et al. between the recollection of their parents’ manner of 1998). Besides, men who are solely responsible for the rearing them and the intensity of their desire for a child infertility show a more negative attitude to sexuality (Schumacher et al. 2002). (Fischer et al. 1996) as they often equate sexual In the event of childlessness social pressure on the with fertility. Often disappointment about infertility couple can reduce their self-esteem considerably. turns into loss of interest in sex (Chap. 26). When infertile couples are asked about their wish to have a child, they normally mention the motives listed in Table 25.1. 25.5 Psychosocial Aspects of the Desire These motives clearly show the wish not only to be there for oneself and one’s partner. Frequently the for Children motives for a pregnancy are ambivalent, i.e., together with the wish for a child, there is also the fear of the The motivation for offspring is essentially formed by pressures and limitations related to it. Together with parental upbringing and society. the “fi rst” decision to want to have a child, the decision It is well known from research on bonding that becomes of importance for unwillingly childless cou- individual experiences with most important role mod- ples whether, and to what extent, medical help is taken els can decisively infl uence later expectations, behav- to fulfi l their desire for children. ior and experience in relationships (Gloger-Tippelt For a long time, the investigation into the male 2001). A study carried out on 331 persons aged from desire to have children was neglected. The representa- 18 to 50, on recollections of parental upbringing and tive study “Männer leben” (men’s lives) (Federal their own wishes for parenthood indicated that the Centre for Health Education (BZgA) 2004), found a behavior of parents which was recalled as “negative/ time window for becoming a father ranking from “too disapproving, overprotective and not emotionally young” to “too old”. Thus 60% of 25Ð34-year-old men warm enough” was connected with such motives (e.g., do not have children as opposed to only 25% among fears regarding personal limitations and a lack of sup- the 35Ð44-year-old men. Compared to the study port) which tend to be opposed to fulfi llment of one’s “Frauen leben” (women’s lives) (BzgA 2001), it is 526 R. Oberpenning et al.

Fig. 25.1 The infl uence of net income on the number of 2 1.9 children of 40-54 year old 1.7 1.7 men (n=660) (“Men’s lives”, BZgA 2004) 1.5

1.2

1 Number of Children

0 <1500 € -2000 € -2500 € -3000 € >3000 € Net Income clear that men only manage to complete the transition emotional and cognitive level of decision, women who into parenthood later than the women. Furthermore, cannot have children become less accepting of multiple highly qualifi ed men rather tend to have children than pregnancies (Grobman et al. 2001; Kowalcek 2008). poorly qualifi ed ones (Fig. 25.1), whereas in the case Couples are frequently unrealistic in their assess- of women, it is the other way around. Poorly qualifi ed ment of the burden of stress brought about by multiple women more frequently have children than those births, especially since there is a great lack of informa- highly qualifi ed. The higher their income, the earlier tion on this aspect of the question. For example, when men marry and have children. Forty percent of men the amount of work related to families with triplets in with a net income below €1,000 live without children the fi rst postnatal year was investigated, a theoretical and without a permanent partner. On the other hand, level of 190 h per week was achieved (Mariano and the highest income group (>€2,500 and more) com- Hickey 1998). Behind the wish of many couples for a prises only a small number of men without children. multiple birth at the beginning of reproductive medical treatment there might well be, apart from the motives of rational family planning, unconscious concepts of 25.5.1 Acceptance of Multiple repairing the “hurt through infertility” (Bindt 2001). Pregnancies 25.6 The Role of Clinical Before they started their fi rst IVF cycle, 95% of and Psychosocial Factors in the American couples stated that they would prefer a preg- Indication and Contraindication nancy with triplets, and, in 70% of the cases, even a pregnancy with quadruplets rather than not become of Therapeutic Procedures pregnant (Goldfarb et al. 1996; Bindt 2001). In addi- tion, an analysis of new studies relating to the desire to When considering psychological developmental have children between 1990 and 2004 indicated that research on life-span, parenthood is given as a struc- couples wishing to have children have a great prefer- tural point of the normative transition in the course of ence for a pregnancy with twins and a medium-to-great life (Gloger-Tippelt 1988). Coping or not coping with preference for a pregnancy with triplets, and, it must be a psychosocial task is decisive for favorable or unfa- said, that the older the woman, the stronger her prefer- vorable development of the individual. A mature adult ence for multiple pregnancy (Borkenhagen et al. 2004). must feel that he is needed (Erikson 1976). Accordingly, If, however, the problem of multiple births is discussed if a pregnancy does not occur, the individual or the between the physician and the patient regarding the couple may experience a development crisis. 25 Psychology of Fertility Disorders 527

Under certain circumstances, infertility may be seen Deutschland (BkiD), the British Infertility Counselling as the worst critical life event, followed by divorce and Association (BICA), the Mental Health Professional the death of a loved one. Group (MHPG), the American Society for Reproductive Apart from somatic criteria, psychosocial criteria play Medicine (ASRM) among others. a comparatively marginal role in the indication for If persons concerned contact an independent outside assisted fertilization. organization, the latter should refer them to a medical reproductive center regarding medical care. Although all professional groups of an ART team, such as physi- Psychosocial counselling and possibly therapy in cians, psychologists, social workers etc. basically agree the context of infertility therapy should be offered about the need for psychosocial support for a couple to everyone affl icted by unwanted childlessness who remain unwillingly childless, there are consider- before, during and after treatment. This seems able differences in the basic psychosocial qualifi cations imperative, particularly in the cases of psychogenic required (Kentenich and Tandler-Schneider 2008; sterility as well as gamete donation. Thorn and Wischmann 2008). The basic precondition for psychosocial consulta- tion for couples seeking parenthood should always be Contraindications for medical therapy in the case of the couple’s own motivation, which can be stimulated fertility disturbances, from a psychosomatic point of and supported by information from written brochures, view are (Bundesärztekammer 2006): general literature concerning “unwanted childless- Absolute Contraindications ness” from videos, internet pages and self-help groups. ¥ All contraindications for pregnancy The treating physician should provide an opportunity to ask questions about the treatment. He should explain Limited Contraindications for Pregnancy: its effects and side-effects and its risks (e.g., emotional ¥ In individual cases a pregnancy-related high medi- crises, such as depression, fears, disturbances of sexual cal risk for the health of the woman or the develop- function (Chap. 26), multiple pregnancies, malforma- ment of the child tions). Detailed and honest explanation about the real- ¥ Psychogenic fertility disturbance: This may develop istic chances of success may prevent premature especially when sexual disturbances may be an discontinuation. Three factors characterize the expec- essential factor in infertility (infrequent sexual inter- tations of infertile couples regarding optimal medical course, avoiding intercourse at the optimal time for treatment (Schuth and Keck 2001): conception, non-organically caused disturbance of 1. Correct procedural information and explanation sexual function). In this case, sexual consultation 2. Stressfree diagnosis and therapy according to cur- for the couple should fi rst be carried out rently valid standards 3. Offers of psychosocial help for any crisis Infertile couples have to make many decisions, e.g., 25.6.1 Psychosocial Consultation regarding Within an ART Team for Persons ¥ Whom they consult for treatment Seeking Parenthood ¥ When they undertake treatment for infertility ¥ Form and consequences of treatment (e.g., the genetic father in the case of donor insemination, the The current guidelines of the Federal Medical Board biological mother, in the case of ovum donation, (Hoppe 2006) urgently recommend psychosocial coun- possible step Ð siblings etc.) selling by ART teams of couples seeking help. In ¥ When they want to end treatment Germany at least one member of an ART team should ¥ Alternatives if their desire to have a child is not be qualifi ed in basic psychosomatic care. Doctors work- fulfi lled ing in reproductive medicine should cooperate with the independent counselling networks in their country, such Needless to say, ensuing confl icts and tensions are under- as, for example, the advisory network Kinderwunsch in standable. As well as coping with such typical confl icts, 528 R. Oberpenning et al. psychotherapeutic procedures should be offered to the Table 25.2 Guidelines for recording the psychosocial situation couples to help deal with the experiences of loss. of patients during offi ce hour/consultation on fertility (Lalos Within the framework of initial psychosocial con- et al. 1985) sultation couples who have developed an alternative Anamnesis/ anamnesis of couple/ history of couple life plan (e.g., life without children, further profes- Getting to know one another, development of the couple’s relationship sional qualifi cation, adoption and fostering a child), Couple’s motivation for wanting to have a child can, as a rule, better deal with unsuccessful treatment. Assigning special roles within the couple’s relationship Table 25.2 presents the areas which can be dis- Changes in the couple’s relationship as a result of the cussed with an infertile couple together with clinical diagnosis of infertility data to help medical professionals survey the couple’s Subjective theories psychological as well as social situation. Subjective assessment of the cause of childlessness Possible accusations (e.g., earlier abortions, infections etc.) Fantasies regarding the as-yet unborn child Sexuality (cf. also Chap. 26) 25.6.2 Aims of Psychotherapeutic Contentment with one’s current sex life Intervention Frequency and quality of sexual intercourse Sexual role identity as male/female, or as the case may be Importance of sex for the relationship The aim of psychotherapeutic intervention is, fi rst Possible changes in one’s sexuality as a consequence of and foremost, to support the couple, rather than to one’s unfulfi lled desire for a child discover confl icts or initiate a pregnancy. Couples Psychosomatic aspects and coping processes for involun- who are clearly psychogenetically sterile (cf. criteria tary childlessness (how does the couple deal with it for contraindication Ð Sect. 25.2), should be referred emotionally, intellectually, in concrete actions and in the to sexual therapy, or individual and group therapy couple’s relationship?) before beginning invasive infertility treatment. This is Typical psychological complaints, such as depression, fear, etc. Psychosomatic complaints, such as tension headaches required before the ART team can decide whether Sleep disturbances, stomach complaints etc. medical treatment is promising. In general, however, offering the couples psychosocial advice regarding Body image and health behavior the physically and emotionally burdensome treatment Dealing with, and attitude to one’s own body (e.g. health) Behavior in general and in stress situations, subjective suffi ces. Assessment of physical defi cits, such as a small breast or Couples from other cultures or with a strong reli- penis etc. gious orientation may have reservations about certain Social situation methods of treatment; these have to be resolved prior to Economic conditions the beginning of therapy (Gacinski et al. 2000). Professional position/contentment Moreover, possibilities for dealing with the fertility Social/emotional support by friends, acquaintances, close disorder should be discussed. A conscious period of family members mourning for the loss of a prospect of “life with a child” Leisure-time behavior is important to be able to cope with long-term child- Alternatives to the desire for children lessness. Coping strategies, such as “brooding” or Attitude to adoption/fostering “remaining stuck in a feeling of powerlessness,” as well Considering possible professional/social compensations as “focusing on children as an essential aim in life” Further goals in life, with or without a child have proven disadvantageous (Strau§ 2000). At present, short-term psychotherapeutic proce- a psychotherapeutic procedure for the involuntarily dures for supporting infertile couples are increasingly childless (Atwood and Dobkin 1992; BkiD 2007): being implemented. In this context, from the begin- ning of the fi rst session, the therapist focuses on areas 1. Acceptance of the infertility crisis in which the client has already been successful, thus 2. Acquisition of appropriate styles of communica- enhancing potential for self-reinforcement. No attempt tion, and learning how to deal creatively and con- is made to solve the problem comprehensively because, structively with the unfulfi lled wish for a child, as in the theory of short-term therapy, it is assumed that well as recognizing and changing obstructive the solution itself is its own best explanation. The fol- behavior (e.g., professional stress, poor eating lowing consultation and therapeutic aims demonstrate habits, alcohol and nicotine abuse) 25 Psychology of Fertility Disorders 529

3. Provision of information (e.g., surgery, prospects eral was achieved following an 8-week group psycho- of success, limitations of psychology, academic therapy once weekly for 2 h (Stewart et al. 1992). medicine, alternative medicine and other thera- Similarly, 17 couples with male factor infertility peutic procedures (e.g., relaxation exercises) underwent intervention based on behavior therapy 4. In the case of gamete /embryo donation, the ques- (repeated sexual contacts during the fertile period, emo- tion of long-term consequences of this way of tional stress reduction by exercises based on behavioral founding a family therapy, cognitive restructuring of those couples who at 5. Redefi nition of the problem with infertility (e.g., fi rst seemed to be unable to induce a pregnancy). The with the help of metaphors) therapeutic group showed a higher birth rate, improve- 6. Clarifying the effects of infertility on the partner- ment of sperm concentration, reduction of negative ship, family, friends and job thoughts, such as a sense of helplessness, as well as an 7. Raising awareness that starting a pregnancy can- improvement of the partnership. Moreover, 6 months not be controlled by the couple after the end of the therapy, the couples who had been 8. Raising awareness of the couple’s exceptional sit- unsuccessfully treated had gained greater distance to uation or the alternative positive rewards (e.g., their desire to have a child (Florin et al. 2000). questions such as: is it true that you always think Psychosocial interventions have, in cases of infer- of your infertility?) tility, positive effects on the psychological condition of 9. Redefi ning the couple’s real situation the persons concerned. However, they do not have any 10. Presenting future perspectives signifi cant infl uence on rates of pregnancy or the spe- cial personality traits of the persons concerned. During or after such a consultation/therapy, the couple Basically psychotherapeutic intervention should be then defi ne for themselves the importance of the fertil- offered to the couple as a whole, even if it is well- ity problem. Nowadays, when they are older, women known that women are more commonly prepared to and men without children of their own are frequently undergo psychological counselling (cf. also Strau§ painfully reminded of their former own inability to et al. 1999). In selected cases individual therapy ses- have children, when in their circle of friends of the sions should also be considered. same age, grandchildren are born (Wirtberg et al. 2007). To date no concept for advising and treating this clientele has been developed.

A meta-analysis of 25 individual investigations 25.6.3 Effects of Psychotherapeutic showed that although group therapy (psychological Intervention education, relaxation procedures) was, in fact, more effective than individual therapy (Boivin 2003) and a further meta-analysis showed positive effects on The research presented below essentially includes the persons’ psychological reactions (e.g., anxiety behavioral therapy, discussion psychotherapy, psycho- and depression), there was no positive effect on the analytically oriented concepts of therapy, as well as pregnancy rates of the women (de Liz and Strauss methods from relaxation procedures. 2005). Nevertheless, no negative effects of therapy Thus fi ve out of 15 patients became pregnant 4 months have been heretofore reported in the literature. after the end of behavioral therapy for couples à la Hahlweg et al. (1982). Moreover increased sperm num- bers, improved communication as well as reduced levels of fear were ascertained in the couple’s relationship 25.6.4 Further Psychosocial (Bents 1991). In seven out of 15 patients, a pregnancy Developments Following Infertility was initiated after short-term psychotherapy (threeÐfour Treatment with Special Reference sessions) prior to IVF-therapy (Brandt and Zech 1991). to Family Constellations Essential improvement of infertile patients’ level of knowledge regarding infertility and its causes, conjugal Family conditions and constellations after successful communication and communication strategies in gen- medical reproductive treatment may differ considerably. 530 R. Oberpenning et al.

First of all, successful achievement of parenthood may family sociologist Hans Bertram emphasizes: curtail marital contentment for a period of time. During “Family members are mostly relations, although pregnancy, IVF mothers fear often that their pregnancy they do not have to be. From the point of view of will not continue. Thus the child’s room may only be those questioned, however, not all persons who could assembled in the postnatal period. Men, on the other belong to the family are, in fact, members of their hand, frequently express fear that the ICSI child may family. On the other hand, persons are considered as be physically impaired. At the present time there may being part of their own family who do not in fact be some statistical support for these fears. Palermo belong to it, according to general understanding” et al. (1996) found that the frequency of serious physi- (Bertram 1991). This statement and the following cal impairments among ICSI children was not greater. forms of family presented indicate what great variety However, in a more recent meta-analysis of 25 studies, of family forms are possible by means of ART. the authors come to a different conclusion, namely ICSI children have an increased risk of 30Ð40% for serious malformations or chromosomal anomalies (Hansen et al. 2005). In a prospective study among 25.6.4.1 Twin and Multiple Birth Families 3,372 children, serious malformations were seen in 8.7% of the cases, in comparison to 6.1% of a group of Reports based on the experiences of twin and multiple 8,016 children born after spontaneous conception birth families show that these have underestimated the (Ludwig and Katalinic 2005). This means that in every degree of prenatal complications in pregnancy, as well 12th pregnancy after ICSI and in every 15th pregnancy as psychosocial burdens, particularly the social isola- after spontaneous conception malformations must be tion of the mother (Bindt et al. 1998). They also show expected. The study also showed an increased risk for that premature birth and a birth weight <1,500 g are the development of the pregnancy and birth after ICSI. associated with impairment of the cognitive and Here the degree of the male’s subfertility was not social development of the child, which only mani- relevant. fest themselves when the children start school The authors, however, attribute this increased rate (Bindt 2001). of malformations less to the procedure as such, but IVF parents with twins, in comparison to the con- rather more to the genetic constellation of the parents. trol group, feel under greater stress by having to rear This is why it is important to inform couples about twins (Cook et al. 1998). The parental, especially the risks when conception takes longer than 12 months. maternal burden, is particularly high with regard to The parentÐchild relationship among IVF children bringing up triplets. Thus in a prospective study over a and their psychological as well as social development period of 2 and 4 years Garel et al. (1997) found that is generally considered to be unproblematic (Strau§ the mothers felt “seriously” to “very seriously” emo- et al. 2004). Nevertheless, IVF mothers tended to tionally stressed throughout the whole period of inves- worry more about their child’s well-being in the fi rst tigation. The majority complained about stress year of life, which can probably be seen in relation to situations in child rearing (dealing with children’s the period of waiting for fulfi lment of their desire to aggressions and confl icts regarding closeness and dis- have a child (Gibson et al. 1998). Golombok et al. tance to their three children), as well as about the 2002 found that such parents had a tendency to over- increased fatigue caused by caring for three children at protect their IVF children. All in all, however, the the same time. Of the 11 mothers of triplets, four had mothers and fathers of IVF children excel in their high levels of depression and were taking tablets/med- extraordinary parental competence and warmth. ication. During the questioning four mothers reported spontaneously that after 4 years they regretted having The fi elds of family sociology and family psychol- triplets because of great physical and psychic pressure. ogy have created a new defi nition of the concept Even if this research represents only a random sam- “family” in recent years, since in Germany too the pling it makes the extremely high pressure on multipa- classical father-mother-child family can no longer be rous families abundantly clear. considered as the most common way of life. The The parentÐchild relationship among multiparous parents is always quantitatively reduced. They are 25 Psychology of Fertility Disorders 531 required to build up a parentÐchild relationship to sev- 25.6.4.2 Family Bonding Through Donor eral potentially diffi cult babies at the same time. As a Insemination result, mothers of triplets establish a delayed or impaired bonding relationship to their children (Garel The reasons for founding a family through donor et al. 1994). insemination are mostly serious disturbances of male Mothers of triplets tend to withdraw emotionally fertility, together with rejected or failed reproductive from all their children (Robin et al. 1991). In the case medical treatment. Moreover, avoiding the possibility of 54 triplets, a rate of 20% deaths at birth and early of transferring an inherited disease to the child can be deaths of children were ascertained (Roest et al. 1997). a motive. Of 18 parents of triplets in this random sampling, six In the USA, about 30,000 infants per year are born were confronted by the death of at least one of their after donor insemination. For Europe, the European children. Generally, multiparous children tend more Society of Human Reproduction and Embryology towards disturbances of behavioral and language (ESHRE) recorded altogether 15,000 intrauterine insem- development (Bindt 2001). More recent research on inations with donor sperm which were carried out in vari- families with multiple births following ART, in com- ous European countries in 2002 (Andersen et al. 2006). parison to families with individual children, indicated The leaders among them are Great Britain, with 5,338, that the birth of twins or triplets causes considerable France, with 3,321, Spain, with 1,893, and Denmark, problems for the parents bringing them up during in with 1,594 annual donor inseminations. According to the fi rst years. Individual twin and triplet children estimates, more than 50,000 persons are currently living themselves also showed a low degree of delay in lan- in Germany who have been conceived by donor semen guage development throughout this investigation. On since 1970. Since the introduction of ICSI in 1993, how- the other hand, psychological behavior-associated ever, the number of children born after donor insemina- problems of multiple birth children were not discov- tion has been reduced to 1,000 births per year. ered (Golombok et al. 2007). Many couples deal discretely with the way their Because of these pressures on families with child was conceived in their social surrounds since multiple births, the Federal Medical Board recom- they fear that their child, who was conceived by donor mends that for patients under 38 years only two semen, will be stigmatized. As in Germany the rights embryos be transferred in the fi rst and second cycles. and obligations of the father as well as the semen donor In the case of more than four fetuses, the Medical have only been established for heterosexual married Board favors selective abortion with a view to reduc- couples (¤ 1,600 BGB, para. 4), donor insemination ing risks for mother and child, even at the risk of a (DI) is restricted to these. Donor insemination presents possible complete loss of pregnancy. At the present a collision of two interests: the possible desire of the time single-embryo-transfer is being discussed on the child to learn about his/her parental extraction, on the international level. one hand, as well as the donor’s possible claim to ano- It is clear that families with multiple births need nymity, on the other hand (Katzorke 2008). suffi cient social support from members of their family, Currently the latter issue is unclear. Court decisions friends or helpers, such as day mothers, babysitters or and legal interpretations allow the assumption that au-pairs. The latter can usually not be paid for by the every person of legal age has the right to know from family alone in the long run. whom he descends (BkiD 2008). These results show the importance of specialists Since 2006, physicians are thus obliged to preserve from the fi eld of psychotherapy and social work within documentation about semen donors and the recipient an ART team. They can make the future parents aware couple safely for at least 30 years. A notarial deposition of forthcoming psychosocial as well as fi nancial pres- about the right of the child to inspect these documents sures and can offer them possibilities and help to should be considered and the parents should inform the unburden themselves and their children. Well-informed attending physician who carried out the insemination parents can take precautions in advance to provide about the birth of the child. adequate care of their children, thus allowing for a In countries without anonymous semen donation, more carefree pregnancy and fewer complications in the rate of disclosure among the conceived children is, parentÐchild bonding. on the other hand, low. In a survey in Sweden, for 532 R. Oberpenning et al. example, even 20 years after receiving anonymous the two. These results are supported by further investi- donor insemination, 89% of the parents had still not gations (Golombok et al. 2004). told the children the truth about their extraction. Only In countries such as the Netherlands, Australia, and 20% of the couples are in favor of informing the chil- Canada, lesbian couples also have donor inseminations dren from the very beginning. The following can be performed. Initial fears that the absence of a father counted among the psychological reasons for this res- could affect the child’s development negatively have ervation (Schilling 1995): not been confi rmed to date. Indeed, the children of les- bian mothers also express the wish to know more about ¥ The fears of infertile men that they could break with the semen donor (Vanfraussen et al. 2001). their own parents ¥ The fantasies of the men that the child might later prefer the biological father 25.6.4.3 Starting a Family by Egg Donation ¥ Their own feelings of insuffi ciency because of infertility According to the Law for the Protection of Embryos, Many German couples are still not at ease with DI. The egg donation is forbidden in Germany at the present question of remaining silent or being frank with the time. In the case of egg donation, the mother bearing child has remained an unsolved problem up to today. the child is called the social mother, the father is the This is also refl ected by the fact that concepts such as biological father. German couples can, for example, “DI-family” and “DI-father”, common in English have egg donation carried out in neighboring countries usage, do not exist in German, in contrast to other fam- such as Spain, the Czech Republic, Slovakia as well as ily concepts such as “adoptive family”, “foster family” Russia, but also in the USA. Up to now there have been or “patchwork family” (Thorn 2000). Since, however, no studies on families who had egg donation carried family secrets can negatively affect the well-being of out abroad, although roughly 450 children are born in all family members, psychosocial experts plead in favor Germany every year as a result of the procedure of disclosing the biological identity of the donor, as (Kentenich and Utz-Billing 2006). this Ð similarly to cases of adoption Ð can, under certain Studies which have examined family development circumstances, be of great importance for the develop- after egg donation found nothing conspicuous, either ment of the child’s personality. More recent studies among the children or the parents (Golombok et al. indicate that the rate of disclosure has been increasing 2005; Murray et al. 2006). In comparison to IVF in recent years (Daniels et al. 2007). children, children conceived by egg donation showed Research carried out on young adults, who were only considerable advantages in language development informed after puberty about how they were conceived, (Söderström et al. 1998). reported about the concerned persons’ feelings of a loss Couples deciding for egg donation abroad must, of trust towards their parents, as well as feelings of frus- however, face the fact that the identity of the donor is tration and a desire for information about the semen not revealed in all countries. As a result, the child is donor (Turner 2000). The fact that the child conceived not given the opportunity to fi nd its real identity or it by DI is told early on about his father can also affect the is, at least, more diffi cult. family system favorably was shown in the study by Lycett et al. (2004), in which informed and uninformed children were compared. The parental competence was 25.6.4.4 Starting a Family by Embryo Donation more highly esteemed and there was less fi ghting in the family among the children who had been informed. Embryo donation is also described as prenatal adop- Comprehensive research on the psychological social tion because, as in the case of adoption, there are par- development of DI-children in comparison to children ents who give, and parents who receive. Not only born after infertility treatment, adoption and spontane- parents who have completed their family are motivated ous conception showed no signifi cant differences in to donate an embryo, but also couples who are under- the development of the children (Golombok et al. going infertility treatment and would like to help other 2002). The fatherÐchild relationship was unproblem- infertile couples (Newton et al. 2003). In a study on the atic although there was no genetic relationship between attitudes of IVF patients to egg and embryo donation, 25 Psychology of Fertility Disorders 533 it was found that two-thirds would be willing to donate In contrast to donor insemination, adopted children an egg or an embryo. Approximately 47% would in Germany have, by 16 years at the latest, the right to decide to accept an egg, and approximately 40% an learn the names of their biological parents, their pro- embryo. Up to now, there are no studies on family fession/job, where they live, their nationality and their dynamics (Weghofer et al. 2002) and the situation of religion. Generally this information is provided by the the children in this kind of family system. agency responsible for the adoption. This chapter cannot deal with the more or less costly At the present time children from the more complex process of adoption/fostering a child. Interested cou- family systems (e.g., lesbian couples with donor ples should be referred by their physician to the respon- insemination, single mothers with donor insemina- sible local authority Ð this also applies to adoptions of tion) do not differ from children from a traditional foreign children which are recognized in Germany. It family with regard to their social and psychological must be noted that the number of children who are free development (Brewaeys et al. 2005) for adoption is decreasing. This may well result from decreasing birth rates, as well as from improved psy- chosocial support of the families of origin, which are The way a child is conceived thus has relatively little often problematic. infl uence on its development as a human being. What is important for the child is, above all, how the parents build up a relationship to their child and whether they 25.6.5 Outlook and Future Psychological love him/her unconditionally. Research

25.6.4.5 Starting a Family by Adoption Undesired childlessness often represents a critical life or Fostering experience for the couple, which they must cope with, along with the help of specialized physicians and psy- Those couples who, instead of having their own bio- chosocial experts. Comparative psychological research logical child, decide in favor of adopting or fostering a projects between fertile and infertile couples largely child can receive much help especially from authori- come to the conclusion that there are no signifi cant dif- ties, such as the Youth Offi ce in charge. It is more com- ferences between these couples. So too studies con- mon for women to decide in favor of adopting or cerned with the psychological differences between fertile fostering than men. Men seem clearly to have greater and infertile men in particular arrive at similar results. diffi culties with accepting a non-genetic child into The connections between psychic stress and infertil- their family (Leiblum et al. 1998). ity as a cause or simply as a reactive effect have not been The basic precondition for starting an adoption or clarifi ed, even after 40 years of research (Wischmann fostering process is, however, that it be the shared and 2006a). For this reason, studies which aim to prevent unconditional decision of the couple to take a child. infertility should be carried out on a much wider basis. Nor can the acceptance of a child be seen as an alter- Even if women are more intensely involved in the native to a biological child. It has proven favorable if medical-therapeutic process than men, men often the couple’s own unfulfi lled wish to have a child has suffer just as much from their undesired childlessness been worked through as far as possible up to this as women. Investigations into the male desire for time, so that the couple are as free as possible to build offspring indicate that the male desire to have children up a healthy parent-child relationship and they are is just as strong as that of women, although it comes able to dedicate themselves to their adopted child into play at a later time. Men are much more con- without reservations. Couples who have been in ther- cerned with keeping their infertility secret. This prob- apy for several years who continue to feel at odds lem becomes particularly clear in the context of with their fate should not see adoption or fostering as psychological investigations regarding foundation of a the next step towards the goal of having a child. The family by donor insemination. distress not of having become pregnant is too great Because of the varied and complex types of fami- for such a couple (von Schelling 1994). lies which can be formed with the aid of reproductive 534 R. Oberpenning et al. medicine, it is time to think about a new defi nition of ¥ Psychological studies on using ART or surrogate the concept of family. When the guidelines for psycho- motherhood in constructs beyond conventional social care of couples who do not wish to remain child- family structures (homosexual couples, single men less were revised by the Federal Medical Board (BÄK) or women) in 2006, psychosocial consultation of the couple was ¥ Psychological studies on the persons undergoing urgently recommended. This is important before, dur- pre-implantation diagnosis in countries where this ing and after therapy, and especially during therapy is legal crises when multiple births take place, after successful ¥ Investigations on psychological and social conse- heterologous insemination, as well as termination of quences, as well as legal formulation of problems in unsuccessful therapy. cases of anonymous versus open sperm donation For this reason, contributions on a routine basis by ¥ Studies on the use of ART in countries with differ- social workers/psychologists in fertility centers and ent cultures, religious or ethical and moral concepts practices, as well as by external agencies are impera- tive, as they provide relief for the couple as well as for medical personnel. Besides informal offers, such as discussion rounds, psychological telephone counsel- References ling on IVF/ICSI/DI, physicians’ referrals to special internet pages of professional associations and self- Andersen AN, Gianaroli L, Felberbaum R, de Mouzon J, Nygren KG (2006). Assisted reproductive technology in Europe, help groups, as well as copious multilingual informa- 2002. Results generated from European registers by ESHRE. tion brochures, have proven useful. The European IVF-monitoring programme (EIM) for the Essential research questions have not yet been suf- European Society of Human Reproduction and Embryology fi ciently answered, so that, above all, the following (ESHRE), ESHRE Central Offi ce, Grimbergen. Belgium Hum Reprod 21:1680Ð1697 psychosocial and ethical topics of concrete relevance Apfel RJ, Keylor RG (2002) Psychoanalysis and infertility. to persons under treatment, to the doctor-patient rela- Myths and realities. 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(BKiD) birth families, also after intrauterine or postpartum (2007) Richtlinien “Psychosoziale Beratung bei unerfülltem Kinderwunsch”. http://www.bkid.de/richtlinien.pdf child death, with particular consideration of the Beratungsnetzwerk Kinderwunsch Deutschland e.V. (BKiD) childhood development of remaining siblings (2008) Richtlinien “Psychosoziale Beratung bei ¥ Recording the psychological problems and confl ict Gametenspende”. http://www.bkid.de/gs_leitlinien.pdf situation of families founded by DI abroad Bertram H (1991) Die Familie in Westdeutschland. Opladen, Westdetuscher Verlag ¥ Studies on the effects of psychosocial counselling Beutel M, Kupfer J, Kirchmeyer P; Kehde S, Köhn FM, and care of ART-families Schroeder-Printzen I, Gips H, Herrero HJG, Weidner W ¥ Studies on the advantages and disadvantages of (1999) Treatment-related stresses and depression in couples “open” versus “anonymous” gamete donation undergoing assisted reproductive treatment by IVF or ICSI. 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Hum Reprod 20:286Ð293 deutsches-ivf-register.de Golombok S, Olivennes F, Ramogida C, Rust J, Freeman T Eckert H, Sobeslavsky I, Held HJ (1998) Psychische Merkmale (2007) Follow-Up team parenting and the psychological bei Paaren mit unerfülltem Kinderwunsch vor IVF. In: development of a representative sample of triplets conceived Brähler E, Goldschmidt S (eds) Psychosoziale Aspekte by assisted reproduction. Hum Reprod 22:2896Ð2902 von Fruchtbarkeitsstörungen. Huber, Bern, Göttingen, Grobman WA, Milad MP, Stout J, Klock SC (2001) Patient per- pp 27Ð50 ceptions of multiple gestations: An assessment of knowledge Erikson EH (1976) Identität und Lebenszyklus. Suhrkamp, and risk aversion. Am J Obstet Gynecol 185:920Ð924 Frankfurt Guttormsen G (1992) Unfreiwillige Kinderlosigkeit: ein Fenster L, Katz DF, Wyrobek AJ, Pieper C, Rempel DM, Oman Familienproblem. Praxis Kinderpsychol Kinderpsychiat 41: D, Swan SH (1997) Effects of psychological stress on human 247Ð252 semen quality. J Androl 18:194Ð202 Hahlweg K, Schindler R, Revenstorf D (1982) Partner- Fischer C, Rohde A, Kla§en R, Marneros A, Dietrich K (1996) schaftsprobleme. Springer, Heidelberg Einstellung zu Sexualität, Schwangerschaft und Geburt bei Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ (2005) männlichen Patienten einer Kinderwunschsprechstunde. Assisted reproductive technologies and the risk of birth Z Med Psycho 4:176Ð1985 defects Ð a systematic review. Hum Reprod 20:328Ð338 Florin I, Tuschen B, Krause W, Pook M (2000) Psychologische Hellhammer DH, Hubert W, Freischem CW, Nieschlag E (1985) Therapie bei idiopathischer Infertilität: Ein Stressreduk- Male infertility: Relationships among gonadotropins, sex 536 R. Oberpenning et al.

steroids, seminal parameters and personality attitudes. Tages-Aktivitäts-Rhythmik und Schlafqualität bei idio- Psychos Med 47:58Ð66 pathisch infertilen Männern. In: Brähler E, Felder H, Strauß Hjelmstedt A, Andersson L, Skoog-Svenberg A, Bergh T, Boivin B (eds) Fruchtbarkeitsstörungen. Jahrbuch der Medizinischen J, Collins A (1999) Gender differences in psychological Psychologie 17. Hogrefe, Göttingen, pp 165–174 reactions to infertility among couples seeking IVF- and Murray C, MacCallum F, Golombok S (2006). Egg donation ICSI-treatment. Acta Obstet Gynecol Scand 78:42Ð48 parents and their children: Follow-up at age 12 years. Fertil Hölzle C, Lütkenhaus R, Wirtz M (2000) Psychologisch- Steril 85(3):610Ð618 prognostische Kriterien für den Verlauf medizinischer Nachtigall R, Becker G, Wozny M (1992) The effects of gender- Sterilitätsbehandlungen. In: Brähler E, Felder H, Strauß B specifi c diagnosis on men’s and women’s response to infer- (Hrsg) Fruchtbarkeitsstörungen aus psychosozialer Perspektive. tility. Fertil Steril 57:113Ð121 Jahrbuch der Medizinischen Psychologie 17. Göttingen, Newton CR, McDermid A, Tekpetey F, Tummon IS (2003) Embryo Hogrefe, 177Ð205 donation: Attitudes toward donation procedures and factors Hoppe JD (2006) (Muster-)Richtlinie zur Durchführung der predicting willingness to donate. Hum Reprod 18: 878Ð884 assistierten Reproduktion der Bundesärztekammer – Novelle Onnen-Isemann C (2000) Ungewollte Kinderlosigkeit und ihre 2006. Deutsches Ärzteblatt 20:1392–1403 Auswirkungen der Reproduktionsmedizin: Der Fall Hubert W, Hellhammer DH, Freischem CW (1985) Deutschland. Forum Qualitative Sozialforschung vol 1, No 1 Psychobiological profi les in infertile men. 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Hum Reprod 19:954Ð959 Kentenich H, Tandler-Schneider A (2008) Kommentar zu Thorn, Robin M, Josse D, Tourrette C. (1991) Forms of family reorga- P, Wischmann, T.:Eine kritische Würdigung der Novellierung nization following the birth of twins. Acta Genet Med der (Muster-) Richtlinie der Bundesärztekammer 2006 aus Gemellol (Roma) 40:53Ð61 der Perspektive der psychosozialen Beratung. Roest J, van Heusden AM, Verhoeff A, Mous HV, Zeilmaker J Reproduktionsmed Endokrinol 5:153Ð154 GH (1997) A triplet pregnancy after in vitro fertilization is a Kentenich H, Utz-Billing, I. (2006) Verbot der Eizellspende. procedure-related complication that should be prevented by Gynäkologische Endokrinologie 4:229Ð234 replacement of two embryos only. Fertil Steril 67:290Ð295 Kowalcek I (2008) Die Mehrlingsproblematik aus psychologis- Sanders KA, Bruce NW (1999) Psychosocial stress and treat- cher Sicht. J Reprod Endocrinol 5:280Ð284 ment outcome following assisted reproductive technology. Lalos A, Jacobsson L, Lalos O, von Schoultz B (1985) The wish Hum Reprod 14:1656Ð1662 to have a child. A pilot-study of infertile couples. Acta Schilling G (1995) Zur Problematik familiärer Geheimnisse am Psychiatr Scand 72:476Ð481 Beispiel der heterologen Insemination. Psychother Langer, M. (1953) Maternidad y sexo. Buenes Aires, Ediciones Psychosom Med Psychol 45:16Ð23 Paides Schuerman H (1948) Über die Zunahme männlicher Leiblum S, Kemman E, Lane M (1987) The psychological con- Fertilitätsstörungen und über die Bedeutung psychischer comitants of in vitro fertilization. J Psychosom Obstet Einfl üsse für die zentralnervöse Regulation der Gynaecol 6:165Ð178 Spermiogenese. Med Klin 13:366Ð368 Leiblum SR, Aviv A, Hamer R (1998) Life after infertility treat- Schumacher, J., Stöbel-Richer Y, Brähler E (2002) Erinnertes ment: A long-term investigation of marital and sexual func- Erziehungsverhalten der Eltern und eigener Kinderwunsch Ð tion. Hum Reprod 13:3569Ð3574 Gibt es hier Zusammenhänge? Psychother Psychosom Med Lintsen AME, Verhaak CM, Eijkemans MJC, Braat DDM 52:314Ð322 (2006) The prognostic value of pschological factors on the Schuth W, Keck C (2001) The ideal reproduction medicinal outcome of IVF. Hum Reprod 21:i71 treatment Ð as seen by the involved persons. Geburtsh Ludwig M, Katalinic A (2005) Die deutsche ICSI-Follow-up- Frauenhilk 61:476Ð482 Studie Ð Zusammenfassung der Ergebnisse publizierter Seibel MM, Taymor ML (1982) Emotional aspects of infertility. Arbeiten und Einordnung in die aktuelle Studienlage. Journal Fertil Steril 37:137Ð145 für Reproduktionsmedizin und Endokrinologie, J Reprod Snarey J, Son L, Kuehne V, Hauser S, Vaillant G (1987) The role Med Endocrinol 2:151Ð162 of parentin in men’s psychological development: A Lycett E, Daniels K, Curson R, Golombok S (2004) Offspring longitudinal study of early adulthood infertility and midlife created as a result of donor insemination: A study of family generativity. Develop Psychol 23:593Ð603 relationships, child adjustment, and disclosure. Fertil Steril Söderström-Anttila V, Sajaniemi N, Tiitinen A, Hovatta O 82:172Ð179 (1998) Health and development of children born after oocyte Mariano C, Hickey R (1998) Multiple pregnancy, multiple donation compared with that of those born after in-vitro fer- needs. Can Nurse 94:26Ð30 tilization, and parents’ attitudes regarding secrecy. Hum Matzen K, Pook M, Schnapper U, Krause W, Florin I (1999) Reprod 13:2009Ð2015 25 Psychology of Fertility Disorders 537

Stauber M (1979) Die Psychosomatik der sterilen Ehe. Grosse, Thorn P, Wischmann T (2008) Eine kritische Würdigung der Berlin Novellierung des (Muster-) Richtlinie der Bundesärztekammer Stauber M (1989) Psychosomatische Aspekte der Sterilität. In: 2006 aus der Perspektive der psychosozialen Beratung. Bettendorf G, Breckwoldt M (eds) Reproduktionsmedizin. J Reproduktionsmed Endokrinol 5:39Ð44 Fischer, Stuttgart pp 390Ð398 Turner AJ, Coyle A (2000) What does it mean to be a donor Stewart DE, Boydell KM, McCarthy K, Swerdlyk S, Redmond offspring? The identity experiences of adults conceived by C, Cohrs W (1992) A prospective study of the effectiveness donor insemination and the implications for counselling and of brief professionally-led support groups for infertility therapy. Hum Reprod 15:2041Ð2051 patients. Int J Psychiatry Med 22:173Ð182 Ulrich, D (1988) Zur Psychosomatik des unerfüllten Stieve H (1952) Der Einfl u§ des Nervensystems auf Bau und Kinderwunsches: Literaturübersicht. In: Brähler E, Meyer A Tätigkeit der Geschlechtsorgane des Menschen. Thieme, (eds) Partnerschaft, Sexualität und Fruchtbarkeit. Springer, Stuttgart Berlin, 101Ð113 Stöbel-Richter Y, Borkenhagen A, Wisch S, Brähler E (2006) Vanfraussen K, Ponjaert-Kristoffersen I, Brewaeys A. (2001) An Wissen und Einstellungen der deutschen Bevölkerung zu attempt to reconstruct children’s donor concept: A compari- Aspekten der modernen Reproduktionsmedizin. Ergebnisse son between children’s and lesbian parents’ attitudes towards einer aktuellen Bevölkerungsbefragung. In: Stöbel-Richter Y, donor anonymity. Hum Reprod 16:2019Ð2025 Ludwig A, Franke P, Neises M, Lehmann A (Hrsg) Anspruch von Schelling C (1994) Wir wollen ein Kind adoptieren. Mosaik, und Wirklichkeit in der psychosomatischen Gynäkologie und Verlag München Geburtshilfe. Gie§en, Psychosozial-Verlag, pp 163Ð171 Weghofer A, Margreiter M, Gerhold B, Edjalipour C, Renezeder Strau§ B (2000) Herausgeber. Ungewollte Kinderlosigkeit. K, Sowelem H, Feichtinger W (2002) Attitudes of women Hogrefe, Göttingen undergoing IVF regarding supernumerary embryos, oocyte Strau§ B, Beyer K (2004) Gesundheitsberichterstattung des donation, and embryo adoption. Geburtsh Frauenheilk 62: Bundes. Heft 20 Ungewollte Kinderlosigkeit. Robert-Koch- 574Ð577 Institut, Statistisches Bundesamt, Berlin Wirtberg I, Möller A, Hogström L, Tronstad SE, Lalos A (2007). Strauß B, Brähler E, Kentenich H (Hrsg) (2004) Fertilitätsstörungen Life 20 years after unsuccessful infertility treatment. Hum Ð Psychosomatische Diagnostik und Therapie (Leitlinien und Reprod 22:598Ð604 Quellentext). Schattauer, Stuttgart Wischmann T (2006a) The Psychogenesis of infertility: An Strauss B, Hepp U, Städing G, Mettler L (2000) Fokale Beratung Overview. Geburtsh Frauenheilk 66:34Ð43 von Frauen und Männern mit Kinderwunsch: Ein dreistu- Wischmann T (2006b) Unerfüllter Kinderwunsch – Stereotype fi ges Modell. In: Straus (Hrsg) Ungewollte Kinderlosigkeit und Fakten. J Reproduktionsmed Endokrinol 3:220Ð225 Göttingen, Hogrefe, pp 119–148 Wischmann T, Stammer H (2001) Der Traum vom eigenen Kind. Strauß B, Städing G, Hepp U, Mettler L (1999) Fokale Psychologische Hilfen bei unerfülltem Kinderwunsch. Beratungskonzepte in der Fertilitätsmedizin. In: Bräher E, Stuttgart, Kohlhammer Felder H (eds) Jahrbuch der Medizinischen Psychologie 17. Zitzmann M, Rolf C, Nordhoff V, Schräder G, Rickert-Föhring Hogrefe, Göttingen, pp 272–290 M, Gassner P, Behre HM, Greb RR, Kiesel L, Nieschlag E. Sturgis SH, Taymor ML, Morris T (1957) Routine psychiatric (2003) Male smokers have a decreased success rate for in interviews in an sterility investigation. Fertil Steril 8: 521Ð526 vitro fertilization and intracytoplasmic sperm injection. Thorn P, Daniels K (2000) Psychosoziale Fragestellungen, die Fertil Steril 9(Suppl 3):1550Ð1554 bei der Familienbildung mit donogener Insemination entste- hen. Reproduktionsmedizin 16:202Ð207 Sexual Medicine and Andrology 26 Klaus M. Beier

Contents 26.1 Sexual Medicine in Clinical Practice

26.1 Sexual Medicine in Clinical Practice ...... 539 Sexual medicine is concerned with recognition/ identifi cation, treatment, prevention and rehabilitation 26.2 Interdisciplinary References of disorders and diseases in sexuality. These may involve in Sexual Medicine ...... 540 sexual functions, sexual and/or partnership experience 26.3 Basic Understanding of Human Sexuality ...... 540 and behavior (also possibly resulting from other ill- nesses and/or their treatment), gender identity, or be 26.4 The Spectrum of Sexual Disorders ...... 541 associated with sexual trauma. Sexual medicine places 26.4.1 Sexual Dysfunction ...... 543 priority on the dimension of attachment as well as draw- 26.4.2 Disorders of Sexual Development ...... 545 ing on scientifi c knowledge and proceedings of medical, 26.4.3 Disorders of Gender Identity ...... 546 psychological and sociological disciplines (Vogt et al. 26.4.4 Disorders of Sexual Preference 1995). Scientifi c fi ndings on the psychology of behavior (Paraphilias) ...... 547 and development are especially useful for sexological 26.5 Impact of disorders of Sexual Preference, Sexual methods, showing that mammals, especially primates Behavior and Sexual Reproduction ...... 547 and certainly humans are “relational” beings pro- 26.5.1 Disorders of Sexual Behavior grammed to depend on attachment: their chances of sur- (Dissexuality) ...... 548 vival depend on the satisfaction of existential elementary 26.5.2 Disorders of Sexual Reproduction ...... 549 needs such as acceptance and belonging. These are most 26.6 Principles of Diagnosis in Sexual Medicine ...... 549 likely to be fulfi lled and particularly intensive during 26.6.1 Exploration of a Sexual body contact in (intimate) relationships providing feel- Disorder/Dysfunction ...... 550 ings of comfort and security. All sexological interven- 26.6.2 Exploration of the Three tions are based on this elementary understanding. Dimensions of Sexuality ...... 551 In some areas there are considerable parallels 26.7 Principles of Therapy in Sexual Medicine ...... 552 between sexual medicine and andrology. According to 26.7.1 Sexological Consultation ...... 553 the current postgraduate curriculum of the German 26.7.2 Sexual Therapy ...... 553 Federal Medical Board, the defi nition of andrology 26.7.3 Integration of Somatic Therapy Options ...... 554 covers the “prevention, diagnosis, conservative treat- ment and rehabilitation” of “attachment disorders” and References ...... 554 “erectile dysfunction including disorders in libido, ejaculation and cohabitation”. K. M. Beier Thus the andrological examination of patients and Institute of Sexology and Sexual Medicine, Center for Human couples offers an appropriate opportunity for simulta- and Health Sciences, Charité-Universitätsmedizin Berlin, neously recording existing sexologically relevant dis- Freie und Humboldt-Universität zu Berlin, Luisenstrasse 57, D-10117 Berlin orders in addition to the primarily presented symptom e-mail: [email protected] (e.g., childlessness).

E. Nieschlag et al. (eds.), Andrology, 539 DOI: 10.1007/978-3-540-78355-8_26, © Springer-Verlag Berlin Heidelberg 2010 540 K. M. Beier

Sound sexological competence on the part of andro- Jurisprudence logical specialists is highly desirable. At the very least, Psychology they should be involved with a network providing an Sociology option for postgraduate education, and offering the Forensic Medicine opportunity of referring potential couples to special- Internal Medicine ized sexologists. Psychiatry Psychotherapy A positive development is that since 2007 sexual medicine has been recognized as a subspecialty accord- SEXUAL MEDICINE Psychosomatic ing to the postgraduate curriculum of the Berlin Medicine Medical Board. Colleagues from various fi elds of spe- Endocrinology cialization such as gynecology, dermatology, internal Urology medicine, general medicine, psychosomatic medicine, psychotherapy or urology can apply for recognition Gynecology after qualifi cation in theoretical knowledge and practi- cal skills. This postgraduate education qualifi es par- General Medicine Andrology ticipants for diagnosis and therapy of all sexual and gender identity disorders (Sect. 26.3) Ethology Anthropology By defi nition sexual medicine derives its substance Ethnology from anthropological, biomedical, psychological and Cultural Science sociocultural aspects of gender, and is by nature inter- disciplinary and constantly integrates know-how from Fig. 26.1 Interdisciplinary references in sexual medicine other specialized fi elds such as general medicine, gyne- cology, urology, andrology, endocrinology, psychiatry, psychosomatic medicine, psychotherapy as well as satisfaction), are considered, the spectrum of sexual from adjoining human sciences, especially biology, disorders (see Sect. 26.3) and the challenges to medi- psychology, sociology etc. cal options become obvious.

26.2 Interdisciplinary References 26.3 Basic Understanding of Human in Sexual Medicine Sexuality

Consequently, the variety of patients is large: For Sexuality can be defi ned as a biologically, psychologi- instance, the diabetes patient complaining of sexual cally and socially determined experience quality in disorders at some stage during his chronic disease human beings, which is formed by the unique develop- (erectile dysfunction in men, arousal and orgasm prob- ment of a person’s own life history. From the functional lems in women); the hypertonic patient whose medica- point of view, one can speak of the multifunctionality tion affects his sexual reactions negatively; the patient of sexuality containing single aspects interacting with suffering depression, lacking sexual desire (as well as one another, and which may be differentiated by the perhaps having to cope with arousal and orgasm diffi - following terms: culties). All these patients fi t the pattern, as does the young man with sexual performance anxiety; the cou- • The dimension of desire encompasses sexuality in ple, whose unresolved confl icts or struggles for power all conceivable ways of experiencing and increas- within their partnership lead to sexual symptoms; the ing desire by sexual stimulation woman, who suffers pain during coitus caused by lack • The reproductive dimension stands for the signifi - of lubrication after menopause (Fig. 26.1). cance of sexuality for reproduction purposes When the increasing numbers of disorders in sexual • The dimension of attachment emphasizes the reproduction (including the often massive effects of importance of sexuality for the fulfi llment of bio- involuntary childlessness on sexual and partnership sociological fundamental needs for acceptance, 26 Sexual Medicine and Andrology 541

closeness, warmth and security by sexual communi- would also explain the assumption of earlier authors cation in partnerships (Beier and Loewit 2004; Beier who did not have imaging means as evidence, like the et al. 2005). observations of M. Balint (1965) about the “primeval forms of love” as being the core and basis of adult inti- Of the three dimensions, the reproductive dimension macy, or why A. Montagu (1987) called sexual interac- of sexuality is the phylogenetically oldest. For women tion between adults “in some ways a recapitulation of this dimension is limited to the time span of reproduc- the tender love between mother and child”. tive capability extending from puberty to menopause; The dimension of desire provides sexuality with it is also dependent on biographical decisions, making the unique sensual experience of sexual arousal and it optional. The availability of reliable contraceptive orgasm, which distinguishes it from other human expe- methods on one hand, and the progress of reproductive rience. It establishes the motivational quality of sexu- medicine on the other, has made it possible to separate ality and simultaneously provides the impulse and the dimension of reproduction from the other two reward of sexual behavior. The dimension of desire dimensions of desire and attachment. predominates in subjective experience in autoeroticism In evolutionary development the dimension of and in experienced attachment, passion and ecstasy. It attachment occurs later, but for today’s human beings it is, however, diffi cult to view it in isolation because it is is without doubt an integral and essential element of closely connected to other functions. sexuality. Its huge signifi cance derives from the fact At the same time data from neuroscientifi c research that humans are “relational” beings: from the very justify the assumption that, along with specialized brain beginning of life, their fundamental needs for accep- areas (such as the limbic system), basal cerebral areas tance, security, trust, warmth and closeness can only be close to the midline area play a decisive role in causing satisfi ed in relationships (Bowlby 1969–1980, Brisch directly physiologically observable sexual reactions. 1999). This is fulfi lled during infancy by body contact Here the area preoptica of the hypothalamus seems to and the emotional experience of being taken care of, be of central importance and in animal experiments for instance by the sheltering manner in which an infant increased activity in this core region, anatomically con- is held during breastfeeding. By this parental loving nected with other hypothalamic regions, has been care the modus of satisfying psychosocial fundamental observed during sexual activity. Steroid hormones needs by skin contact is learned by the infant and rein- modulate the activity of the area preoptica; in both male forced on a neuronal level, the way all processes of and female animals conductance experiments showed learning elementary skills generally are (Rüegg 2003). selective activation in sexually promising or coitus- Feelings transmitted by interaction and body lan- relevant situations (Pfaff 1999). In the human this core guage determine human development from birth is “wired” so that androgen or estrogen metabolites can onward and remain a core characteristic of partnership be recognized nasally as signals. Activation is depen- organization: At fi rst, they are not dependent on geni- dent on sexual orientation and not on gender: androgen tal involvement, but indeed allow deep satisfaction metabolites activate core regions of women who are obtained by skin and eye contact as well as by all other oriented to men, and of male-oriented men, while in senses. They are therefore the fi rst dimension of “sex- men who are female-oriented this region is activated by ual” experience, broadened later in life by the option estrogen metabolites (Savic et al. 2005). The depen- of genital-sexual communication. dence of central sexual activation patterns on sexual Today imaging methods are able to show (Bartels orientation (and not on gender) was shown by Ponseti und Zeki 2004) that the same brain regions are deacti- et al. (2006) for visual stimuli. vated when mothers are shown pictures of their children as when they see pictures of their spouses (compared to pictures of known persons as control persons). Possibly, the functions for anxiety and rejection, functionally- 26.4 The Spectrum of Sexual Disorders anatomically located in the amygdala, are deactivated at the same time. This means that any apprehension The suggested categories of the clinical classifi cation concerning the partner is “turned off” (as in the proverb systems ICD-10 (WHO 1993) and DSM-IV-TR (APA “love is blind”) in order to enable close interaction. This 2000) are purely descriptive and random concepts which 542 K. M. Beier fail to do justice to the complexity of human sexuality. restlessness” or additionally as “emotionally caused state Even on closer examination, the differentiation of the of restlessness”. So it can be assumed that in many areas three dimensions of sexuality required from a sexologi- of medicine male and female patients with varying dis- cal point of view exemplify the inadequacy of such cat- orders or dysfunctions consult a practitioner, because – egorization. Thus sexual dysfunction cannot only again for different reasons – of a lack of availability of a infl uence the dimension of desire, but very likely the functioning and therefore emotionally stabilizing social/ dimension of attachment as well; not only disturbed sex- intimate attachment. Also included are chronically ill or ual function but moreover the disturbance of partnership older persons, suffering from psycho-social destabiliza- comfort ends up being the actual reason for suffering. tion due to reduced opportunities for contacts. This explains why very different symptoms can dominate the clinical impression, as a result various According to present knowledge, chronic lack of medical disciplines may come into contact with the security transmitted by body communication (frus- patient concerned: tration of psycho-social fundamental needs) The orthopedist for muscle tension, the general prac- increases the probability of developing psychologi- titioner for symptoms of the autonomic nervous system, cal and physical disorders. Furthermore it hinders the psychiatrist for intrapsychological tension or states overcoming prevailing diseases (Egle et al. 1997). of depression or the andrologist concerning involuntary childlessness. Also, other sexual dysfunction may per- The symptoms presented by the patient seen in clini- haps be only one of many possible symptoms (apart cal practice are usually described as “psychosomatic ail- from, of course, sexual dysfunction caused by illness, ments”, “depressive state of mood”, “anxiety and/or e.g. condition after paraplegia). The special quality of nervous restlessness” i.e., “nervous anxiety, tension and sexological therapy lies in the fact that it deals with the

Sexual medi- cal indication

Single Partner Couple Family

Muscle tension Vegetative dystony, Intrapsychic Dysfunctional com- Sexual Atmosphere (e.g. headache, dysphoric mood tension munication disorders of tension backache, (e.g.self-doubt,anxie- (e.g.misunderstan- (e.g. arousal disor- (e.g.aggressive- prostatopathy) ties, obsessions, dings, arguments, der, erectile ness, violence, helplessness, refusal of communi- dysfunction, addiction,adult / hopelessness etc.) cation and love and orgasm disorder) child problems) care)

Syndyastic Sexual Therapy

not disturbed (any more)

disturbed feeling of general well-being

fulfilled again

frustrated fundamental needs (e.g. acceptence / attachement)

Fig. 26.2 Connection between psychosocial fundamental needs and various symptoms 26 Sexual Medicine and Andrology 543 actual roots (the frustrated basic social needs) of possi- on these aspects guarantees an appropriate description ble causes at a level not reached elsewhere because it and consequently effective treatment. Because sexual aims to restore the feeling of complete attachment by dysfunction not only affects the patient, but also has an accepting physical intimacy with the partner, which impact on the well-being of the partner involved, treat- also has curative effects on symptoms and positive con- ment should principally be carried out with both part- sequences in other areas of life (Fig. 26.2). ners. Moreover, all dysfunctions can occur independently So, even when spinal pains are successfully cured from other illnesses and disorders, or they may result by an orthopedist, there is nevertheless no change on from other illnesses and/or their treatment. the level of fundamental needs. Potential frustration of With regard to sexual dysfunctions in men, the fol- these needs is not resolved and may lead to a recur- lowing is based mainly on the latest fi ndings by Rösing rence or cause other symptoms. et al. (2009). These limited and only partially useful systematic In a representative random sample of 18–59-year- categorizations notwithstanding, clinically signifi cant old US-Americans. Laumann et al (1999) found that sexual disorders are compactly characterized as fol- 5% of the test persons had desire dysfunction, 5% erec- lows, along with their coding possibilities – according tile dysfunction and 21% orgasmic dysfunction in the to the international classifi cation systems (ICD-10 and form of ejaculatio praecox. In international comparison DSM-IV-TR) (Ahlers et al. 2005). results were partly concurrent, but partly showed sig- nifi cant intercultural variations, which verifi es the bio- 1. Sexual Dysfunctions (ICD-10: F 52.0 ff.; DSM- psycho-social roots of such disorders (Laumann et al. IV-TR: 302.71 ff.) 2005). Since then, several studies have also verifi ed the 2. Disorders of Sexual Development (ICD-10:F 66.0 ff.; negative impact of sexual dysfunctions on partnership coded in a generalized category designated “not oth- and life quality (Chevret et al. 2004; Rosen et al. 2004; erwise specifi ed” in DSM-IV-TR: 302.9) Fisher et al. 2005; Abraham et al. 2008). (a) Disorder of Sexual Maturity (b) Disorder of Sexual Orientation (c) Sexual Identity Disorder 26.4.1.1 Disorders of Sexual Desire (d) Sexual Partnership Disorder 3. Disorders of Gender Identity (ICD-10: F 64; DSM- These disorders are becoming an ever growing problem IV-TR: 302,85) in men seeking sexological treatment, although the 4. Disorders of Sexual Preference/Paraphilias (ICD- patients themselves often state erectile dysfunction as 10: F 65.O ff.; DSM IV-TR: 302.81 ff.) their reason for seeking help. The cause is often found to 5. Disorders of Sexual Behavior/Dissexuality (a gen- be hidden, frequently revealing sub-depressive condi- eralized category designated “not otherwise speci- tions of exhaustion (with and without substance abuse), fi ed” in ICD-10: F 63.8 and DSM-IV-TR: 312.30) disharmonies in partnership and – always recurrent – dis- 6. Disorders of Sexual Reproduction (coded in a gen- orders of sexual preference. Organic causes (testosterone eralized category called “not otherwise specifi ed” defi cit, hyperprolactinemia, side effects of medication) in ICD-10: F 69 and DSM-IV-TR: 309.9) are defi nitely signifi cant for differential diagnosis, but are sometimes overestimated in somatomedical literature.

26.4.1 Sexual Dysfunction 26.4.1.2 Erectile Dysfunction

The sexual response cycle can be subdivided into the fol- The prevalence of erectile dysfunction is well investi- lowing phases: desire, excitement, orgasm and resolution/ gated. In 17% of the 40–70-year-old men questioned, relaxation. Disorders of sexual response may occur at the Massachusetts Male Aging Study (MMAS) estab- one or more of these phases (Masters and Johnson 1966). lished a minimal, in 25% a moderate, and in 10%, a Like psychological and behavioral disorders, all sexual complete failure of erection (Feldman et al. 1994). dysfunction reveals biological and psychological as well Braun et al. (2000) found erectile dysfunction in 19.2% as sociological aspects, so that only a holistic viewpoint of their 4,489 30-year-old respondents, in whom the 544 K. M. Beier authors were able to show that absolutely not all test 2007). In giving valid prevailing fi gures, however, two persons with reported erectile dysfunction were not problems arise: fi rst, the normal ejaculation/orgasm satisfi ed with their sexual life. time period is assessed highly subjectively and is sub- Here, as well as in frequency of dysfunctions, there ject to great interindividual and also cultural variability was a signifi cant age effect. The same is true for the (Althof 2006; Montorsi 2005); secondly, exactly at this Berlin Male Study (Schäfer et al. 2003; Englert et al. point it becomes obvious that “impairment of func- 2007), in which the authors support the idea of differ- tion” and clinically relevant disorders are not identical entiating between “erectile dysfunction” and “erectile or concurrent (see above). disorder”. In their opinion, only an “erectile disorder” Practically every clinical medical department takes is to be regarded as a pathological disorder, because care of patients possibly suffering from sexual dys- the diagnosis is made according to DSM-IV-TR only function through an illness and/or its treatment. if the disturbance causes “marked distress or interper- Primarily cardiovascular diseases (heart failure, coro- sonal diffi culty”. An important fi nding in these surveys nary heart disease, myocardial infarction and hyperto- was the high coincidence between general medical nia) are the main ones which are sexologically relevant. symptoms (especially diabetes, heart disease and high In addition there are metabolic diseases such as diabe- blood pressure). It is often overlooked that the occur- tes mellitus, serious general illnesses, especially can- rence of an erectile disorder beyond the age of 40 can cer, locomotor restrictions (e.g., arthritis), neurological be a fi rst indication for chronic ischemic coronary dis- illnesses such as multiple sclerosis or Parkinson dis- ease (Görge et al. 2003; Chew et al. 2008). ease, but also neurologically related handicaps, psy- chiatric illnesses like anxiety disorder or depression, but also mental retardation and fi nally gynecological 26.4.1.3 Premature Ejaculation and urogenital illnesses. An independent specifi c coding of illness-related or Premature ejaculation, defi ned as a constant occur- treatment-related sexual dysfunctions is as compli- rence before or immediately after penetration over cated in DSM-IV-TR as it is in ICD-10. In ICD-10 the which the patient has no or very little control and is primary illness is coded separately, while in DSM- unable to experience the satisfaction of orgasm, is the IV-TR the dysfunction is identifi ed, but the primary most frequent sexual dysfunction in men. Approximately illness has to be fi lled in by free text. The multitude of 20–25% of men questioned in modern industrial coun- possible reasons for the development of erectile dys- tries have premature ejaculation accompanied by psy- function caused by illness or treatment are shown in chological stress (Mathers et al. 2007; Porst et al. Fig. 26.3 (in Rösing et al. 2009).

Condition post radical prostatectomy in prostate cancer Pharmaceutics effecting Condition post radical cystectomy in bladder cardiovascular diseases cancer Psycho pharmaceutics Diseases of the penis (induratio penis plastica, Pharmaceutics with endocrine penis fracture, auto-erotic accidental injuries) effects Condition post rectum carcinoma, carrier of colostomy, pelvis trauma Pharmacology Urology Surgery

Chronic pain Psoriasis Dermatology Erectile Disorders Orthopedics syndrome in vulgaris cinetosis (motion Contagious diseases) sexual Neurosurgery diseases Internal Medicine Neurology Psychiatry

Cardiovascular diseases Paraplegia, skull-brain trauma, brain tumor Fig. 26.3. Erectile disorders Artheriosclerosis Depression, anxiety disease Multiple sclerosis, morbus parkinson caused by illnesses and/or Diabetes mellitus Schizophrenia, Apoplexy, epilepsy Alcohol disease, drug abuse Sacral root lesion, polyneuropathy their treatment 26 Sexual Medicine and Andrology 545

26.4.2 Disorders of Sexual Development and is not to be defi ned as pathological or any kind of disorder, but as a possible variation of human sexuality (see Sect. 26.4). Problematic or pathological disorders This area deals with disorders surfacing in the context may develop when a confl ict in processing strategies and of somatosexual, psychosexual and sociosexual devel- inadequate integration of the preferred orientation is opment over a whole lifespan and which interfere with involved, causing the person to suffer. the persons’ sexual interaction abilities, even as far as The most frequent manifestation of sexual orienta- making sexual contact altogether impossible for them. tion disorder is to be found in self-alien homosexual ori- Often, these disorders lead to a secondary appearance entation (so-called “ego-dystonic homosexuality”). Not of other psychic behavioral disorders, which then least: in the light of a sociocultural background of a het- become the pretext for visiting the practitioner, replac- erosexual population majority there are fears of actually ing the original problem itself. It is believed that most being homosexual or of being unable to accept a realis- sexual development disorders themselves remain tic awareness of one’s own homosexuality and certainly unconsidered and are only treated on the (secondary) of not being integrated into one’s own sexual identity symptom level – often because the individual is unable (see below). Consequently denial or suppression to state exactly that the diffi culties originally (or also) attempts follow which are usually of short duration and are rooted in personal sexual development. often lead to outright rejection of one’s own sexual ori- This is even more so, when the problem is embed- entation: the result is a desire to change this condition. ded within complete development delay (retardation) (physical and psychological development disorder) or when the patient is altogether retarded. Retardation as 26.4.2.3 Sexual Identity Disorders a handicap does not alter the need for sexual contact and longing for a sexual relationship. A “sexual identity disorder” is defi ned as an uncertain approach towards one’s masculinity or femininity but 26.4.2.1 Disorders of Sexual Maturity without questioning affi liation to one of these genders (compare Sect. 26.3.3.) The category “disorders of sexual maturity” deals with If gender identity is expressed by the question: “Am psychosexual and sociosexual effects of delayed or I a man or a woman?”, then sexual identity is expressed undeveloped physical sexual maturity (e.g., “pubertas by the question: “Am I a real male or female, i.e., suf- tarda”). In many cases it causes disturbances of gender fi ciently male or female?” So it is all about feelings of and sexual identity formation and fi nally leads to adequacy and whether or not affected persons esteem developmental delay on the psychosexual/sociosexual themselves as being a real man or a real woman, espe- level; it results in retardation of sexual development cially in the sense of sexual attractivity. and diffi culties in taking up sexual contact with poten- While in gender identity sexual attractivity does not tial partners of the patients’ own age. play a leading role, in sexual identity the question Disorders of sexual maturity are especially serious arises whether one’s own gender-typical qualities can when they manifest themselves as sexual assault on be integrated into a sexual self-concept and whether children, because in such a case an adult suffering from gender-typical sexual behavior can be put into practice. somatosexual, psychosexual or sociosexual retardation Taking on substantial, continuous sexual relationships is unable to form adequate sexual relationships with may be especially diffi cult for men suffering from persons his own age and, seeking substitute gratifi ca- strong self-doubt and fear of failure concerning their tion, uses children to meet his needs (Beier et al. 2005). sexual performance and potency, triggering anxiety. This is a case of “male identity disorder” with result- ing consequences for self-evaluation and an inner atti- 26.4.2.2 Disorders of Sexual Orientation tude toward the male gender role, as well as toward trust in their own (sexual-) functional adequacy as a “man”. Sexual orientation towards one or the other gender is an (This often is the basis for wishing to alter physical fea- axis of the human sexual preference structure, regardless tures, such as employing breast and buttock implants and of which type (homosexual, bisexual or heterosexual) penis extensions.) This development can be described as 546 K. M. Beier

“sociosexual self-insecurity”, which far exceeds general, disorder, for instance, when one partner aims at sexual i.e., surmountable “shyness in the face of the other sex” contact only for reasons of reproduction, while per- and can be one reason for affected persons remaining haps the other partner does not share the strong desire without desired partnerships over a long period of time. for offspring and would refuse sexual intercourse. Often a disorder of sexual partnership again expresses itself in the absence of sexual reactions or even in 26.4.2.4 Disorder of Sexual Partnership sexual dysfunction.

A sexual partnership disorder is given when, over a long period of time, a person suffers from the incapa- bility to enter into or maintain a sexual relationship. 26.4.3 Disorders of Gender Identity The psychological stress arising from this condition is often a negative factor infl uencing life quality in general Patients with this disorder show insecurities, irritation and health in particular. The reasons for these problems and misperception concerning their own gender cate- may well lie in the spectrum of other sexual disorders, as gorization. An inner feeling of belonging to the oppo- well as in psychological and behavioral disorders, which site gender is dominant, contrary to their own biological make taking up and/or maintaining sexual relationships birth gender, they are living in the “wrong” body, giv- diffi cult or impossible. This nearly always places a disor- ing rise to a desire to change this situation. der of sexual partnership in a secondary position; the Within this disorder group there are different levels impossible or disturbed sexual relationship is usually a and stages with varying causes and must to be dealt sociosexual expression of a different, mainly primary with in different ways. For this reason these problems problem which generally emerges within the context of a are summarized under the generic term gender identity non-integrated social dimension of sexuality. disorders. A passing (not persistent) sense of discom- If, for instance, the dimension of desire is separated fort in one’s own gender, discontentment and insecurity from the attachment dimension, this can result in an regarding ones own social gender role, cosmetic or exaggeration of the dimension of desire at the expense other subjectively founded personal needs for measures of the attachment dimension, which is more often to alter body contours have nothing whatsoever to do found in men than in women. These men are then so with this group. Persons with a genuine gender identity focused on pleasure and its satisfaction in sexual expe- disorder nearly always need specialized psychothera- rience, that they do not experience this within the con- peutic treatment, the therapy aim of which is not “com- text of being connected with a partner (social) bat or reversal” of the desire to achieve a change in relationship. Their partner often reacts by sexual with- gender, but solely to offer these persons a strategy for drawal, because during sexual interaction they do not tackling their own gender identity insecurity over a long feel “wanted” or even feel “abused”. period of time and with an open outcome. At the same This disassociation can also take place during phar- time, therapeutic guidance allows the patient to test the maceutical symptomatic treatment of erectile dysfunc- gender genuinely felt under all circumstances and in all tion (e.g., PDE-5-inhibitors) without any sexual social areas of their own everyday life (so-called every- therapy treatment and without including the partner in day life test). With skilled help and advice the patient this treatment. It may cause an unintended increase of will be able to understand and process the developing the sexual partnership disorder. One reason why many impressions, experiences and feelings. men use erection-enhancing medication for only a The strongest and irreversible form of gender short period of time – aside from the high costs – is identity disorder is described as transsexuality. In because their partners signal that obviously the male’s such (more seldom) cases the origin lies in a lifelong focus is on erection and thus on the experience of lust persisting conviction of an irreversible i.e., fi nal disin- so that the woman’s own need for attachment, warmth tegration of one’s own masculine or feminine body and security is neglected and ignored; she feels disre- feeling. These cases often have to be treated with cross- garded and even degraded. gender hormone medication and in some cases with Even when the dimension of reproduction is unbal- sex-reassignment surgery, along with the necessary anced, i.e., overemphasized, it can lead to a sexual psychotherapeutic sessions. In the far more frequent 26 Sexual Medicine and Andrology 547

non-transsexual forms of gender identity disorder, Table 26.1 Disorders of sexual preference/paraphilias by ICD10/ however, body-altering measures (hormones, surgery) DSM-IV-TR are not considered as being indicated; the priority is on F65.0 Fetishism 302.81 Fetishism psychotherapy accompanying attainment of a suitable F65.1 Transvestic fetishism 302.3 Transvestic fetishism identity (Beier et al. 2005). F65.2 Exhibitionism 302.4 Exhibitionism F65.3 Voyeurism 302.82 Voyeurism F65.4 Pedophilia 302.2 Pedophilia F65.5 Sadomasochism 302.83 Sexual masochism 26.4.4 Disorders of Sexual Preference 302.84 Sexual sadism 302.89 Frotteurism (Paraphilias) F65.6 Multiple disorders of sexual preference Patients with disorders of sexual preference (paraphil- F65.8 Other disorders of sexual preference ias) experience deviating sexual impulses. F65.9 Sexual disorder not 302.9 Not otherwise Therefore, persons who have such inclinations, but otherwise specifi ed specifi ed paraphilia do not suffer by them, are not considered as disturbed, ill or in need of treatment, as long as they do not impair the prevalence of erectile dysfunction, its age-depen- or endanger others or themselves by acting out their dency and its relation to general health variables as deviating sexual needs. well as quality of life measures were determined in It is regarded as a special quality of sexual prefer- 6,000 men aged 40–79. In the fi rst phase of this study ence structure, which is manifest in every human on 1915 men took part (Schäfer et al. 2003). These men three basic axes: (a) with regard to the preferred gen- were then invited to take further part in a comprehen- der of the sex partner (male and/or female), (b) regard- sive sexological study by fi lling out an extensive ques- ing the preferred (bodily development), age of the sex tionnaire on sexual experiences and behavior, including partner (children, teenagers, young adults, adults, their (female) partners (later also questioned). The out- elderly persons) and (c) regarding the preferred kind come was a sample of 373 men, of whom 63 were and modus of sexual activity with and without sex single and 310 involved in a relationship (108 female partner(s) (type, object, method etc.). partners were additionally involved and personally Final manifestation of sexual structure takes place interviewed). The data give an impression of possible during youth and remains a constituent for life in its paraphilia-related tendencies within the general popu- basic features and is invariable. This includes invari- lation for arousal patterns which were characterized ability of certain special sexual inclinations, which are according to frequency of occurrence in sexual phanta- also manifest from youth on and which partly or com- sies, during masturbation (as contents of phantasies) pletely characterize the sexual structure of the person and during actual practice (Ahlers et al. 2008). involved (Sect. 26.4). 57.6% of the questioned men recognized one of Table 26.1 gives a summary of the most important these arousal patterns as part of their phantasies, 46.9% disorders of sexual preference (paraphilias) in DSM- used them for arousal enhancement during masturba- IV-TR (APA 2000)/ICD-10 (WHO 1993) tion and 43.9% acted out these patterns on the behav- ioral level. Even though the obligatory, almost unavoidable selection effects do not allow these fi gures 26.5 Impact of Disorders of Sexual to be applied to the general population, there is never- Preference, Sexual Behavior and theless a relevant hint given about the presumptive dis- tribution, which explains the extent and diversity of Sexual Reproduction offers by the pornography industry (Table 26.2). It is, however, to be assumed that most “deviating” First epidemiological data shows (Langström and sexual impulses are rooted in “normal” sexual response Zucker 2005; Ahlers et al. 2008) that the prevalence of and only turn into pathological disorders by their isola- paraphilia-related sexual arousal patterns is higher than tion or generalization. assumed. This is valid for German-speaking countries The DSM-IV-TR (APA 2000) takes this into account based on data of the Berlin Male Study (BMS) in which by admitting a diagnosis conditional upon the involved 548 K. M. Beier

Table 26.2 Prevalence of paraphilia-associated sexual arousal patterns on different experience levels in men between 40 and 79 years (no clinical population-based sample); results of the Berlin male study II Levels of Experience Sexual Fantasies Fantasies Accompanying Sexual Behavior Masturbation n % n % n % Non-human objects (e.g. material 110 29.5 97 26.0 90 24.1 or shoes) (fetishism) Wearing female clothes (transvestic 18 4.8 21 5.6 10 2.7 fetishism) Being humiliated (masochism) 58 15.5 50 13.4 45 12.1 Torturing other persons (sadism) 80 21.4 73 19.6 57 15.3 Secretly watching others in intimate 128 34.3 90 24.1 66 17.7 situations (voyeurism) Presenting one’s genitals to 13 3.5 12 3.2 8 2.1 strangers (exhibitionism) Touching strangers in public 49 13.1 26 7.0 24 6.4 (frotteurism, toucheurism) Childrens’ bodies (pedophilia) 35 9.4 22 5.9 17 3.8 Not otherwise specifi ed 23 6.2 23 6.2 17 4.6 Sexual response to at least one 215 57.6 175 46.9 163 43.7 arousal pattern/stimulus n = 373; Responses for different arousal patterns were prompted on a 5-step rating-scale with gradings: few - moderate - strong - very strong. All answers from “few” to “strong” were rated as a response to a sexual arousal pattern. person’s claims to suffer on account of this paraphilic subject to prosecution. Dissexuality is defi ned as fail- inclination or if it causes restrictions in signifi cant ure to conform to social norms – regarding less whether social or vocational life functions, or, if paraphilias that failure has been prosecuted or is subject to prose- potentially endanger others (e.g., a pedophile inclina- cution. It concerns all harmful sexual conduct (physi- tion), if the involved person has acted out his impulses cal or psychological) and is defi ned as irresponsible (regardless of any possible psychological pressure). sexual behavior which disregards the individual rights On the basis of these fi ndings it is quite remarkable of others (Beier 1995). that a signifi cant number (nearly one third) of the ques- Attempts at or actual performance of sexual acts on tioned men taking part in BMS II regarded paraphilia- or with children or juveniles or other persons unable to related sexual arousal patterns as inadequate and consent to these also belong in the category of sexual voluntarily relinquished acting them out – even if these behavior disorders (so-called “pedo-sexual” acts; in do not involve harming or endangering others (e.g., criminal law: “sexual abuse of children”). fetishistic). Nonetheless an also remarkable number of On the one hand disorders of sexual behavior can be participants revealed a potential for sexual infringe- attributed to acting out certain paraphilias, i.e., a ment (e.g., exhibitionism, voyeurism, frotteurism) or paraphilic impulse pattern can be the root of disturbed had already taken part in sexual (e.g., pedosexual) sexual behavior, defi ned as acts of inclination. In infringement in the past. other cases dissexual behavior is related to a different primary problem (e.g., a personality disorder, reduced intelligence or drug-abuse etc.): such irresponsible 26.5.1 Disorders of Sexual Behavior sexual acts are understood as substitute acts, compen- sating for the actually desired sexual interaction with a (Dissexuality) partner, which for several reasons is not realizable in a socially acceptable form. For sexological diagnosis This category summarizes all forms of sexual behavior this implies that disorders of sexual preference and by which health and well-being of others is damaged sexual behavior have to be well differentiated and not or their sexual self-determination is endangered, being confused, or even equated. 26 Sexual Medicine and Andrology 549

processes normally assigned to a manifest preg-

rs nancy (suspended menstruation, weight gain, child Sexual preference e Sexual behavior disorders d disorders n (Dissexuality) movement) are not perceived by the woman or are e f f

o

(Paraphilias) l Cases not covered up (kept secret); abortions and miscar-

a

i t

n Cases officially

e riages.

t o known

p officially known • Postnatal Disorders: e.g., postpartal depression, certain characteristics in educational behavior such as child abuse, but also treating the child as a self- Fig. 26.4 Spectrum of disorders in sexual preference and object (Beier 1995, 2000). behavior In all these disorders the reproductive dimension of Figure 26.4 is a schematic representation of sexual sexuality in its various phases – preconceptional, pre- preference and disturbances showing that within the natal and postnatal – is physically and psychophysio- whole spectrum of paraphilias the preponderant part logically impaired and leads to clinical symptoms has nothing to do with harmful sexual contact, i.e., dis- causing much suffering and/or endangering social sexuality. Conversely, dissexuality is usually not attrib- integration. uted to paraphilia. In simple terms, the majority of men Moreover, disorders of sexual reproduction are gen- with disorders of sexual preference (“paraphilia”) are erally linked with disorders of sexual relationship (see not dissexual, and the large number of men with sexual above), which can open up useful aspects for therapeu- behavior disorders (“dissexuality”) are not paraphilic. tic procedures. Moreover, only a minor number of dissexual acts are performed openly, meaning that they mostly do not come to the attention of the judiciary or police – but do, how- ever, play an important role in clinical sexual medicine. 26.6 Principles of Diagnosis in Sexual Medicine 26.5.2 Disorders of Sexual Reproduction In order to tackle the problem of a disturbed partner- ship and/or sexual life, it is essential to address the issue adequately and to explore sexual disorders as These disorders are characterized by psychological and well as to evaluate physical fi ndings and laboratory psychophysiological impairment of reproduction in its parameters competently. various phases ([pre]conception, pregnancy, birth as well The therapist offers a model for the opportunity of as child care and raising); they cause signifi cant suffering speaking openly about sexuality as a basic element of and/or diffi culties within human relationships. Adequate human life. This is one of the most important founda- coding by the international classifi cation systems (ICD- tions of sexological skills and defi nitely shows thera- 10 and DSM-IV-TR) is not possible. Clinically, however, peutical effects. It is long proven that patients actually they are distinguishable (Beier et al. 2006): wait for certain signals (Vincent 1964; Buddeberg • Preconceptional Disorders: e.g., involuntary child- 1996; Zettl and Hartlapp 1997; Fröhlich 1998). For lessness; phantasized pregnancy: In such cases, instance, on prescribing a new medication, the thera- non-existing physical and psychophysiological con- pist can provide a signal in terms of a question (e.g., version processes normally assigned to a manifest “Should the illness or its treatment lead to problems or pregnancy (suspended menstruation, weight gain, changes in your sexual life, we can talk about that and child movement) are defi nitely experienced by the look for solutions”). It is stressed, however, that the woman and presented convincingly to her social therapist should not retreat into the role of an expert. environment. He/she will always be confronted by subjective inter- • Prenatal Disorders: e.g., denied pregnancy: In such pretations – the patient’s, as well as his/her own – mak- cases physical and psychophysiological conversion ing personal compassion inevitable. 550 K. M. Beier

26.6.1 Exploration of a Sexual Disorder/ Table 26.3 Sexual preference structure: exploration tools Dysfunction Three Axes The human sexual preference structure is generally confi gured on three axes, i.e. Successfully carrying out treatment with decisiveness • Gender (of the desirable partner): the other or the same is based on extensive information on the specifi c sexual gender (or both); experience and behavior of a patient/couple. In the case • Age (of the desirable partner): children, adolescents, adults of an ongoing partnership, the information has to pro- or the elderly; and vide the investigator with insight into the level of sexual • Way (of the desirable partner or object or of an interac- tion): type, object, mode, procedure etc., functions and the sexual preference structure of both partners; otherwise therapeutic steps remain ineffective all intermingling with one another and of which all (from or can even cause harm (e.g., if a preference disorder nonconform to paraphilic) should be explored. remains undetected as a reason for dysfunction). Three Levels When a couple is involved, it must be decided Sexual experience and behavior should be investigated into whether the sexual anamnesis should be taken with on three different levels, i.e.: each partner alone or immediately with both partners • the sexual self-concept together. • the sexual phantasies and • the concrete sexual behavior, Single anamnesis has the advantage that the partner may be more uninhibited and speak more openly than all intermingling with one another and of which all should be in the presence of the other, particularly on subjects explored. like masturbation phantasies or topics like paraphilic Three Forms inclinations and past relationships. This can, however, The concrete sexual behavior should again be explored within three forms: make of the therapist a “keeper of secrets”, which could make future work with the couple diffi cult. • masturbation: self-stimulation and self-satisfaction; It is not crucial for the therapist to know every detail • extragenital sexual interaction: e.g. stroking, cuddling, kissing and about each partner. In fact, it is more important to gather • genital stimulation: manual, oral or other stimulation, e.g. information of relevance for both partners as a couple petting incl. sexual intercourse (penis or penis surrogate because it can be referred to later during couple therapy. penetrating vagina or anus, In view of this, the sexological anamnesis as a direct and these should also all be explored. couple-interview has great advantages, because all information issues are gathered together and processed treatment(s) only become evident through outright ques- from the beginning, which can demonstrate and tioning. Involvement of the partner in the interview increase the extent of openness and trust among the comes about automatically, because sexuality is a sub- partners involved. ject concerning both partners and in situations of inti- It is important to know which kind of disorder (e.g., macy, wishes and expectations of the partner have to be direct or indirect sexual dysfunction/function disorder; taken into account if the partnership is to be successful. disorder of sexual partnership) is being dealt with and This is demonstrated in the latest interview-study under which circumstances or conditions it arises (e.g., by Kleinplatz et al. (2007), in which men and women primary or secondary; generalized or situative). What (older than 65 years and involved in a long-term part- is the partner’s opinion on this disorder complained nership) comment on “great sex”, mentioning experi- about? Who takes the initiative in sexual contact? Are enced features such as authenticity, intense emotional there differences and where and how are they expressed? connection, communication and acceptance. Which preferences or aversions are there and how are Here functioning genital sexuality is not necessarily they dealt with? a condition for this experience; on the other hand, sex- This inevitably leads to analysis of possibly exist- ual functioning alone is not suffi cient for achieving ing peculiarities of sexual preference structure, but can sexually fulfi lling experiences. and should be investigated unreservedly (Table 26.3). Therefore, from a sexological point of view, the fol- It must also be said that effects on sexuality and part- lowing questions are diagnostically of special nership caused by aging or illnesses and/or their interest: 26 Sexual Medicine and Andrology 551

What is communication like within the partnership 26.6.2.2 Dimension of Reproduction in general and in sexual matters in particular? Can feelings, needs and wishes be communicated and does What signifi cance does reproductive capability have; this happen? Are set limits respected? Are there self- what role do children (the child) play within the rela- strengthening mechanisms, “vicious circles” or self- tionship? Do the partners have different views and atti- fulfi lling prophecies and how do these affect partnership tudes on this? Are there any problems, which may, for communication? Can misunderstandings due to misin- instance, cause an exaggerated desire to have children? terpretations of partner-behavior play any sort of role?

26.6.2.3 Dimension of Desire

26.6.2 Exploration of the Three How much signifi cance, which priority and what posi- Dimensions of Sexuality tion within the three dimensions is given to genital sex? (How) has the degree of signifi cance concerning desire Diagnostically and therapeutically it is essential to changed during the course of the relationship? Are there note the subjective classifi cation of the patients/the disturbing discrepancies between the partners? Are the couple on the three dimensions (reproduction, desire partners aware of the complexity of experiencing lust? and attachment). This usually involves fi rst-time anal- ysis and discussions about their own sexuality and 26.6.2.4 Individual and Partner-Related partnership which may already cause therapeutic Interaction of these Three Dimensions effects. In the end, the aim is to gain an idea of what “sexuality” actually means to the patient/couple Are there imbalances detectable by the individual part- (“What does sleeping with your partner mean to ner or by the couple that could be connected to a cur- you?”). In many patients, this may lead to the observa- rent sexual disorder? Here, the possibility of (a) the tion that some things are not so taken for granted as discrepancy between phantasized and sexuality experi- they might have thought to be (“we/I have never enced in reality and (b) the predominance of one of the thought about that” is a frequent answer to the above dimensions at the expense of the other or (c) a com- question). pletely different distribution must be taken into consideration.

26.6.2.1 Dimension of Attachment 26.6.2.5 History of Diseases and Somatic Is there a connection between sexuality and partnership Findings and how is it seen? Which contents and values are indispensable within the relationship? How well are All signifi cant illnesses treated medically at the pres- fundamental needs fulfi lled on the basis of this rela- ent time or previously should be taken into account, tionship? To what extent is sexuality understood as a but particularly those which might be connected with way of communicating these elementary needs on one the sexual disorder. This includes all urological, gyne- hand and satisfying them by communication on the cological or psychosomatic illnesses and surgery as other, so that showing affection, cuddling up or having well as medication and/or substance abuse or addic- coitus can be experienced as “mimic and gesture” in tion. It is also important to record all information con- this relationship? For example, is physical closeness cerning pregnancies and childbirth. In addition, all and acceptance obtained during coitus also an expres- therapy relevant to sexual disorders and previous psy- sion and implementation of psychosocial closeness and chotherapeutic treatment need to be looked into. acceptance existing in partnership? Is this communica- Bio-psycho-social anamnesis needs to include diag- tive point of view realized, implicitly acted upon or nostics for somatic fi ndings. This concerns sexual does it fail to play any part, neither in theory nor in functions as well as general physical functions. An practice? overview on the necessary physical diagnostics 552 K. M. Beier

Table 26.4 Organ diagnostics in sexual dysfunctions in men (Rösing et al. 2009) Physical Diagnostics Diagnostic Method For Exclusion Indication Clinical examination Inspection, palpation, pulse, Urogenital, neurological and General examination in exercise tolerance test cardiovascular diseases connection with risk factors (e.g. age, overweight) Laboratory Blood sugar Diabetes mellitus General examination Lipids Dyslipidosis General examination Testosterone Hypogonadism If necessary in arousal disorder or erectile dysfunction (ED), depending on further hypogonadism symptoms Prolactin Prolactinoma Imaging Duplex sonography with Cavernous insuffi ciency If necessary in ED; in the case intracavernous pharmaco- of no response to oral testing medication and wish for SKAT Neurophysiology (e.g. Neurogenic defi cit (e.g. If necessary in ED when corpus-cavernosum-EMG) following an accident) expertise or scientifi c issues are concerned Penile angiography Pelvic vascular occlusion Only in planned revasculari- sation surgery concerning sexual dysfunctions in males is shown in maintained an unchanged high value (Rösing and Table 26.4 (Rösing et al. 2009). Berberich 2004). The high rating of satisfaction of psycho-social intimacy, closeness and security in com- 26.7 Principles of Therapy in Sexual parison to aiming at sexual erotic satisfaction has also been validated by other studies (Deneke 1999). Medicine Sexological interventions, therefore, are absolutely based on consideration of bio-psycho-social aspects of The described bio-psycho-social cause of sexual disor- sexuality and on systematic involvement of aspects of ders calls for an appropriate therapeutic approach, a partnership and communication. Such modifi cations combination of methods of “talking medicine” with of the conventional patient concept also lead to a dif- those of somatic-/and pharmacological intervention ferent understanding of therapy. (Rösing et al. 2009). The familiar relationship of “therapist-patient” is Taking the treatment of post-prostatectomy erectile extended – especially in the case of sexual disorders – dysfunction caused by prostate cancer in Germany as to a new “therapist-couple” relationship. Advocacy an example, Herkommer et al. (2006) show that in for the patient turns into plural advocacy for the couple long-term exclusive use of medication or mechanical and their partnership, as long as this is the mandate treatment options, the patients were clearly less satis- given to the therapist. According to a Paracelsus quota- fi ed than their treating urologists would have imagined. tion: “The patient is the doctor and the doctor is his Even concerning selection of therapy options the assistant”, here lies the real therapeutically effective patients’ comments were clearly discrepant to the work with a couple; the “assistant” accompanying – judgment of their treating physicians. Questions con- making suggestions, settling problems, supporting, cerning the importance of partnership, of non-genital confronting, possibly acting as interpreter between dif- sexuality (the exchange of affectionate words and ferent personalities and genders. He enables the couple deeds) and genital sexuality (intercourse) put to pros- to gain new insights, especially new experiences which tate cancer patients and their partners showed that are designed to improve life quality. So the therapeutic before and after radical prostatectomy only the impor- aim is focused on partnership and sexuality. tance of genital sexuality decreased. Partnership in As patients with all sexual disorders described general and the meaning of physical attachment (the (Sect. 26.3) may attend an andrological clinical prac- exchange of affectionate words, gestures and touches) tice, various common links would very well serve as a 26 Sexual Medicine and Andrology 553 basis for the application of sexological therapy options. ners concerning the signifi cance of the different In everyday practice an indication-based cooperation dimensions of sexuality between andrology and sexual medicine has already proved itself: this applies particularly to the use of pharmacological options in the treatment of sexual preference disorder and/or behavioral disorders (cypro- 26.7.2 Sexual Therapy terone acetate, LHRH-analoga) as well as use of cross- gender hormone treatment in transsexual gender A largely negative experience of sexuality may create identity disorders. and continue sexual disorders which are bound to put strain on a partnership. Here, within the setting of sex- ological treatment, the (newly found or rediscovered) 26.7.1 Sexological Consultation understanding about the interrelatedness of the three dimensions of sexuality can be combined with well- directed evaluation and openness in talks about new The foremost principle is to create awareness in the physical experiences. In this way, partnership intimacy patient/couple concerning the attachment dimension may revive because of new shared sexual experiences of sexuality and to apply this therapeutic aspect. and change intimacy previously experienced. Many patients/couples do not realize that genital/ The general aim of therapy is, as mentioned coital sexuality is only one of many ways of satisfy- before, to enable both partners to satisfy each others’ ing wishes within a partnership concerning needs fundamental human needs – which are based on full for authenticity, appreciation, satisfaction, closeness, acceptance – through their sexual behavior in part- security etc. nership again. Accordingly sexological counselling will be adapted The method developed by Beier and Loewit (2004) to the specifi c needs of the patient/couple, in which the called Syndyastic Sexual Therapy (this new term “syn- following priorities alone or combined may play a dyastic” is derived from the Greek word “syndyas- role: tikós” – “inclined to intimate relations in the sense of Passing on knowledge (where defi cits are obvious) “affi liation” of two people, i.e., a couple or partnership”, concerning anatomic, physiological or psychological was fi rst applied by Aristoteles in his Nicomachean processes of sexual reaction, and, if necessary, correct- Ethics) puts fulfi llment of psychosocial fundamental ing false ideas in the sense of sexual myths (e.g., mas- needs into therapy focus. This makes it quite different turbation causes harm) which one or both of the from all other treatment methods (Rösing et al. 2009). partners may believe in. The priority is not to restore sexual function, the Assessment of mutual hopes and expectations therapeutic aim is to broaden the context of sexuality concerning sexuality and partnership. Teaching com- (particularly to appreciate the dimension of attach- municative strategies, if diagnostics have established ment), thereby gathering new experiences of (sexual) that general communication diffi culties are a reason body communication and improving (sexual) partner- for the development or continuation of the disorder/ ship satisfaction on the whole. (The option of effective dysfunction concerned. medication or other aids is no contradiction and can be When basic illnesses are involved, specifi c informa- a helpful supplement at times) (see Sect. 26.5.3). tion must be obtained: Thus, within the course of therapy, new, mutually • About the time elapsed between surgery and agreed upon, intimate experiences for the couple resumption of sexual contact (usually after approxi- emerge, allocating a new signifi cance of sexuality in a mately 6 weeks) much broader sense. These are not “prescriptions”, • About the use of lubrication gel, if, for instance, the because it is not possible to “prescribe” anything in a vaginal epithelium is altered by radiological or che- relationship; they are genuine, holistic and consciously motherapy or due to menopause lived partnership experiences. • In some cases concerning the use of aids (such as an It is immediately evident that, in an existing partner- erection ring, a vacuum pump, oral or injectable ship, the syndyastic focus is most effectively carried out medication options) – but not before dealing with by genuine involvement of the partner, placing the part- discrepancies in the relationship between the part- nership itself, i.e., the couple into the center of attention. 554 K. M. Beier

Particularly by sexually-lustful bodily acceptance and partnership points of view and to persuade them about intimate closeness basic needs are likely to be most the quality of a bio-psycho-social context of sexuality. intensively fulfi lled. It is, however, to be noted, that this This succeeds only (or at least better) if the thera- involves activation of basically already existing poten- pist is well informed about the advantages and disad- tial. Something is retrieved and nothing is “added”, vantages of medical treatment options. If the therapist which also discloses the limits of this treatment method. is able to convey to the patient that he sees their pos- Finally it must be stressed, that the syndyastic sexual sibilities and limits and wants to consider them with therapy method is not restricted to certain specialized the patient, particularly with regard to the dimension fi elds or schools. It merely relies on a basic psychoso- of relationship, then there is a good chance of building matic understanding and the willingness not to project up a strong working relationship and a solid basis for oneself into the role of the objective expert, but to actu- dealing with psychological and partnership problems. ally concentrate on the syndyastic focus – trusting in the knowledge that improvement of the fulfi llment of psychosocial fundamental needs can lastingly affect all other areas of life and health. References

Abraham L, Symonds T, Morris MF (2008) Psychometric vali- dation of a sexual quality of life questionnaire for use in men 26.7.3 Integration of Somatic Therapy with premature ejaculation or erectile dysfunction. J Sex Med 5:595–601 Options Ahlers CJ, Schaefer GA, Beier KM (2005) Das Spektrum der Sexualstörungen und ihre Klassifi zierbarkeit im ICD-10 und Including somatic options within sexual therapy takes DSM-IV. Sexuologie 12:120–152 Ahlers CJ, Schaefer GA, Mundt IA, Beier KM (2009) Diversity the bio-psycho-social etiology of sexual dysfunction and prevalence of paraphilia-associated sexual arousal pat- into consideration. Often it makes invasive somatic terns (PASAPs): First results of the Berlin Male Study II. interventions unnecessary, can, however, restrict the J Sex Med (in press) duration of sexual therapy, improve compliance and APA (American Psychiatric Association) (2000) Diagnostic and statistical manual of mental disorders, 4th edn rev. (DSM- prognosis of all treatment approaches – but is unfortu- IV-TR). APA-Press, Washington, DC nately hardly ever put to use in clinical practice. Althof SE (2006) Prevalence, characteristics and implications of As in all therapies, a combined course implies both premature ejaculation/rapid ejaculation. J Urol 175: problems and opportunities which have to be weighed 842–848 Balint M (1965) Die Urformen der Liebe und die Technik der up against one another in each single case: The patient/ Psychoanalyse. Huber, Klett, Bern/Stuttgart the couple may misunderstand the application of medi- Bartels A, Zeki S (2004) The neural correlates of maternal and cation as a form of an uncomplicated “quick-repair romantic love. NeuroImage 21:1155–1166 method”, which paralyzes the self-healing energy of Beier KM (1995) Aurorismus: Klinische Erscheinungsform einer “weiblichen Analogie” zur Perversion. Geburtsh Frauen- the couple and can reduce the motivation to deal with heilk 55:323–330 personal or partnership problems. Beier, KM (2000) Female analogies to perversion. J Sex Marit On the other hand, a combined course of action Ther 26:79–93 Beier KM, Loewit K (2004) Lust in Beziehung. Einführung in • Improves the effectiveness and prognosis of the die Syndyastische Sexualtherapie. Springer, Heidelberg treatment in many cases Beier KM, Bosinski HAG, Loewit K (2005) Sexualmedizin. München/Jena/Elsvier/ Urban & Fischer 2, Aufl age • Conveys to the patient that the therapist takes seri- Beier KM, Wille R, Wessel J (2006) Denial of pregnancy as a ously the patient’s own viewpoint, often fi xed on reproductive dysfunction: A proposal for international clas- somatic causes sifi cation systems. J Psychosom Res 61:723–730 • Establishes an initial working relationship and Bowlby J (1969, 1973, 1980) Attachment and loss, vol. 1, 2, 3. Basic Books, New York • By taking the patient seriously, opens a pathway to Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann consideration of psychosocial aspects U (2000) Epidemiology of erectile dysfunction: Results of the ‘Cologne Male Survey’. Int J Impot Res 12:305–311 Male patients are often convinced their problems are Brisch KH (1999) Bindungsstörungen. Von der Bindungstheorie of physical nature. In clinical sexological practice the zur Therapie. Klett-Cotta, Stuttgart purpose is to lead them towards psychological or Buddeberg C (1996) Sexualberatung. Eine Einführung für Ärzte, 26 Sexual Medicine and Andrology 555

Psychotherapeuten und Familienberater, 3. erw. Aufl . Brown, Boston (dt.: Die sexuelle Reaktion. Reinbek, Stuttgart, Enke Rowohlt 1970) Chevret M, Jaudinot E, Sullivan K, Marrel A, De Gendre AS Mathers MJ, Schmitges J, Klotz T, Sommer F (2007) Einführung (2004) Impact of erectile dysfunction (ED) on sexual life of in die Diagnostik und Therapie der Ejakulatio praecox. female partners: Assessment with the Index of Sexual Life Dtsch Arztebl 104:A-3475–3480 (ISL) questionnaire. J Sex Med 5:595–601 Montagu A (1987) Körperkontakt. Stuttgart, Klett-Cotta Chew KK, Bremner A, Jamrozik K, Earle C, Stuckey B (2008) Montorsi F (2005) Prevalence of premature ejaculation: a global Male erectile dysfunction and cardiovascular disease: Is and regional perspective. J Sex Med 2(Suppl 2):96–102 there an intimate nexus? J Sex Med 5:928–934 Pfaff DW (1999) Drive. Neurobiological and molecular mecha- Deneke FW (1999) Psychische Struktur und Gehirn: die nisms of sexual motivation. MIT Press, Cambridge Gestaltung subjektiver Wirklichkeiten. Schattauer, Stuttgart/ Ponseti J, Bosinski HAG, Wolff S, Peller M, Jansen O, Mehdorn New York HM, Büchel C, Siebner, HR (2006) A functional endophenotype Egle UT, Hoffmann SO, Steffens M (1997) Psychosoziale for sexual orientation in humans. NeuroImage 33:825–833 Risiko- und Schutzfaktoren in Kindkeit und Jugend als Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, Alexander Prädisposition für psychische Störungen im Erwachsenenalter. J (2007) The premature ejaculation Prevalence and Attitudes Nervenarzt 68:683–695 (PEPA) survey: Prevalence, comorbidities, and professional Englert H, Schaefer G, Roll S, Ahlers C, Beier K, Willich S. help-seeking. Eur Urol 51:816–823 (2007) Prevalence of erectile dysfunction among middle- Rosen RC, Seidman SN, Menza MA, et al ( 2004) Quality of aged men in a metropolitan area in Germany. 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Dtsch Arztebl (in press) Fröhlich G (1998) Psychosomatik männlicher Sexualität. Rüegg JC (2003) Psychosomatik, Psychotherapie und Gehirn. Sexuologie 5:203–211 Neuronale Plastizität als Grundlage einer biopsychosozialen Görge G, Flüchter S, Kirstein M, Kunz T (2003) Sexualität, Medizin. Schattauer, Stuttgart erektile Dysfunktion und das Herz: Ein zunehmendes Savic I, Berglund H, Lindström, P (2005) Brain response to Problem. Herz 28:284–290 putative pheromones in homosexual men. Proc Natl Acad Herkommer K, Niespodziany S, Zorn C, Geschwend JE, Sci USA 102:7356–7361 Volkmer BG (2006) Versorgung der erektilen Dysfunktion Schäfer GA, Engert HS, Ahlers ChJ, Roll S, Willich SN, Beier KM nach radikaler Prostatektomie in Deutschland. Urologe (2003) Erektionsstörungen und Lebensqualität: Erste Ergebnisse 45:336–342 der Berliner Männer-Studie. 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Contents 27.1 Requirements and Perspectives

27.1 Requirements and Perspectives ...... 557 Making contraceptive methods available to men is 27.1.1 Contraception, Family Planning one of the tasks of andrology. Such methods are and World Population ...... 557 27.1.2 Global Goal of WHO: necessary both to maintain stable populations in Reproductive Health ...... 560 industrial nations, as well as to diminish population 27.1.3 Acceptability of Male Contraception ...... 560 growth in developing countries. 27.1.4 Possibilities ...... 561 27.2 Existing Methods ...... 562 This chapter deals with the reasons for male contra- 27.2.1 Coitus Interruptus ...... 562 27.2.2 Periodic Abstinence ...... 562 ception as well as social and demographic factors and 27.2.3 Condoms ...... 563 the conventional methods for male contraception are References ...... 564 described. A separate chapter is devoted to vasectomy and refertilization (Chap. 28), while research and development in the fi eld of male contraception are dealt with in Chaps. 29 and 30.

27.1.1 Contraception, Family Planning and World Population

When giving advice about contraception and family planning as well as prescribing contraceptives, the physician must always concentrate on the desires and problems of the individual couple. Over and beyond this he should be aware that contraception also has demographic implications and infl uences population dynamics. While the individual couple may have its own ideas about the number of children they want, rep- resentative opinion surveys on the ideal size of the family show that these wishes have hardly changed in the course of the history of the German Republic and have remained at about two children per family; how- E. Nieschlag ever, the actual number of children per couple had Centre of Reproductive Medicine and Andrology of the University, Domagkstr. 11, D-48149 Münster/Germany already started to decline from the beginning of indus- e-mail: [email protected] trialization in the nineteenth century i.e., a trend which

E. Nieschlag et al. (eds.), Andrology, 557 DOI: 10.1007/978-3-540-78355-8_27, © Springer-Verlag Berlin Heidelberg 2010 558 E. Nieschlag

Number of children per family women (Benagiano et al. 2007). Deliberate birth con-

4 4 trol, e.g., for economic reasons, was already practiced 3.2 actual during earlier centuries (Bengtson and Dribe 2006). • Today’s contraceptive methods enable the couple to 3 2.7 3 • realize their goals more closely. Conversely, it is incor- 2.1 rect to assume that the mere availability of contracep- • • 1.9 2 2.2 2.2 • • 2 tives leads to a reduction of population in lesser • • developed countries; the individual couple’s motiva- 1.5 1.4 1 desired 1 tion and desires remain decisive. In 2007, the world population was 6.6 billion, having tripled in the last 50 years. Even conservative prognoses 1950 1969 1989 2004 estimate that 8 billion will populate the earth by 2020 (Fig. 27.2). Lesser developed countries bear the onus of Fig. 27.1 Desired vs. actual number of children per family; rep- resentative surveys among Germans over 16 years of age in 1950, this enormous population growth, while the population 1969, 1989 and 2004 (Allensbach Opinion polls 32, 2043, 5053 of industrial nations is largely stable. The population and 5177) explosion creates hardly surmountable ecological and economic problems. India can be taken as an example, began in Germany and Europe even prior to modern where one sixth of the world’s population occupies contraception (Birg 2001). However, with the intro- 2.5% of the earth’s land surface, and where uncontrolled duction of oral contraception and other modern meth- population growth wipes out the country’s economic ods in the 1960s, the number of births began to slowly progress, which has in part been spectacular. Medical decline and today the actual birthrate lies even lower progress has decisively lowered mortality, particularly than the desired goal (Fig. 27.1). of children, so that life expectancy worldwide is cur- The introduction of modern contraceptive methods rently 64.2 years for men and 68.6 for women. Ever led to a social revolution which has above all benefi ted more people reach reproductive age.

Population (in billions)

10

2000 8 6.1 billion

Less 6 developed countries

4

2

0 More developed countries 1750 1800 1850 1900 1950 2000 2050 2100 2150

Fig. 27.2 Worldwide population growth from 1750 to 2150. Medium level projection by the United Nations World Population Prospects 2007 27 Male Contribution to Contraception 559

Life expectancy has increased due to possibilities in western industrial nations and the generally stable offered by effective medical intervention. In contrast, demographic status are of decisive importance for pros- medicine offers only limited possibilities of adjusting perity and are largely due to contraceptive methods. reproduction to altered social and cultural life circum- It is, however, of much concern that research in the stances. Thus even today abortion, considered ethically fi eld of contraception has greatly declined in recent and culturally unacceptable in many countries, is used years. Especially industrial nations have reduced their for “family planning.” As a consequence, of the approxi- efforts. Leading pharmaceutical fi rms have drastically mately 1,000,000 conceptions taking place daily, of reduced studies on female methods and some have which about 50% are unplanned and 25% unwanted, even terminated research programs dealing with male 150,000 are terminated daily worldwide by abortion. contraception (Strauss and Chaudhuri 2007). Of these terminations, 500 end lethally for the woman. Publicly funded programs exist only in the USA (on Comparative investigations have shown unequivocally a modest level) and only a few organizations such as that the highest numbers of abortions are performed in the WHO and the World Bank, as well as philanthropic those countries where effective contraceptive methods foundations (Population Council, New York) have are not available (Fig. 27.3). Thus the Netherlands and active research programs (Vogelsong et al. 2008). To Germany have the lowest rate, while the formerly east- date the EU has systematically excluded contraception ern block states (with the exception of Catholic Poland), from its funding. and Cuba have the highest numbers. The example of In the meantime researchers have become alarmed Russia illustrates this reciprocal relationship: just prior (Nieschlag and Henke 2005; Nieschlag 2009) and poli- to the dissolution of the old Soviet empire the rate of ticians are beginning to acknowledge the problem. legal abortions was 64 per 1,000 inhabitants. With the Thus a committee of the British Parliament has clearly fall of the Iron Curtain the use of modern contraceptives recognized that without limitation of population rose rapidly and the abortion rate fell to below 40 growth the “Millenium Development Goals” cannot be per 1,000 inhabitants in 1996 and has now reached met (All Party Parliamentary Group 2007). The con- 19.3 per 1,000 inhabitants (Fig. 27.3). The low birth rates nection between world population growth, prosperity

Greece Poland India Finland Germany Canada Italy Israel Iceland Japan France New Zealand Norway USA Sweden Fig. 27.3 Number of annual Cuba abortions per 1,000 Hungary inhabitants in various Bulgaria countries (Most recent available data compiled by Russia United Nations Human Development Report 2009) 0 5 10 15 20 560 E. Nieschlag for all and uncontrollable ecological problems is offspring, as well as of controlling and planning fertil- becoming evident to ever growing circles. Ultimately ity. Contraceptive methods for men and women are however, research can only provide the means for con- considered essential components of strategies which traception. Its application in the sense of “reproductive should lead to a high standard of reproductive health rights” remains with the couple and the decision to use worldwide. contraceptive methods depends on other factors such as education and professional training of young women. Thus a clear correlation between reduction of 27.1.3 Acceptability of Male illiteracy and the use of contraception was found. Contraception

27.1.2 Global Goal of WHO: Recently public interest in male methods for contra- ception has notably grown. It is increasingly expected Reproductive Health that men share with their partners not only the advan- tages but also the risks of family planning. As risks Deeply aware of the situation, WHO introduced the tend to increase with duration of use, sharing contra- concept of “Reproductive Health” as its goal in this ception between men and women would reduce dan- area. Reproductive health means that reproductive gers for each partner. Population conferences and processes and functions should take place under condi- women’s world forums have explicitly called for new tions of “complete physical, mental and social well- methods. being” and signifi es not only freedom from disease Worldwide one quarter of all couples practicing and from possible disturbances of reproductive func- contraception rely on male methods, albeit with tions. A child, once conceived, should have optimal varying preferences (Fig. 27.4) and the proportion of conditions for undisturbed gestation and birth as well men practicing contraception is increasing. Thus in as for healthy childhood and development. Reproductive the Netherlands the percentage of vasectomized men health implies the possibility of realizing the desire for whose wives were of reproductive age rose from 2%

World

None; 36.9% D/P/S; 0.7% CI/PA; 7.0% Inject./implant; 3.4%

Condom; 5.7%

Hormonal Vasectomy; 2.7% contraceptives; 8.5% IUD; 15.5% Tubal ligation; 19.7%

Germany

D/P/S; 6.0% None; 29.9% Inject./implant; 0.0% Fig. 27.4 Use of contracep- CI/PA; 4.5% tive methods worldwide and Condom; 1.1% in Germany. D/P/S: diaphragms, cervical cap, Vasectomy; 0.5% spermicides etc. CI/PA: coitus interruptus, periodic Tubal ligation; 5.5% abstinence (UN Population Oral contraceptives; IUD; 5.3% Division, New York 2007) 52.6% 27 Male Contribution to Contraception 561

Vasectomy Condoms

World more developed less developed

UK New Zealand Singapore Canada South Korea Netherlands USA Australia Switzerland China Southern Europe India Germany Eastern Europe Turkey Pakistan Africa 0 5 10 15 20 25 20 15 10 5 0

Fig. 27.5 Worldwide and country-specifi c use of vasectomy and condoms. Figures represent percentages of women who are mar- ried or in union in 2007 (www.unpopulation.org)

to 10.5% from 1975 to 2008 and from 8% to 12.2% in 27.1.4 Possibilities the USA; the highest rate of vasectomized men is found in the United Kingdom and in New Zealand. In general men’s willingness to contribute to contra- Worldwide, however, only 2.7% of men are vasecto- ception can be considered to be high. However, before mized. Similarly, the use of condoms for contracep- men accept such a contraceptive method certain pre- tion varies from country to country with a worldwide requisites must be fulfi lled. The method should: average of 5.7% (Fig. 27.5). It is to be expected that the percentage of men willing to practice contracep- 1. Be as effective as comparable female methods tion varies between cultures and with methods 2. Be acceptable to both partners available. According to a survey in Hongkong and 3. Be rapidly effective Shanghai 10 years ago, half the men interviewed were 4. Be free of side-effects and especially be without willing to take a daily contraceptive pill; in Edinburgh infl uence on masculinity, libido and potency and Capetown two thirds were willing to do so 5. Be without infl uence on progeny (Anderson and Baird 1997). After almost 50 years of 6. Be reversible in regard to fertility female oral contraception, the attitude of men towards 7. Be easily available and fi nancially affordable new methods of male contraception has changed. Worldwide and also in Germany surveys showed men These criteria provide guidelines for evaluating exist- willing to use pharmacological contraceptive meth- ing methods and experimental innovations. Basically ods (Heinemann et al. 2005) (Fig. 27.6). these methods can be characterized as follows: 562 E. Nieschlag

Fig. 27.6 Multinational male 80 fertility control survey among Willing 9,342 men. “If available 70 Uncertain would you be willing to use Disapproving the new male fertility control 60 method?” (Heinemann et al. 2005) 50

% 40

30

20

10

0 GER FRA SPA SWE USA ARG BRA MEX INDON n = 1021 725 1049 1023 1500 1000 1000 1024 1000

1. Those preventing sperm transport into the 27.2 Existing Methods female genital tract 2. Those suppressing spermatogenesis or 3. Those preventing sperm maturation or function 27.2.1 Coitus Interruptus

All existing methods belong to the fi rst group, whereas The criteria given in Sect. 27.1.4 can be used to evalu- current research concentrates on infl uencing germ cell ate existing and new methods for male contraception. development and maturation. The method practiced longest, coitus interruptus, has the advantage of being completely free of side-effects, requires nothing additional and costs nothing. It does, The possibilities of effective and reversible contra- however, require dexterity and self-discipline and ception are limited to female methods. Periodic reduces sexual pleasure. Moreover, its failure rate is abstinence, the condom and coitus interruptus, as high, as a pregnancy occurs in 19 out of 100 couples relatively unsafe methods, or vasectomy, as a method during the fi rst year of practice. Other non-penetrating with limited reversibility, are available to the male. sexual practices (“dry sex”) probably have lower preg- nancy rates, but no exact fi gures are available. The distribution of male and female methods used worldwide and, for example in Germany, shows (Fig. 27.4) that basically only a narrow spectrum of methods is actively available. All pharmacological 27.2.2 Periodic Abstinence methods derive from one principle, namely . The danger of overdependence on this Periodic abstinence, on which the various methods of method becomes apparent when one considers a pos- natural family planning (NFP) are based, limits sex- sibly drastic reduction in its use. This should provide ual activity to so-called “safe days” on which the likeli- suffi cient impulse to search for new methods. As no hood of conception is low. Even if this method relies on male pharmacological method for contraception yet observations based on the female cycle, it does require exists, research in this fi eld remains a major task (see a male contribution as spontaneity and intercourse must Chaps. 29 and 30) (Fig. 27.6). be foregone for relatively long phases of the cycle. The Existing and experimental methods are described in methods’ safety increases with the number of days of the following section. abstinence from intercourse. On average a large number 27 Male Contribution to Contraception 563 of failures is presumed in which 20 of 100 couples per Today the manufacture of condoms is subject to year conceive (Trussell et al. 1998). In a German wom- standardized quality control and specifi cations of the en’s hospital 38 of 87 (= 45%) women gave birth after WHO (2004). Since 1996 condoms sold in Europe pregnancies occurring despite contraception based on must fulfi ll quality requirements as prescribed in the “safe days” (Knuth and Mühlenstedt 1991). DIN EN 600, international ISO 4074 (since 2002). If a portable monitoring device (Persona¨) is used These norms prescribe a size of 17 or 16 cm length and to indicate days on which abstinence is to be practiced a maximum diameter of 5.6 cm. In addition, the con- by measuring LH and -3-glucuronide in urine, traceptives must undergo serial tests for impermeabil- the pregnancy rate drops to 12% (Bonnar et al. 1999). ity, infl atability, elasticity and microbiological purity. On average 13 days within a cycle must be considered Even if manufacturing is subject to quality control, “unsafe” or other contraceptive methods must be used in a high percentage of cases the condom may tear dur- during this time. ing intercourse. The older the condom, the higher the When evaluating coitus interruptus, periodic absti- risk of damage (Steiner et al. 1992). Apparently sexual nence and non-penetrating sexual practices it must be practice also plays a role, as some couples always report considered that despite their low effectiveness, in a higher rate of tearing than others, as seen in trials with demographic terms these methods may contribute to motivated and experienced couples who had no prob- population control, even if the risk of pregnancy lems with tearing (Rosenberg and Waugh 1997). remains high for the individual couple. Reports on contraceptive effectiveness of the condom show considerable variation. In general, it is assumed that 19 out of 100 couples will conceive during the fi rst year of condom use (Trussell 1998). This is considerably 27.2.3 Condoms better than the 85% of conceptions arising from unpro- tected intercourse, but ranges far behind the 3% probably The condom is the oldest contraceptive method available achieved by female oral contraceptive methods. today. Early Egyptian drawings show men wearing con- Contraceptive protection is lower for polyurethane con- doms. In 1200 BC fi shbladders were used at the Minoan doms than for latex condoms (Gallo et al. 2006). In addi- court on Cyprus to prevent disease and pregnancies. In tion, effectiveness drops if condoms are used for a longer 1564 the Italian anatomist Fallopio described linen bags timespan. This depends not only on technical defects of saturated with medication to be used to avoid venereal the product but on the fact that condoms must be used in disease. In seventeenth century England condoms were direct connection with the sexual act and require con- fi rst used for birth control. It is not certain whether the stant motivation and attention. For this reason many name derives from the English physician Condom, who couples in stable relationships consider condoms only as was active at the court of Charles II from 1660 to 1685 a temporary contraceptive method. and who recommended lamb intestines for contracep- The acceptability of condoms varies greatly with tion. The method was quickly exported to France and socio-cultural factors. It is estimated that in Japan became widely used in Paris. Condoms were known almost four fi fths of couples practicing contraception there as “capote anglaise,” while in England they were use condoms. In Germany about a quarter of all cou- called “French letters.” The latex-based condom was ples of reproductive age use them. made possible by the American Charles Goodyear Since the beginning of the AIDS epidemic and the (1800Ð1860) after he invented the process of vulcaniza- call for “safe sex” the condom has greatly gained in tion. The fi rst large-scale manufacturer was Julius popularity to avoid the risk of infection. Its effective- Fromm, who produced 150,000 condoms daily in 1920. ness in avoiding HIV transmission is, however, mark- At present condoms continue to be manufactured edly lower than in preventing pregnancies. This is not largely from latex, but polyurethane condoms are also surprising in view of the technical failure rate and in available. As these have a higher rupture rate and offer view of the fact that the danger of infection exists not even less contraceptive protection than latex condoms, only at the time of ovulation but during every sexual their use is limited to users allergic to latex (Gallo et al. act. Meta-analyses conclude that the failure rate in the 2006). At present spray-on condoms are being tested, prevention of HIV infections is about 31% (Weller which would solve the problem of size. 1993) to 50% (April et al. 1993). Thus the protective 564 E. Nieschlag effect of the condom against this often lethal disease Gallo MF, Grimes DA, Lopez LM, Schulz KF (2006) Non-latex must be considered inadequate. versus latex male condoms for contraception. Cochrane Database Syst Rev CD 003550 Heinemann K, Saad F, Wiesemes M, White S, Heinemann L (2005) Attitudes toward male fertility control: Results of a multinational survey on four continents. Hum Reprod 20:549Ð556 References Knuth UA, Mühlenstedt D (1991) Kinderwunschdauer, kon- trazeptives Verhalten und Rate vorausgegangener Infertil- itätsbehandlung. Geburtsh Frauenheilk 51:1Ð7 All Party Parliamentary Group on Population, Development and Nieschlag E (2009) Male hormonal contraception: love's labour’s Reproductive Health (2007) Return of the population growth lost? J Clin Endocrinol Metab 94: 1890Ð1892 factor: Its impact upon the Millennium Development Goals. Nieschlag E, Henke A (2005) Hopes for male contraception. House of Commons, London Lancet 365:554Ð556 Anderson RA, Baird DT (1997) Progress towards a male pill. Rosenberg MJ, Waugh MS (1997) Latex condom breakage and IPPF Med Bull 31:3Ð4 slippage in a controlled clinical trial. Contraception 56:17Ð21 April K, Köster R, Schreiner W (1993) Wie effektiv schützen Steiner M, Foldesy R, Cole D, Carter E (1992) Study to Kondome vor einer HIV-Übertragung? Med Klinik 88: determine the correlation between condom breakage in 304Ð311 human use and laboratory test results. Contraception 46: Benagiano G, Bastianello C, Farris M (2007) Contraception: 279Ð288 A social revolution. Europ Contracept Reprod Health Care Strauss JF, Chaudhuri G (2007) The accelerated pace of pharma 12:3Ð12 abandonment of research and development in family plan- Bengtson T, Dribe M (2006) Deliberate control in a natural fer- ning and fertility: Will reproductive health technology be tility population: Southern Sweden, 1766Ð1864. Demography frozen in time? Fertil Steril 87:818Ð718 43:727Ð746 Trussell J (1998) Contraceptive effi cacy. In: Hatcher RA, Birg H (2001) Die demographische Zeitwende. 4. Aufl age, Trussell J, Stewart F (eds) Contraceptive technology. New C.H. Beck, München York Ardent Media, New York, pp. 779Ð844 Bonnar J, Flynn A, Freundl G, Kirkman R, Royston R, Snowden Vogelsong K, Gabelnick HL, Nieschlag E (2008) Partnerships R (1999) Personal hormone monitoring for contraception. offer promise in developing systemic methods of male fertil- Br J Fam Plann 24:128Ð134 ity regulation. Global Forum Update on Research for Health Connelly M (2008) Fatal misconception: The struggle to control 4:128Ð130 world population. Belknap Press of Harvard University Weller SC (1993) A meta-analysis of condom effectiveness in Press, Cambridge, MA reducing sexually transmitted HIV. Soc Sci Med 36: De Vincenzi I for the European Study Group on Heterosexual 1635Ð1644 Transmission of HIV (1994) A longitudinal study of human WHO (2004) The male latex condom: Specifi cations and guide- immunodefi ciency virus transmission by heterosexual part- lines for condom procurement. Geneva ners. N Engl J Med 331:341Ð346 Vasectomy and Refertilization 28 U. Engelmann and Oliver Gralla

Contents 28.1 History of Vasectomy

28.1 History of Vasectomy ...... 565 It is impossible to date the earliest vasectomy. At the 28.2 Social and Demographic Relevance ...... 566 end of the nineteenth century such operations were not 28.3 Indications for Vasectomy ...... 566 performed for sterilization, but for other medical indi- 28.4 Informed Consent ...... 567 cations. At the time of the earliest vasectomies it was believed that severing the vas deferens would improve 28.5 Surgical Vasectomy Techniques ...... 567 prostate disease, heal impotence or extend life expec- 28.6 Technical Modifi cations ...... 568 tancy. Vasectomy was advocated as a “fountain of 28.7 Effectiveness and Cost Effi ciency ...... 568 youth” (Isnardi 1896; Wolfers and Wolfers 1974). Eugenic aspects also played an important role 28.8 Complications ...... 568 among the indications for sterilization, as did elements 28.9 Vasectomy and Long-Term Morbidity ...... 569 of social control as advocated by Ochsner (1899) and 28.10 Psychosexual Effects ...... 570 Sharp (1902). In the 1920s and 1930s a series of nations 28.11 Refertilization ...... 570 passed laws justifying sterilization for eugenic reasons. Along with the other cruelties practiced by the Third 28.11.1 History of Refertilization Surgery ...... 570 28.11.2 Current Demand and Frequency Reich, compulsory sterilization for eugenic purposes of Refertilization ...... 570 achieved worldwide notoriety following the end of 28.11.3 Vasovasostomy ...... 571 World War II. This resulted in the abrogation of the 28.11.4 Epididymovasostomy ...... 573 legal basis for eugenic sterilization in most states. Some 28.11.5 Future Developments in Surgical Refertilization ...... 573 states, however, maintained these laws and later some 28.12 Future Development of Vasectomy ...... 574 tried to apply them. Drake et al. (1999) describe the varied history of vasectomy and its changing indica- References ...... 575 tions over the course of time. Vasectomy as a means of contraception became popular in the 1960s, fi rst in the USA, then in Europe and Third World nations. Countries with particularly rapid population growth such as India and Thailand (Nirapathpongporn et al. 1990) established vasectomy camps and, according to Smith et al. (1985), in the USA sterilization became the form of fertility control most frequently chosen by married couples over 30 years of  U. Engelmann ( ) age. According to a survey, in Germany a frequency of Urologic University Hospital, Joseph-Stelzmann-Str. 9, D-50924 Köln about 50,000 vasectomies per year can be extrapolated e-mail: [email protected] (Deindl 1990).

E. Nieschlag et al. (eds.), Andrology, 565 DOI: 10.1007/978-3-540-78355-8_28, © Springer-Verlag Berlin Heidelberg 2010 566 U. Engelmann and Oliver Gralla

28.2 Social and Demographic Relevance of vasectomy as compared to tubal ligation has increased over the years in England (Rowlands and Hannaford Countries with high birth rates should be considered 2003), as well as in Canada. The use of oral contracep- apart from industrial nations. Contraceptive vasectomy tives and tubal ligation in the Canadian population is is not popular in all developing countries, and in some it decreasing, while requests for vasectomies are steadily plays no role at all. In India and China, and, to a lesser rising (Martin and Wu 2000). With advanced and ongo- extent, in Korea, Sri Lanka and Bangladesh, vasectomy ing aging of the population, vasectomy is no longer is widely performed (Ross and Huber 1983). Generally, only an issue for young men. Older men also engage in sterilization in the male always competes directly with sexual activity and favor vasectomy for contraception. corresponding measures in the female, i.e., tubal liga- In an Australian study of middle-aged males, 25.1% tion, which ironically has become increasingly popular had been vasectomized, 5.6% of the vasectomized men because of improved techniques, although vasectomy did not have children and 37% of men above 70 years was always technically simple (Ross and Huber 1983). of age were still sexually active (Holden et al. 2005). In any event, the introduction of minimally invasive In Germany, Schirren (1983) above all drew atten- “no scalpel” techniques serves to make vasectomy tion to the subject of vasectomy, to indications for the much more acceptable (Xiaozhang and Shungiang intervention and to its possible complications. In 1983 1993; Reynolds 1994; Ozvaris et al. 1998). These are he propagated the incorrect, and unfortunately still based on percutaneous electrocoagulation or chemical prevalent, opinion that vasectomy represented an irre- denaturing of the vas, or specialized puncture instru- vocable intervention which, if performed without suffi - ments which are used to minimize surgical trauma. cient consultation with one’s partner and “inner circle”, Particular ethical considerations concerning male could be considered a “dangerous undertaking”. sterilization apply in developing countries (Rizvi et al. Considerable consequences for the personality structure 1995) and explain the former preference for female of the man and thus for the partnership were postulated. over male sterilization (3:1) with the rationale that On the contrary, it has since been demonstrated that vasectomy is hardly reversible and thus unpopular. men who are prepared to undergo vasectomy usually New and advanced technologies such as sperm cryo- live in relationships with a strong emphasis on part- preservation are only available in wealthy countries. nership. Under certain conditions, positive and benefi - Sixty-seven to 88% of the American population use cial effects for a relationship can even be expected contraceptive methods for obviation of pregnancy, as (Goebel et al. 1987). This infl uences patient selection reported by the “Behavioral Risk Factor Surveillance made by counselling and operating physicians, result- System”. According to this survey, women favor oral ing in the fact that in Germany predominantly men liv- contraceptives, while men primarily rely on the surgi- ing in stable relationships are vasectomized. The number cal approach, i.e., vasectomy (Bensyl et al. 2002). of vasectomized men varies in German-speaking coun- Another study found that about 25% of eligible cou- tries: in Germany 422 men per million inhabitants are ples in the USA rely on sterilization for birth control, vasectomized annually; in Austria the number is only with distinct differences between black and white popu- 81 (Engelmann et al. 1990). lations: among Caucasians vasectomy and tubal ligation are performed about equally, while among blacks tubal ligation is clearly preferred (Forste et al. 1995). In the USA vasectomized men generally have above-average 28.3 Indications for Vasectomy education, their family planning is complete and they learned about vasectomy methods in newspapers or In contrast to formerly held but still widely accepted magazines (Kohli 1973). Thirty years later, no signifi - opinions, we believe that the indication for contracep- cant changes can be ascertained: vasectomized men in tive vasectomy is easily established. the USA are typically well-educated, married Caucasians with good medical insurance (Barone et al. 2004). Every man of legal age and able to give consent In England only minimal differences between social may decide in favor of vas ligation or occlusion for classes were found with respect to the acceptance of the purpose of sterilization. vasectomy (Wright et al. 1977). The general acceptance 28 Vasectomy and Refertilization 567

No special medical or social indication is necessary. But to consent to the procedure themselves. Due to many physicians performing vasectomy require certain Germany’s recent past, this is a particularly sensitive preconditions, mostly to provide backup support for the subject there. Various lobbies as well as the German physician. In such cases, for example, a certain number Society of Medical Law (DGMR) have discussed this of children are required, a stable relationship with writ- subject in publications, lectures and workshops. In ten consent given by the partner is desired; fi nally, the Germany, vasectomy policy for patients who are not chances for refertilization are deliberately and falsely able to consent to the procedure is regulated by law. minimized. These measures represent a bias concerning Consent demands the authorization of a guardianship the affected persons; only those highly determined to court. Vasectomy of minors is forbidden in Germany. undergo vasectomy will be accepted. This procedure Neither the underage patient nor his parents can con- may be understandable, but it is not in the best interest sent to sterilization (Hiersche and Hiersche 1995). of the responsible citizen and patient. He has the right to objective counselling about the chances and risks con- cerning the intervention he wishes. Well-meaning, but false-negative counselling of the patient must not deprive 28.5 Surgical Vasectomy Techniques him of the possibility of deciding in favor of vasectomy. This does not limit the surgeon’s right to decline to per- Vasectomy is a good example of how simple matters form a vasectomy in individual cases. can be made complicated. What is to be achieved? The goal of the operation is to occlude the ducts reliably to prevent passage by spermatozoa, permanently or as long as the patient desires it. The following procedure 28.4 Informed Consent has been established:

As in all other surgical procedures, the patient must be In the ambulatory patient both spermatic cords are informed and his consent obtained at least 1 day prior infi ltrated with an anesthetic. Only in rare and excep- to the operation itself. We observe the procedures tional cases is the intervention performed under gen- generally accepted for surgery without any special eral or regional anesthesia. The cords are digitally modifi cations. Neither consent of the female partner, localized through the scrotal skin and, if necessary, nor even her existence is required. Information is pro- local anesthesia is supplemented by deeper infi ltra- vided about the procedure, which is almost always car- tion. After ascertaining the effectiveness of the anes- ried out on an outpatient basis. The chances for thesia, the ejaculatory duct is clamped through the subsequent refertilization are explained according to skin, using a small clamp, and the scrotal skin is statistics in the literature with patency rates of 70Ð90%. incised over a distance of 0.5Ð1 cm. The vas is sepa- Acute complications consisting of bleeding and infec- rated from the sheath and divided over two mosquito tions, usually negligible, rarely occur, but are men- clamps. The vas is then dissected and a piece of tioned. Possible connections between vasectomy and approximately 1 cm is excised and fi xed in formalin. other diseases, e.g., arteriosclerosis or prostate cancer, The vasal ends are ligated and electrocoagulated. The discussed in the past and again recently, are mentioned entrance wound is sutured with a single suture (Figs. to the patient with reference to the relevant investiga- 28.1 and 28.2). The identical procedure is performed tions. In cases of doubt, the physician’s explanation on the contralateral side. The wounds are covered with and personal interpretation may be helpful. The need two small dressings. After 1 h the area is checked and for postoperative semen analysis is stressed. Although the patient can be discharged to home care. other surgeons proceed differently, we do not regularly use written forms for informing the patient and we do not even insist on a written statement of consent. We The following is important: the patient must be well- do, however, note in the patient’s chart that informa- informed and not be afraid of the procedure. In dubi- tive counselling has taken place. ous cases, premedication is highly effective. In Special considerations are involved when vasecto- sensi tive patients placement of a venous catheter is mies are performed on patients who are not able recommended. It should not be forgotten that even in 568 U. Engelmann and Oliver Gralla

28.6 Technical Modifi cations

The technique described above, practiced and well- documented for over 30 years, represents a combina- tion of several important features. The use of a special puncture device has obtained general acceptance as a “no scalpel” technique; the same is true for electroco- agulation of the cut edges of the vas deferens or the interposition of connective tissue (fascial interposi- tion: FI). Labrecque et al. (2004) concluded in a sys- tematic review that the “no scalpel” vasectomy is the safest surgical approach to the vas deferens and that a combination of FI and electrocoagulation yields the most effective occlusive results. Comparable data were reported by Cook et al. (2007a, b) in two Cochrane Reviews: the “no scalpel” technique is associated with Fig. 28.1 Following a longitudinal incision of the scrotal skin a lower rate of hematoma and infection and less post- along the vas deferens the vas is lifted by a small clamp operative pain compared to the conventional technique. Moreover, fascial interposition reduces the occurrence of vasectomy failures.

28.7 Effectiveness and Cost Effi ciency

When correctly performed, vasectomy is among the safest contraceptive methods. In most larger-scale studies the failure rate lies below 1% (Trussell et al. 1990), or between 0% and 2% (Awsare et al. 2005). This makes vasectomy as effective as tubal ligation. Failure is due to recanalization of the divided duct in up to 1.5% of cases (even possible in the form of late recanalization after two negative spermograms in 0.04Ð 0.2% of patients), or to the extremely rare occurrence of a double vas or incomplete division of the duct. Failure rates increase with lack of experience, inferior operat- ing techniques and diffi cult anatomical circumstances. Vasectomy is the most cost-effi cient method of con- traception (Nakhaee et al. 2002); thus, its implementa- tion could achieve considerable cost savings in public health (Sonnenberg et al. 2004). Fig. 28.2 Distal ligation of the vas deferens and cauterization of the proximal lumen such minor surgery emergency measures may become 28.8 Complications necessary. Acute complications are rare, but when they do occur, they are extremely irritating. Even minor Acute postoperative complications must be distin- bleeding can spread throughout the soft tissue, result- guished from long-term complications. Hematoma of ing in scrotal hematoma up to the size of a fi st. various degrees, epididymitis or wound infections up 28 Vasectomy and Refertilization 569 to formation of an abscess occur with a frequency of advisable to perform histological examinations of the up to 1Ð6% (Alderman 1991; Schwingl and Guess resected parts of the duct to demonstrate the resection 2000). While this rate seems high, it should be remem- in complete tubal diameter. bered that vasectomy is a minor operation performed by many surgeons with only limited experience with this procedure. Its supposed harmlessness tempts some 28.9 Vasectomy and Long-Term surgeons to perform it on an outpatient basis, quickly and inattentively. The price is necessarily an increased Morbidity rate of acute complications. These lead to short-term absence from work of an average of 2.3 days (Randall Complaints of congestion, a feeling of obstruction and Marcuson 1985). Serious complications virtu- or heaviness in the testis and epididymis as well as ally never occur; deaths during or after vasectomy pain of different degrees are occasionally described by have not been reported, whereas in the USA 14 deaths/ the patient, but are usually temporary. Chronic epididy- year are attributed to female sterilizations. Concerning mal pain is in all events rarely seen; its appearance is costs, vasectomy is more economical than tubal liga- sparsely documented in the literature. Sperm antibod- tion, with the short-term costs of tubal ligation about ies in the serum can be found in up to 70% of those three to four times higher (Smith et al. 1985; Hendrix sterilized (Heidenreich et al. 1994). Their presence is et al. 1999). often associated with sperm granulomas. If refertiliza- Long-term surgical complications include reca- tion is desired, we are not infl uenced by the presence nalization on the one hand and the development of of sperm antibodies nor by the titre, but perform refer- sperm granuloma on the other. Recanalization rates tilization in any case. are reported to be about 0Ð3%. The actual rate depends In the past, various diseases have been causally on the surgical technique used. Resection of larger sec- attributed to vasectomy. Based on monkey studies in tions of the vas, burying the ends of the ducts in differ- 1978 it was concluded that vasectomy could enhance ent planes of tissue, the use of fi brin glue or fulguration arteriosclerosis. Several large-scale investigations of the lumen are all useful methods for minimizing the involving over 10,000 men determined that vasecto- rate of recanalization. The use of minimally invasive mized men bore no higher risk for arteriosclero- techniques can, on the one hand, increase the chance of sis, diabetes mellitus or immunological diseases later refertilization, but, on the other hand, it can also (Nieschlag 1987; Giovannucci et al. 1992). The risk of greatly increase the chance of recanalization by up to cardiovascular diseases after vasectomy is not increased 50% (Goldstein 1983). The occurrence of sperm gran- in the long term, as Manson et al. reported in the uloma is likewise correlated with surgical procedures “Physicians’ Health Study” in 1999. A few years ago a used and varies considerably. The data in the literature possibly higher incidence of prostate carcinoma in vary between 3% and 75%. In terms of refertilization vasectomized males was suggested by retrospective chances, a sperm granuloma can be evaluated posi- investigations (Giovannucci 1993). Follow-up studies tively as it reduces pressure in the epididymis and and risk factor analyses were unable to prove a con- epididymal tubule and thus reduces the risk of a “blow- nection. Various national urological societies, includ- out”. This is an intraoperative tubal rupture, requiring ing the American Urological Association (AUA) and an epididymovasostomy, which may be made impos- the German Society for Urology (DGU), have recom- sible by the anatomical localization of the rupture. mended informing the patient about current fi ndings It is important to explain acute complications to and leaving the decision to him as a consenting adult. the patient and particularly to make him aware of the The basic problem lies in the retrospective nature of possibility of failure; he must be informed that, in these studies. Prospective, adequately controlled stud- individual cases, recanalization may occur even when ies are necessary (Roth and Hertle 1994; NIH 1993; postoperative semen analysis shows azoospermia on Farley et al. 1993; John et al. 1995). In the case of several occasions. If recanalization is to be completely prostate cancer, these studies must additionally be excluded, the duct should be resected over several cen- designed over a 5-year or, even better, a 10-year period. timeters. Furthermore, polyorchidism and a duplex Neither large population-based case control studies vas must be ruled out. For liability reasons, it is (Lesko et al. 1999), population-based cohort-studies 570 U. Engelmann and Oliver Gralla

(Lynge 2002), nor systematic literature reviews (Bernal- namely vasovasostomy and epididymovasostomy, fol- Delgado et al. 1998) have been able to demonstrate an lowing deliberate ligation of the ducts became more increased risk for the development of prostate carci- frequent, and in 1948 O’Connor presented the fi rst noma after vasectomy. national survey on vasovasostomy. It is astonishing From the present state of knowledge, vasectomy that at that early stage nationwide surveys were imple- does not promote a higher risk for the development of mented to establish the indications, frequency and suc- prostate carcinoma. cess of refertilization surgery. In the USA such surveys were repeated in 1973 (Derrick et al. 1973) and in 1979 (Wicklund and Alexander 1979). 28.10 Psychosexual Effects In German-speaking countries the following situa- tion prevails (Engelmann et al. 1990): along with the increase in vasectomies, there is a rising number of The history of vasectomy has already shown that psy- patients who wish to reverse the procedure. Of the chosexual effects associated with vasectomy need not many reasons, three concerns emerge. First, the higher always be negative. On the contrary, the fact that the divorce rate plays an essential role; the main reason for problem of contraception has been responsibly resolved refertilization is divorce followed by remarriage or a usually has a positive effect on a relationship (Weidner new partnership. The second most frequent request and Weissbach 1992). The fear of unwanted pregnancy comes from couples whose family planning had been may disappear and sexual enjoyment may increase completed by vasectomy, but who now have changed (Vaughn 1979; Miltsch and Senn 1999; Bertero et al. their minds or who have suffered the unexpected 2005). Conversely, those men who are pressured into death of one of their children. The third reason is being vasectomized (e.g., vasectomy camps!), whose improved economic standing and the resulting pos- religion discourages or even forbids such procedures sibility of being able to afford offspring. and whose partners are opposed to it or who are not Refertilization vasovasostomy has been performed suffi ciently informed, may experience vasectomy as for more than 40 years, but the technique has under- associated with increased confl icts and complications. gone major changes during that time. Initially, the Thus the initial situation of the person, the expectations macroscopic one-layer anastomosis technique, per- he places in vasectomy and how well informed he is haps even with splinting of the small vas lumen, was are key factors for success. Correct information, pre- applied. Increasing use of the operating microscope surgical counseling and post-operative care and atten- brought with it excellent postoperative results reported tion are important. These measures can prevent fear mainly by Silber (1977). This prompted the develop- concerning a loss of male identity and masculinity. ment of microscopic two-layer anastomosis without The long-term benefi ts and effectiveness of vasec- splints. Improved surgical results affected the mechan- tomy continue to be discussed controversially (Jequier ical patency of anastomosis, which must be considered and Pryor 1998), even to the extent of spurious argu- the true control parameter of surgical quality. However, ments that cryopreservation of sperm may replace there is a discrepancy between surgical patency of the refertilization or Ð even worse Ð replace information restored vas deferens and pregnancy rates, which are and counseling about vasectomy. distinctly lower. Today refertilization surgery is largely performed with optical devices, i.e., with loupe magni- fi cation or surgical microscopes. Patency rates of 90% 28.11 Refertilization are common and are achieved by many.

28.11.1 History of Refertilization Surgery 28.11.2 Current Demand and Frequency Isolated cases of vasovasostomy following accidental of Refertilization dissection of the vas deferens, mostly during hernia surgery, have been reported since the beginning of this The potential demand for refertilization surgery can be century. After World War II true refertilization surgery, roughly extrapolated from the number of sterilization 28 Vasectomy and Refertilization 571 vasectomies performed, from the divorce rate and 28.11.3.2 Vasovasostomy Technique from other (secondary) parameters. It has been esti- mated to be 250,000Ð300,000 in the USA per year The patient is placed in supine position; usually a scro- (Cos et al. 1983). In German-speaking countries a sur- tal incision bilaterally or in the median of the raphe vey taken in 1990 revealed that the vasectomy reversal scroti is chosen. Less frequently an inguinal or infra- rate was 3.5% and requests for reversal were twice as pubic approach is used. Usually the surgeon operates high (Engelmann et al. 1990). In Sweden, the refertil- while seated, avoiding interference with the operating ization rate was 0.5Ð5.4/100,000 residents (Ehn and table pillar; the operating microscope should be placed Liljestrand 1997). It can be assumed that the number before the patient is positioned. Operating time of of refertilization operations will continue to increase 2Ð3 h should be anticipated; for this reason an indwell- due to improved counselling. ing catheter is sometimes inserted. Differing tech- niques have been described: initially macroscopic techniques with or without splinting of the lumen, fol- lowed by microsurgical techniques with loupe mag- 28.11.3 Vasovasostomy nifi cation or the operating microscope. Macrosurgical techniques. Initially, surgical tech- 28.11.3.1 Indications, Counseling, niques without magnifi cation and relatively coarse Consent, Costs suturing material of 4-0 or 5-0 were used. Results were relatively poor because of complications such as sperm The typical patient desiring refertilization contacts his leakage and bad anatomical adaptation of the lumen. doctor, usually his urologist, often the same one who The advantages lay in simple and rapid performance of performed the vasectomy. The indication is the patient’s surgery and for these reasons some surgeons prefer request, which in turn arises from the arguments macroscopic techniques even today. As late as 1999 described above. As for other surgery, refertilization Feber and Ruiz saw advantages in the shorter operat- requires truthful counseling. Invasiveness is compara- ing time, reduced costs and the need for fewer surgical ble to that of vasectomy, with the exception that vaso- skills (despite a patency rate of 87% and pregnancy vasostomy requires more diffi cult surgical techniques. rate of 50%). For this reason, general anesthesia is recommended Silber (1977) made a great contribution when he and hospitalization of 1–2 days should be planned. described the anatomical peculiarities of the severed As a general rule, we estimate patency rates of 80%; vas, with sizes differing between the dilated side proxi- pregnancy rates are lower, at 60%. If vasectomy was mal to the testis and the non-dilated side, and demon- performed more than 5 years prior, we reduce these strated that good operating results were best achieved estimates by a further 20%. The surgeon’s experience with anatomically correct adaptation of the lumina. with this operation (both positive and negative) should Microsurgical techniques. In our view, using be considered. The possibility of a “blow-out” in the solely macrosurgical techniques for refertilization epididymis or even in the rete testis should be men- is obsolete. While they may be applied for vas-anasto- tioned. This would then necessitate epididymovasos- mosis, although inferior in patency, patent epididymo- tomy or can make surgery impossible for technical vasostomy is achieved purely by coincidence or not at reasons. all. Whether loupes with a two- to eightfold magnifi - In most countries, including Germany, expenses for cation or an operating microscope with the advantage surgical refertilization are not covered by insurers as of variable magnifi cation and increased fi eld of vision a general rule. In some special cases, such as the death is used depends on the personal preference of the sur- of a child with concomitant parental distress, or persis- geon, even though the best patency results are achieved tent pain due to sperm granuloma, exemptions are with the operating microscope. granted. In these cases, cost transfer agreements should In the event of scrotal vasectomy, we dissect the be arranged preoperatively. According to Heidenreich ends of the vas deferens via a lateral scrotal incision. et al. (2000), the expenses per childbirth after vasova- The scarred ends of the vas are excised. Patency of the sostomy account for only a fi fth of those after MEAS/ proximal vas deferens is determined after insertion of TESE and ICSI. a small fl exible Tefl on canula by careful injection of 572 U. Engelmann and Oliver Gralla

Fig. 28.3 Clean cuts of the two ends of the vas and careful bipo- lar hemostasis

saline solution. The fl uid emerging from the distal vas Fig. 28.4 Tension-free adaptation of the two ends of the vas by end is assessed in the operating room under the operat- use of an approximator. Anastomosis of the mucosa is performed ing microscope. If necessary, the epididymis is digi- with nylon 10-0 double sutures tally massaged to obtain fl uid. If no fl uid is present, a “blow-out” must be assumed and the epididymis is examined. In such case we perform epididymovasos- tomy. Typically, whitish or yellowish fl uid emerges containing viable or dead sperm. In this event, surgery is continued as vasovasostomy. The best anatomical adaptation of the lumen is achieved using a two-layer technique by which mucosal approximation is accomplished with six interrupted sutures using 9-0 or 10-0 suturing material. Special vasovasostomy needles that are doubly armed and whose degree of curvature is adapted to the size of the vas have proven useful. The vas ends can be aligned by using an approximator, facilitating placement of sutures. First, the inner mucosal layer is sutured and should Fig. 28.5 Adaptation of the muscle layer of the vas by nylon ensure a leak-proof connection. Precise positioning of 9-0 sutures the sutures will ensure optimal patency rates; Goldstein et al. (1998) were able to achieve rates of 99.5% using their “microdot marking technique” and eight mucosa results from surveys. Similar variations are seen stitches. The mechanical strength of the anastomosis is depending on whether patency rates are compared, achieved through the second muscular layer, also using describing surgical success, or pregnancy rates, which 9-0 or 10-0 sutures, however, with a single-sided and is the factor that most interests patients. Individual spatulated cutting needle. The short scrotal wound is authors report patency rates of 100% and pregnancy closed in two layers. A well-fi tting dressing supporting rates slightly below. Nationwide surveys report average the scrotum is preferred by most patients and is left in results more accurately: in 1948 O’Connor had a cumu- place for a few days (Figs. 28.3Ð28.5). lative success rate of 38Ð40%; in 1973 Derrick calcu- lated a patency rate of 38% and pregnancy rate of 11Ð26%. In 1990, Deindl found a cumulative patency 28.11.3.3 Results of Vasovasostomy rate of 73% in German-speaking Europe and a preg- nancy rate of 47%. Centers with a high operating fre- Results of vasovasostomy are quite variable, depending quency, with skilful techniques and thin sutures, achieve on whether one reads reports by individual authors or better results. The time period between sterilization 28 Vasectomy and Refertilization 573 vasectomy and refertilization plays a role; even if these limits are arbitrary, the best results can be expected within the fi rst 2 years, while 10 years after vasectomy the chances for refertilization are markedly reduced (Belker et al. 1991).

28.11.3.4 Complications Following Vasovasostomy

The rate of acute complications is comparable with that for vasectomy or scrotal exploration, but for differ- ent reasons. Specifi c long-term complications result from re-obstruction after initial patency. A 3% chance of such obstruction because of scar tissue formation must be expected. If patients remain azoospermic fol- lowing refertilization, it is probably due to surgical failure or a more distal “blow-out” that had not been verifi ed at the time of surgery. In these cases re-operation is indicated. Oligozoospermia can be the result of par- tial obstruction Ð in such cases re-operation may be successful Ð or due to limited testicular production. If Fig. 28.6 A tubule is prepared and incised longitudinally vasectomy dates back more than 5 years, we inform all patients about the option of concomitant cryo-TESE.

28.11.4 Epididymovasostomy

If the epididymal tubule is damaged by a “blow-out”, epididymovasostomy must be carried out. For techni- cal reasons this procedure is only successful at the cor- pus or the cauda epididymidis. In the caput region, the diameter of the tubule is too small to accomplish fully patent anastomosis. Epididymovasostomy urgently requires microsurgical techniques, preferably using an operating microscope. We prefer to employ the end-to- side technique; others prefer side-to-side. After excis- ing an oval window of the epididymal tunica, a single tubule containing sperm is chosen and is opened longi- tudinally. By placing four interrupted 11-0 sutures, Fig. 28.7 Adaptation of the muscle layer of the vas and the anastomosis of the tubule with the mucosa of the vas tunica of the epididymis at the posterior circumference by nylon deferens is completed. The anastomosis is then fi n- 9-0 single sutures ished by means of further interrupted sutures between the epididymal tunica and the muscularis of the vas 28.11.5 Future Developments in Surgical (Figs. 28.6Ð28.10). End-to-end anastomosis is more diffi cult. The pat- Refertilization ency rates of microsurgical tubulovasostomy are between 39% and 100%, including single-case reports. Refertilization surgery will become more common in The average patency rate is 45% and pregnancy rates future along with contraceptive vasectomy. The good are 18% (Deindl 1990). results achieved have reached a stable level and have 574 U. Engelmann and Oliver Gralla

Fig. 28.8 Anastomosis between the tubule and the mucosa of the vas by nylon 10-0 doubly armed sutures

Fig. 28.10 Ligation of the epididymal tunic

We do not believe in abstaining from refertilization surgery and instead fi rst harvesting sperm testicularly or Ð even worse Ð epididymally for use with ICSI. This method can by no means measure up to “conventional” Fig. 28.9 Adaptation of the muscle layer of the vas and the tunica of the epididymis. Interrupted sutures at the anterior cir- refertilization surgery Ð either in terms of pregnancies cumference with nylon 9-0 sutures achieved, the cost and effort involved, or with regard to complication rates. not seen any further improvements during the past 10 years. Microsurgical training must continue to be 28.12 Future Development emphasized for the surgeons involved. The intraoperative harvesting of sperm which Ð of Vasectomy cryopreserved Ð can be made available for later ICSI in case of a non-patent anastomosis (especially in the case Both from a demographic and political point of view, of epididymovasostomies) should be discussed with as well as for the individual selecting a contraceptive patients even during the initial consultation (Djerassi method, vasectomy represents a highly safe option that and Leibo 1994). For those who wish to have children can be performed rapidly at low cost, with few incon- after vasectomy, surgical refertilization remains the veniences for the patient. Without doubt it is superior method of choice from the standpoint of costs and to the equivalent female operation. It is hoped that chances for success. changes in the understanding of the male role and 28 Vasectomy and Refertilization 575 better knowledge will bring about wider acceptance of Farley TMM, Meirik O, Mehta S, Waites GMH (1993) The vasectomy, especially in view of the fact that it is no safety of vasectomy: Recent concerns. Bulletin of the World Health Organisation 71:413Ð419 longer to be considered fi nal as in a high percentage of Feber KM, Ruiz HE (1999) Vasovasostomy: Macroscopic patients refertilization can be achieved by vasectomy approach and retrospective review. Tech Urol 5:8Ð11 reversal. Forste R, Tanfer K, Tedrow L (1995) Sterilization among cur- rently married men in the United States, 1991. Fam Plann Perspect 27:100Ð107, 122 Giovanucci E, Tosteson TD, Speizer FE, Vessey MP, Colditz GA (1992) A long-term study of mortality in men who have References undergone vasectomy. N Engl J Med 326:1392Ð1398 Giovanucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC (1993) A prospective cohort study of vasectomy Alderman PM (1991) Complications in a series of 1,224 vasec- and prostate cancer in US men. JAMA 269:873Ð877 tomies. J Fam Pract 33:579Ð584 Goebel P, Ortmann K, Blattner TH (1987) Vasektomie und Awsare NS, Krishnan J, Boustead GB, Hanbury DC McNicholas Beziehungssituation Ð eine empirische Untersuchung an 156 TA (2005) Complications of vasectomy. Ann R Coll Surg Männern (Paaren). Zschr Psychosom Med 33:119Ð138 Engl 87:406Ð410 Goldstein M (1983) Vasectomy failure using an open-ended Barone MA, Johnson CH, Luick MA, Teutonico DL, Magnani RJ technique. Fertil Steril 40:699Ð700 (2004) Characteristics of men receiving vasectomies in the Goldstein M, Shihua PhL, Matthews GJ (1998) Microsurgical United States, 1998Ð1999. Persps Sex Reprod Health 36:27Ð33 Vasovasostomy: The microdot technique of precision suture Belker AM, Thomas AJ, Fuchs EF, Konnak JW, Sharlip ID placement. J Urol 159:188Ð190 (1991) Result of 1,469 microsurgical vasectomy reversals by Heidenreich A, Bonfi g R, Wilbert DM, Strohmaier WL, the vasovasostomy study group. J Urol 145:505Ð511 Engelmann UH (1994) Risk factors for antisperm antibodies Bensyl DM, Iuliano DA, Carter M, Santelli J, Gilbert BC (2002) in infertile men. Am J Reprod Immunol 31:69Ð76 Contraceptive use Ð United States and territories, Behavioral Heidenreich A, Altmann P, Neubauer S, Engelmann UH (2000) Risk Factor Surveillance System, 2002. MMWR Surveill Die mikrochirurgische Vasovasostomie im Zeitalter der Summ 54:1Ð72 modernen Reproduktionsmedizin Ð eine Kosten-Nutzen- Bernal-Delgado E, Latour-Pérez J, Pradas-Arnal F, Gómez-López Analyse. Urologe A 39:240Ð245 LI (1998) The association between vasectomy and prostate Hendrix NW, Chauhan SP, Morrison JC (1999) Sterilization and cancer: a systematic review of the literature. Fertil Steril its consequences. Obstet Gynecol Surv 54:766Ð777 70:191Ð200 Hiersche HD, Hiersche F (1995) Die Sterilisation geistig Bertero E, Hallak J, Gromatzky C, Lucon AM, Arap S (2005) Behinderter. Gynäkologe 28:452Ð458 Assessment of sexual function in patients undergoing vasec- Holden CA, McLachlan RI, Cumming R, Wittert G, tomy using the international index of erectile function. Int Handelsman DJ, de Kretser DM, Pitts M (2005) Sexual activ- Braz J Urol 31:452Ð458 ity, fertility and contraceptive use in middle-aged and older Cook LA, Pun A, van Vliet H, Gallo MF, Lopez LM (2007a) men: Men in Australia, Telephone Survey (MATeS). Hum Scalpel versus no-scalpel incision for vasectomy. Cochrane Reprod 20: 3429Ð3434 Database Syst Rev CD 4112 Isnardi L (1896) Die Behandlung der senilen Dysurie mit Cook LA, van Vliet H, Lopez LM, Pun A, Gallo MF (2007b) Durchschneidung und doppelseitiger Ligatur der vasa defer- Vasectomy occlusion techniques for male sterilization. entia. Therap Wschr 111:25Ð36 Cochrane Database Syst Rev CD 3991 Jequier AM, Pryor JP (1998) Is vasectomy of long term bene- Cos LR, Valvo JR, Davis RS, Cockett ATK (1983) Vasovasostomy: fi ts? Hum Reprod 13:1757Ð1760 Current state of the art. Urology 22:567Ð575 John EM, Whittemore AS, Wu AH, Kolonel LN, Hislop TG, Deindl F (1990) Die Refertilisationssituation in der Bundes- Howe GR, West DW, Hankin J, Dreon DM, Teh CZ (1995) republik Deutschland, der Republik Österreich und der Vasectomy and prostate cancer: Results from a multiethnic Schweiz – eine Dreiländerumfrage. Inaugural Dissertation, case-control study. J Natl Cancer Inst 87:662Ð669 Ruhr-Universität Bochum Kohli KL (1973) Motivational factors and socioeconomic char- Derrick FC, Yarbbrough W, Agostino JD (1973) Vasovasostomy: acteristics of vasectomized males. J Biosoc Sci 5:169Ð177 Results of questionnaire of members of the American Labrecque M, Dufresne C, Barone MA, St-Hilaire K (2004) Urological Association. J Urol 110:556Ð557 Vasectomy surgical techniques: A systematic review. BMC Djerassi C, Leibo SP (1994) A new look at male contraception. Medicine 2:21 Nature 370:11Ð12 Lesko SM, Louik C, Vezina R, Rosenberg L, Shapiro S (1999) Drake MJ, Mills IW, Cranston D (1999) On the chequered his- Vasectomy and prostate cancer. J Urol 161:1848Ð1853 tory of vasectomy. Br J Urol Int 84:475Ð481 Lynge E (2002) Prostate cancer is not increased in men with Ehn BE, Liljestrand J (1997) Female and male sterilization in vasectomy in Denmark. J Urol 168:488Ð490 Sweden. Gynecol Obstet Invest 44:182Ð186 Manson JE, Ridker PM, Spelsberg A, Ajani U, Lotufo PA, Engelmann UH, Schramek P, Tomamichel G, Deindl F, Senge Hennekens CH (1999) Vasectomy and subsequent cardiovas- TH (1990) Vasectomy reversal in central Europe: Results of cular disease in US physicians. Contraception 59:181Ð186 a questionnaire of urologists in Austria, Germany and Martin K, Wu Z (2000) Contraceptive use in Canada. Fam Plann Switzerland. J Urol 143:64Ð67 Perspect 32:65Ð73 576 U. Engelmann and Oliver Gralla

Miltsch B, Senn E (1999) Vasektomie: Präoperative Bedenken Schwingl PJ, Guess HA (2000) Safety and effectiveness of und postoperative Akzeptanz. Akt Urol 30:237Ð241 vasectomy. Fertil Steril 73:923Ð936 Nakhaee N, Mirahmadizadeh AR, Gorji HA, Mohammadi M (2002) Sharp HC (1902) The severing of the vasa deferentia and its Assessing the cost-effectiveness of contraceptive methods in relation to the neuropsychopathic constitution. NY Med J Shiraz, Islamic Republic of Iran. East Mediterr Health J 8:55Ð63 75:411Ð414 National Institutes of Health (NIH) (1993) Does vasectomy Silber SJ (1977) Perfect anatomical reconstruction of vas defer- cause prostate cancer? JAMA 269:2620 ens with a new microscopic surgical technique. Fertil Steril Nieschlag E (1987) Vasektomie Ð pro und contra. Dtsch med 28:72Ð77 Wschr 112:1107Ð1109 Smith GL, Taylor GP, Smith KF (1985) Comparative risks and Nirapathpongporn A, Huber DH, Krieger JN (1990) No-scalpel costs of male and female sterilization. Am J Pub Health 75: vasectomy at the King’s birthday vasectomy festival. Lancet 370Ð374 335:894Ð895 Sonnenberg FA, Burkman RT, Hagerty CG, Speroff L, Speroff T Ochsner AJ (1899) Surgical treatment of habitual criminals. (2004) Costs and net health effects of contraceptive meth- JAMA 33:867Ð868 ods. Contraception 69:447Ð459 O’Connor VJ (1948) Anastomosis of the vas deferens after pur- Trussell J, Hatcher RA, Cates W, Stewart FH, Kost K (1990) poseful division for sterility. J Urol 59:229Ð233 Contraceptive failure in the United States: An update. Stud Ozvaris SB, Dogan BG, Akin A (1998) Male involvement in Fam Plan 21:51Ð54 family planning in Turkey. World Health Forum 19:76Ð78 Vaughn R (1979) Behavioral response to vasectomy. Arch Gen Randall PE, Marcuson RW (1985) Absence from work follow- Psychiatry 36:815Ð821 ing vasectomy. J Soc Occup Med 35:77Ð78 Weidner W, Wei§bach L (1992) Freiwillige Vasektomie in der Reynolds RD (1994) Vas deferens occlusion during no-scalpel Familienplanung Ð Gedanken zur Nutzen-Risiko-Analyse. vasectomy. J Fam Pract 39:577Ð582 Akt Urol 23:328Ð331 Rizvi SAH, Naqvi SAA, Hussain Z (1995) Ethical issues in male Wicklund R, Alexander NJ (1979) Vasovasostomy: Evaluation sterilization in developing countries. Brit J Urol 76:103Ð105 of success. Urology 13:532Ð534 Rowlands S, Hannaford P (2003) The incidence of sterilisation Wolfers D, Wolfers H (1974) Vasectomy and vasectomania. in the UK. BJOG 110:819Ð824 London, Mayfl ower Books Ross JA, Huber DH (1983) Acceptance and prevalence of vasec- Wright N, Johnson B, Wiggins P, Vessey M (1977) The use of tomy in developing countries. Stud Fam Plan 14:67Ð73 sterilisation as a method of birth control among participants Roth S, Hertle L (1994) Verursacht die Sterilisations-Vasektomie in the Oxford/Family Planning Association Contraceptive ein Prostatakarzinom? Dt Ärztebl 91:409–410 Study. Fertil Contracept 1:41Ð44 Schirren C (1983) Erfahrungen mit der Vasektomie. Urologe A Xiaozhang L, Shungiang L (1993) Vasal sterilization in China. 22:29Ð34 Contraception 48:255Ð265 Approaches to Hormonal Male Contraception 29

Eberhard Nieschlag and Hermann M. Behre

Contents 29.1 Principle of Hormonal Male Contraception 29.1 Principle of Hormonal Male Contraception ...... 577 29.2 Androgens Alone ...... 578 Of all the different experimental approaches and 29.2.1 Testosterone Enanthate ...... 578 pharmacological methods tested so far for male contra- 29.2.2 Testosterone Buciclate ...... 579 ception, hormonal methods come closest to fulfi lling 29.2.3 Testosterone Undecanoate ...... 579 29.2.4 Testosterone Pellets...... 581 the criteria set out above (see Chap. 27). The endocrine 29.2.5 19-Nortestosterone ...... 581 feedback mechanism operating between hypothalamus, 29.2.6 7α-Methyl-19-Nortestosterone pituitary and testes is the basis on which hormonal (MENT) ...... 581 approaches to male contraception rest. Its goal is to 29.3 Androgens Combined with GnRH Analogues ... 581 suppress spermatogenesis and to reduce sperm concen- 29.3.1 GnRH Agonists ...... 581 tration, if possible to azoospermia or at least to a sperm 29.3.2 GnRH Antagonists ...... 581 concentration low enough to provide contraceptive pro- 29.4 Androgens Plus Gestagens ...... 582 tection (<1 million sperm per ml ejaculate). Sperm production and secretion of testicular testos- 29.4.1 Depot Medoxyprogesterone Acetate (DMPA)...... 583 terone are so closely interwoven that it has remained 29.4.2 ...... 583 impossible to interrupt spermatogenesis by hormonal 29.4.3 ...... 583 means without inhibiting androgen production (see 29.4.4 Acetate ...... 583 Chap. 2 and Fig. 29.1). Inhibition of FSH alone, e.g., 29.4.5 and ...... 584 by antibodies, leads to reduction of sperm concentra- 29.5 Résumé and Outlook ...... 584 tion but not to azoospermia, as monkey studies have References ...... 585 shown. Suppression of both FSH and LH would indeed lead to azoospermia, but would also induce symptoms of androgen defi ciency which affects libido, potency, male role behavior and general metabolic processes (erythropoesis, protein, mineral and bone metabolism). For this reason inhibition of gonadotropins will always necessitate androgen administration. Thus the principle of hormonal male contraception is based on 1. The suppression of LH and FSH 2. Depletion of intratesticular testosterone and atro-  E. Nieschlag ( ) phy of spermatogenesis Centre of Reproductive Medicine and Andrology of the University of Münster, D-48149 Münster, Germany, 3. Substitution of peripheral testosterone to maintain e-mail: [email protected] androgenicity

E. Nieschlag et al. (eds.), Andrology, 577 DOI: 10.1007/978-3-540-78355-8_29, © Springer-Verlag Berlin Heidelberg 2010 578 E. Nieschlag

a At fi rst sight testosterone itself would be the ste- Hypothalamus roid of choice as it suppresses the gonadotropins and maintains androgenicity simultaneously. However, GnRH + studies showed that by administration of testoster- one alone azoospermia could only be achieved in Pituitary two-thirds of Caucasian men, so that another gonadotropin-suppressing agent must be added to LH FSH interrupt spermatogenesis as completely as possible. + + - GnRH analogues and several different steroid combi- Testes DHT nations and delivery systems such as oral, transder- Leydig cells + Sertoli cells Testosterone Testosterone Spermatogenese mal, subcutaneous and intramuscular have been examined. Each has its respective merits and draw- Estradiol Spermien + backs (Fig. 29.2). This chapter provides a broad overview of the vari- Androgen effects Fertility ous hormonal approaches to male contraception. For further details recent reviews (e.g., Kamischke and b Nieschlag 2004; Wenk and Nieschlag 2006; Page et al. Hypothalamus 2008) and the individual studies should be consulted. - Testosterone GnRH - 29.2 Androgens Alone Pituitary

LH FSH 29.2.1 Testosterone Enanthate

Testes DHT Leydig cells Sertoli cells Soon after testosterone was synthesized and became Testosterone Testosterone Spermatogenese available for clinical use in the late 1930s, its

Estradiol spermatogenesis-suppressing effect was recognized + (Heckel 1939), but not until the 1970s did investigations start to exploit this phenomenon for male contraception. Androgen effects Fertility As in most hormonal male contraceptive studies to date, in the early studies sperm concentrations and counts c were used as surrogate parameters for effi cacy. Hypothalamus The fi rst effi cacy study of testosterone-based hor- - - monal male contraception was sponsored by the WHO Testosterone GnRH Gestagen (1990) and included ten centers on four continents. - - Pituitary Healthy fertile participants were given 200 mg of the longer-acting testosterone enanthate weekly by intra- LH FSH muscular injection. One hundred and fi fty-seven men

Testes (70%) reached azoospermia after 6 months of treatment DHT Leydig cells Sertoli cells and entered the effi cacy phase for a further year, during Testosterone Testosterone Spermatogenese which no other contraceptive was used by the couple. Estradiol + Only one pregnancy was reported in this fi rst proof-of-principle study. Although the effi cacy of this Androgen effects Fertility study was very high, it cannot be used to determine the overall effi cacy of testosterone alone as a contraceptive Fig. 29.1 Schematic representation of the endocrine mechanism because only men who became azoospermic could enter controlling testicular function (Figure a). Figure b shows the the effi cacy phase while the others were excluded. principle of hormonal contraception using testosterone; fi gure c shows the principle of hormonal contraception using testoster- In order to clarify the question whether men devel- one plus gestagens oping oligozoospermia can be considered infertile, a 29 Approaches to Hormonal Male Contraception 579

Fig. 29.2 Contraceptive effi cacy of testosterone enanthate (250 mg weekly) in 6 364 volunteers: pregnancy rates per 100 person-years in relation to sperm concentra- 5 tion (WHO 1996) (11) 4 (9)

3

2 (5) (4) (3) 1 (2)

Pregnancy rate (per 100 person-years) (0) 0 Azoospermia <=1.0 M/ml <=2.0 M/ml <=3.0 M/ml <=4.0 M/ml <=5.0 M/ml All sperm concentrations Cumulative sperm concentration second worldwide multicenter effi cacy study involv- much longer than the 4.5 days of testosterone enan- ing 357 couples followed (WHO 1996). In this study thate (Behre et al. 1995, 2004). Suppression of sper- azoospermia again proved to be a most effective pre- matogenesis was comparable to that of weekly requisite for contraception. If sperm concentration, testosterone enanthate injections, reaching azoo- however, failed to drop below 3 million/ml ejaculate, spermia in three out of eight volunteers after a single resulting pregnancy rates were higher than when using injection of 1,200 mg of testosterone buciclate. Despite condoms. When sperm concentrations decreased its promising pharmacokinetic profi le, no industrial below 3 million/ml, which was the case in 98% of the partner could be found to undertake the development participants, then protection was not as effective as for of this preparation. azoospermic men, but was better than that offered by condoms (Fig. 29.3). Even if these WHO studies represented a break- through by confi rming a principle of action, they did 29.2.3 Testosterone Undecanoate not offer a practicable method. For a method requiring weekly i.m. injections is not acceptable for broad use. Initially testosterone undecanoate was studied as an Moreover, several months, often up to 1 year, are oral preparation in volunteers of Caucasian origin required before sperm production reaches signifi cant (Nieschlag et al. 1978). Subjects were given a daily dose suppression. For this reason current research is con- of 240 mg over a period of 12 weeks, but only one out of centrating on the development of long-acting testoster- seven volunteers reduced sperm output suffi ciently for one preparations and on methods to hasten the onset of contraception. This low effectiveness is probably due to effectiveness. the short half-life of testosterone undecanoate when given orally. Even if administered four times a day, the peaks are not suffi cient to suppress gonadotropins con- sistently and thereby to achieve azoospermia. 29.2.2 Testosterone Buciclate While testosterone undecanoate had been devel- oped as an oral preparation in Europe (see Chap. 21), As long-acting testosterone preparations appeared it was turned into an injection in China, using tea more promising in terms of practicability and accept- seed oil as a vehicle and is used as such in China for ability, WHO and the NIH initiated a synthesis pro- hypogonadism and in trials for male contraception. gramme for such preparations (Waites 2003), through Back in Europe, the half-life of this Chinese prepara- which the long-acting testosterone ester testosterone tion could be extended even further when dissolved in buciclate was identifi ed. This molecule showed a half- castor oil and is now available for clinical use in life of 29.5 days when tested in hypogonadal men, 1,000 mg depot injections (see Chap. 21). 580 E. Nieschlag

Fig. 29.3 Gestagens derived a from (a) testosterone or (b) OH Testosterone CH OH progesterone that have been 3 CH3 CH CN used successfully in male CH3 2 contraceptive trials O O

Etonogestrel OH Desogestrel 19-Nor- CH3 OH H3C CH OH testosterone H3C 2 H2C H2C C CH COH

O O

OH OH 19-Nor- CH3 H3C CH2 C CH CCH

O O Levonorgestrel

b

CH3

Progesterone 20 C O CH3

16 CH3

CH3 3 5 4 6 O C O CH3

- - - -OCOCH3 CH3 17α-Hydroxy- CH progesteronacetate 3

O C O CH3 - - - -OCOCH3 CH3 Medroxyprogesterone acetate 6 CH O 3 CH 3 CO CH3 - - - - OCOCH3 H2C CH3 Cyproterone 1 2

acetate 6 O Cl

In the clinical trials in China testosterone undecano- suppression phase and no pregnancies were caused by ate alone administered every 4 weeks resulted in azoo- men exhibiting azoospermia or severe oligozoospermia spermia in all Chinese men who received a dose of (Gu et al. 2009). However, reappearance of sperm 1,000 mg and in azoospermia or severe oligozoo- occurred in six men during the effi cacy phase; one spermia in 95% of Chinese men who received a dose pregnancy was attributed to “sperm rebound.” Side- of 500 mg during a 4–6 month suppression phase effects observed in subjects were all typical of elevated (Zhang et al. 1999). In the ensuing Phase III study testosterone serum levels. The largest effi cacy study to involving 305 couples an effi cacy phase followed the date was also performed in China, based on monthly 29 Approaches to Hormonal Male Contraception 581 injections of 500 mg testosterone undecanoate. Eight Although effective in suppressing spermatogenesis hundred and fi fty fi ve men entered the effi cacy phase and without any notable side-effects in the studies, it during which only nine pregnancies were recorded. could not be determined whether this synthetic andro- This represents a pregnancy rate of 1.1/100 person gen would have any unwanted effects under long-term years (Gu et al. 2009). Thus, in China testosterone use. The lack of negative reports from widespread use undecanoate provides better protection against of 19-nortestosterone in athletics cannot be taken as pregnancy than condom use. evidence for its clinical application as systematic eval- In a fi rst contraceptive trial of testosterone undecano- uations in athletes have not been published. ate in castor oil 1,000 mg were injected into 14 Caucasian volunteers at 6-week intervals. 8/14 men achieved azoo- spermia (Kamischke et al. 2000a). Although this rate of 29.2.6 7α-Methyl-19-Nortestosterone azoospermia is not different from that achieved with (MENT) testosterone enanthate alone, the three-fold longer injec- tion interval represents a signifi cant advantage. A later The synthetic androgen 7α-methyl-19-nortestosterone pharmacokinetic study concluded that 8-week intervals (MENT) offers an approximately ten-fold higher of 1,000 mg injections would be suffi cient for contra- potency to suppress pituitary gonadotropins than does ceptive purposes (Qoubaitary et al. 2006). testosterone. In contrast to testosterone there is no Considering that ten to 14-week intervals of 1,000 mg 5α-reduction so that effects on the prostate could be testosterone undecanoate are required for substitution minimal. A fi rst dose-fi nding study showed that MENT of hypogonadal men, about 1/3 more testosterone is administered in subcutaneous implants was as effec- required for contraception in normal volunteers. tive as testosterone given alone (von Eckardstein et al. 2003). The potential of these implants either alone or in combination with gestagen implants is currently 29.2.4 Testosterone Pellets being investigated by the Population Council.

Pellets consisting of pure testosterone are used for 29.3 Androgens Combined with GnRH substitution in hypogonadism in some countries (see Chap. 21). In male contraceptive studies the sperm- Analogues suppressing effect was comparable to weekly testoster- one enanthate injections (McLachlan et al. 2000). The 29.3.1 GnRH Agonists disadvantage of minor surgery required for insertion under the abdominal skin is compensated for by their low The pituitary-inhibiting effects of GnRH agonists are price. Spontaneous extrusion may be a disadvantage. well known from their use in females and in the ther- apy of prostate cancer. After an initial phase of gonad- otropin stimulation they suppress gonadotropins and, 29.2.5 19-Nortestosterone consequentially, intratesticular testosterone by GnRH receptor down regulation. However, trials for hormonal male contraception in which mostly testosterone was When searching for preparations with longer lasting added showed that sperm numbers were only insuffi - effectiveness 19-nortestosterone-hexoxyphenylpro- ciently reduced, thus rendering these agonists unsuit- pionate was tested whose spectrum of effects is very able as male contraceptives (Nieschlag et al. 2004). similar to that of testosterone and which had been used as an since the 1960s. The 19-nortes- tosterone ester injected every 3 weeks enabled azoo- spermia to be reached by as many men as by testosterone 29.3.2 GnRH Antagonists enanthate. Thus the 19-nortestosterone ester is as effective as testosterone enanthate but allows a longer GnRH antagonists lack the effect of initial gonado- interval (Knuth et al. 1985). tropin release as they competitively inhibit pituitary 582 E. Nieschlag

GnRH receptors, thus leading to a more immediate 29.4 Androgens Plus Gestagens onset of azoospermia. This could be demonstrated by small clinical studies using various GnRH antagonists The potency of gestagens to suppress gonadotropins is in addition to a testosterone preparation (summarized in well known from female contraceptives where gesta- Nieschlag et al. 2004). Out of 47 volunteers participat- gens effectively supplement estrogens. Numerous stud- ing in various clinical trials with different GnRH- ies combining androgens (mainly testosterone) with antagonists, azoospermia was achieved in 39 subjects various gestagens have been performed over the past 4 and oligozoospermia <1 million sperm per ml ejaculate decades in order to identify a regimen suited for male occurred in one further volunteer, while only three men contraception (Fig. 29.4). Unfortunately, a systematic maintained sperm concentrations above 3 million per ml comparison of the different gestagens with regard to ejaculate. Of the more recently developed GnRH antag- their contraceptive potency in males has never been onists Acycline has been tested in male contraceptive performed. Even worse, a Cochrane Review analyzing trials. Although Acycline given alone had a potent 45 clinical trials came to the conclusion that the studies gonadotropin-suppressing effect (Page et al. 2008), the comprised too small numbers of volunteers so that sig- addition of Acycline to a combination of testosterone nifi cant differences between the various steroid combi- gel plus DMPA did not increase the suppression of nations could not be detected (Grimes et al. 2007). Not sperm achieved by the steroids alone (Page et al. 2006). all studies followed strict criteria for randomized con- Despite these encouraging results, the requirement trolled trials. However, it should be kept in mind that for daily or weekly injections and the high costs of the single centers are fi nancially and logistically unable to available preparations have hindered the further devel- cope with the numbers of volunteers and criteria opment of GnRH antagonists for hormonal male con- demanded by regulatory agencies. Stimulated by traception. Promising attempts to use the GnRH researchers and by public demand, the pharmaceutical antagonists only to initiate azoospermia and then main- industry fi nally performed a trial fulfi lling the Cochrane tain this by androgens alone were not pursued further criteria – and left the fi eld! (Mommers et al. 2008). In (Swerdloff et al. 1998; Behre et al. 2001). the following, important studies are briefl y summarized

Most promising testosterone/progestin combinations

implants intramuscular oral

Sydney / Melbourne T implant + DMPA

Münster/ Bologna T undecanoate + NETE WHO/CONRAD Schering Fig. 29.4 Most promising T undecanoate + NETA testosterone/progestin combinations currently tested T undecanoate + ETN Schering/Organon in clinical trials. (MENT, 7 α-methyl-19- T implant + DSG nortestosterone; DMPA, Edinburgh / depot-medroxyprogesterone T implant + ETN acetate; NETE, norethister- Organon one enanthate; NETA, ; ETN, T decanoate + ETN etonogestrel; DSG, des- ogestrel; LNG, MENT + LNG Pop. Council N.Y. levonorgestrel) 29 Approaches to Hormonal Male Contraception 583 to highlight the cumbersome and often frustrating additive effect of levonorgestrel was seen in Caucasian development. men, but not in Chinese men who responded equally The gestagens used in these studies derive either well to testosterone pellets alone (Wang et al. 2005). from 19-nortestosterone or from 17-hydroxyproges- When MENT implants were combined with terone and are all being used in female contraceptives levonorgestrel implants in different doses, a clear dose- (Fig. 29.3). dependent effect could be observed, but it remains undetermined whether implants with suffi ciently long duration can be manufactured; non-biodegradable 29.4.1 Depot Medroxyprogesterone implants that have to be removed surgically from the implantation site when contraceptive protection is no Acetate (DMPA) longer required appear impractical for widespread use unless they can be left in situ for long periods (Wang From early studies in the 1970s initiated by the WHO et al. in preparation). and the Population Council, DMPA emerged as a gestagen with great potential in male contraception (Barfi eld et al. 1979). The combination of DMPA with 19-nortestosterone in 3-week intervals fi rst tested in 29.4.3 Norethisterone Caucasians (Knuth et al. 1989) was especially promis- ing in Indonesian men (WHO 1993). The injectable depot preparation norethisterone enan- One of the very few effi cacy studies aiming at preg- thate (NETE) and the orally effective norethisterone nancy rates also used DMPA, however, in combination acetate (NETA) are hydrolysed to release the active with testosterone pellets (Turner et al. 2003). In this compound norethisterone, which can be 5α-reduced Australian study, 53/55 volunteers suppressed to azoo- to 5α-norethisterone and aromatized to ethinyl estra- spermia and during the 1-year effi cacy phase no preg- diol. While norethisterone has strong androgenic activ- nancy occurred. However, the discontinuation rate in ity (∼10% of testosterone), 5α-noresthisterone also this study was high and onset of and recovery from shows anti-androgenic properties. azoospermia took several months. 13/14 men who received 200 mg NETE combined In order to test whether one of the two steroid enti- with 1,000 mg testosterone undecanoate every 6 weeks ties could be self-administered, the addition of a tes- achieved azoospermia (Kamischke et al. 2001). Further tosterone transdermal gel to the DMPA injections investigations showed that the injection intervals could (300 mg/3 months) was tested (Page et al. 2006). The be extended to 8 weeks (Meriggiola et al. 2005) or that results were comparable to those from trials where testosterone undecanoate could be combined with oral DMPA was combined with injectable testosterone. NETA without loss of effectiveness (Kamischke et al. 2002). Based on these fi ndings, together with CONRAD WHO is planning a Phase II effi cacy study involving 400 couples in eight centers worldwide (WHO 2005). 29.4.2 Levonorgestrel

Oral levonorgestrel, when combined with testoster- one enanthate i.m. slightly enhanced the effect of tes- 29.4.4 tosterone enanthate alone (Bebb et al. 1996). Similarly, when combined with testosterone undecanoate i.m. the The orally effective antiandrogen cyproterone acetate additional effect of oral levonorgestrel remained mar- (CPA) has strong gestagenic properties. In early studies ginal in Caucasian men (Kamischke et al. 2000b), but combining oral CPA with testosterone enanthate injec- seemed to increase effectiveness in Chinese men tions, the sperm-suppressing effects were considerable, (Wang et al. 2007). but the antiandrogenic effects (e.g., refl ected by In a comparative study, when levonorgestrel decreased hematocrit) were undesirable. However, when implants were combined with testosterone pellets, an combining 1,000 mg testosterone undecanoate every 6 584 E. Nieschlag

Fig. 29.5 Percentage of 333 100 men with sperm concentra- tions below or equal to 90

different cutoff values, cut off participating in a double- ≤ 80 blind, randomized, placebo- controlled multicentre trial using various combinations 70 of etonogestrel implants and testosterone undecanoate 60 injections (from Mommers Cutoff: < detection limit <= 0.1 million per ml et al. 2008) 50 <= 1 million per ml <= 3 million per ml 40

30

20

10 Percentage of men with a sperm concentration 0 0 6 12 16 20 24 30/34 42/44 Week weeks with 20 mg CPA daily initially, followed by only testosterone undecanoate every 10–12 weeks with two 2 mg CPA/day the initial suppression of spermatogenesis doses of etonogestrel for 42–44 weeks. 90% of treated could be maintained and antiandrogenic effects pre- men suppressed spermatogenesis ≤1 million/ml ejacu- vented (Meriggiola et al. 2003). late (Fig. 29.5). Although the combination of an implant with injections may not appear too attractive for practical use, the study showed a high success rate and could have formed the basis for a Phase III effi - 29.4.5 Desogestrel and Etonogestrel cacy study. Unfortunately, both companies discontin- ued their male contraception programs when they were Desogestrel is an orally effective gestagen which taken over by other fi rms. becomes active after conversion to etonogestrel. Etonogestrel can be administered directly as an implant (Implanon®). In combination with testosterone enan- thate or testosterone pellets desogestrel showed good 29.5 Résumé and Outlook suppression of spermatogenesis (Wu et al. 1999; Kinniburgh et al. 2001). A multitude of smaller and larger studies using testos- Etonogestrel implants combined with testosterone terone in combination with gestagens or GnRH antag- pellets s.c. resulted in a high azoospermia rate, although onists has demonstrated the principle of hormonal male it took up to 28 weeks to reach this goal in individuals contraception. Beyond the proof of principle, fi ve (Brady et al. 2004). effi cacy studies (WHO 1990 and 1996; Gu et al. 2003, In the fi rst (and so far last) industry-sponsored 2009; Turner et al. 2003) resulted in pregnancy rates trial, Organon and Schering decided to test etonogestrel below the rates of condoms (when properly used) and implants with testosterone undecanoate injections in close to that of female oral contraceptives. Yet no defi - various combinations (Mommers et al. 2008). This nite steroid combination could be established and the study involved 354 volunteers in seven treatment search for a marketable steroid combination and appli- groups receiving either placebo or 750–1,000 mg cation form must continue, a target that would be a 29 Approaches to Hormonal Male Contraception 585 genuine task for the pharmaceutical industry which, injections per year required for the substitution of a unfortunately, left the fi eld prematurely. hypogonadal man cost as much as 560. At that price the In view of the many single studies varying in scope ±7 injections required per year for male contraception it is puzzling that no greater coordination of efforts and would cost 980 and costs for the gestagens need to be resources ever emerged. The latter became all too evi- added. In order to compete with female contraceptives, dent when WHO terminated the Task Force for the the annual price of which is less than 100, the price for Regulation of Male Fertility in 1996 and thereby sur- testosterone undecanoate would have to be drastically rendered the leadership role it had maintained for reduced and industry would destroy the lucrative market almost 3 decades. for hypogonadism (and other applications). Under these Recognizing this vacuum, investigators initiated the circumstances, only hope remains that a governmental Annual Summit Meetings of Male Contraception in or philanthropic organization would undertake the fi nal 1997, a private forum for the exchange of ideas and steps needed for development of a usable product which results. From this forum two important analyses of pre- would allow a reasonable price for the end-product. vious studies emerged. In the fi rst, an integrated multi- variate time-to-event analysis of 1549 participants in 30 studies published from 1990–2005 was compiled and showed that all the various hormonal male contracep- References tive regimens resulted in full reversibility of suppres- sion of spermatogenesis (Liu et al. 2006). A second Barfi eld A, Melo J, Coutinho E, Alvarez-Sanchez F, Faundes A, analysis of the same studies showed that the rate of Brache V, Leon P, Frick J, Bartsch G, Weiske WH, Brenner P, suppression of spermatogenesis was enhanced by the Mishell D Jr, Bernstein G, Ortiz A (1979) Pregnancies asso- addition of gestagens to testosterone and that East Asian ciated with sperm concentrations below 10 million/ml in and younger men suppressed better than Caucasian and clinical studies of a potential male contraceptive method, monthly depot medroxyprogesterone acetate and testoster- older men, respectively (Liu et al. 2008). one esters. Contraception 20:121–127 Encouraged by these results, the participants of the Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner Summit Meetings envisioned an effi cacious and WJ Matsumoto AM (1996) Combined administration of marketable product that could be licensed by the regu- levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone latory authorities and drafted recommendations for alone: A promising male contraceptive approach. J Clin studies and prerequisites leading to such a product Endocrinol Metab 81:757–762 (Nieschlag and 10th Summit Meeting Group 2007). Behre HM, Kliesch S, Keck C, Simoni M, Nieschlag E (1995) Active participation by the pharmaceutical industry in Potential of testosterone buciclate for male contraception: Endocrine differences between responders and nonre- the search for a hormonal male contraceptive sponders. J Clin Endocrinol Metab 80:2394–2403 (Mommers et al. 2008) reinforced this view. This fi rst Behre HM, Kliesch S, Lemcke B, von Eckardstein S, Nieschlag placebo-controlled study also showed that side-effects E (2001) Suppression of spermatogenesis to azoospermia by of a testosterone-gestagen regimen were tolerable and combined administration of GnRH antagonist and 19-nort- estosterone cannot be maintained by this non-aromatizable consisted mainly of moderate weight gain caused by androgen alone. Hum Reprod 16:2570–2577 the anabolic effects of testosterone, which could prob- Behre HM, Wang C, Handelsman DJ, Nieschlag E (2004) ably be mitigated by dose-reduction. Pharmacology of testosterone preparations. In: Nieschlag E, In the light of these overall positive fi ndings and Behre HM (eds) Testosterone: Action, Defi ciency, Substitution, 3rd edn. Cambridge University Press, Cambridge, pp anticipated good acceptance of a male contraceptive by 405–444 the consumer (Heinemann et al. 2005), the sudden with- Brady BM, Walton M, Hollow N, Kicman AT, Baird DT, drawal by industry from the fi eld came as a surprise. Anderson RA (2004) Depot testosterone with etonogestrel Reasons for this withdrawal may be manifold, but fi nan- implants result in induction of azoospermia in all men for long-term contraception. Hum Reprod 19:2658–2667 cial considerations of public companies may be prevail- Grimes DA, Lopez LM, Gallo MF, Halpern V, Nanda K, Schulz ing. Basically, the components of a hormonal male KF (2007) Steroid hormones for contraception in men contraceptive would be relatively cheap and competitive (review). Cochrane Database Syst Rec 004316 with female methods, but are currently sold at high Gu YQ, Wang XH, Xu D, Peng L, Cheng LF, Huang MK, Huang ZJ, Zhang GY (2003) A multicenter contraceptive prices. For example, one injection of testosterone unde- effi cacy study of injectable testosterone undecanoate in canoate costs almost 140 in a German pharmacy; four healthy Chinese men. J Clin Endocrinol Metab 88:562–568 586 E. Nieschlag

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Wang C, Wang XH, Nelson AL (2005) Levonorgestrel implants WHO Task Force on Methods for the Regulation of Male enhanced the suppression of spermatogenesis by testoster- Fertility (1996) Contraceptive effi cacy of testosterone- one implants: Comparison between Chinese and non-Chi- induce azoospermia and oligozoospermia in normal men. nese men. J Clin Endocrinol Metab 91:460–470 Fertil Steril 65:821–829 Wang C, Cui YG, Wang XH, Jia Y, Hikim AS, Lue YH, Tong JS, WHO (2005) Controlled trials register NET-EN plus TU as a male Qian LX, Sha JH, Zhou ZM, Hull L, Leung A, Swerdloff RS contraceptive (WHO-HRP ID A25165) (accessed 2005-11-29). (2007) Transient scrotal hyperthermia and levonorgestrel http://www.who.int/reproductive-health/rhl/a25165.html enhance testosterone-induce spermatogenesis suppression in Wu FC, Balasubramanian R, Mulders TM, Coeling-Benning HJ men through increased germ cell apoptosis. J Clin Endocrinol (1999) Oral progestogen combined with testosterone as a Metab 92:3292–3304 potential male contraceptive: additive effects between des- Wenk M, Nieschlag E (2006) Male contraception: a realistic ogestrel and testosterone eanthate in suppression of sper- option? European Journal of Contraception and Reproductive matogenesis, pituitary-testicular axis, and lipid metabolism. Health 11:69–80 J Clin Endocrinol Metab 84:112–122 WHO Task Force on Methods for the Regulation of Male Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ (1999) A Fertility (1990) Contraceptive effi cacy of testosterone- clinical trial of injectable testosterone undecanoate as a induced azoospermia in normal men. Lancet 336:955–959 potenctial male contraceptive in normal Chinese men. J Clin WHO Task Force on Methods for the Regulation of Male Fertility Endocrinol Metab 84:3642–3647 (1993) Comparison of two androgens plus depot-medroxy- progesterone acetate for suppression to azoospermia in Indonesian men. Fertil Steril 60:1062 Pharmacological Approaches to Male Contraception 30

Trevor G. Cooper and Ching-Hei Yeung

Contents 30.1 Introduction

30.1 Introduction ...... 589 Alternatives to suppressing spermatogenesis by exoge- 30.2 Attacking Sperm Production in the Testis ...... 590 nous hormones for male contraception (see Chap. 29) 30.2.1 Chemically Blocking include chemical approaches to destroy pituitary gona- Spermatogenesis ...... 590 totrophes, immunological targeting of the hypothalamic 30.2.2 Physically Blocking GnRH, physically damaging the testis by local heating Spermatogenesis ...... 590 and ultrasound application or administering toxicants 30.3 Preventing Sperm Maturation that compromise or germ cell function (Page and Survival in the Epididymis ...... 591 et al. 2008). They all lead to the same end result of 30.3.1 Altering the Epididymal Transport azoospermia and, as for hormonal contraception, these of Spermatozoa ...... 591 30.3.2 Modifying the Composition approaches take months for sperm numbers to be of Epididymal Fluid ...... 592 reduced suffi ciently for effective contraception. Mechani- 30.3.3 Attacking Epididymal Spermatozoa ...... 594 cally blocking seminal emission pathways, such as 30.4 Preventing Seminal Emission...... 595 vasectomy (see Chap. 28), also aim to induce azoo- spermia but without loss of androgenic status and are 30.4.1 Surgical Approaches ...... 595 30.4.2 Pharmacological Blockade quicker in onset. of Seminal Emission ...... 596 Between halting the production of spermatozoa in the testis and preventing them from leaving the body 30.5 Sperm-Specifi c Targets ...... 596 through the vas deferens, lies an alternative approach, 30.6 Overall Conclusion ...... 596 that of producing non-functional spermatozoa (“func- References ...... 597 tional sterility”). This is being pursued by both chemi- cal and immunological interference with epididymal epithelial cells and spermatozoa within the epididymis with the aim of discovering druggable targets (enzymes, receptors, channels). Some of these aim to mimic the natural infertility stemming from epididymal dysfunc- tion observed in several domestic species and some transgenic mice (see Cooper and Barfi eld 2006). The advantage of a post-testicular, epididymal, contracep- tive lies in the rapid onset of infertility and the fast return to fertility once therapy is withdrawn. This is because they target already formed spermatozoa in the  T. G. Cooper ( ) epididymis; the short transit time (less than 1 week in Centre of Reproductive Medicine and Andrology of the University, Domagkstrasse 11, D-48129 Münster, Germany man) means that freshly produced testicular spermato- e-mail:[email protected] zoa, unaffected by the contraceptive, would rapidly

E. Nieschlag et al. (eds.), Andrology, 589 DOI: 10.1007/978-3-540-78355-8_30, © Springer-Verlag Berlin Heidelberg 2010 590 T. G. Cooper and C-H. Yeung replace the non-fertilizing population. It could be used • Retinoic acid receptor antagonists. These are cur- together with a hormonal contraceptive to initiate rapid rently being tested as retinoic acid receptor-α contraception before the onset of azoospermia. knockout mice are infertile

30.2 Attacking Sperm Production 30.2.1.1 Targeting Drug Accumulation in the Testis Within the Testis

Species’ differences in action refl ect a drug’s metabo- 30.2.1 Chemically Blocking lism and and its access to the targeted cells. Spermatogenesis A drug in the circulation passing through the capillar- ies in the testicular interstitium only has access to the spermatogonia, outside the blood-testis barrier. For A wide range of chemicals is able to upset spermato- drugs affecting post-meiotic cells, passage through the genesis and current knowledge can locate their site of blood-testis barrier is necessary. Adjudin coupled to an attack on specifi c cell types (Sertoli or germ cells or inactive, mutated FSH molecule that binds to the FSH- their regions of contact). The following list is not receptor can be targeted to Sertoli cells and far lower exhaustive (Mruk 2007), but the major classes of sper- doses of drug (mg/kg v. mg/kg) are required for anti- matotoxic compounds in animals include: spermatogenic activity (Wong et al. 2007). • Alkylating agents, e.g., busulphan, now used rou- tinely to deplete the spermatogenetic epithelium for stem cell transplantation studies 30.2.1.2 Clinical Observations • Imidazole derivatives, e.g., metronidazole (1-(2-chloroethyl)-2-methyl-5-nitro-imidazole) Initiated by Chinese observations during the 1980s, • Alkylated iminosugars, e.g., miglustat (N-butylde- comprehensive clinical studies on the contraceptive oxynojirimycin), but not unalkylated iminosugars, effectiveness of gossypol were carried out under the that inhibit glucosyceramide synthesis in mice, but auspices of the WHO. Because of unsurmountable are not contraceptive in rabbits or men toxic effects on spermatogenesis, these studies have • Indenopyridines, developed as antihistamines, e.g., been abandoned; however, studies were continued CDB-4022 (Mruk 2007) that cause detachment of elsewhere. In a multinational study in which gossypol germ cells (except spermatogonia) from Sertoli cells acetate was administered orally at 15 mg/day for 12–16 and have deleterious effects on the blood-testis bar- weeks, sperm concentrations fell between 4 and 12 rier in rats, with less effect on monkeys weeks of treatment and remained low during subse- • Indazole-carboxylic acid derivatives, e.g., adjudin, quent treatment with 7.5 mg or 10 mg per day for 40 that interferes with adhesion of the Sertoli cell with weeks in the responders. Over the next 52 weeks sperm most spermatids, few spermatocytes and no sper- concentration rose to exceed 20 × 106/ml but not to the matogonia (but causes liver infl ammation in male rats) pre-treatment values (Coutinho et al. 2000). A system- and gamendazole, active at lower doses than adjudin atic review of attempts at non-hormonal contraception • Many compounds of plant origin, e.g., papaya seed concluded that neither gossypol nor Tripterygium extracts (Carica papaya), neem leaf, bark or seed (Lopez et al. 2005) was effective or safe. extracts (Azadirachta indica), myrtle tree fl ower extracts (Eugenia jambolana). Most information is known about the polyphenolic binaphthyl dialdehyde gos- 30.2.2 Physically Blocking sypol, from cotton plant seeds (Malvaceae) and the multiglycoside extracts of Trypterygium wilfordii Spermatogenesis and hypoglaucum whose active ingredient triptolide is a diterpenoid triepoxide that acts on the immune The position of the testes in the scrotum, a natural system. They have either been shown to be toxic or cooling device, has invited the use of scrotal heating as ineffective as antifertility agents a means of male contraception. Scrotal warming can 30 Pharmacological Approaches to Male Contraception 591 be caused by a variety of factors that are met in the secretions that infl uence sperm fertilizing ability. workplace and have been put forward as causes of Approaches to inducing infertility in animals can thus male infertility. These include diseases (varicoele, be categorized as those that (i) interrupt sperm fever), occupational exposure to excessive heat (fur- transport, (ii) modify luminal fl uid composition or (iii) nace workers), continuous exposure to mild heat (sit- attack spermatozoa themselves. ting at desks, in vehicles, on heated seats or fl oors), clothing (tight-fi tting underwear or trousers) and life- style choices (laptop computers, hot water baths, sau- nas, exercise). Although many of these situations lead 30.3.1 Altering the Epididymal Transport to increased scrotal or intra-testicular temperature, for of Spermatozoa most of them, data on semen quality is lacking or inter- pretation is compromised by confounding factors The aim is to speed up or arrest sperm transport through (Jung and Schuppe 2007). the epididymis. The former should reduce the time that In a study in which heat was used as a supplement to sperm spend in contact with epididymal secretions and hormonal contraception, in the control arm of the study, lead to the ejaculation of immature, potentially non- immersion of the scrotum in water held at 43°C for fertilizing spermatozoa; it may also deplete the caudal 30 min a day for six consecutive days led to a decrease in sperm reserve so that suboptimal numbers of sperm are sperm concentration by 3 weeks, a maximum decline by ejaculated. Arresting distal epididymal sperm transport 6 weeks and a return to pre-heating values by 12 weeks should prevent seminal emission from the cauda and associated with unchanged circulating steroid and epididymidis and produce temporary azoospermia. gonadotropin concentrations (Wang et al. 2007). Increased germ cell apoptosis on testicular biopsies was noted. A decline in sperm motility was also measured 30.3.1.1 Effective Classes of Compounds 6 but sperm concentration never fell below 3 × 10 /ml. in Animal Studies This is a mild heat treatment and higher temperatures have led to greater declines in sperm concentration in • Drugs that act on sympathetic innervation other studies but azoospermia was never achieved, so that the method is considered inconsistent and unsafe as Compounds tested in rats include sympathomimetics, a contraceptive method (Jung and Schuppe 2007). e.g., methoxamine, that induce rapid infertility as a The daily wearing of close-fi tting athletic supports consequence of reduced ejaculated sperm numbers; with additional insulation for 52 weeks was effective in parasympatholytic agents, e.g., oxyphenonium, that raising scrotal temperature 0.8–1.0°C but had no sig- cause a temporary reduction in fertility owing to nifi cant change in semen volume, sperm concentration, reduced ejaculated sperm numbers; sympathoplegic motility or vitality (Wang et al. 1997). In other studies, agents, such as α-receptor blockers e.g., phenoxyben- azoospermia was induced in some men whose testes zamine, prozasin, tamsulosin, that interfere with semi- were held in close apposition to the inguinal region, but nal emission, cause sperm retention in the tail of the this could not be confi rmed (Jung and Schuppe 2007). epididymis and decrease vaginal sperm numbers post- copulation. These drugs can either decrease vaginal Effective non-hormonal approaches to arresting sperm numbers and cause infertility as a result of an spermatogenesis in man, whether by chemical or ejaculation and but the effects may be incomplete physical means, are not far advanced. when preimplantation losses are observed; sympatho- lytic agents, e.g., guanethidine, that deplete noradrena- 30.3 Preventing Sperm Maturation line from local short adrenergic neurones. Guanethidine induces irreversible infertility at high doses, and rapid, and Survival in the Epididymis but temporary, infertility at lower doses, by reducing ejaculated sperm numbers. The spermatozoa them- The post-testicular maturation of sperm involves their selves, however, are viable, motile, display normal generally slow transport through the epididymal canal chromatin condensation and can fertilize eggs by uter- (see Chap. 3) during which they take up specifi c ine insemination (Kempinas et al. 1998a, b). 592 T. G. Cooper and C-H. Yeung

• Drugs that act on peptidergic receptors 30.3.2 Modifying the Composition The male tract hosts peritubular receptors for endothe- of Epididymal Fluid lin, angiotensin, oxytocin, whose presence implies an involvement of paracrine and endocrine protein factors As luminal epididymal fl uid is important for the mainte- in epididymal motion. Vasopressin, oxytocin, endothe- nance of spermatozoa and specifi c aspects of their matu- lin and angiotensin increase epididymal contractions ration and storage (see Chap. 3), altering its composition in vitro, although the fertility of treated males has not should have repercussions on sperm function (Gong et been examined. al. 2000). Creating a hostile luminal environment would • Drugs that act on purinergic receptors prevent the acquisition of sperm functions or kill the spermatozoa. As fl uid constituents are transported from P2α purinergic receptors are present in the epididymis blood, synthesized by the epithelial cells or secreted into (Ventura and Pennefather 1991) and a rapid and revers- the lumen (Cooper 1998), any agent that modifi es epi- ible impairment of fertility of male rats follows thelial cells, or interferes with resorption, synthesis and intra-epididymal administration of the P2α-receptor secretion, could be a potential contraceptive. desensitizing agent α,β-methylene ATP.

• Other compounds affecting epididymal sperm 30.3.2.1 Compromising Epithelial Structure transport Other agents that increase sperm transport through the In a natural murine model of primary carnitine defi - epididymis of rats and mice include lowered serum ciency (“juvenile visceral steatosis”), with a mutant, testosterone, raised serum oestrogen, oxytocin, the inactive carnitine transporter, the males are infertile anti-androgen hydroxyfl utamide, sulphapyridine and (Toshimori et al. 1999). Azoospermia results from chloroethyl-methanesulphonate. The hormonal effects thinning of the epididymal epithelium, rupture of the are not purely epididymal, for infertility caused by proximal duct and appearance of granulomata. A trans- oestrogens can be due to effects in the testis, and tes- genic infertile male mouse model, lacking the retinoic α tosterone depletion/blockade can be explained by acid receptor- model, presents a squamous rather reduced androgen-dependent epididymal secretions. than pseudostratifi ed epithelium (Costa et al. 1997). Chloroethyl-methanesulphonate is an effective antifer- Here the distal epididymal and vasal epithelia cannot tility agent in the presence of normal androgen levels resorb water; inspissated fl uid accumulates and azoo- but has additional effects on sperm proteins (Klinefelter spermia results from ductal blockage. and Suarez 1997) and the epididymis that may contrib- ute to the infertility. These results demonstrate the importance of normal For drugs administered to reduce sperm transit time, epithelial function but lead to irreversible infertility failure to reduce potentially fertilizing sperm num- with the possibility of anti-sperm antibody forma- bers below those required for fertilization may pro- tion that is not desired in a male contraceptive. duce pre-implantation losses or retarded embryo development (Mieusset 1995; Ricker et al. 1997). For drugs intended to block seminal emission, dis- 30.3.2.2 Interfering with Transepithelial advantages of persistent paralysis of the genitouri- Transport and Fluid Secretion nary tract include immotility and decapitation of and Resorption stored spermatozoa, rupture in the distal cauda epididymidis with infl ammation, antibody genera- Studies in rats show that interfering with fl uid trans- tion and irreversible infertility (Evans et al. 1972). port in the epididymis can be associated with These problems could be avoided by permitting infertility. intermittent sexual activity to relieve epididymal • Epididymal fl uid resorption in vivo is inhibited by pressure, which is the aim of most post-epididymal, the antifertility agents α-chlorohydrin (Wong and vasal-acting, contraceptive procedures. Yeung 1977) and 6-chloro-6-deoxyglucose (Wong 30 Pharmacological Approaches to Male Contraception 593

et al. 1980), but infertility is thought to be mediated • Male rat fertility is not affected by abolishing the by their anti-glycolytic actions. activity of an epididymal enzyme (α-glucosidase) • Epididymal fl uid secretion in vitro is enhanced by with castanospermine (Yeung and Cooper 1994). adrenalin (through α-receptors), endothelin, vaso- • Immunoglobulins can gain access to the epididymal pressin, angiotensin, pituitary adenylyl cyclase-acti- lumen to reduce fertility in vitro and in vivo after pas- vating polypeptide, purinergic agonists and sive immunization with murine sperm-specifi c anti- prostaglandins. In vivo, inhibition of prostaglandin bodies and active immunization against rat epididymal production by the cyclo-oxygenase-1 inhibitor indo- proteins PES or D/E (see Cooper and Yeung 1999). methacin does not alter fl uid secretion, sperm motil- • Intrasplenic immunization with hamster sperm- ity or male fertility (Gong et al. 2000). Epididymal derived epididymal P26h is completely effective in fl uid secretion is inhibited by the alkaloid reserpine preventing fertilisation in vivo (Berubé and Sullivan and both sperm concentration and fl uid viscosity are 1994). increased under treatment whereas sperm motility is unaffected (Wen and Wong 1988). Whereas immunological contraception is being • Glucose transport to the epididymis is reduced by used to control wildlife at the population level the antifertility agents α-chlorohydrin and 6-chloro- (Barfi eld et al. 2006), the unpredictability of indi- 6-deoxyglucose (Hinton et al. 1983). However, vidual responses makes immunological contracep- these agents are thought to be contraceptives because tion risky (Nieschlag and Henke 2005). they inhibit sperm glucose metabolism (see below). • Carnitine transporters are present in the rat epididymis (Rodriguez et al. 2002) but the effect of transport 30.3.2.4 Inducing a Hostile Epididymal inhibitors on fertility has not been studied. Epididymal Environment carnitine can be lowered by adding pivalate to the drinking water, as a result of increased urinary excre- If the peculiar composition of epididymal fl uid is nec- tion of (pivaloyl)carnitine and a subsequent lowering essary for sperm survival, gross changes to it may of blood carnitine. Neither male rats nor hamsters cause infertility (Gong et al. 2000). administered pivalate become infertile following this treatment (Lewin et al. 1997; Cooper et al. 1997). • Osmolality. Cauda epididymidal fl uid has a higher • There are epididymal transporters for glutamate in osmolality than blood in every species examined mice (EAAC1: Wagenfeld et al. 2002.) When lack- (Cooper and Yeung 2003) so that lowering that ing, as in c-ros KO mice, epididymal and sperm osmolality, by reducing osmolyte secretion by the glutamate levels are depressed (Yeung et al. 2004), epithelium, should produce hypotonic swelling of spermatozoa are unable to regulate their volume spermatozoa within the lumen. and the males are infertile. • Oxidative death. In vitro spermatozoa can generate superoxide anions (Fisher and Aitken 1997) which are potentially damaging. Contraceptive agents Although theoretically satisfying, these approaches could stimulate enzymes producing oxygen radicals require more research to determine if specifi c or inhibit enzymes removing them. Targets could be epididymal inhibition of these transport processes the epididymis-specifi c, extracellular isoenzymes is feasible. of glutathione peroxidase (GPX5) and superoxide dismutase (SOD) present in epididymal fl uid (Vernet et al. 1997; Williams et al. 1998) or tissue 30.3.2.3 Interfering with Specifi c Epididymal indoleamine 2,3-dioxygenase (IDO) and tryptophan Proteins dioxygenase (TDO) (Britan et al. 2006). • pH. Intra-luminal acidifi cation is thought to maintain Interference with specifi c epididymal proteins may epididymal spermatozoa in a quiescent state (Carr et have contraceptive effects, but only limited evidence al. 1985) and raising pH has been proposed as a con- from immune-suppression experiments in animals are traceptive (Breton et al. 1996). Epithelial apical, nar- compelling. row and clear cells, responsible for epididymal 594 T. G. Cooper and C-H. Yeung

luminal acidifi cation, contain a cytoplasmic carbonic loss of sperm SP22 in males administered anhydrase (providing H+) and a vacuolar-type proton ethanedimethanesulphonate is predictive of fertiliza- pump (H+)-ATPase (V-ATPase). In animals, the car- tion after uterine insemination (Klinefelter et al. 1997). bonic anhydrase inhibitor acetazolamide, has no effect on the pH of epididymal fl uid in situ (Cafl isch Some of the compounds that displace sperm pro- and DuBose 1990). teins with deleterious effects on fertility have other effects on male rats in vivo (via Leydig cells, No organ- or cell-specifi c inhibitors of any of these epididymal clear cells) and as such are not organ- or enzymes, transporters or channels are known, so that cell-specifi c. no attack in this way is currently possible.

30.3.3.2 Inhibiting Sperm Glycolysis 30.3.2.5 Clinical Observations The concept is to block the metabolism of epididymal As human spermatozoa undergo similar maturational spermatozoa irreversibly so they remain inhibited after processes as do spermatozoa from other species (see ejaculation. Whether glycolysis (Miki et al. 2004) or Chap. 3), post-testicular approaches to contraception respiration (Ford 2006) supports the energy require- for animals based on physiological principles of ment of spermatozoa remains controversial (Ruiz- sperm transport, maturation and storage should be Pesini et al. 2007) but α-chlorohydrin inhibits the applicable to man. Although epididymal malfunction sperm-specifi c isoenzymes of glyceraldehyde 3-phos- may account for 20% of cases of human necrozoo- phate dehydrogenase (GAPDH, Gapds) and triose- spermia (Nduwayo et al. 1995), it is diffi cult to prove, phosphate isomerase (TPI) and causes “functional and there are only a few cases of human male infertil- sterility” (Jones and Cooper 1999). ity unequivocally caused by epididymal dysfunction Male rats are healthy after continuous daily feeding (De Kretser et al. 1998). of α-chlorohydrin for 60 weeks (Jones and Cooper The many secreted human epididymal glycoproteins 1999) and ornidazole for 2 years (von Richle et al. that bind to particular sperm membrane domains and 1978), but side effects are observed at the higher doses are involved in facilitating sperm-ovum interaction (see required for toxicological testing, although there are Chap. 3) are targets for immune-contraception: a poten- questions about the purity of the compounds used in tial target is the zona binding protein P34H. Immuno- early studies (Jones and Cooper 1999). targeting another epididymal secretion, the protease inhibitor Eppin, in monkeys led to incomplete, and not To avoid side effects associated with circulating always reversible, infertility (O’Rand et al. 2006). drug inhibition of GADP in somatic tissues, inhibi- tors should be targeted to or accumulated in the epididymis, but none has been identifi ed so far. 30.3.3 Attacking Epididymal Spermatozoa 30.3.3.3 Preventing Sperm Volume Regulation 30.3.3.1 Displacing Fertility-Related Sperm Proteins Spermatozoa need to regulate their volume upon ejac- ulation in order to progress within the female tract (see One protein displaced from spermatozoa of infertile Chap. 3) and this provides a novel contraceptive toxicant-treated rats is “contraception associated opportunity. When regulatory volume decrease (RVD) protein 1” (CAP: Wagenfeld et al. 1998) or SP22 fails, male infertility ensues (Cooper and Barfi eld (Klinefelter et al. 1997). This is normally present on 2006) as swollen spermatozoa with angulated fl agella the entire sperm head but is missing from a distinct fail to pass the uterotubal junction. In the mouse the distal equatorial region of spermatozoa from ornidazole- cause of the sperm swelling may be insuffi cient osmo- fed rats (Wagenfeld et al. 2000). A dose-dependent lyte reserves (Xu et al. 2003; Yeung et al. 2004) so 30 Pharmacological Approaches to Male Contraception 595 mimicking this situation to create infertile males could bound to the fi brous sheath (Westhoff and Kamp cited be achieved by: in Cooper and Yeung 1999) and are susceptible to gly- colytic inhibitors. The rodent antifertility agent ornida- • Preventing the secretion of osmolytes by the zole is used in the clinic for treatment of genital tract epididymal epithelium. Epididymal transporters infections but human semen quality under treatment have been identifi ed for glutamate in mice has not been examined. Although safe under the acute (Wagenfeld et al. 2002) and carnitine in rats conditions of use, the doses employed therapeutically (Rodriguez et al. 2002) and man (Enomoto et al. are 20–30 times lower than the antifertility dose for 2002). rats and its cleavage to the potentially active side chain • Preventing the uptake of osmolytes into spermato- in man is less extensive than that in the rat, so that zoa. Transporters in spermatozoa have been charac- changes are unlikely (Cooper and Yeung 1999). terized for carnitine from rats (Kobayashi et al. Osmolyte channels involved in human sperm vol- 2007) and for glutamate in spermatozoa from mice ume regulation include K+ and Cl− channels. That sper- and man (Hu et al. 2004). matozoa from patients display less volume regulating • Blocking the channels used by effl uxing osmolytes. ability than those of fathers (Fetic et al. 2006) or nor- These include K+ channels, Cl− channels and KCC mozoospermic donors (Yeung and Cooper 2008) sug- co-transporters (see Yeung et al. 2006; Cooper and gests that inhibiting RVD may well be a fruitful Yeung 2007) but only non-specifi c and reversible contraceptive approach. Furthermore, when voltage- inhibitors are known. sensitive K+ channels are blocked with quinine, human spermatozoa swell and fail to penetrate far into surro- No tissue-specifi c inhibitors are currently known for gate mucus (Yeung and Cooper 2001). For a contra- epithelial transporters, or channels mediating sperm ceptive action initiated in the male to continue in the osmolyte infl ux and effl ux to make this approach female in the absence of the inhibitor, such inhibitors feasible. should be irreversible.

30.3.3.4 Targeting Drug Accumulation Despite good evidence for epididymal dysfunction in the Epididymis being responsible for male infertility in domestic species, the prospect of mimicking this for human Targeting the drug to the epididymis would reduce the contraception is bleak, since sperm-proteins are not dose of administered compounds, and ameliorate side specifi c and there is a lack of specifi c inhibitors of effects. This may be achieved by making use of the glycolytic enzymes or channels mediating volume highly active, pro-luminal epithelial transporters in the regulation. epididymis to force entry of the compound into the lumen, but more research on the nature of these transporters is required. 30.4 Preventing Seminal Emission

30.3.3.5 Clinical Observations 30.4.1 Surgical Approaches

CAP1 is present in human ejaculated spermatozoa 30.4.1.1 Use of a Scalpel (Wagenfeld et al. 2000) but only on the sperm tail (Whyard et al. 2000). As it is now known that the struc- The procedures for vasectomy are covered in Chap. 16. ture of CAP1/SP22 is identical to that of the human proto-oncogene DJ-1, the RS subunit of an RNA- binding protein and the Parkinson’s protein PARK7, all 30.4.1.2 No-scalpel Approaches of which are ubiquitous, attacking this protein is unlikely to have a specifi c effect on spermatozoa. Various extra-luminal and intra-luminal devices to Human spermatozoa contain a specifi c form of close the vas deferens reversibly are being developed GAPDH analogous to the murine Gapd-s, which is (Barfi eld et al. 2006) but none is 100% successful. The 596 T. G. Cooper and C-H. Yeung use of intra-luminal plugs that solidify after insertion, 30.5 Sperm-Specifi c Targets including RISUG (Reversible Inhibition of Sperm Under Guidance) are being tested. They can block the There are now several sperm-specifi c sperm proteins passage of spermatozoa within a month and reduce the that may be amenable to attack to achieve male contra- secretion into semen of neutral α-glucosidase, but not ception. Spermatozoa could be targeted in the male fructose and acid phosphatase (Chaki et al. 2003). tract, or after ejaculation in the female tract by admin- istration to the male (or the female) partner. They include:

30.4.2 Pharmacological Blockade • Calcium channels. Reports of a widely available calcium channel blocker nifedipine inducing infer- of Seminal Emission tility have not been confi rmed. • The catsper calcium channels (1–4). These are spe- 30.4.2.1 Animal Studies cifi c to the principal piece and evolutionarily simi- lar to potassium channels but inhibitors for them The importance of purinergic receptors in the ejacula- have yet to be developed. tory process is highlighted in the P2X1 knockout • Soluble sodium-hydrogen exchangers (sNHE). mouse, which is sterile owing to an inability of the vas These regulate intracellular pH which is crucial for deferens to contract at ejaculation, despite normal motility but no inhibitors are known. adrenergic input (Mulryan et al. 2000). • Soluble adenylyl cyclase (sAC). No inhibitors for these are yet known. • Spermicides. Used as female contraceptives these contain detergents that destroy sperm membranes 30.4.2.2 Clinical Observations but also damage the vaginal wall. The contain nonoxynol-9, gramicidin or benzalkonium chloride The use of α-adrenergic blockers for human contracep- but more potent spermicides are being developed tion was suggested from clinical observations that men that could be used in the male, if delivery to and receiving sympatholytic agents present with ejaculatory activation in the epididymis could be achieved failure (Kedia and Markland 1975). Phenoxybenzamine (Hughes et al. 2007). was the fi rst α1-blocker studied intentionally as an oral contraceptive (Homonnai et al. 1984); it reduces semen volume, sperm concentration and eventually causes aspermia (anejaculation). Intermittent administration 30.6 Overall Conclusion was recommended and normal ejaculate volumes were produced at the end of treatment. Treatment from 7 days This review has highlighted the possibilities that non- before to 5 days after ovulation was suggested, with hormonal testicular and pharmacological post-testicu- treatment withheld during menstruation to permit lar approaches offer to male contraception; most of unprotected intercourse. The side effects of one putative them under-researched. Of the three approaches contraceptive, thioridazine, were suffi cient to have the reviewed, those involving arrest of muscular contrac- drug withdrawn (WHO 2005). tion at ejaculation could be quite close to clinical test- Peptidergic agonists are present in the peritubular ing since autonomic drugs are known, tested and musculature of the human epididymis (Tainio 1994) available, and only small developments are required on and endothelin is a potent stimulator of epididymal timing and modes of delivery. Modulating the compo- contractility in vitro (Peri et al. 1997). Thus peptider- sition of epididymal fl uid for contraceptive purposes gic agonists or antagonists may affect sperm transport does not currently seem promising because of the lack through the human epididymis: paralysis of the vas of organ-specifi city of epithelial synthetic, secretory deferens solely at ejaculation by receptor antagonists and transport processes, the unpredictability of immune may be a feasible way of providing rapid, post- responses and the lack of characterization of transport- epididymal contraception. ers in the epithelium and spermatozoa. To avoid 30 Pharmacological Approaches to Male Contraception 597 systemic side effects, any drug acting on spermatozoa Enomoto A, Wempe MF, Tsuchida H, Shin HJ, Cha SH, Anzai within the epididymal canal should be accumulated in N, Goto A, Sakamoto A, Niwa T, Kanai Y, Anders MW, Endou H (2002) Molecular identifi cation of a novel carnitine the epididymis, but this is also an area where research transporter specifi c to human testis. Insights into the mecha- needs to be targeted. nism of carnitine recognition. J Biol Chem 277:362–371 Evans B, Gannon BJ, Heath JW, Burnstock G (1972) Long– lasting damage to the internal male genital organs and their References adrenergic innervation in rats following chronic treatment with the antihypertensive drug guanethidine. Fertil Steril 23:657–667 Barfi eld JP, Nieschlag E, Cooper TG (2006) Fertility control in Fetic S, Yeung CH, Sonntag B, Nieschlag E, Cooper TG (2006) wildlife: Man as model. Contraception 73:6–22 Relationship of cytoplasmic droplets to motility, migration Bérubé B, Sullivan R (1994) Inhibition of in vivo fertilization by in mucus, and volume regulation of human spermatozoa. active immunization of male hamsters against a 26-kDa J Androl 27:294–301 sperm glycoprotein. Biol Reprod 51:1255–1263 Fisher HM, Aitken RJ (1997) Comparative analysis of the ability Breton S, Smith PJS, Lui B, Brown D (1996). Acidifi cation of of precursor germ cells and epididymal spermatozoa to gen- the male reproductive tract by a proton pumping, H+-ATPase. erate reactive oxygen metabolites. J Exp Zool 277:390–400 Nature Med 2:470–472 Ford WLC (2006) Glycolysis and sperm motility: does a spoon- Britan A, Maffre V, Tone S, Drevet JR (2006) Quantitative and ful of sugar help the fl agellum go round? Hum Reprod spatial differences in the expression of tryptophan-metabo- Update12:269–274 lizing enzymes in mouse epididymis. Cell Tiss Res Gong XD, Leung GPH, Cheuk BLY, Wong PY (2000) 324:301–310 Interference with the formation of the epididymal microen- Cafl isch CR, DuBose TD (1990). Effect of α-chlorohydrin on in vironment – a new strategy for male contraception. Asian J situ pH in rat testis and epididymis. Contraception 41: Androl 2:39–45 207–212 Hinton BT, Hernandez H, Howards SS (1983) The antifertility Carr DW, Usselman MC, Acott TS (1985) Effects of pH, lactate, agents α-chlorohydrin, 5-thio-D-glucose, and 6-chloro- and viscoelastic drag on sperm motility: a species compari- 6-deoxy-D-glucose interfere with sugar transport across the son. Biol Reprod 33:588–595 epithelium of the rat caput epididymidis. J Androl 4:216–221 Chaki SP, Das HC, Misro MM (2003) A short-term evaluation of Homonnai ZT, Shilon M, Paz GF (1984) Phenoxybenzamine – semen and accessory sex gland function in phase III trial an effective male contraceptive pill. Contraception subjects receiving intravasal contraceptive RISUG. 29:479–491 Contraception 67:73–78 Hu JH, Yang N, Ma YH, Jiang J, Zhang JF, Fei J, Guo LH (2004) Cooper TG (1998) Epididymis. In: Neill JD, Knobil E (eds) Identifi cation of glutamate receptors and transporters in Encyclopedia of reproduction 2. Academic, San Diego, CA mouse and human sperm. J Androl 25:140–146 Cooper TG, Barfi eld JP (2006) Utility of infertile male models Hughes LM, Griffi th R, Aitken RJ (2007) The search for a topi- for contraception and conservation. Mol Cell Endocrinol cal dual action spermicide/microbicide. Curr Med Chem 250:206–211 14:775–786 Cooper TG, Yeung CH (1999) Recent chemical approaches to Jones AR, Cooper TG (1999) A re-appraisal of the post-testicu- post-testicular, epididymal contraception. Hum Reprod lar antinfertility action and toxicity of chlorinated antifertil- Update 5:141–152 ity compounds. 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of the enzyme inhibitor castanospermine. J Reprod Fertil Yeung CH, Anapolski M, Setiawan I, Lang G, Cooper TG (2004) 102:401–410 Effects of putative epididymal osmolytes and the chan- Yeung CH, Cooper TG (2001) Effects of the ion-channel blocker nel blocker quinine on sperm volume regulation of fertile quinine on human sperm volume, kinematics and mucus and infertile transgenic mice. J Androl 25:216–233 penetration, and the involvement of potassium channels. Yeung, CH, Barfi eld, JP, Cooper TG (2006) Physiological vol- Mol Human Reprod 7:819–828 ume regulation by spermatozoa. Mol Cell Endocrinol 250: Yeung CH, Cooper TG (2008) Potassium channels involved in 98–105 human sperm volume regulation – quantitative studies at the protein and mRNA levels. Mol Reprod Dev 75: 659–668 Ethical Aspects of Reproductive Medicine* 31 Klaus Demmer

Contents 31.1 Social and Cultural Context

31.1 Social and Cultural Context ...... 601 31.1.1 A Shared Intellectual 31.1.1 A Shared Intellectual Responsibility ...... 601 31.1.2 The Structures of Interdisciplinary Responsibility Dialogue ...... 602 31.1.3 The Dilemma of the Theologian ...... 602 Medical research and clinical practice are not impris- 31.2 Church Statements ...... 603 oned in a self-suffi cient ivory tower of scholars. Rather, 31.2.1 Previous History: Artifi cial within enlightened democratic society there is a public Insemination ...... 603 interest in all matters touching upon the responsible 31.2.2 In Vitro Fertilization ...... 604 handling of human life over which, thanks to medical 31.2.3 The Dignity of Man and the Right to Life ...... 604 research, mankind has been given increasing control. Critical and constructive solidarity with all poten- 31.3 The Coordinates of Ethical Discussion ...... 606 tially affected persons is therefore called for which 31.3.1 The Basic Understanding lays the foundation for consentual legal standards; of Marriage ...... 606 31.3.2 Concern for Psycho-Social Health ...... 607 effective laws do not arise from unconcerted efforts by 31.3.3 Rights and Certainties ...... 608 legislators or monopoly-seeking lobbyists, but refl ect the intellectual responsibility of the whole community. 31.4 The Context of in Vitro Fertilization (“Dignitas Personae” nn. 24–35) ...... 609 For the physician this provides welcome relief. Serious decisions that have far-reaching consequences in shap- 31.5 Challenges to Tolerance ...... 610 ing the lives of individual patients must not be made by 31.6 Conclusions ...... 611 the scientist in the solitude of his conscience, even References ...... 611 though certain tensions between truth’s claim for uni- Church Documents ...... 612 versal validity and any consensus achieved will never be fully resolved. Ethicists and moral theologians share in the efforts to form opinion in our pluralistic and largely frag- mented society; as part of the intellectual elite, they contribute solutions to problems with which society can live responsibly and with intellectual honesty. This * Translated by S. Nieschlag is also true for the offi cial teachings of the Christian churches, regardless of whether or not the discussants share a basic Christian understanding of man. When K. Demmer the churches make a statement about medical research Professor emeritus, Moral Theology of the Pontifi cal Gregorian University of Rome, Johanniterstrasse 6, 48145 and its clinical application, they do so under the tacit Münster, Germany presupposition that the content of the message can be

E. Nieschlag et al. (eds.), Andrology, 601 DOI: 10.1007/978-3-540-78355-8_31, © Springer-Verlag Berlin Heidelberg 2010 602 K. Demmer rationally justifi ed and thus be credible. In general upon what authority? Transparency and consistency Christianity has always had a constructive infl uence on will determine the better argument and win the case. the scientifi c culture of the west, and will continue to Patience is required and mutual honesty. The physician do so if it succeeds in introducing into public discourse must not hold back relevant facts nor embroider them guidelines for a meaningful life which are in all with words. Dialogue must not be debased to a politics respects convincing and exemplary. of language. And the ethicist must make it clear that ethical theories are part of a supporting system of thought whose conclusiveness can provide answers. 31.1.2 The Structures of Interdisciplinary Only under these conditions can one dare to make value judgements without being backed into a corner Dialogue or labelled a troublemaker or spoilsport.

It often happens that the public has a mistaken concep- tion of the competency of either philosophical ethicists or moral theologians so that any contribution they may 31.1.3 The Dilemma of the Theologian make is not given its proper or due respect. Different styles of thinking which have become virtually institu- When the moral theologian engages in interdisciplin- tionalized collide with one another, occasionally giv- ary dialogue, he does not propose exclusively his pri- ing the impression that they have come to stand next to vate opinions, regardless of how well-founded they each other with nothing in common. This image, how- may be. He always recognizes that the churches hold a ever, does not correspond to reality; it is better to envi- privileged place for sound moral instruction and teach- sion underground channels developing and running ing; there is an initial reliance on and confi dence in the here and there linking the various disciplines. In this church’s intellectual tradition. Furthermore, as a Roman way, the medical researcher makes tacit assumptions Catholic, the theologian considers his mandate in which touch on fi elds usually claimed by philosophy, terms of partnership with the Church’s authority which scientifi c theory and anthropology; he is not autono- fi nds institutional expression in the magisterium of the mous, but thinks and acts within the framework of an pope and bishops. Nor is the concept of the magiste- open system in which compatibility must be achieved: rium foreign to the Protestant theologian, albeit with bridgeheads must be established continuously and varying emphases, comprehensiveness and linguistic connections must be made. forms. The same is true for the ethicist, be he philosopher A precarious relationship of trust exists between or moral theologian. He does not design a self-suffi - offi cial church representatives and professional theolo- cient body of thought to whose rigorous and unyield- gians. Their relationship is not always an unclouded ing logic every knee must bend; his thought is open to one. For the theologian, often the fi rst to be confronted the entire range of human scientifi c experience and with problems, is not able to withdraw to a “secure remains fl exible in light of the variety of human corner” and leave it to others to debate and set policy. endeavors. He is capable of learning, true to the axiom This carries unavoidable risks for his work; at times he that facts cannot be argued with. And he becomes cannot proceed beyond hypothetical answers which acutely aware of his limited competence, whenever he demand the courage to revise his position. It is his task is confronted by the professionalism of the physician. both to anticipate and then to interpret offi cial Church This does not condemn the ethicist or moral theologian statements. This requires much time; he must put up to silence. He is always available when the physician with the continuous tension between ethical insight touches upon the implicit presuppositions with which and its convincing presentation. The physician or med- he works but oversteps his professional limits and, as a ical researcher will understand this; they know, too, the result, draws ethical conclusions. For purely scientifi c provisional character of their knowledge. Mutual rec- results are ambivalent: whether they are considered a ognition of each other’s limitations makes the dialogue blessing or a cruse depends on the underlying under- all the more credible. standing of humanity. Finding a sustainable consensus It is a different situation for the magisterium. Who- is diffi cult in a pluralistic society. Who decides and ever speaks with the teaching authority of the church, 31 Ethical Aspects of Reproductive Medicine 603 be it ever so differentiated can take fewer risks. safeguarded, insofar as a third person Ð via donor Occasionally an impression of balking cannot be sperm Ð invades the intimate union of the couple. In avoided. However, the theologian always appeals Ð purely objective terms, it was thus quite understand- though in a nuanced variety of ways – to his opposite’s able to speak of adultery. It is not surprising that the freedom of conscience which is not abrogated. Author- pope acknowledged the emerging legal and demo- ity has no intention of trumping plausibility. graphic policy consequences of this problem, nor is it Differentiated positions will begin to emerge and surprising that those issues helped confi rm his negative patience is required on the part of all. Inspired by stance. Finally, when public debate introduced the growing insight, the magisterium strives towards issue of a “right to a child,” he was persuaded to inter- greater clarity and consistency; by learning it conquers vene; the existence of a human being is always a free its own tradition. In feedback with the institutional and unmerited gift, never a product which is rightfully community of dialogue, the theologian assumes the owned; in the end, that would imply a deliberate instru- role of mediator, always pushing forward and seeking mentalization of human existence. to resolve emerging diffi culties in understanding. This The ethical discussion immediately following was is anything but a one-way street. able to introduce fi rst, more precise distinctions. One point of criticism focused on the interpretation of mas- turbation. Similar to the collection of sperm for diagnos- tic purposes, its underlying intention was underscored: 31.2 Church Statements the purpose of the act is conception and not masturba- tion. The phenomenal structure of the act itself should 31.2.1 Previous History: Artifi cial be interpreted in this light; neither by itself nor in the fi nal analysis does the act itself determine its morality. Insemination Similarly the papal understanding of the conjugal act also became subjected to question. Without want- The criticism of artifi cial insemination by Pope Pius ing to detract from the fundamental unity that exists XII († 1958) worthy of consideration set the stage for between the openness to procreation and the expres- all further discussions surrounding the pros and cons sion of love in the conjugal act, it should not be over- of the various forms of infertility therapy. The argu- interpreted so as to excessively burden or strain ments put forward can be briefl y summarized as fol- practice. The fundamental dual meaning of the conju- lows: what was deplored by Pope Pius XII was the gal act is not undermined by any medical intervention artifi cial separation of the procreative purpose from but is rather borne out by the couple’s primary goal; the bodily expression of marital love; they belong technology must not necessarily burden the spontane- essentially together. Here is a line of argumentation ity of the couple’s expression of love. If a certain that will reemerge in connection with in vitro fertiliza- uneasiness continued to persist, then because of the tion, and which continued to infl uence the thinking of spontaneous feeling that the independent expressivity Pope John Paul II († 2005). of conjugal love fell by the wayside; that wherein Man is a bound steward, not an arbitrary creator of nature and culture are joined, is torn apart. Does tech- a given order of nature, which is interpreted as God’s nical progress create cultural relapse? good creation. It does not fetter or restrain the indi- In general, however, the pope and his critics were to vidual, but, over the entire spectrum of its expression it a large extent in agreement in their evaluation of the protects the dignity of the person. In consistent fash- population policy issues, and the legal and psychologi- ion, Pope Pius XII spoke out against the collection of cal problems associated with heterologous protocols; sperm through masturbation. Although the end Ð the the dangers were seen clearly and there is no need to conception of new life Ð may be good, it does not jus- list them here, except perhaps to mention that sperm tify the use of a means that is “in itself” evil. donation required in heterologous protocols epito- Moreover, the underlying understanding of the mizes the tendency to trivialize human sexuality. The institution of marriage became a matter for discussion. child falls victim, as a rule the child is denied the right In heterologous protocols, for instance, the exclusivity to know his own father. And the (genetic) father of the community of life is apparently no longer removes himself from any responsibility for the child. 604 K. Demmer

Should it ever be the case that he not remain anony- human situation. This judgement is defi nitive; the mous, as is currently required, e.g., by German and motives of those involved or concrete circumstances English lawgivers, there is an enormous risk of inner brook no alterations. A threshold value is established confl ict. Whether and to what extent the child so con- which necessarily polarizes belief. The opinion of the ceived is a lingering reminder of the absent father, thus Protestant Churches of Germany published under the putting pressure on the marriage or even leading to its title “Von der Würde des menschlichen Lebens” (On ultimate failure, depends on the basic attitudes of the the Dignity of Human Life) (1985) lacks this decisive legal parents. clarity. Nonetheless there is the fear, held in common, that understanding the child as a “gift” may take sec- ond place to that of a “product”. For the present time, and in somewhat declamatory 31.2.2 In Vitro Fertilization fashion, in his encyclical “Evangelium vitae” Pope John Paul II diagnosed the “culture of death” and con- The stage was now set for later confl icts concerning in trasted it with a “culture of life.” vitro fertilization. The prohibition expressed by offi - Such an emphatic choice of words may be surpris- cial teaching was unequivocally clear. The decisive ing in the context of reproductive medicine which texts are contained in the Instruction “Dignitas avowedly serves the transmission of life (n. 13 ff.). The personae” nn. 11–23 issued by the Congregation of the expression is clarifi ed in view of the possibility of Doctrine of the Faith (2008) and Pope John Paul II’s using spare embryos as raw material or “biological encyclical “Evangelium vitae” (1995). Corresponding waste” in human experiments that are unnecessary to the rejection of artifi cial insemination, here too except for the sake of so-called high ranking research the hard core of the argument is the underlying and therapeutic goals. This is in no way an exclusively anthropology of the conjugal act. With reference to Catholic concern. The Council of the Evangelical- Pope John Paul VI’s encyclical “Humanae vitae” Lutheran Church of Germany and the Catholic German (1968), the inseparable unity of the two meanings of Bishops Conference share the same fears in their joint the conjugal act Ð the expression of the couple’s mutual statement “Gott ist ein Freund des Lebens” (God is a love and the openness to new life – is affi rmed as part Friend of Life) (1989). Here there is complete agree- of the continuous offi cial church teaching. Man does ment which does not exclude the perception that, seen not have the right to separate them artifi cially, as usu- as a whole, Catholic statements are clearer and more ally occurs in all technical variations of assisted pronounced. fertilization. The reasons and fears looming in the background are manifold. On the one hand they are connected with the 31.2.3 The Dignity of Man and the Right morally questionable previous history of this technol- ogy. Does the use of IVF necessarily affi rm it? On the to Life other hand, reservations arose from the feared mecha- nization and accompanying despiritualization of the A consensus crossing confessional boundaries con- most spontaneous expressions of human life and expe- cerning both the ontological as well as the moral status rience. Not without reason there was talk of “cold con- of the early embryo is presently beginning to dissolve. ception.” The new context is the aseptic laboratory. Is The offi cial Catholic position is that specifi cally human a cultural relapse paving its way? Ultimately the link- life that is owed protection begins with the syngamy or ing of both elements is a cultural achievement which fusion of the gametes, even though this fusion does not has nothing to do with naturalism or even biologism; it occur at any one moment but is understood as an ongo- is aroused by the introduction of technology into one ing process. A determining factor of this concept is the of the most spontaneous expressions in human life. theological theory of simultaneous ensoulment propa- Reproductive technologies that, as Pope John XXIII gated by the early church, later taken up by the Council noted earlier, could be legitimately used with non- of Vienne (1311/12), the 5th Lateran Council (1513) human species, cannot be transferred directly to the and confi rmed by Pope John Paul II (Enc. Evangelium 31 Ethical Aspects of Reproductive Medicine 605 vitae, n. 60 f.). This is in contrast to successive ensoul- carried over into the act. Moreover, potentiality is not ment which, under the infl uence of Aristotle, who, to be considered synonymous with capacity. And this, referring back to mythological concepts, was intro- under differing conditions, pertains to the totality of duced into Catholic theology by way of Thomas human development. Aquinas († 1274) in disagreement with his teacher It is not a case of a life less worthy of protection. Albert the Great († 1280); up to the very present day The concept of the individual cannot be conceived in this concept has maintained a lasting infl uence. quantitative categories; one cannot be “more” or “less” With syngamy, a new entity Ð distinct from the a person. At this stage of vulnerability and weakness mother and with its own genetic programme Ð is the demands to protect human life should increase all brought forth, and begins its own course of develop- the more, and this in terms of advocacy. ment. That this process is subject to both endogenous To be sure, a capacity for abstraction is challenged as well as exogenous risks does not change its basic when a human being with his/her own rights is ontological and moral status. expected to be seen in a being the size of a pinhead. This is also true in view of the extremely weak autar- But how much greater a capacity is demanded by the chy as well as individuality of the early embryo. The fi elds of physics or mathematics! Abstraction is the maternal environment certainly is indispensable for its price of science. Not all Protestants share this view. survival and thereby exerts concausal infl uence on its Occasionally when theoretical doubts remain, tenden- epigenesis. But that such an infl uential process can take cies to consider graduated solutions are observed. place at all presupposes an individual counterpart with Here underlying confessional assumptions have proved independent activity, be it ever so slight. Pure passivity themselves effective which play a role in the use of does not exist, it is nothing than an intellectual construct. terms such as dilemma, compromise, tragic guilt and And moreover, the metaphysical category of autonomy the lesser evil. should not be reduced to the physical category of autar- When it speaks out in these matters the Catholic chy, if confusion of categories is to be avoided. Church does not adopt any particular philosophical As the most fundamental of rights, the logic of the system as its own when it speaks of “man” or “per- right to life is equally compelling at all times. It is not son”, only the transparency of argument counts. In the constrained by achievement of a certain developmental encyclica “Evangelium vitae” (n. 60 f.) “person” is stage which can never be fi xed arbitrarily, free of used with reference to biological events, in connection instrumentalization. If, in this context, the idea of cul- with a rhetorical question. Facts, however, are not tural attribution arises, it is fi rmly founded in an unde- compelling, they suggest independent processes of niable reality. Whoever shall set such boundaries and comprehension and interpretation, underlain by a on what authority: society, the physician, the mother? theologically grounded thought process which should The right to life precedes any acknowledgement, by refrain from forcible distortion of facts. The acceptance whomsoever. Is it thus not more consistent to reduce of personal life appears as the relatively most befi tting the self-purpose of human life to its very beginnings? alternative; in contrast, the distinction between pre- The embryo does not develop into a person but as a personal and personal life seems arbitrary. A broadly person. The bioethical argument put forth by the formulated concept of person is assumed which fol- German Evangelical Church, “Im Geist der Liebe mit lows on from observed stages of development. dem Leben umgehen” [Dealing with Life in the Spirit This affi rms the legitimate desire for a maximum of Love] (2002) speaks of the developing person with- amount of protection for human life; it acts as a dam. out claiming a fi nal position for the Protestant view- The task of natural philosophical discussion is to rec- point. This process is continuous without natural stages oncile the classical categories of understanding which allowing total disposability of human life. It retains its had been developed against the background of past sci- identity in the dynamism of its beginnings and at all entifi c concepts with the current knowledge of embryo moments of its development. It possesses an active development. This concerns key terms such as sub- potentiality to form whatever higher degrees of differ- stance, teleology and individuality. Here culturally entiation. Whatever exists Ð to whatever differing determined patterns of thought are of infl uence, but degrees Ð arises from potentiality which is already cannot be used arbitrarily. 606 K. Demmer

31.3 The Coordinates of Ethical function by providing security; the child is robbed of Discussion this protection. This is equally the case when advanced age of the woman makes long-term performance of parental duties more diffi cult. This is particularly the 31.3.1 The Basic Understanding case if a younger woman is involved as egg-donor. of Marriage Parents exist for the sake of the child, not vice-versa. In every case this principle demands respect. Offi cial church statements have the merit of providing The tendency to delay childbearing for professional indispensable guideposts to those engaged in public reasons and then, when nature fails, to make use of all discourse. They are focal points or axes around which possible medical technologies, creates a great pressure discussion turns regardless of the outcome. Ethical for justifi cation on the part of the would-be parents. refl ection within the Church is especially requested, Nature’s odds are defi ed to produce a child. This cre- further distinctions and clarifi cation can be made with ates an urgent appeal to social and labor laws to enable various degrees of authority; positions that are taken parenthood to be achieved at the timepoint biologically are not wholly specifi c to any one confession. Morality best suited for mother and child. has an autonomous character which permits universal In vitro fertilization by donor will continue to cause communication transcending confessional and even disagreement as it presents unsurmountable diffi cul- philosophical boundaries. ties. The precipitous use of the word “adultery” should One genuine concern in this discussion is the under- be avoided because it connotes an element of unfaith- lying understanding of sexuality and marriage. Those fulness on the part of the individual which may never who believe that relevant principal issues of reproduc- be assumed. This limitation, however, cannot over- tion are fundamentally tied to the institution of marriage come the concerns mentioned earlier. They arise from will consistently apply these principles to homologous the separation of genetic and legal parenthood. This protocols. Reproductive medicine is bound by this applies equally to both sperm and egg donors, whereby logic; it may not claim criteria or norms all its own. the latter is exposed to health risks. In terms of giving These concerns render an extension to quasi-homolo- life to a child, the bodily and spiritual aspects of the gous protocols meaningless. Responsibility for the relationship are separated, revealing the danger Ð perhaps social context of sexuality and reproduction fades in already a burden on the couple Ð of a dualistic importance. The dominating criterion is the care for the anthropology. child conceived, in particular providing the child a Certainly the child as the weakest part is affected to home with a stable heterosexual couple, as it is of the extent that he no longer has an unambiguous and supreme importance for the formation and development manifest genetic identity. Is there a subliminal fear of a mature and well-integrated personality as well as here of losing one’s sense of belonging? Ultimately, for the discovery of one’s identity. In light of this, there self-awareness of the person depends on knowledge arises a question for the physician: regardless of the about his origin; renouncing this legitimate expecta- procedures’ legality, is this extension of strict regula- tion seems unjust, and society shares in the harm that tions meant to be interpreted as evidence of responsible is done. The couple’s wish for a child Ð a wish that is tolerance? The main goal of reforms in the laws of completely understandable Ð must not ignore the social inheritance sometimes referred to in this context is to responsibility they also share; the price paid to fulfi l protect the illegitimately conceived child from unjust such a wish is the loss of any sense of proportion. harm. They must not undermine the shield afforded by Adoption of embryos may be considered as an open the institutions of marriage and family. question. Is the phrase a semantic trick, which reverses Ethical reservations multiply when the desire for a the original meaning? So that childless parents can be child arises quite outside the limits of such a socially provided with a child instead of children without par- supportive background. In that case it is irrelevant ents being provided with father and mother? But why whether the desire for a child is on the part of a single should such a reversal be so subject to criticism? parent or same-sex couple. In either case, the wish for Moreover, couples affected will ask themselves offspring is fulfi lled at the cost of the child. It is com- whether classic adoption is an option. And, last but not pletely ignored that social contexts have a supportive least, the possibility of accepting one’s own fate might 31 Ethical Aspects of Reproductive Medicine 607 be considered, for it too offers the chance to consoli- must also be taken into account. One such consider- date the partnership and release forces beyond the ation is the free decision of the couple; couples should limitations of the partnership. Openness for concep- not undertake therapeutic procedures under any emo- tion is not to be equated with fi xation. tional or psychological pressure from whatever source Reproductive medicine renews the challenge to because such coercion will unquestionably affect the intellectual plausibility which revolved around artifi - child negatively. It is necessary for the couple, then, to cial insemination. It concerns the anthropology of the examine very carefully whether or not available alter- conjugal act, in particular the inseparability of the natives offer more acceptable choices. Whoever sin- act’s two meanings (see Sect. 31.2.2). The ethical cerely considers all the alternatives available will debate has dealt with the basic issue for a long time, achieve a greater understanding of their desire for off- although under the aspect of contraception; it has also spring as well as a mature sense of peace. been discussed in scholarly circles within the Catholic Consultation with a trained psychologist can help in church. The question is: does the separation of procre- this regard. This is true especially in those situations in ation from its expressive qualities through techniques which the fate of childlessness proves to threaten the of assisted fertilization that provide relief from infertil- stability of the marriage. In such a situation, just hav- ity Ð albeit temporarily Ð merit such condemnation? Is ing a child is not the solution; one risks the danger of a the connection between the couple’s expression of love subliminal but real disregard for the child. Such a point and their openness to offspring understood too restric- of departure can have adverse effects on the child’s tive and narrow? later development; perhaps expectations are sublimi- Ethical discussions have focused on a fl exible inter- nally imposed on the child which, even with the best pretation of human action per se. Although the phe- intentions, cannot be fulfi lled. nomenal aspect of the act is surely an important When disillusionment sets in, repercussions will indicator, it is with certainty not the exclusive criterion also be felt throughout the marriage. A human person is determining the act’s morality. The whole ensemble of never a “therapy” for a couple in a precarious relation- factors and circumstances likewise has to be taken into ship. Their healing must be sought at a deeper level; account. When a couple accepts the burden of tech- fulfi lling the wish for a child can easily be a diversion- niques accompanying assisted reproduction in order to ary tactic saving the couple from the challenge of fulfi l their wish for a child this may indeed be inter- deeper emotional and psychological therapy. Emotional preted as a valid expression of marital love. The gov- and psychological distress cannot be redressed through erning intention unites both meanings of the conjugal proxy. Moreover, the welfare of the larger community act; technical separation will be counterbalanced by should be kept in mind. The perspective may not only this intentional unity. Precipitous moral evaluations of be focussed on the immediate world Ð perhaps at the reproductive technologies must take notice of this. expense of longstanding social structures. Nor should it Whosoever maintains his reservations concerning in be ignored that such a perfect “dream child” can all too vitro fertilization and simultaneously affi rms the per- easily be saddled with great expectations, exaggerated mitted use of contraception, must be prepared to defend wishes which can be projected onto the potential a contradiction in his thinking. For he too accepts a mother, who is put under pressure. In the event of fail- separation of the two aspects, albeit in reverse direc- ure, the disappointment will be all the greater. A more tion. In his favour he might note a more intensive per- relaxed approach in dealing with involuntary childless- ception in the case of IVF. ness is therefore desirable. The moral evaluation of surrogate motherhood in its various forms follows relatively easily. Pregnancy is not a purely physiological process and moreover, 31.3.2 Concern for Psycho-Social Health should not be commercialized. Rather, a deep and per- sonal bond is formed affecting both the pregnant Those facilities that offer reproductive technologies to woman as well as the child to be born. The relationship couples aim at protecting comprehensive well-being of between them cannot end at the moment of birth sim- the child; his well-being is the foremost concern. At ply on the basis of an agreement without doing vio- the same time, all psychological and social factors lence to nature. Moreover, it cannot be ignored that 608 K. Demmer resolution of confl icts possibly arising is made exceed- advanced age, if the patient accepts the risk of multiple ingly more diffi cult. Who decides in the case of a high- pregnancy, the physician has the duty to inform her risk pregnancy? Is it the surrogate mother alone who and ensure her acceptance of that risk. bears the responsibility or does the genetic mother The defi nition of the embryo as a being unto itself have a right to speak, and if so, to what extent? Can the implies the rejection of experiments using human assumption of higher risks be settled through a con- material. The individual is never exclusively a means tractual waiver? Could it be legally enforced? Here to achieve an end independent from his own self. This unresolved confl icts arise which are at the expense of variation on the categorical imperative guides the the child, as the one primarily affected but having no researcher who shares the anthropological premises voice at all in the matter. For this reason moral reserva- previously mentioned. The right to intrude into the tions need no further justifi cation. bodily integrity of the embryo in its earliest stages must be considered along similar lines. Deliberate abuse or disregard of the bodily integrity of the embryo cannot be allowed as it is the case whenever the well- 31.3.3 Rights and Certainties being of the child – the fi rst one to be affected Ð is no longer given absolute priority. The unequivocalness of The demand for a precarious reconciliation between this position places strict requirements on the researcher rights and certainties arises with regard to determining to prevent the dangers from a breach in the dyke. This the quality of embryos conceived “in vitro” as it occurs also applies to the embryo eliminated because of its in connection with single-embryo-transfer (SET). As is inability to survive; it does not lose its dignity. And known, from among several embryos the most ideal fi nally, the physician must rely on proxy decisions. embryo, i.e., the one most capable of survival is selected Without doubt the embryo is in the weaker and more and transferred. The others are “set aside”, that is, the vulnerable position. The instruction of the Congregation basic conditions for survival are withdrawn and they of the Doctrine of the Faith “Dignitas personae” (2008) are left to die. The goal of SET is the precision landing, is the advocate for these considerations. that is, to avoid precarious pregnancies and to increase It then follows from this line of argument that the the success rates of IVF. This reduces the stress factors genetic manipulation of the embryo is not admissable. for the patient. The German Law for the Protection of At the basis of this proscription is the recognized right Embryos secretly mutates into a Law for the Protection to unadulterated genetic patrimony. This touches on of Pregnancy. A balance is directly struck between the eventual possibility of germ line therapy. The res- high ranking qualities of life such as the mother’s ervations emerging here envisage not only the medical health and the child’s right to life. The idea of a suicide consequences of such research, but they also seek to mission comes to mind. But the laboratory is not a war prevent the danger of a eugenic mentality. To raise a theatre. Moreover, the question arises what degree of veto at this point is not a sign of naturalism or even certainty is offered by such quality control. Must one biologism, rather only the natural preconditions for not decide, in doubtful cases, in favour of the embryo? personal identity are protected. The German Law for In cases of dubious facts which affect the right of life, the Protection of Embryos, ¤ 8 embraces the fears protective strategies and not probabilistic ones are to mentioned. Admittedly it does not fail to recognize be favoured. This represents good ethical tradition. that even other means may rob a person of his identity, SET appears acceptable only under the condition of of which not the least and perhaps more effective graded protection of the embryo. means, is intellectual indoctrination. However, SET should not be rejected all too easily. Now the objection could be raised that absolute Even an approach which is protective in principle genetic identity is an abstract utopia. Medical technol- allows certain degrees of certainty, so that selection is ogy does nothing more than to hasten entirely normal not unacceptable in every case. There may be suffi - processes. The objection, however, is not fully con- cient certainty founded on experience for not perform- vincing, because the supposed risks are not only know- ing a transfer. The slogan of the “survival of the fi ttest” ingly provoked but condensed in time and made is not always applicable. The ability to differentiate is increasingly unclear. It may remain an open question expected of the ethicist. In the case of a patient’s whether or not the same apprehensions hold in the case 31 Ethical Aspects of Reproductive Medicine 609 of sex determination because of eugenic indications, avoided completely. Weighing and ranking benefi ts also its extension in the sense of “family planning”. Is and calculable risks cannot be avoided. There is also a a natural balance disturbed? The same restrictive atti- tendency to fearful over-refl ection. However, careful tude should be applied to the attempt at targeted dealing with nature is always the motto. Avoidance of enhancement of genetic material. Are there operable over-stimulation and in vitro maturation are part of this criteria free of a racist-materialistic concept of man? perspective. “Pure chance” may be the best guarantee for achieving the end in and of itself, irrespective of any protective regulation through choice of partner. 31.4 The Context of In Vitro Initially microinjection (intracytoplasmatic sperm Fertilization (“Dignitas Personae” injection: ICSI), the method used in cases of disturbed male fertility, had to defend itself against the suspicion nn. 24–35) of a manipulative intervention: it was not left to the natural process which of the many sperm contained in In vitro fertilization marked a crossing of the Rubicon the semen would fuse with the egg. However, the tar- which was followed by others. It opened the door to geted intervention demonstrably serves to increase the preimplantation diagnosis (PGD) and the attendant success rate; selection made by nature is supported. controversies. The ethical problems are polarized This offers the advantage of avoiding an abnormal between arguments of status and purpose. The prob- child early on without resorting to illegal measures. lem is on-demand conception. Here selection is made Should, however, damages occur, they will rest with purely according to genetic criteria or tissue compati- the parents. Thus a point of criticism mentioned ini- bility with a putative cell recipient. In this context, the tially becomes invalid. word “reprogenetics” is fully justifi ed. The dominant The duty to minimize risks applies to all techniques concept is that in its earliest phase, life is generally used. Early reservations against assisted fertilization exchangeable. Moreover, in the background stands a arose because of the implied disproportionality. But is genetic determinism of questionable understanding. this still justifi ed? When comparing these risks with What prognostic value can be claimed by such diagno- those complications arising from naturally induced sis? The lack of clearcut criteria as well as the rejection pregnancies they are almost identical. And the same of damaged cells suggest an analogy to roulette. All applies to the baby-take-home rate. The two-embryo those involved are sucked into the vortex of technol- transfer reduces risks similarly. The physician’s prin- ogy. This is in view of the human burden and the ever ciple of “nil nocere” is not invalidated. Are therefore increasing costs, be they for the parents of a handi- any small, remaining differences still valid in ethical capped child, or for society, of which normally an terms? Any exact balancing seems neither warranted expression of solidarity is expected. The horror vision nor covered by ethical tradition. One is reminded of of being stigmatized threatens both child and parents previously sanctioned attempts by the woman to and cannot be ignored. And the physician and his team, achieve pregnancy despite proven tendencies toward burdened by sheer limitations of time, is pressured into spontaneous abortion. Or has there been a rise in ethi- making decisions. The teleology of clinical action is cal sensibility? put to the extreme test. Finally PGD brings with it the Ethicists and physicians working in reproductive willingness to abort. The ethical problems associated medicine doubtlessly agree that biological nature can with single-embryo-transfer recur under the label of never be understood as the authority for ethical action. eugenics. They deal with nature that is accessible empirically but When, in expectation of abnormal offspring follow- also introduce into their data a projection that goes ing prenatal diagnosis, couples are determined to abort beyond it and humanizes it, subject to the underlying and consider PGD as the lesser evil, they are depen- assumptions of the person. This is the perspective from dent on purely descriptive categories. These recom- which to deal with artifi cially induced risks Ð especially mend themselves through the lack of sensation of pain for the embryo, which has deliberately been placed in during early embryonic stages. In the background this precarious position. This was heavily refl ected stands the slogan: no brain, no pain, no person. with regard to cryoconservation. Risks can never be Nevertheless it seems inappropriate to speak of the 610 K. Demmer choice of lesser ethical problems. One never chooses a engineering is open. Is this another Rubicon? In the problem, but rather the more convincing solution. background basic questions are hidden. They concern Protestant authors show a careful acceptance of PGD, the tension between scientifi c and philosophical think- a certain pluralism is recognizable. ing: in order to avoid reductionistic monism this ten- Comparisons with prenatal diagnosis are inevitable. sion should be maintained. Does the extremely weak Regardless of differences of principle, in the event of teleology provide a legal case for controlling interven- diagnosis of incurability, abortion tends to be the rule. tion or does it demand a case for protection according This puts the coherency of medical action to the test. to anthropological assumptions? Aside from the physician’s duty to inform the patient, The advantage of clear decisions is obvious, espe- should he also be prepared to carry out the abortion cially with regard to legal regulations. Those who legal- demanded, or can he delegate such a demand to oth- ize consuming embryo research must scrutinize existing ers? Is his refusal free of double morality? Or, in the legislation governing abortion. Is the Fristenlösung view of such a vicious circle in the sense of ethical (arrangement allowing abortion within the fi rst trimes- prophylaxis, should he not get involved? ter) a consistent postulate? If life becomes disposable Ethical considerations of in vitro fertilization in virtual confl icts, how much more so under actual cir- should at least mention cloning techniques. All previ- cumstances! Deadlines, whether fi xed or not, make no ously mentioned arguments return within a new con- difference. Whoever seeks the goal also desires the text. There is great controversy concerning the question means. of status. The ethicist will refrain from any suspicion of representing researchers’ interests and will not question the therapeutic goal. Rejection of reproduc- tive cloning will be understood, not only for reasons to 31.5 Challenges to Tolerance do with technology, but also because of injuring the right to genetic identity. Whether this argument is con- Strenuous efforts to achieve a moral consensus upon vincing is open to question. Moreover it contributes to which sound legal standards are built will never biological impoverishment, which cannot be desired. resolve all confl icting points of view. There remain In therapeutic cloning, also called research cloning, areas open for discussion and grey areas which can there is no doubt about the intention. Generally the become a burden for anyone working in reproductive classical principles of transplantation medicine apply. medicine who is sensitive to ethical issues. He sees Concern arises about the means used, i.e., the con- himself confronted with expectations by those who sumption of embryos or totipotent cells. Research do not share his convictions. A pluralistically struc- stands before a provoked dilemma: in order to possibly tured society reinforces the lack of agreement between save lives and heal disease in the distant future, present legal and moral spheres. Quick recourse to what is life must be sacrifi ced or the chance for its develop- legally allowed can never free one from the burden of ment must be deliberately be withheld. Whether alter- independent moral judgment. Whoever is satisfi ed natives are sought or not depends on the answer to the with plumbing the depths of the grey zones of legal- question of status. ity to his own advantage or that of his patients avoids The stem cell researcher will argue that he “rededi- the challenge of the pluralistically structured demo- cates” supernumerary embryos produced during in cratic state. Occasionally the courage to say no is vitro fertilization for a good purpose. Here the goal of demanded. The physician is never a living tool in the healing is given preference over that of protection. An hands of the patient. Active tolerance, such as is uncertain future is preferred to the secure present, only demanded from every citizen, cannot avoid drawing convincing those who call for graded protection of life boundaries. Ethical pluralism may be a fact, but it is in the status question. not a maxim for action. Whoever overlooks this con- Treating egg cells with stopper genes, which pro- tinuously provokes new claims and promotes a con- duces an artefact and no viable organism, can be con- sumer mentality which exercises pressure to conform sidered harmless when seen in isolation. Who, however, on the physician. Whether and if corresponding car- extends his vision to the consequences, will likely have tels of opinion exist to increase this pressure cannot strong reservations because the road to genetic be dealt with here. 31 Ethical Aspects of Reproductive Medicine 611

The self-understanding of the physician is also uncontrolled arbitrariness Ð especially in a pluralistic tested. His partnership with the patient certainly environment? Of what value are ethical traditions to demands a non-directive approach. Results of consul- the individual? And which sacrifi ces can society tations must remain open. But fi rmness of position is demand for their defense? Are aspects of feministic not identical with hegemonization. The danger of ethics dealt with suffi ciently? reverse paternalism is a threat when human problems The fi nal conclusion is therefore divided. The ethi- are reduced to their technological aspects and are thus cist should not deprecate the tragedy of involuntary “solved.” One withdraws from the right to mutual childlessness. If nonetheless reservations concerning autonomy. This danger is particularly great in an the mechanization of the most spontaneous and inti- increasingly globalized society. For it is utterly impos- mate situations of life remain, then because of consid- sible to fi nd legal regulations across borders. Different erations that the expression of human sexuality could legal cultures make the prevailing ethical pluralism less suffer, and the prevailing intention could obscure the controllable than in a relatively homogenous national value of individual action. Past experience has demon- legal and cultural domain. Available formulaic com- strated that drifting dunes threaten to uncover new, promises are then so insubstantial that they lack any underlying problems. This especially concerns the sta- power and are reduced to comforting formulas. Can an tus of the embryo. Couples affl icted should therefore independent national solution be made internationally ask themselves whether they really want such treat- plausible? ment and the physician is obliged to inform them about Contradictions of judgement within the legal sys- the ethical dilemma, thereby considering that in vitro tem may occasionally be confusing. The different stan- fertilization is only a segment of the “therapeutic” pos- dards in embryo protection and abortion laws are sibilities available. recalled to mind: the embryo created in vitro is obvi- ously better protected than the embryo and fetus dur- ing natural pregnancy. It should be remembered in this proper context that legal possibilities are not always References equivalent and that they react to different situations of confl ict. How strong and how certain are the confl ict- Bainbridge D (2001) Making babies: The science of pregnancy. ing rights? Are these confl icts actual or virtual? Harvard University Press, Cambridge, MA Imposed or provoked, avoidable or without alterna- Deech R, Smajdor A (2007) From IVF to immortality: Contro- tive? Contradictory evaluations therefore appeal to the versy in the era of reproductive technology. Oxford University Press, New York autonomy of moral judgment. The same applies to the Gerris J, Olivennes F, De Sutter P (eds) (2004) Assisted repro- legal treatment of : punish- ductive technologies: Quality and safety. Taylor & Francis, ment can only be considered when a crime can be Boca Raton, FL proven. This, however, does not apply to the current Hull RT (ed) (2005) Ethical issues in the new reproductive tech- nologies. Prometheus Books, 2nd edn. Amherst, New York case. Generally, a legal vacuum should not be confused Jackson TP (2005) The morality of adoption: social-psycholog- with moral approval by the lawmaker. ical, theological, and legal perspective. Eerdmans, Grand Rapids, MI Kilner JF, Cunningham PC, Hager WD (eds) (2000) The repro- duction revolution: A Christian appraisal of sexuality, repro- 31.6 Conclusions ductive technologies, and the family. Eerdmans, Grand Rapids, MI Rothschild J (2005) The dream of the perfect child. Indiana Whatever the attitude to IVF is, there are concerns University Press, Bloomington, IN Shenfi eld F, Sureau C (2006) Contemporary ethical dilemmas in across confessional borders. These are caused, on the assisted reproduction. Taylor & Francis, Boca Raton, FL one hand, by the diffi culty of maintaining strict criteria The President’s Council on Bioethics (2004) Reproduction and in day-to-day practice, and on the other hand, by the responsibility: The regulation of new biotechnologies. necessity for further embryo research unless one wants Washington, DC Warnock M (2002) Making babies: Is there a right to have chil- to freeze the standard currently achieved. The social dren? Oxford University Press, New York context must also be considered: will natural structures Wildes KW (1997) Infertility: A crossroad of faith, medicine, with cultural values be dissolved and be exposed to and technology. Kluwer, Dordrecht, NL 612 K. Demmer

Church Documents Pope John Paul II, Encyclical letter “Evangelium vitae” (1995) Gemeinsame Erklärung des Rates der Evangelischen Kirche Deutschlands und der deutschen Bischofskonferenz, “Gott Pope Paul VI, Encyclical letter “Humanae vitae” (1968) ist ein Freund des Lebens” (1989) Congregation for the Doctrine of Faith, Instruction “Dignitas personae” (2008) Index

A AFP, 229 Abdominal circumference, 95 Age, 392–393, 396, 397, 407, 411, 416, 419, 421, Abortion, 248, 559 425, 429, 431 Abstinence, 125, 128, 129, 483, 560, 562–563 of the female partner, 4, 5 Abstinence period, 69 of the male partner, 4 Abuse anabolie steroids, 452–453 Agglutination, 126, 127, 131, 132, 483 Acceptability of male contraception, 560–561 Aggregation, 126, 127 Acceptance of multiple pregnancies, 526 Aging, 239–258 Acceptance of penile implants, 316 Alcohol, 343, 350, 355, 376, 395, 430 Achondroplasia, 248, 367 abuse, 289 Acid phosphatase, 72, 132 and social drugs, 376 Acne, 329 Algopareunia, 394 Acquired anorchia, 195–197 Alkaline gel electrophoresis, 149 Acquired immune defi ciency syndrome (AIDS), 352, Alkylated iminosugars, 590 353, 398, 511, 563 Alkylating agents, 590 Acquired penile deviation, 281–282 Alloimmunity, 430–431 Acromegaly, 256 Alopecia, 96 Acrosin, 66, 68, 69, 77 Alopecia areata, 419 Acrosomal phase, 19 Alpha-adrenergic substances, 484 Acrosome, 126, 130 Alzheimer disease, 348 Acrosome reaction, 66, 68, 74–78, 141, 143–145, 273, 274 Amenorrhea, 404, 408–411, 413, 414, 417, 418, 427 Acrosome reaction to ionophore challenge (ARIC), 144, 145 Aminoglutethimide, 341 Actin, 14 Amygdala, 541 Activating and inactivating mutations of the gonadotropin Amyloidosis, 354 receptors, 31 Anabolic steroids, 355, 441, 449, 452–453 Activating LH receptor mutations, 225 Anamnesis, 93–100 Activating mutations, 224, 226, 231 Anatomical variations of the vagina, 420 Activin, 23, 35 Andractim®, 445 Acts of inclination, 548 Andriol®, 439, 443, 448 Acupuncture, 464 Androderm®, 442, 445 Acute bacterial prostatitis, 264, 266 Androgenetic alopecia, 325–326 Acute epididymitis, 264 Androgen insensitivity (AI), 323–328 Acute orchitis, 206 Androgen receptor (AR), 14, 24, 33, 34, 39, 43, 44, 46–52, Acute toxicity, 365 253, 256, 324, 325, 327, 328, 335, 457 Acycline, 582 antagonists blocking, 341 Addison’s disease, 419 CAG repeats, 113 Adnexitis, 265 polymorphism, 52, 113 Adolescent gynecomastia, 331–334 Androgens, 459–463 Adoption, 522, 524, 528, 532, 533 action, 34, 36, 39, 44–50 Adoption of embryos, 606 bioactivity, 115 Adrenal tumors, 333 defi ciency, 93–95, 243, 250–253, 340–345, 347, 350–356 Adrenarche, 54 plus gestagens, 582–584 Adrenocorticotropic hormone (ACTH), 395, 415 Andrological factor, 525 Adrenomedullin, 14 Andropatch®, 442 Adriamycin, 509 Androstane-3a, 12, 44 Adverse side-effects, 294 Androstendione, 439

613 614 Index

D4-Androstendione, 223 Atherosclerotic cardiovascular disease, 354 Androstenedione, 33, 42, 47, 115, 116 Autoantibodies, 351, 352, 419 , 33, 42 Auto-antigens, 38 Androtop®, 443, 445 Autoimmune diseases, 419, 430 Anejaculation, 317 Autoimmune factors, 395 Aneuploidy, 248, 346 Autoimmune orchitis, 352 Angelman syndrome, 496 Autoimmunity, 430 Angiographic occlusion, 205 Autoinjection therapy, 281, 311–313, 315 Angiotensin, 411 Autonomic nerve fi bers, 299 Ankylosing spondylitis, 352 Autotransplantation, 199 Anorchia, 98, 194–197, 199, 222 Average path velocity (VAP), 141 Anorexia, 345, 351 Axillary, hair 48, 51 Anorexia nervosa, 351, 418 Axonemal complex, 67, 72, 73 Anosmia, 96 Axoneme, 67, 72–73 Antagonists of androgen action, 341 Azathioprine, 342, 343 Antegrade ejaculation, 484 AZFa, 218, 495 Antegrade sclerosing of the spermatic vein, 205 AZFa deletions, 218, 219 Anterior pituitary, 21, 22 AZFb, 218 Anthropology of the conjugal act, 604, 607 deletions, 218, 219 Antiandrogens, 196, 257 regions, 495 Antibodies of the IgG- and IgA-class, 273 AZFc, 218 Antibody testing, 428 deletions, 218–220 Anticholinergics, 484 regions, 123, 495 Anticonvulsants, 341, 348 Azoospermia, 126, 128, 132, 135, 198, 208, 212, 213, Antidepressants, 290 218–221, 229, 231, 264, 267–269, 272, Antiestrogens, 416, 459–461 509–511, 577–584, 589–592 Antihistamins, 290 Azoospermia factors, 218 Antihypertensive drugs, 290, 307 Anti-mullerian hormone (AMH), 52, 115–116, 194, B 195, 220, 221, 323, 392, 400, 414 Bacterial orchitis, 206 Antimycotic drugs, 290 Balanced and unbalanced structural chromosomal Antioxidants, 463–464 anomalies, 217 Anti-sperm antibodies (ASA), 70, 141, 145, 268, Balding, 95 273–275, 349, 481 Bands, 309 Apert syndrome, 248, 367 Barbiturates, 341 Aplasia of the mullerian duct, 421 Barr bodies, 212 Aplastic and renal anemia, 437 Basal body temperature, 403, 405, 408 Apomorphine, 301, 302 Basal cell naevi, 248 Apoptosis, 21, 37, 366–368, 370 Basal cells, 63, 70 AR mutation, 325, 328 Basedow’s disease, 419 Aromatase gene (CYP19A1), 333 Beard growth, 51, 93, 95, 329, 331, 447 Aromatase inhibitors, 416, 417, 426–428, 459–460 Beckwith-Wiedemann syndrome, 496 Array CGH, 120, 122 Behçet disease, 354 Arterial infl ow, 284–286, 288, 310 Benign prostate hyperplasia (BPH), 48, 50, 254, 256–257, 449 Arterial insuffi ciency of the penile vessels, 288 Bifurans, 374 Arterial penile circulation, 295 Bilateral congenital anorchia, 194, 195 Arteriosclerosis, 567, 569 Bilateral obstruction of the ejaculatory ducts, 266, 272 Arteriosclerotic alterations, 244 Bilateral testicular biopsy, 268 Artifi cial insemination, 603–604, 607 Bilateral testicular tumor, 510 Ascorbic acid, 464 Birth weight, 475, 496 Asherman’s syndrome, 410 Blastocyst, 80 Aspermia, 50, 317 Blood-brain-barrier, 39 Assays of chromatin compaction, 147–149 Blood pressure, 52 Assisted hatching, 478, 491–492 Blood-testis barrier, 13, 16, 35, 38, 273, 369, 590 Assisted reproduction, 268–271, 465, 470–471, 483–485, Blow-out, 571–573 493–497, 607 Blunt trauma, 281, 291 Assisted reproductive techniques (ART), 61, 68, 521, Body communication, 542, 553 527–528, 530, 531, 534 Body fat, 242, 250 Asthma, 397 Body mass, 27, 30 Asymptomatic infl ammatory prostatitis, 264 Body mass index (BMI), 241, 249, 251, 253, 351 Ataxia, 347, 348 Body weight, 410, 416, 418, 446, 447 Index 615

Bone age, 106, 447, 452 Chromosomal analysis, 122, 248, 496 Bone density, 50, 250, 446, 450 Chromosomal anomalies, 530 Bone mass, 450–451 Chromosomal defect, 429, 430 BRCA-1, 334 Chromosomal disorders, 122 BRCA-2, 334 Chronic abacterial prostatitis, 264 Breast cancer, 327, 334 Chronic active hepatitis, 343, 352 Breast carcinoma, 212 Chronic anovulation, 414 Bromocriptine, 413, 464 Chronic bacterial prostatitis, 264–266 Bronchiectasis, 272–273, 344 Chronic coronary heart disease, 284 Bronchitis, 94, 344 Chronic epididymitis, 264, 266 Buccal administration, 441 Chronic hepatitis, 398 Chronic liver failure, 343 C Chronic obstructive pulmonary disease (COPD), 344 Cabergoline, 413 Chronic opioid consumption, 354 Cadmium, 373, 374 Chronic orchitis, 206 Caffeine intake, 430 Chronic sinobronchial disease, 272 CAG repeats, 213, 253, 324, 328, 333, 335, 447 Chronic sinusitis, 344 CAG triplets, 49 , 341, 349 CAG triplets on the androgen, receptor 256 Circadian rhythm, 54, 112, 116, 243 Calcifi cations, 281, 282 Circumcision, 266 cAMP, 287, 293, 294, 304 Cirrhosis, 343, 352 Cancer risk after assisted reproduction, 494–495 Cisplatin, 229–231 Capability for cohabitation, 280 Cisplatinum/vinblastine/bleomycin, 345 Capacitation, 61, 62, 74–75, 77, 141, 143, 151, 421 Citric acid, 72, 132 Carcinogenesis, 365, 370 Classifi cation of andrological disorders, 87–92 Carcinoma in situ (CIS), 199, 222, 227, 370, 379, 484 Clinical picture and diagnosis, 264–265, 267–269, 271–274 Carcinoma in situ of the uterine cervix, 398 Clitoromegaly, 327 Cardiac disease, 397 Clofi brates, 290 Carnitin, 464 Clomiphene, 335, 407, 416–418, 459, 488, 489, 493 Castration, 195–197 Cloning techniques, 610 Causes of obstruction in the seminal ducts, 267 Clotting system, 449 Cavernosal autoinjection, 281, 311 Cluster headache, 349 Cavernosal insuffi ciency, 289, 293, 296, 298, 309, Cocaine, 355, 376 310, 312, 314, 315 Coeliac disease, 349 Cavernosal occlusion mechanism, 288, 289, 293, 297, Cognitive and social development of the child, 530 309, 310 Cohabitation, 279–318 Cavernosography, 297–299, 312, 314 Cohabitation problems, 280 Cavernosometry, 297–299, 314 Coital frequency, 393, 394 Cavernous sinusoids, 285 Coitus interruptus, 560, 563 Cell death, 366, 367, 370, 372 Cold shock, 513 Central nervous system (CNS), 30, 51 Colitis ulcerosa, 506 Central sheath, 72, 73 Collection of semen, 483–485 Cervical mucus, 67, 73, 74 Color-coded duplex sonography, 103, 105, 297 contact (Kremer) test, 74 Comet assay, 148–150 production, 403, 420 Comparative genomic hybridization (CGH), 120–122 CF alleles, 268, 269 Complete androgen insensitivity (CAI), 30, 324–327 CFTR gene, 123, 124, 268–270, 272, 273, 495, 496 Complete bilateral obstruction, 267 CFTR gene mutation, 268, 269–273, 344, 457 Complete phimosis, 280 cGMP-dependent protein, 287 Complication of autoinjection therapy, 312 Charles Goodyear, 563 Complications of assisted reproduction, 493–495 Chemiluminescence assays, 143 Complications of cavernosometry and cavernosography, 298 Chemo/radiotherapy, 345–346 Complications of intracavernosal testing, 295 Chemotaxis, 76 Compounds of plant origin, 590 Chlamydia trachomatis, 132, 264–266, 420, 422–424, 430 Computer-aided sperm analysis (CASA) systems, 127, 133, Chlomipramine, 318 134, 140, 141, 143, 146 6-Chloro-6-deoxyglucose, 592, 593 Computer-assisted sperm motion analysis, 476 Cholesterol, 40–42, 45 Conceptions, 559, 563 Chorion carcimoma of the testis, 333 Condoms, 561–564 Chromatin, 61, 66, 68, 76, 79 Congenital adrenal hyperplasia, 101, 105, 350 Chromatin condensation, 68 Congenital bilateral absence of vas deferens (CBAVD), 65, Chromosomal abnormalities, 495, 496 105, 270–273, 344, 457 616 Index

Congenital bilateral agenesis of the vas deferens, 510 Cytoplasm, 140, 142, 147 Congenital bilateral anorchia, 195 Cytoplasmic droplets (CDs), 142 Congenital germ cell aplasia, 207 Cytotoxic drugs, 341, 345, 352 Congenital numerical chromosome aberration, 210 Congenital penile deviation, 280, 282, 292 D Conservative therapy of IPP, 282 , 335, 426, 427 Constitutionally delayed puberty, 437 Dapoxetine, 318 Contraception, 565, 566, 568, 570, 589–597 Decapacitation factors, 75 Contraception associated protein 1 (CAP), 594, 595 Deferent ducts, 99–100 Contraceptive effi cacy, 579 (DHEA), 115, 241, 242, 255, 439 Contraindications Dehydroepiandrosterone sulphate (DHEAS), 241, 242 for autoinjection, 311 Delayed puberty, 216, 224, 340–342, 344, 349 for intracavernosal vasoactive testing, 294 Deletions of the Y chromosome, 208, 217, 218 for medical therapy, 527 Density gradient centrifugation, 485–487 Contralateral testicular tumor, 227 Depot medroxyprogesterone acetate (DMPA), 582–584 Controlled, prospective, randomized and, if possible, Depressed mood, 250 double-blind clinical studies, 7 Depressions, 524 Conventional semen analysis, 471, 476 Descending phase, 36 Cooling of the scrotal organs, 464 Desire for a child, 522, 525, 528 Coping, 522–528 17,20-Desmolase-defect, 222 Copy number variations (CNV), 120 Desogestrel, 582, 584 Corona radiata, 476–478 Detumescence, 71 Coronary heart disease, 242, 254, 256 Detumescence phase, 286 Corporal resection, 280 Development, 605–607, 610 Corpus cavernosum, 71, 280, 285, 288, 294, 296–299, 314 DHEA substitution, 255 Corpus luteum, 399, 402, 404, 405, 407, 408, 412 Diabetes mellitus (DM), 212, 241, 242, 249, 250, 255, Corpus spongiosum, 71 280, 284, 288–290, 292, 310, 311, 313, 315, Corticosteroids, 274, 275 350, 351, 569 Corticosteroids for treatment of immunological Diabetes mellitus type II, 242, 250, 251, 254 infertility, 275 Diagnosis in sexual medicine, 549–554 Corticotropin-releasing hormone (CRH), 395 Diagnostic evaluation of the cycle, 405–408 Cortisol, 241 Dibromochloropropane, 371, 373 Counselling, 523, 525, 527, 529, 534 , 371, 374 Couple-interview, 550 Differential diagnostic workup, 290 Couples, 521–534 Diffquik, 130 Crohn’s disease, 349, 397 Dignitas personae, 604, 608–610 Cross contamination, 512, 514 Digoxin, 341 Cryoconservation, 609 5a-Dihydrotestosterone, 26, 33, 34, 42–44, 47, 50–53, Cryopreservation, 505–518 115, 116, 438, 441 of oocytes, 492–493 Dihydrotestosterone (DHT), 244, 256, 324, 328 of oocytes in pronucleate stage, 492–493 g-Diketones, 369 and sperm extraction, 156 Dilatations of the ejaculatory ducts, 105 Cryoprotectants, 512–514 Dimension of attachment, 539–542, 551, 553 Cryoprotective medium, 514 Dimension of desire, 540–542, 546, 551 Cryostorage, 340, 346, 356 Dimension of reproduction, 541, 546, 551 Cryptorchidism, 98, 101–103, 105, 195, 198–200, 221, Dimensions of sexuality, 542, 551, 553 222, 340, 452 17b-diol, 12, 44 Cumulative pregnancy rates, 6, 9, 203, 247 Dioxins, 374 Cumulus cells, 141, 144 Di(n-butyl) , 375 Cumulus oophorus, 75–76, 476–478 Direct intraperitoneal insemination (DIPI), 473 Cyclicguanosine monophosphate (cGMP), 287, 303, 304, 307 Disintegrins, 78 Cyclophosphamide, 367, 371 Disorders in sexual preference and behavior, 549 Cyproterone acetate (CPA), 341, 514, 583–584 Disorders of gender identity, 543, 546–547 Cystic fi brosis (CF), 65, 94, 268–270, 344, 495 Disorders of liquefaction, 273 Cystic-fi brosis transductance regulator-gene (CFTR), Disorders of sexual behavior (dissexuality), 543, 548–549 483, 495, 496 Disorders of sexual desire, 543 Cytochrome 450 aromatase, 329 Disorders of sexual development (DSD), 90, 323, Cytochrome P450ssc, 42 543, 545–546 Cytogenetic methods, 120–121 Disorders of sexual maturity, 545 Cytokines, 341, 345, 349, 352 Disorders of sexual orientation, 545 Cytokines (IL 6, IGF-1), 345 Disorders of sexual partnership, 546 Index 617

Disorders of sexual preference (paraphilias), 543, 547–549 Embryo, 604–606, 608–611 Disorders of sexual reproduction, 543, 549 donation, 529, 532–533 Disruption of spermatogenesis, 340, 341 transfer, 477, 492 Dissexuality, 543, 548–549 Emission, 316, 317 Disturbances of lipid metabolism, 284, 288 Emphysema, 345 Diurnal variations, 112 Empirical therapy, 92, 458–464 DNA, 141, 143, 144, 147–151 Empty-sella syndrome, 412 demethylation, 79 Endocrine erectile dysfunction, 289 fl ow cytometry, 133 Endocrine functions, 522 fragmentation, 148, 149 Endocytosis, 12, 28, 40–42, 45 methylation, 149 Endometrial biopsy, 407, 408 synthesis, 17, 35 Endometriosis, 406, 410, 420, 422, 424–429, 471, 495 DNA-binding domain, 44, 46, 47 Endometrium, 403–407, 409, 410, 418, 422, 425 Donor, 603, 606 Endothelial nitric oxide synthase (eNOS), 287 insemination, 522, 527, 531–533 Endothelins, 14 semen, 506, 511, 517 End-to-end anastomosis, 573 Dopamine, 411–413 Environmental factors, 395–396, 416, 430 Doppler sonography, 103–105 Enzyme defects, 222, 223 of the penile vessels, 293, 295 Enzyme-linked immunosorbant assays (ELISA), 110 of the plexus pampiniformis, 103–105 Eosin test, 131 Droplet, 142, 144 Epidemiology, 283–284, 288 Drug history, 291 Epidermal growth factor (EGF), 35, 36 Drug-induced erectile dysfunction, 289 Epididymal corpus and cauda, 269 Drug-induced hyperprolactinemia, 341 Epididymal fl uid, 592–594 Drugs, 341, 345, 348, 349, 352, 353, 355 Epididymal maturation, 62–71 Drug toxicity testing, 380 Epididymal occlusion, 64, 70 Dual energy X ray absorptiometry (DXA), 106 Epididymal transport of spermatozoa, 591–592 Dual regulation system, 33 Epididymidal-blood-barrier, 38 Ductus epididymis, 324 Epididymis, 61–72, 75, 77 Duplex sonography, 296–297 Epididymitis, 102, 264, 266, 568 Duplex sonography of the cavernosal artery, 296 Epididymoorchitis, 264 Duration of the spermatogenic cycle, 19 Epididymovasostomy, 569–573 Dutasteride, 34, 341 Epilepsy, 196, 212 Dynein arms, 72, 73 Epiphyseal maturity, 451, 452 Dysfunction of cohabitation and ejaculation, 264 Epispadias, 279–280 Dysfunction of the seminal vesicle, 105, 106 Epithelial cells, 127 Dyskinetic cilia syndromes, 344 Erectile disorders, 544 Dyspareunia, 394 Erectile dysfunction (ED), 241, 242, 245, 249, 250, 257, 281, Dysthymic disorders, 349 283–285, 288–293, 295, 297, 299–316, 438, 539, 540, 542–544, 546, 547, 552 Erection frequency, 93 E Erection phase, 286, 300 Ecstasy, 355 Erections, 51, 71 Ectopic testis, 98, 106 Erythrocyte count, 446, 448 Ectopic veins, 288, 298, 314 Erythrocyte production, 52 Effects of psychotherapeutic intervention, 529 Erythropoetin, 342 Efferent ducts, 62–66 Escherichia coli, 264, 265 Effi cacy studies, 583, 584 Escitalopram, 318 Egg donation, 532 Estradiol, 26, 29, 34, 42–44, 47, 50, 52, 116, 392, 399, 400, Egg-donor, 606 402, 406–408, 410, 415, 416, 418, 419, 427, 438, Ejaculate, 61, 65, 67, 69, 71–72, 74, 264–269, 271–274 444–446, 448 Ejaculate volume, 242, 245, 246, 265, 267, 269, 446, 449 Estradiol (E2), 244, 250 Ejaculation, 63, 69, 71, 75, 241, 242 Estrogens, 24–26, 29, 30, 34, 36, 38, 42–44, 48, 50–52 Ejaculation disorders, 316–318 defi ciency, 329 Ejaculatio praecox, 317 resistance, 329 Ejaculatory frequency, 244 substitution, 256 Electroejaculation, 483 Estrone (E1), 244 Electromagnetic fi elds, 396 Etonogestrel, 582, 584 Electromagnetic radiation, 376–377 Eugenic aspects, 565 Electrophoresis, 487 Eugenic mentality, 608 Elongated spermatid injection (ELSI), 65 Eunuchoid bodily proportions, 447 618 Index

Eunuchoidism, 195, 196 Flowchart for the diagnosis and principal therapeutic Eunuchoid tall stature, 94, 95 options for erectile dysfunction, 291 Eunuchs, 196 Flow cytometry, 15, 274 European Academy of Andrology (EAA), 1, 2, 123 Fluorescence in-situ hybridization (FISH), 119–122, 147 European Association Urology (EAU), 155, 157 Fluorescence probes, 143 European molecular genetics quality network Fluoxetine, 318 (EMQN), 123 Fluoxymesterone, 441 Evaluation of the ovaries, 406 Focal SCO, 457 Evaluation of venous drainage, 297–299 Follicle maturation, 399, 400, 405, 419 Evangelium vitae, 604 Follicle selection, 399, 400 Evidence-based andrology, 7–9 Follicle-stimulating hormone (FSH), 21–23, 25–34, 54, Evidence-based medicine, 7, 8, 458 109–111, 115, 116, 244, 246, 267, 268, 272, 343, Evolutionary development, 541 345, 352, 392, 399, 400, 402, 410, 411, Ewings sarcoma, 508 414–419, 427 Excessively tall stature, 437, 451 Follicular phase, 392, 394, 402–404, 414, 415 Exogenous estrogen substitution, 326, 328 Foreign nationality, 524 Exploration of a sexual disorder/dysfunction, 550–551 Fostering, 528, 533 External quality control, 134–135 Four-specimen test, 264 External vacuum devices, 300, 309 Fractures, 43, 50, 95, 241, 250, 251 Extragonadal germ cell tumor, 227 Fragile-X syndrome, 347 Extratesticular metabolism of testosterone, 43–44 Free testosterone, 112–115 Frequency of coitus, 4 Frequency of ejaculations and sexual intercourse, 447 F Friedreich, 348 Fallopian tube, 74, 75, 393, 406, 410, 419, 421–426, 429 Frontal hairline, 95 Fallopio, 563 Frozen-thawed, 482, 492 Familial mediterranean fever (FMF), 354 Fructose, 132, 245, 265, 267, 269, 271, 272 Family constellations, 522, 529, 534 FSH receptor mutation, 110, 111 Family medical history, 94 FSH receptors, 29, 30, 33, 34, 399 Fas–fas-ligand system, 367 Fucoidan, 77 Father–child relationship, 532 Fucose, 77 Fear, 523–525, 527–532 Functional sterility, 589, 594 Female, 392–396, 398–400, 405, 406, 411, 412, 415, Fusion of the labioscrotal folds, 327 416, 419, 421–423, 427–429 Female partner, 266, 270, 271 G Female pronucleus, 61, 76, 79, 80 Gamete intra-fallopian transfer (GIFT), 476 Female sexual interest, 394 G banding, 120 Female-to-male transexuals, 416 General physical functions, 551 Feminization, 231, 232 Genetic change, 366, 370 Fertility, 2–5, 7–9, 268–271, 274 Genetic counselling, 124, 270, 271 Fertility of the aging male, 246–247 Genetic counselling assisted reproduction, 495–496 Fertilization, 61–80, 399, 421, 422, 428, 429, 431 Genetic disease, 483, 487 Fertilizing capacity, 64–65 Genetic disturbances and advanced paternal age, 248–249 FGF8, 25 Genetic mutations, 248 FGFRI, 25 Genetic risk, 517 Fibroids and adhesions, 421 Genetic testing, 119, 123–124 Fibrosis incidence, 15 Gene transcripts, 150 Fibrous sheath, 72, 73 Genome, 119–122 Filtration, 485 Germ cell aplasia (SCO Syndrome), 206–207 Finasteride, 34, 257, 334, 336, 341 Germ cell tumors, 227–231 Findings of scrotal sonography, 105 Gestagens, 578, 580–585 Fine needle aspiration, 510 Glass beads, 485 Fine needle biopsy, 268 Glasswool, 484 First pass effect, 439 Globozoospermia, 130, 208–209, 481, 482 First polar body, 399 Glomerulonephritis, 398 FISH analysis, 212 Glucocorticoids, 399, 416, 429, 430 Five erectile phases, 286 Glucose tolerance, 43 Fixation of testicular biopsies, 158 a-Glucosidase, 265, 267, 269 Flagellar function, 140–141 Glutathione, 464 Flagellation, 73 Glycerol, 506, 513 Flagellum, 19 Glycerol-egg yolk-citrate (GEYC), 513 Index 619

Glycerophosphocholine (GPC), 63, 72, 132 Hematological diseases, 349–350 Glycol ethers, 371 Hematoma, 568 Glycoprotein hormones, 28 Hemochromatosis, 333, 343, 344, 349 Glycosylation, 27–29 Hemodynamic factors, 285 GnRH-antagonists, 489, 490 Hemoglobin, 446, 448 GnRH-I, 24, 27 Hemophilia, 350 GnRH-II, 24, 27 Hepatic enzyme inducers, 341 GNRHR, 123 Hepatitis, 342, 343, 352, 356 Golgi apparatus, 15 Hepatitis A, 397 Golgi complex, 22, 25 Hepatitis B, 397, 398 Golgi phase, 19 Hepatitis C, 397 Gonadal dysgenesis, 198, 217, 221–222, 226, 227 Hereditary angioedema (HAE), 354 Gonadotropin genes, 110 Heterologous insemination, 534 Gonadotropin receptor genes, 110 Heterologous protocols, 603 Gonadotropin releasing hormone (GnRH), 22–31, 33, HGH pulse frequency, 241 437, 447 High density lipoprotein (HDL), 52 agonists, 581 High ligation, 204, 205 agonist treatment, 427 Highly purifi ed FSH, 459, 460 analogs, 426, 427 Hirsutism, 222 down-regulation, 417 Histones, 68, 76, 79 gene, 111 HIV infections, 266 pump test, 111 HIV-positive men, 352, 353 receptor, 26–28 hMG and FSH, 417 receptor gene, 111 hMG/FSH-stimulation, 416 test, 111 hMG or hCG/FSH directly, 416 Gonadotropins, 15, 21–35, 54, 446, 448 Hodgkin disease, 345, 346, 507, 508 Gonadotropin therapy, 437 Hormonal contraception, 562 Gonorrhoea, 264, 266, 353 Hormonal male contraception, 577–585 Gossypol, 590 Hormonal stimulation GPR54, 22–26, 30, 123 of ovarian function, 494 Graft-versus-Host disease, 346 of the ovaries, 474, 477 Gram-negative bacteria, 264, 265 Hormone receptor complex, 28, 47 Granulocyte elastase, 265 Hormones and female sexuality, 394 Granulosa and theca cells, 399 Hormone therapy, 301–302 Group therapy, 528 HOS test, 209 Growth factors, 14, 15, 25, 33, 35, 36 Hostile epididymal environment, 593–594 Growth hormone (GH), 241, 255, 256 Hot fl ushes, 340 Guidelines for recording the psychosocial situation, 528 HPLC of DNA oxidation products, 149 Gynecomastectomy, 335 Humanae vitae (1968), 604 Gynecomastia, 97, 211, 212, 214, 215, 226, 229, 231, 232, 323, Human chorionic gonadotropin (hCG), 28–30, 32, 33, 327–335, 340, 342, 343, 347, 350, 447, 448, 453 35, 38, 54, 480, 490, 494 Human immunodefi ciency virus (HIV), 483, 487, 511, H 512, 563 Habitual miscarriages, 122, 124 Human urinary gonadotropins, 489 Hair, 23, 43, 48, 51 Huntington disease (HD), 347 Hair patterns, 96 Hyaluronic acid (HA), 141, 144, 147 Hamster oocyte penetration (HOP) test/Sperm penetration Hyaluronidase, 478, 480 assay (SPA), 145 Hydraulic implants, 315, 316 Hamster-ovum-penetration test, 244 Hydrocele, 101, 102, 202, 205 Haploid germ, 16, 18, 38 17-Hydroxyprogesterone, 33, 42 Hashimoto thyroiditis, 419 17b-Hydroxysteroid-dehydrogenase-defect, 222 b-HCG, 229 Hyperactivated motility patterns, 140, 141 HCG and GnRH therapy, 199, 200 Hyperactivation, 73, 75, 140, 141 HCG/hMG treatment, 458, 459 Hyperandrogenemia, 414–418, 427 Head injuries, 349 Hypercortisolism, 350 Health of the offspring after assisted fertilization, 496–497 Hyperestrogenism, 335 Heat, 367, 371, 374, 377 Hypergonadotropic azoospermia, 481, 484 Heat shock protein 90 (HSP 90), 47 Hypergonadotropic NOA, 155, 157, 163 Heavy metals, 371 Hypergonadotropic oligoasthenoteratozoospermia, 481 Helical patterns, 20 Hyperprolactinemia, 341, 342, 410–413, 415 Hematocrit, 446, 448, 449 Hypersecretion of LH, 430 620 Index

Hypertension, 284, 353 INSL3 levels, 116 Hyperthyroidism, 332, 333, 335, 350, 419 Insulin-like factor 3 (INSL3), 11, 34–37, 115–116 Hypertonic patients, 307 Insulin-like growth factor (IGF), 400 Hypogonadism, 87, 89, 94, 95, 97, 100, 105, 210, 213, 222, Insulin-like growth-factor-1 (IGF-1), 16, 35, 241, 255, 256, 400 224, 228, 289, 292, 300, 437, 438, 441, 443, Insulin-like growth factor 2 (IGF 2), 400 444, 446–451, 453 Insulin resistance, 251, 254, 416, 418 Hypo-osmotic swelling (HOS), 131 Integration of somatic therapy options, 554 Hyposmia, 96 Integrins, 78 Hypospadias, 100, 279–280, 327–329, 332, 340, 472 Intellectual psychomotoric development, 496 Hypospermatogenesis, 160, 161, 163, 199, 341, 347–349 Interdisciplinary references in sexual medicine, 540 Hypothalamic amenorrhea, 410, 417, 418 Interleukin-1, 19, 27 Hypothyroidism, 341, 350 Internal quality control, 131, 134 Hysterosalpingography, 410, 420, 423–425, 430 International classifi cation of diseases (ICD), 89 Hysteroscopy and laparoscopy, 424 International classifi cation systems, 543, 549 International germ cell cancer classifi cation, 230 I International prostate symptom score (IPSS), 256, 257 ICSI/IVF, 155 International recommendations for LOH, 438 Idiopathic infertility, 89, 90, 92, 393, 431, 457–465 Intersexuality, 323 Idiopathic male infertility, 437, 475 Interstitial compartment, 11–14 IGF-I receptors, 416 Intracavernosal pressure, 285, 286, 294, 297, 298 Imidazole derivatives, 590 Intracavernosal testing with vasoactive substances, 292–295 Imipramin, 317 Intracervical insemination (ICI), 471, 472 Immotile cilia, 344 Intracytoplasmic sperm injection (ICSI), 62, 65, 67, 68, 79, Immotility, 127 155–157, 162, 163, 165, 207, 209, 214–216, 220, Immune effector cells, 70 268, 270–273, 275, 376, 464, 465, 471, 475, 478, Immune system, 69, 70 479, 481, 482, 488, 506, 508–511, 514, 516, 521, Immunoassays, 110–115 522, 524, 530, 531, 534, 609 Immunobead test, 132, 274 Intra-fallopian transfer of zygotes (ZIFT), 477 Immunocytology, 265 Intrafollicular insemination, 473–474 Immunofl urometric assays (IFMA), 110 Intramuscular testosterone, 442–445 Immunological diseases, 569 Intraoperative harvesting of sperm, 574 Immunological infertility, 92, 273–275 Intraprostatic cysts, 105 Immunological modulation and stress, 395 Intrapsychological motives, 525 Immunoradiometric assays (IRMA), 110 Intratesticular calcifi cation, 105 Implantation, 69, 80, 395, 407, 425, 429 Intratubal insemination (ITI), 473 Impotentia coeundi, 472 Intratubular concentric microliths, 162 Inactivating FSH receptor mutations, 225 Intraurethral application of prostaglandin E1, 302 Inactivating LH receptor mutations, 224–225 Intrauterine insemination (IUI), 275, 280, 472–473, 509, 511 Inactivating mutations, 30, 31, 33, 40, 43, 48, 224 In vitro bioassays, 110, 115 Income, 526 In vitro fertilization (IVF), 275, 376, 392, 396, 397, 400, 402, Increased pregnancy rate after adoption, 395 405–407, 423, 424, 428–431, 471, 474–476, 508, Increased sweat chloride concentration, 269 509, 511, 517, 518, 603, 604, 606–611 Indazole-carboxylic acid derivatives, 590 In vitro fertilization by donor, 606 Indenopyridines, 590 Involuntary childlessness, 204, 212, 213, 227, 607, 611 Indirect immunobead test, 132, 428 Ionizing radiation, 370, 372 Induced acrosome reaction, 66, 68, 74 Iron defi ciency anemia, 350 Infections, 264–266, 272, 274 Iron overload, 343, 344, 349, 350, 355 Infertility, 1–3, 5–9, 87, 89–92, 94, 100, 102, 103, 105, Irradiation, 341, 345, 346, 348 264, 267, 271, 273–275, 340–345, 350–356 Isodicentric Y chromosome, 218 Infl ammation, 264–266 Izumo, 78 Infl ammatory bowel disease (IBD), 349, 397 Inguinal hernias, 325 J Inguinal testis, 98, 198 Juvenile diabetes, 419 Inguino-scrotal phase of descent, 36 Inhibin B, 23, 30, 31, 392 K Innervation, 285, 287, 291, 299, 300, 310, 317 KAL1, 123 Insemination, 471, 488–489 KAL1 gene, 25 Insensitivity, 30, 44, 48 Kallikrein, 463 In situ hybridization assays, 149 Kallmann syndrome, 25, 93, 96, 119, 123, 218 In situ nick translation assays, 149 Kartagener syndrome, 94, 209, 344 INSL3 gene, 116 Karyotype, 119–121, 123, 210–218, 220–222, 226, 495 Index 621

Karyotyping, 147 Lower urinary tract symptoms (LUTS), 256 Kennedy disease, 46, 328, 332, 335, 347 Low ligation, 204 , 341, 353 LUF syndrome, 407 Kidney stones, 398 Lumbago, 95 Kinase G (PKG), 287, 303 Luteal phase, 398, 402, 403, 408, 410, 418 KISS1 gene, 22, 24 Luteal quality, 407–408 Kisspeptin-GPR54 system, 22–24 Luteinizing hormone (LH), 14, 21–35, 40, 41, 54, 109–111, Klinefelter, 156, 157, 161, 163, 165 115, 116, 243, 244, 252 patients, 441, 447 assays, 110 syndrome, 157, 198, 210–214, 216, 248, 331, 332, 448 pulsatility, 109 Kremer test, 132 surge 399, 402, 403, 406, 407 Lymphocytes, 162 L L-acetyl carnitin, 464 M Lactate dehydrogenase (LDH), 229 Macroorchidism, 347 Laron dwarfi sm, 16 Macrophages, 14, 38, 39, 63, 70 Larynx, 51, 447 Macroprolactin, 112 Latency phase, 286 Macroprolactinemia, 112 Late-onset hypogonadism (LOH), 113, 239–258 Macrosurgical techniques, 571 Laurence-Moon-Biedl syndrome, 348 Magisterium, 602, 603 Lazzaro Spallanzani, 506 Magnetic, 376, 377 L-carnitine, 63, 72, 132 Magnetic bead sorting (MACS), 487 Lead, 366–375, 377–379 Magnetic resonance imaging, 105, 106 Legal castration, 196 Maldescended testes, 98, 197–200, 207, 215, 216, 224, 227 Length of childlessness, 393 Male breast cancer, 334 Lepromatous leprosy, 353 Male climacteric, 242 Leptin, 24, 25, 27, 30 Male hair pattern, 447 Leriche syndrome, 354 Male hormonal contraception, 437 Leukemia, 372, 376, 507, 508, 513 Male hypogonadism, 437, 453 Levonorgestrel, 582, 583 Male immunological infertility, 472, 481, 483 Levonorgestrel implants, 583 Male pseudohermaphroditism, 194, 222, 224, 225 Leydig, 324–326, 332–335 Malignant disease, 345–346, 506, 507, 517 Leydig cells, 11–14, 23, 31, 34–38, 40–42, 49, 50, 53, Malignant germ cell tumor, 227, 228, 326 54, 161, 162, 165, 324–326 Malignant ovarian tumors, 398 adenoma, 326, 369 Mamma carcinoma, 451 agenesis, 224 Mammography, 97 damage, 369 Mannose, 77 hypoplasia, 224–225 Marfan syndrome, 248 number, 244 Marijuana, 353, 355, 376 tumor, 105, 225, 231, 232 Marker substances, 267, 268 Leydig, F., 12 MAR test, 127, 131, 132, 274 LH to FSH ratio, 415, 416 Mass spectrometry (MS), 113, 114 Libido, 212, 213, 438, 446 Mast cells, 15, 35, 38, 39 Libido dysfunction and orgasmic disturbances, 394 Masturbation, 51, 483, 603 Life expectancy, 196, 197, 239, 240, 558, 559 Maternal estrogens, 29 Limbic system, 541 Maturation arrest, 160, 163 Lipid metabolism, 449 Maturation of the follicle, 406 Lipomastia, 97, 329, 332 Mechanism of action of phosphodiesterase inhibitors, 303 Liposome markers, 145–146 Median eminence (ME), 22, 25 Lisuride, 413 Medical counselling, 523 Liver, 24, 29, 43, 44, 49, 51 Medical risk, 527 disease, 342–344 Megaloblastic anemia, 350 function, 449 Megalospermatocytes, 160, 161, 163 toxicity, 441, 453 Meiosis, 16, 18, 21, 79, 368, 370, 399 Local anesthesia, 318 Meiosis I, 210 Local control of erection, 287 Meiosis II, 210 Localized or generalized fi brosis of corpora cavernosa, 312 Meiotic division, 15–18, 20, 32, 35 Long-acting GnRH-agonists, 489 Meiotic recombination, 370 Long-term consequences, 493 Melatonin, 242 Loss of vigor, 438 Melatonin substitution, 255, 256 Lower social status, 524 Membrane fl uidity, 68, 75 622 Index

Menstrual blood fl ow, 404 Motory or sensory lesions, 299 Menstrual cycle, 402–409, 417, 418 MRI scan, 412 MENT implants, 583 Mucus penetration tests, 141 Mercury, 373, 374 Mucus production, 403, 422 Mercury intoxication, 374 Muellerian ducts, 194, 195, 220, 221, 323, 328 Mesterolone, 461 Muellerian inhibiting hormone (MIH), 220 Mesterolone (Proviron®, Vistimon®), 441 Mullerian dysgenesis, 410 Metabolic syndrome, 52, 212, 213, 250–251, 344, 351 Multimorbidity, 239, 241 Metagoline, 413 Multiple lentigines syndrome, 348 Metaphase II, 399, 478–480 Multiple pregnancies, 474, 489, 494 Metaphase I oocytes, 480 Multiple sclerosis (MS), 348 Metformine, 418 Multiple testicular biopsy, 157–158 Methotrexat, 509 Mumps, 352 Methoxyacetic acid (MAA), 367, 370 Mumps virus, 206 2-Methoxyethanol (ME), 370, 371 Muscle mass, 249–251, 253, 254, 446, 447, 451, 452 7a-Methyl-19-nortestosterone (MENT), 581 Muscles, 37, 49, 50 Methylation of genes, 68 Mutation of the voice, 447 Methyl testosterone, 441 Mutations, 268–273 Microadenoma, 412, 413 Myasthenia gravis, 419 Micro-assisted fertilization, 477–483, 491 Mycoplasma spp, 264 Microbiological investigations, 265 Myocardial infarction, 284, 307 Microdeletions, 119, 121–124 Myofi broblasts, 14 Microdeletions of the Y chromosome, 457, 495 Myo-inositol, 63 Microdissection techniques, 157 Myotonic dystrophy, 332, 333, 347 Micro-epididymal sperm aspiration (MESA), 65 Microinjection, 609 Microlithiasis, 102, 105 N Microlithiasis testis, 102, 105 Naltrexon, 418 Microphallus, 224 Natural family planning (NFP), 562 Microscopic investigations of the postcoital or Natural fertilization, 71–80 postmasturbatory urine, 317 Natural testosterone, 438, 439, 442, 444, 449 Microsurgical epididymal sperm aspiration (MESA), Nebido®, 443, 444, 448, 449 155, 266, 268, 270–273, 484, 509, 510, 518 Necrosis, 366 Microsurgical techniques, 268, 270, 571, 573 Necrozoospermia, 482 Microtubules, 72, 73, 76, 80 Negative feedback, 24, 26, 27, 31, 32 Mild upper airway disease, 271 Negative result, 293, 297, 305 Millenium development goals, 559 Neonatal malformations, 495, 496 Minimal androgen insensitivity (MAI), 328 Neoplasias, 398, 413 Minisatellites, 370 Nerve growth factor (NGP), 14, 35 Minor variant of cystic fi brosis, 270, 272 Nesbit technique, 282, 283 Minoxidil®, 336 Neurogenic erectile dysfunction, 289, 299, 313, 315 Miscarriage, 247, 248 Neuronal level, 541 Miscarriage and paternal age, 248 Neuronal nitric oxide synthase (nNOS), 287 Misue anabolic sterolds, 452–453 Neurophysiological investigations, 299 Mitochondrial DNA (mtDNA), 147, 149 Neurophysiology, 286–287 Mitochondrial function, 142 Neurotransmitters, 14, 27 Mitosis, 17, 35 Neutral a-glucosidase, 72, 132 Mitotic spindle, 61, 80 Nicotine, 395, 396, 522, 528 Mixed agglutination reaction (MAR), 127 Nicotine abuse, 288, 290, 307 Mixed antiglobulin reaction (MAR), 126, 131, 132 Nightly or morning erections, 446 Mixed atrophy, 160, 162 Nitric oxide (NO), 14, 51, 287 Mixed gonadal dysgenesis, 221 Nitroaromatic compounds, 369 Moderate cardiovascular risk, 308 Nitroglycerine, 295 Monitoring testosterone therapy, 446–451 Nocturnal erections, 287, 289, 292, 300 Mononuclear infi ltrates, 39 Nocturnal penile tumescence (NPT), 241 Monozygotic twinning, 492, 494 Nonarteritic anterior ischemic optic neuropathy (NAION), 307 MOPP, 369 Non-disjunction, 210, 211 MOPP for Hodgkin disease, 345 Non-disjunction in paternal meiosis, 216 Morbus Crohn, 506 Non-Hodgkin lymphoma, 345, 346 Mortality, 239, 241, 249–251, 255, 257 Non-lethal germ cell damage, 367, 370 Morula, 80 Non-progressive motility, 127 Mosaic, 121 Non-responders, 306 Index 623

Non-seminoma, 228–231 P Noonan syndrome, 198, 216 p53-independent intrinsic mechanisms, 367 Norethisterone, 582, 583 Pain during erection, 281 Norethisterone acetate (NETA), 582, 583 Palindromic sequences, 47 Norethisterone enanthate (NETE), 582, 583 Palmar aponeurosis, 281 Normal fertility, 271 Palpation of the penis, 292 19-Nortestosterone, 438, 452, 581, 583 Pampiniform plexus, 37, 99, 200, 202 No-scalpel approaches, 595–596 Pancreatic insuffi ciency, 269 No scalpel technique, 566, 568 Papanicolaou, 130, 131 NO therapy, 307 Papanicolaou staining, 130, 131 No-touch techniques, 156, 157 Papaverine, 293–295, 302, 312 Nuclear DNA (nDNA), 147–149 Para-aminobenzoate (Potaba®), 282 Nuclear receptors, 44, 47 Paraphilia, 543, 547–549 Numerical chromosomal abnormality, 248 Paraphimosis, 280 Parent–child bonding, 531 Parent–child relationship, 530, 531, 533 O Parkinson disease, 348 Obesity, 344, 351, 353, 416 Paroxetine, 318 Obstruction of the seminal ducts, 266–269, 272 Partial AIS (PAIS), 44, 48, 49 Obstructions, 264, 266–268 Partial androgen insensitivity (PAI), 324, 325, 327–328, Obstructive azoospermia (OA), 65, 155, 157, 267–269, 334, 337–338 272, 481, 484, 495 Partial deletions, 324, 325 Occlusion of the spermatic vein, 202, 204, 205 Partial obstructions, 267 Occupational exposure to sex steroids, 368 Partial zona dissection (PZD), 477, 478, 492 Onco-TESE, 510 Partner-related interaction, 551 Ontogenic regression, 340–345, 348, 351, 353, 355 Patency rates, 567, 570–573 Oocyte, 471, 473–482 Pathological or psychological blockade, 483 collection, 484, 488–491 Pathophysiology, 283, 288–290 development, 398–399 Pathophysiology of erection, 288–290 retrieval, 421 D4 pathway, 40 Opiate antagonist naltrexone, 302 D5 pathway, 40 Opiates, 341, 353, 376, 415, 418 Patients with cavernosal insuffi ciency, 310, 314, 315 Oral antidiabetic medication, 418 Patients with high risk, 308 Oral contraceptives, 371 Patients with low cardiovascular risk, 308 Oral testosterone, 439–441, 448 PDE-5, 302–308, 310, 311 Oral therapy, 292, 302–308, 310, 313 PDE-5 inhibitors, 302–308, 310, 311 Orchidopexy, 195, 199, 200 Pedigree, 495 Orchitis, 194, 206, 229, 352, 353 Penetration, 66–68, 75–78, 80 Organ diagnostics in sexual dysfunction, 552 Penetration into cervical mucus, 486 Organ transplantation, 506 Penile alterations, 271–283 Orgasm, 71 Penile deviation, 279–283, 292, 312 Orgasmic dysfunction, 543 Penile induration, 281 Orgasmic phase, 241 Penile rehabilitation, 300, 306 Osteodystrophy, 342 Penis growth, 50 Osteoporosis, 43, 48, 50, 54, 95, 106, 212, 450 Penis size, 50 Otitis media, 344 Pentoxyphylline, 463, 488 Ovarian cycle and ovulation, 398–419 Percutaneous epididymal sperm aspiration (PESA), 266, 484 Ovarian follicular development, 488–489 Percutaneous sperm aspiration, 268, 510 Ovarian hyperstimulation, 480, 488, 495 Peri-and paracentric inversions, 220 Ovarian hyperstimulation syndrome (OHSS), 489, Perineoscrotal hypospadias with pseudovagina 490, 493–494 (5a-reductase 2-defi ciency), 328–329, 332 Ovarian stimulation, 488–489 Periodic abstinence, 560, 562–563 Ovarian torsion, 494 Periodic interval therapy, 311 Ovarian wedge resection, 417 Peritubular cells (PT), 13–15, 33–35, 38, 39, 49 Oviductal epithelium, 140, 143 Pernicious anemia, 419 Oviduct persistence, 220–221 , 365, 371 Ovotestes, 226 Peyronie’s disease, 279, 281–283, 288, 309 Ovotesticular disturbances, 222 pF508del, 268 Ovotesticular disturbances of sexual development pH and fructose concentration of the ejaculate, 271, 272 (DSD), 226–227 Pharmacocavernosography, 297, 314 Ovulation, 398–419 Pharmacology of testosterone, 439–446 Oxytocin, 14, 33, 464 Phentolamine, 294, 295, 302, 312 624 Index

Philosophical motives, 525 Preventive treatment, 91 Phimosis, 100 Priapism, 289, 294, 295, 302, 309, 311, 312, 314, 315 Phosphate diesterases, 287 Primary amenorrhoea, 222 Phosphodiesterase inhibitors, 303, 304 Primary erectile dysfunction, 288, 292, 297, 309, 314 , 369 Primary hypogonadism, 109, 115 Physical impairments, 530 Primary hypothyroidism, 411 Physiology, 283, 285–287, 301 Primary ovarian failure, 411, 418–419 Physiology of erection, 285–290 Principal cells, 63 Pick adenoma, 326 Proacrosin, 77 Pituitary adenomas, 112, 410–413 Processing of sperm, 488 Pituitary gland, 11, 22, 23, 25, 26, 28, 29 Profound inhibition, 341, 351 Pituitary or hypothalamus, 105 Progesterone, 24–27, 33, 34, 40, 42, 44, 47, 490 Pituitary siderosis, 350 levels, 407–408 Placebo-effect, 8 and pregnenolone, 33, 42 Placental alkaline phosphatase (PLAP), 229 secretion, 402, 403 Placentation, 80 Progestins, 422, 426 Plateau phase, 241 Progressive sperm motility, 127, 244 Polyarteritis nodosa, 352 Prokineticin 2 (PK2), 25 Polychlorinated biphenyls, 368, 374 Prolactin, 111–112, 244 Polycystic degeneration of the kidneys, 398 Prolactinoma, 411–413 Polycystic ovarian disease, 413–418, 430, 495 Prolactin-secreting adenomas, 412 Polycystic ovarian syndrome, 410 Prolonged erections, 294, 295, 312 Polycystic ovary (PCO), 406, 414, 415, 431 Pronucleate-stage oocyte transfer (PROST), 477 Polycythemia, 254 Pronucleus, 61, 76, 79–80 Polymorphism of the androgen receptor CAG repeats, 96 Propecia®, 336 Polymorphisms of the androgen receptor, 213 Prostaglandin E1 (PGE1), 306 Polyorchidism, 197 Prostaglandins, 14, 15, 132 Polyploidy, 79 Prostanoids, 287, 294 Polyposis coli, 248 Prostate, 42–44, 46, 48–50, 53, 100, 105, 106, 325, 328, 336 Polyspermy, 76, 79 cancer, 244, 254, 256, 257 Polyvinylpyrrolidone (PVP), 479, 486, 488 carcinoma, 195, 196, 449, 451, 569, 570 Pope John Paul II, 603, 604 hypertrophy, 336 Pope John Paul VI, 604 volume, 105, 106, 449, 450 Population growth, 557–559 Prostate specifi c antigen (PSA), 71, 72, 254, 256, 257, Portacaval shunting, 343 446, 449, 450, 452 Postcoital test, 132 Prostatic function, 132 Postgraduate education, 540 Prostatitis, 264–266, 272 Postnatal disorders, 549–554 Prostatovesiculitis, 265 Postoperative semen analysis, 567, 569 Prosthesis surgery, 315–316 Post-thaw motility, 508, 510 Protamines, 68, 76, 79 Potency, 212 Protein synthesis, 15, 51 Prader-Labhart-Willi syndrome, 348, 496 Proteolytic enzymes, 483 Prader orchidometer, 98 Pseudo-gynecomastia, 329, 332 Precocious epiphyseal closure, 50 Psoriasis, 354 Precocious menopause, 419 Psychic stress, 533 Precocious pseudopuberty, 231 Psychoanalysis, 523 Preconceptional disorders, 549 Psychogenic erectile dysfunction, 287, 289, 300–302 Predisposing illnesses, 290 Psychogenic fertility disturbance, 527 Pregnancy loss, 429–431 Psychogenic infertility, 522 Pregnancy rates, 64, 66, 68, 69, 392, 395, 421, 423, Psychological conditions of unwanted childlessness, 522–523 427, 458–464, 510, 513, 517 Psychological effects of unwanted childlessness, 522–523 Pregnenolone, 33, 40–42 Psychological social development, 532 Preimplantation diagnosis (PGD), 609, 610 Psychological stress, 522, 523 Premature ejaculation, 292, 317–318, 544 Psychological treatment, 300–301 Prenatal adoption, 532 Psychosexual evaluation, 292 Prenatal diagnosis, 270 Psychosocial consultation, 527–528, 534 Prenatal disorders, 549 Psychosomatic complaints, 524, 525, 528 Preparation of sperm, 485 Psychotherapeutic intervention, 522, 528–529 Prevalence of idiopathic varicocele, 201 Pubertal gynecomastia, 331 Prevalence of infertility, 5–7 Pubic hair, 51 Prevalence of paraphilia-associated sexual arousal, 548 Pubic hairline, 95 Index 625

Pulmonary embolism, 212 Respiratory diseases, 344–345 Pulmonary tuberculosis, 397 Respiratory system, 94 Pulsatile GnRH, 416–418, 459 Retinitis pigmentosa, 307 Pulsatile GnRH treatment, 416–418 Retinoic acid receptor antagonists, 590 Pulsatile LH secretion, 341–343 Retractile testis, 98, 198 Pulsatile nature of GnRH secretion, 26 Retrograde ejaculation, 231, 280, 317, 472, 484, 507, 509 Pulsatile secretion of gonadotropins, 30 Retroperitoneal lymphadenectomy, 230, 231 Pulsatility of pituitary secretion, 109 Revascularization Surgery, 314–315 Pure gonadal dysgenesis, 221, 222 Reversible inhibition of sperm under guidance Pyelonephritis, 398 (RISUG), 596 Rheumatic arthritis, 506 Q Rheumatoid arthritis, 352 Q-PCR, 149 Rigidity measurements, 300 Quality, 471, 478, 480–482, 489 Rigidity phase, 286 Quality control, 131, 134–135 Rings, 308, 309 Quality control of semen analysis, 511 Risk of cross-contamination, 512 Quality of life, 451 Robertsonian translocations, 220 Quantitative ultrasound, 106 Rokitansky-Küster-Hauser syndrome, 410 Round cells, 127, 130–133 R Round spermatid injection (ROSI), 65 Radiation, 367–373, 376–377, 382, 383 Round spermatid nucleus injection (ROSNI), 65 Radical prostatectomy, 345 Round spermatids, 482 Radioactivity, 396 Rate of conception, 393, 423 S Rational therapies, 91 Saliva, 115 Reactive oxygen species (ROS), 142–143, 463 Salpingitis, 422–423 Rebound effect, 462 Sarcoidosis, 344 Recanalization, 568, 569 Satellite DNA, 120 Receptor, 242, 251, 253, 256–258 Sclerosing of the spermatic vein, 205 a-Receptor blocking agents, 463 Score count evaluation, 162–165 Reciprocal translocations, 217, 218, 220 Scrotal cooling, 69 Recombinant FSH, 459 Scrotal heating, 590 Recombinant growth hormone, 464 Scrotal palpation, 269 Recombinant zono proteins, 145 Scrotal temperature, 200 Re-counselling, 305, 306 Scrotal ultrasonography, 101–103 Recreational drugs, 355 Sebum production, 49, 50 Reduced body weight, 418 Secondary erectile dysfunction, 292 Reduced libido, 250, 253 Secondary hair and beard growth, 213 Reduced muscle mass, 250 Secondary hypogonadism, 109, 341, 342, 350 5a-Reductase, 34, 43, 44, 48, 50, 51, 53, 116 Secondary oocyte, 399 5a-Reductase activity, 34, 50, 51 Second meiotic division, 18 5a-Reduction, 43 Second polar body, 61, 76, 79, 399 Refertilization vasovasostomy, 570 Seeding, 513 Refl exogenic, 286, 287, 289 Selective abortion, 531 Refractory phase, 241 Selective androgen receptor modulators (SARMs), 48 Registration, evaluation, authorisation and restriction Selective serotonin re-uptake inhibitors, 318 of chemical substances (REACH), 365, 366, 381 Self-injection therapy, 293, 305–308, 310–313 Reifenstein syndrome, 327, 332 Semen analysis, 125–137, 476 Relative phimosis, 280 Semen characteristics, 481 Removal of contaminant infectious particles, 487–480 Semen donation, 471, 482–483 Renal anomalies, 270 Semenogelin I, 71 Renal disease, 341–342 Semen volume, 126–128, 131 Renal failure, 342 Seminal ducts, 263–275 Renal transplantation, 342, 398 Seminal emission, 589, 591, 592, 595–596 Renal ultrasound, 271 Seminal vesicles, 71, 72, 75, 105, 106, 127, 132, 265–267, Repair of non-genetic damage, 368 269, 270, 272, 324 Reproductive and genetic toxicity, 365 Seminiferous tubules, 11, 14–16, 19, 20, 23, 34, 35, 37, Reproductive dimension, 540, 541, 549 38, 156–159, 161, 162 Reproductive health, 1–3, 560 Seminomas, 39, 105, 106, 199, 222, 227–231, 345 Research cloning, 610 Senescent gynecomastia, 331 Residual body (RB), 13, 17–19, 32 Sertaline, 318 626 Index

Sertoli cell-germ cell interactions, 35 Spectrum of sexual disorders, 540–547 Sertoli cell-only syndrome (SCOS), 155, 157, 160, Sperm, 603, 606, 609 161, 207, 219, 510 Sperm agglutination, 127, 131, 274 Sertoli cells, 13–16, 19, 20, 23, 30, 33–36, 38, 42, 49, 62, 156, Sperm antibodies, 127, 131, 132, 134, 428–429, 569 159–163, 332, 325, 366–370, 374 Sperm antibody tests, 428 adenomas, 326 Spermatids, 13, 16–21 tumors, 333 Spermatocele, 99, 102, 105 Severe male infertility, 479 Spermatocytes, 13, 16–18, 21, 32, 35, 38 Sex determining gene on the Y chromosome (SRY), 52 Spermatogenesis, 11, 14–21, 30–35, 37–39, 49, Sex determining region Y (SRY), 194, 215, 217, 221, 226 155–165, 199, 208 Sex hormone binding globulin (SHBG), 29, 34, 42–44, Spermatogenic arrest, 199, 207–208 50–52, 54, 112–115, 242–244, 252, 292, 325, 331, Spermatogenic cycle, 13, 15, 17, 19, 33, 340, 355 333, 341–343, 345, 348–351, 415–417, 427, 446, Spermatogenic effi ciency index, 21 448, 449 Spermatogenic failure, 457 Sexological competence, 540 Spermatogenic suppression, 32 Sexological consultation, 553 Spermatogenic wave, 19, 20 Sexological therapy, 542, 552–554 Spermatogonia, 13, 15–17, 20, 21, 32, 37, 38, 366, Sexual appetite, 446 368–370, 372, 373 Sexual differentiation, 30, 52–54 Spermatogoniogenesis, 16 Sexual dimorphism, 51, 52 Spermatozoa, 482 Sexual disorders, 540–547, 549, 551–553 Sperm centrosome, 146–147 Sexual disturbances, 527 Sperm chromatin dispersion assay (SCD)/Sperm dispersion Sexual dysfunction, 339, 342–345, 348, 350, 356, assay (SDA), 148 542–544, 546, 550, 552, 554 Sperm chromatin sensitivity assay (SCSA), 148, 150 Sexual functions, 539, 550, 551 Sperm concentration, 127, 128, 131, 133, 134, 242, Sexual identity disorders, 545–546 244, 246, 529 Sexual intercourse, 241 Sperm deposition Sexuality, 524, 525 528 Sperm function tests, 244 Sexuality in senescence, 240–241 Sperm glycolysis, 594 Sexually transmitted diseases (STD), 265, 266, 353 Sperm granuloma, 569, 571 Sexual phantasies, 51 Spermiation, 16, 19, 32, 159, 160 Sexual preference structure, 545, 547, 550 Spermicides, 596 Sexual response, 240 Spermiogenesis, 16, 19, 32, 34 Sexual therapy, 542, 546, 553–554 Sperm morphology, 126, 130–131, 134 SHBG test, 325 Sperm motility, 126, 127, 133–134, 507, 508, 512, 514–516 Shorr, 130 Sperm-mucus-interaction, 274 Short tandem repeats (STRs), 44, 46 Sperm numbers, 125, 126, 128–129 Sickle cell anemia, 350 Sperm production, 15, 16, 21, 35 Side effects of PDE-5 inhibitors, 307 Sperm proteomics, 150–151 Sildenafi l, 303–305, 307 Sperm rebound, 580 Silver-Russell syndrome, 496 Sperm RNA, 150, 151 Simultaneous ensoulment, 604 Sperm selection, 487 Single-embryo-transfer (SET), 608, 609 Sperm transport, 371, 421, 422 Single nucleotide polymorphisms (SNP), 120 Sperm-vitellus recognition, 68 Sinusitis, 94 Sperm volume regulation, 594–595 Sitting dwarfs, 95 Spinal cord damage, 348 Six stages of spermatogenesis, Clermont, 159 , 341, 353 Skin, 37, 43, 49, 50, 53 Spontaneous acrosome reactions, 68, 76 Sleep apnea, 344 Spontaneous conception, 471 Sleeping sickness, 353 Spontaneous conception rate, 474 Smoking, 355, 374–376, 396, 430 Squeeze technique, 318 So-called adrenal rest tumors, 101, 105 SRY gene, 194, 217, 221, 323 Social control, 565 SRY HMG-box-related gene 9 (SOX-9), 52 Social situation, 528 SRY-positive men, 215 Socio-cultural castration, 196–197 Staging, 229 Socio-cultural motives, 525 Staging of endometriosis, 426 Solvents, 369, 371 Standing giants, 95 Somatosensory innervation, 285, 299 , 325 Sorting of spermatozoa, 487 Stem cell, 12, 13, 16–18, 32, 33, 35, 36, 52, 610 Specifi c androgen receptor agonists (SARMS), 258 Steps of fertilization, 480 Spectral karyotyping FISH (SKY), 121 Stepwise therapeutic plan, 308 Index 627

Sterility, 3 Testicular biopsy, 155–165, 207, 208, 213, 219, 220, 224, Sterilization for eugenic reasons, 565 228, 229, 268, 269 Steroidogenesis, 11, 14, 22, 35, 40, 41 Testicular cancer, 484 Steroidogenic acute regulatory protein (StAR), 40, 41 Testicular descent, 36–37 Steroid sulphatase defi ciency, 348 Testicular dysgenesis syndrome, 375, 379 Steroid synthesis, 15, 40 Testicular ectopy, 198 Stopper genes, 610 Testicular fi ne needle aspiration (TEFNA), 156, 157, 484 Storage capacity, 69 Testicular function, 339, 341, 342, 346–352, 354, 355 Stress, 394–395, 411, 415 Testicular intraepithelial neoptasia (TIN), 102, 155–158, Stress-induced infertility, 523 161–163, 227–229, 510 Stress theory of infertility, 522 Testicular macrophages, 38, 39 Structural abnormalities of the autosomes, 220 Testicular maldescent, 93 Structural chromosomal aberrations, 216, 217 Testicular sperm extraction (TESE), 65, 102, 155–157, 162, Structural chromosomal abnormalities, 248 163, 165, 268, 270–273, 484, 507, 509, 510 Structural chromosomal anomalies, 517 Testicular stem cells, 13, 17, 18, 32 Structural sperm defects, 208–209 Testicular temperature, 37 Subfertility, 3 Testicular testosterone concentrations, 32, 34, 38 Sub-lethal cell damage, 366 Testicular tissue, 482 Subnormal volume, 272 Testicular tumor, 97, 98, 101–103, 199, 206, 227, 229, 231, Substitute acts, 548 327, 507, 508, 510, 513 a Subunit, 28, 35 Testicular volume, 12, 14–16, 98, 101, 102, 242, 244, Subzonal sperm injection (SUZI), 477, 478 267, 268 Successive ensoulment, 605 Testim®, 443, 445 Sugar residues, 28, 29 Testocaps®, 439, 443 Summit meetings of male contraception, 585 Testogel®, 443, 445 Supernumerary testes, 197 Testolactone, 459, 460 Suppression of FSH, 32 Testopatch®, 443, 445, 448 Surgical ablation, 228 Testosterone, 11, 12, 14, 23, 26, 29–35, 38–40, 42–44, 47, Surgical correction, 313 49–54, 241–244, 246, 249–256, 287, 289, 292, Surgical management, 272 301, 306, 324–329, 331, 333–335, 414–416, 427 Surgical reconstruction, 270 bioactivity, 114 Surgical therapy of penis deviations, 282–283 defi ciency, 339, 342, 351, 438, 451 Surgical treatment, 300, 313–316 depot, 442 Surplus embryos, 494 gels, 439, 445 Surrogate motherhood, 607 implants, 439, 445–446 Swim-up, 485–486 levels, 109, 113–115 Swim-up or centrifugation on density gradients, 513 patches, 444–445 Swyer syndrome, 221 pellets, 581, 583, 584 Sympathomimetic substances, 317 preparations, 438–446, 449, 453 Symptomatic therapy, 91 production, 242, 243, 246, 255 Symptom-specifi c threshold levels, 438 replacement therapy, 342, 343, 348, 351, 353 9 + 0 Syndrome, 209 substitution, 250, 251, 253–255, 438, 439, 446–451 Syndyastic sexual therapy, 542–554 therapy, 437–453 Synthesis of androgens, 40–42, 48 Testosterone buciclate, 579 Systemic lupus erythematosus, 352 Testosterone cyclohexanecarboxylate, 442 Testosterone cypionate, 442 T Testosterone/DHT ratio, 329 Tadalafi l, 304–307 Testosterone enanthate, 439, 442–444, 447–449, 451, Tamoxifen, 335, 416, 417, 459, 460, 463 578–579, 581, 583, 584 Tandem CAG, 347 Testosterone propionate (Testoviron®), 442–443 Task force for the regulation of male fertility, 585 Testosterone undecanoate, 439–444, 447–449, 460–463, Teaching communicative strategies, 553 579–581, 583–585 Tea seed oil, 579 Testosterone undecanoate (Andriol®), 448 Temperature regulation, 37 Testosterone undecanoate (Nebido®), 443, 448, 449 Temporal hair recession, 95 Testosterone undecanoate plus tamoxifen, 460 Temporal lobe epilepsy, 348 Testoviron®, 442, 443 Teratogenesis, 365, 383 Testoviron® depot 250mg, 442 Teratomas, 333, 345 b-Thalassemia, 349, 350 4-Tert-octylphenol, 375 Theories of aging, 240 TESE/ICSI, 163, 165, 207, 215 Therapeutic cloning, 610 Testicular androgens, 34, 39–54 Therapeutic procedures, 522, 526–534 628 Index

Therapist-couple relationship, 552 U Therapy, 266, 268–271, 273–275 Ulcerative colitis, 349, 397 Thermoregulatory systems, 37 Ulcerative disease, 398 Thyreotropin releasing hormone (TRH), 111–112 Ultrasonography, 264, 267 Thyroid cancer, 346, 350 Ultrasound, 282, 295–297, 405–407, 414, 416, 417, Thyroid diseases, 242, 350 424, 429, 430 Thyroid stimulating hormone (TSH), 27, 28 Ultrasound-guided transvaginal puncture of the follicles, 490 Thyrotropin releasing hormone (TRH), 411 Unexplained infertility, 476 Tight junctional complexes, 63, 70 Unilateral absence of the vas deferens, 271–272 Tight junctions, 15, 16, 38 Unilateral maldescent, 198 Time to pregnancy (TTP), 4, 6, 135, 137, 247, 373–375, Unilateral obstruction, 267 377, 379, 381, 382 Unilateral orchidectomy, 345 Timing of coitus, 4 Unwanted childlessness, 521–524, 527 TIN cells, 158, 162 Upper pubic hairline, 95 Topical therapy, 302 Ureaplasma urealyticum, 132, 264–266 Total body irradiation (TBI), 346 Uremia, 342 Toxoplasmosis, 352, 353 Urethral swab, 265 Tramadolol, 318 Urethritis, 264, 265 Tranquilizers, 290 Urinary tract anomalies, 271, 272 Transabdominal phase of descent, 36 Urogenital sinus, 327 Transdermal dihydrotestosterone, 445 Use of assisted reproduction in various countries, 470 Transdermal testosterone, 342, 355, 439, 442, 444, 445, 448 Use of cryopreserved samples, 515–516 patches, 445 Uterine anomalies, 421, 430 substitution, 254 Uterine peristalsis, 74 Transforming growth factor (TGF), 35 Uterine placement of embryos, 492 Transforming growth factor (TGF) b gene, 400 Uterotubal junction, 74 Transient biochemical androgen defi ciency, 341 Translocations, 208, 215–218, 220 Transport of spermatozoa, 69 V Transrectal electrostimulation, 317 Vaccination against mumps, 206 Transrectal sonography of the prostate, 106, 317 Vaginismus, 394 Transrectal ultrasonography (TRUS), 446, 449 Valsalva maneuver, 101, 103, 105, 202, 204 Transrectal ultrasonography of the seminal vesicles, 105 Vardenafi l, 304, 305, 307 Transrectal ultrasound, 269, 272 Variable numbers of tandem repeats (VNTR), 120 Trans-scrotal therapeutic system (Testoderm®), 444 Varicocele grade I, 202 Transsexuality, 546 Varicocele grade II, 202 Transurethral resection, 268 Varicocele grade III, 202 Trazodone, 302 Varicocele in adolescence, 205–206 Triple drug therapy, 294 Varicoceles, 37, 92, 99, 101, 103, 105, 200–206, 229, Triplet repeats, 347 246, 331 Triplets, 526, 530, 531 Varicosis, 212 Tripterygium, 590 Vasa deferentia, 324 Trisomy 21 (Morbus Down), 248 Vasculogenic erectile dysfunction, 288 Troglitazone, 418 Vasectomy, 273, 506, 507, 557, 560–562, 565–575 True hermaphroditism, 222, 226, 227 Vasoactive intestinal peptide (VIP), 411 Tubal ciliary movement, 422 Vasoepididymostomy (vasotubulostomy), 268, 507 Tubal embryo transfer (TET), 476, 477 Vasotubulostomy, 155 Tubal insuffl ation, 423 Vasovasostomy, 155, 268, 506–507, 570–573 Tubal ligation, 566, 568, 569 Veins, 285, 286, 288, 297, 298, 314, 315 Tuberculosis, 353 Venous surgery, 314 Tubular hyalinization, 161 Vesiculitis, 264, 265 Tubular shadows, 160–162 Vincristine, 509 Tumescence phase, 286 Viral orchitis, 206 Tumor patients, 482 Virilization, 211, 221, 222, 224, 226, 324, 328–331, 340, TUNEL, 149, 150 445, 452, 453 Turner syndrome, 216, 217, 221, 248, 409, 419 Visceral fat, 250, 251, 254 Twins, 522, 526, 530, 531 Vitamin E, 464 Two-cell-theory, 399, 400 Vitelline block to polyspermy, 76, 79 Two-embryo transfer, 609 Vitiligo, 419 Type 2 diabetes mellitus, 250, 251, 254 Vitrifi cation, 514 Type 5, 287, 304, 307 Voice mutation, 93, 95 Index 629

W Z Wolffi an ducts, 50, 53, 194, 195, 324 Zinc, 71, 72, 132, 265, 268 World Bank, 559 fi ngers, 47 World Health Organisation (WHO), 1, 2, 5, 8, 559, 560, supplementation, 342 563, 578, 579, 583–585 Zona binding, 67, 75, 77 World population, 557–560 Zona binding tests, 143–144 Wound infections, 568 Zona block to polyspermy, 76, 79 Zona drilling, 477, 478, 492 X Zona-induced acrosome reaction, 145 X chromosome, 210, 212, 215, 218 Zona pellucida, 67, 74–77, 80, 492, 494 , 374, 375, 381 Zona pellucida-induced acrosome reaction (ZPIAR), X-linked spinal and bulbar muscular atrophy (SBMA), 328, 141, 144, 145 333 Zona penetration, 68, 77, 78 X-rays, 281, 282, 371, 396 Zona penetration test, 144 XX male syndrome, 214–215, 331 Zona-preferred spermatozoa, 130 XX men, 198, 214, 215, 226 Zygote, 61, 79, 80, 421, 422, 425 46, XY disorders of sexual development (DSD), 222–224 Zygote intra-fallopian transfer (ZIFT), 476 XYY syndrome, 216

Y Y chromosome, 194, 207, 208, 210, 215, 217–220, 222, 226 Y chromosome microdeletions, 207, 218–220 Yohimbine, 302 Young syndrome, 266, 272–273, 344