Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

Gonadotropin Treatment in Male Zitzmann M, Behre HM, Kliesch S J. Reproduktionsmed. Endokrinol 2013; 10 (Sonderheft 1), 23-28

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Wir freuen uns auf Sie! Treatment in Male Infertility Gonadotropin Treatment in Male Infertility

M. Zitzmann1, H. M. Behre2, S. Kliesch1

Male is often associated with impaired . In special cases, treatment with can induce, maintain or augment . Patients responsive to such regimens are men with secondary hypogonadism, lacking gonadotropin secretion due to pituitary disorders or hypothalamic insufficiency. Such diseases may be inherited or acquired. Available substances are recombinant follicle-stimulating hormone and human chorionic gonadotropin (substituting activity of ). Recommendation based on current research is that treatment should last at least 2 years. Successful induction of spermatogenesis is more likely in men with pituitary disorders than in those lacking hypothalamic GnRH secretion (e.g. patients with Kallman Syndrome). J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1): 23–8. Key words: hypogonadism, gonadotropins, spermatogenesis, Kallmann Syndrome, male fertility

 Introduction GnRH substitution is only effective in strated impressively by the example of a hypothalamic disorders; a pituitary in- hypophysectomised patient, who had Testicular dysfunction often comprises sufficiency always requires administra- full spermatogenesis and was still fertile both production of and tion of gonadotropins (either the con- due to an activating mutation of the FSH spermatogenesis. These functions are ventional choice of human chorionic receptor which was able to induce recep- dependent on gonadotropin action in gonadotropin and human menopausal tor activity (cAMP production) without men, with LH stimulating testosterone gonadotropin, or purified urinary FSH, FSH stimulation [6]. production in Leydig cells and FSH sup- or more recently, recombinant human porting spermatogenesis by stimulating FSH) [1]. FSH plays a pivotal role in the For completely normal spermatogenesis, Sertoli cell function. initiation and maintenance of spermato- FSH and testosterone are important, and genesis. The induction of proliferation the intratesticular location/action of test- While hypogonadism as such is usually of Sertoli cells and spermatogonia de- osterone is pivotal. Thus for treating in- treated with testosterone applied by vari- pends on this gonadotropin [2]. fertility in hypogonadal men, there is a ous methods, for achieving fertility – pos- need for high intratesticular testosterone sible in the hypogonadotropic forms – Concerning maintenance of spermato- levels to initiate spermatogenesis. This temporary treatment with gonadotropins genesis by FSH, several experiments in was demonstrated by treating men with or their clinical substitutes is required, monkeys with long-term immuni sation hypogonadotropic hypogonadism with i.e. human chorionic gonadotropin (hCG) against FSH induced testicular regres- purified FSH and testosterone and com- in combination with human menopausal sion and oligo- or [3]. In paring its effectiveness to hCG/hMG gonadotropin (hMG) or purified urinary the cases of oligozoospermia the few therapy [1]. The latter was able to induce follicle stimulating hormone (FSH) or left were probably functionally spermatogenesis while the FSH/testos- recombinant human FSH (rhFSH) or, impaired, as these monkeys were infer- terone regimen failed [7]. alternatively to gonadotropins, pulsatile tile in mating tests. Similarly, a study GnRH application. Once paternity has conducted in India with human volun- During the course of hormonal treatment been achieved, the treatment scheme teers receiving an FSH vaccine showed to achieve fertility in hypogonadotropic should switch back to the more conve- altered parameters of sperm quality such hypogonadal men, usually sperm counts nient and cost-effective testosterone as acrosome content and chromatin con- below the lower limit of the normal range substitution. Information about the state densation. A marginal suppression of are seen. This does not preclude fertility, of the art of gonadotropin treatment in sperm counts was achieved (around 30– as has been demonstrated in 24 men with infertile men with hypogonadotropic 65%) after the short duration of four IHH who proved fertile after gonadotro- hypogonadism will be given in the fol- spermatogenic cycles, indicating that pin therapy. Seventy-one percent of a to- lowing. elimination of FSH not only causes tal of 40 initiated were con- quantitative, but possibly also qualitative ceived with sperm concentrations ranging  Hormone Replacement by damage of spermatogenesis [4]. from 1 to 20 [8]. Confirming results were Pulsatile GnRH Applica- seen in 42 cases of fertility treatment in tion or Gonadotropin In the setting of a contraceptive trial us- hypogonadotropic hypogonadal men us- ing a testosterone ester, complete azoo- ing pulsatile GnRH therapy or the hCG/ Substitution in General spermia was reached only in those sub- hMG regimen [9, 10]. In hypogonadotropic hypogonadism the jects whose serum FSH levels were sup- origin of the disease influences the pressed below the lower limit of the nor- Initial testicular volume allows predic- choice of treatment to achieve fertility. mal range [5]. The role of FSH is demon- tion of the necessary duration of therapy

Received: September 11, 2012; accepted after revision: December 3, 2012 From the 1Centre of Reproductive Medicine and Andrology of the University, Münster, and, the 2Center for Reproductive Medicine and Andrology of the University, Halle, Germany Correspondence: Prof. Dr. Michael Zitzmann, Centre for Reproductive Medicine and Andrology, D-48149 Münster, Domagkstraße 11; e-mail: [email protected]

J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 23 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Gonadotropin Treatment in Male Infertility until sperm first appear in the ejaculate. Induction of pregnancies was negatively Spermatogenesis can be induced even in influenced by maldescension (p = 0.009), patients with a very small testicular vol- while ejaculate volume (p = 0.005), ume (of less than 3 ml), but this may re- sperm concentration (p = 0.02) and mor- quire treatment for 18–24 months [9– phology (p = 0.001) were positive pre- 11]. During therapy, testicular volume dictors. Similarly, the time until preg- can be monitored carefully by ultra- nancy was dependent on these factors; in sound sonography, in order to detect addition, progressive subtle increases, which precede the first (positive, p = 0.001) and body mass in- appearance of sperm [1]. dex (negative, p = 0.01) exerted influ- ence. The odds ratio for men with a pitu- A review of 42 patients showed that pre- itary disorder in comparison to those vious maldescent (uni- or bilateral) ham- with hypothalamic disorders to induce a pers spermatogenesis and requires a was 1.65 (95%-CI: 1.01– Figure 1: Effects of gonadotropin therapy (see Table 1 longer course of treatment, but does not for modalities) on spermatogenesis in secondary hy- 2.67; p = 0.04) and men with no history preclude patients from gaining fertility. pogonadism. Induction of spermatogenesis – time until of maldescension had an odds ratio of This is especially the case in unilateral appearance of first sperm in ejaculate. 1.41 (95%-CI: 1.08–1.83; p = 0.01) com- maldescent, but there are also reports of pared to those patients with maldescen- patients with bilateral sion. The induction of fertility in men having been treated successfully. The induction of spermatogenesis and unas- with secondary hypogonadism is highly group comprising all patients with uni- sisted pregnancy. In conclusion a larger effective but obviously needs patience in lateral maldescent required 5 months of testis volume is a useful prognostic indi- subgroups with unfavorable confound- treatment until induction of spermatoge- cator of response. The association of ers [1]. nesis (1–16 months); 13 months (12–22 slower responses after prior androgen months) was the average time for pa- therapy suggested that faster pregnancy  Pulsatile GnRH Therapy tients with bilateral maldescent. In com- rates might be achieved by substituting parison all patients with no history of gonadotropin for androgen therapy for Treatment with GnRH requires subcuta- maldescent needed 4.5 months of treat- pubertal induction. neous pulsatile application using a por- ment (2–18 months; [10]). table pump and a butterfly needle placed Confounders of fertility induction were in the abdominal wall and changed every This is in agreement with other trials also described in 83 men with secondary 2 days. The dose ranges from 5 to 20 µg/ [12–14]. Since treatment may be re- hypogonadism [Zitzmann et al., unpub- 120 min, or 100–400 ng/kg body weight quired up to for 2 years or longer, it is lished data] since a marked amount of per 120 min. Low-dose pulsatile GnRH recommended that patients with hypo- uncertainty exists in regard to factors in- therapy (2 µg/150 min) may not elicit a gonadotropic hypogonadism try to in- fluencing fertility induction in men with sufficient pituitary response, reflecting duce spermatogenesis even prior to the secondary hypogonadism. 83 men (Kall- different degrees of central maturation immediate desire for paternity. In repeat- mann syndrome: n = 20, idiopathic hy- [16]. In most cases the induction of sper- edly treated patients, stimulation of sper- pogonadotropic hypogonadism: n = 34, matogenesis is evidenced by the appear- matogenesis tended to be faster, leading postpubertal pituitary disorder: n = 29) ance of sperm in the ejaculate. Therapy to a reduced time to pregnancy [10]. were treated in 107 stimulation cycles lasts on average 4 months, as shown in with hCG/hMG (n = 100) or pulsatily six of seven GnRH therapy cycles in pa- This was later confirmed by another application of GnRH (n = 7); 53/83 men tients with idiopathic hypogonadotropic large study [15]: A total of 75 men, with desired paternity. Spermatogenesis was hypogonadism or Kallman syndrome 72 desiring fertility, was treated at two induced in 72/83 patients. 43/74 treat- [10]. Sperm counts were below the nor- academic andrology centers for a total of ment cycles to achieve pregnancies were mal range 1.2–15.3 mill/ml. 116 courses of therapy from 1981–2008, successful using spontaneous fertilisa- analysis and testicular examina- tion (n = 36) or ICSI (n = 7). Maximum Similar results have been demonstrated tion were performed every 3 months. A durations to induce appearance of sperm in other studies [13, 17, 18]. Despite low total of 38 men became fathers, includ- in the ejaculate or pregnancy were 38 sperm counts, pregnancies can be ing five through assisted reproduction. and 50 months, respectively. Regression achieved, the duration until conception The median time to achieve first sperm models revealed age (p = 0.03), hypotha- being on average 6–7 months. Under was 7.1 months [95%-CI: 6.3–10.1]) and lamic disorder (0.05) and maldescension treatment testicular size will increase for conception was 28.2 months (95%- of at least one testis (0.03) to exert nega- significantly, as demonstrated in the CI: 21.6–38.5). The median sperm con- tive influence on successful induction of above mentioned patients where the centration at conception for unassisted spermatogenesis, while serum testoster- initial mean size of 6.8 ± 2.2 ml rose to pregnancies was 8.0 m/ml (95%-CI: one concentrations under therapy had a 14.9 ± 3.2 ml after 5–12 months of treat- 0.2–59.5). Multivariate correlated time- positive effect (p = 0.002). Subsequent ment with pulsatile GnRH [10]. to-event analyses showed that larger tes- sperm concentrations were then posi- tis volume, previous treatment with go- tively dependent on FSH levels (p = 0.03) When pulsatile GnRH treatment fails, nadotropins, and no previous androgen and bitesticular volume (p < 0.001). Also mutation of the GnRH receptor gene can use each independently predicted faster see Figure 1. be the cause. These defects have been

24 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Gonadotropin Treatment in Male Infertility

Table 1: Modern modalities of gonadotropin substitution therapy in men to achieve  Gonadotropin Therapy spermatogenesis and maintain androgenicity. In order to achieve fertility in cases of Substance Form of Application Dosage pituitary lesions or GnRH receptor gene GnRH pulsatile Subcutaneous by minipump 5–20 mg/pulse every 2 h defects, the regimens using gonadotro- pins must be applied, but they are also a or alternatively useful option in hypothalamic disorders. Human Chorion- Subcutaneous or intramuscular 1500–3000 IU 2 2 to 3 times Historical therapy used hCG and hMG, Gonadotropin (hCG) per week depending on tes- tosterone levels achieved both purified extractions from urine. In recent years, however, purified urinary in combination with FSH and recombinant human FSH have Highly purified or Subcutaneous or intramuscular 150 IU 3ml 3 times per week recombinant FSH replaced hMG in most countries for vari- ous reasons [1]. PHCG preparations are only approved for i. m. application, however, it long clinical experience that a s. c. administration of hCG-preparations is therapeutically very effective and safe. But this is, strictly speaking, an off-label use. Treatment with hCG/hMG As the subunits of hCG and LH are structurally very similar, they act on the same receptor located on Leydig cells. described and are probably transmitted levels were measured serially, and maxi- This effect is used to substitute LH by as an autosomal recessive trait. A vari- mum sperm count was recorded. A lon- purified urinary hCG or recombinant able degree of hypogonadism in an af- gitudinal mixed effects model was used hCG. Human menopausal gonadotropin fected kindred was seen: a male showed to determine predictors of final TV. LH contains both LH- and FSH-activity. no response to pulsatile administration (97%) and T (93%) levels were normal- However, a dose that provides adequate of GnRH, which was effective in his two ized in the majority of IHH men. Groups FSH-activity does not maintain Leydig sisters, all showing clinical patterns of 2 and 3 achieved a normal adult testicu- cell function because the LH-activity is hypogonadotropic hypogonadism [19]. lar size (92%), FSH (96%), I(B) levels low. Thus a combination with hCG is re- (93%), and sperm in their ejaculate quired to achieve fertility. Another cause for failure of pulsatile (100%). However, given their prior com- GnRH treatment was observed in a pa- plete puberty and thus primed gonadot- 95% of hMG consists of co-purified tient who formed anti-GnRH antibodies ropin producing cells and testes; group 3 proteins that lack LH or FSH activity during intravenous administration. This responded faster, normalizing androgen and is believed to cause the hypersensi- was associated with deterioration of production by 2 months and completing tivity reactions occasionally observed testosterone and gonadotropin levels spermatogenesis by 6 months. under hMG therapy, but not under [20]. highly purified FSH or recombinant In contrast, group 1 failed to normalize FSH [22–24]. In an elegant approach using only pulsa- TV (11 ± 0.4 ml) and I(B) levels (92 ± tile GnRH therapy in patients with hy- 6 pg/ml) by 24 months, despite normal- HCG may also induce antibody forma- pogonadotropic hypogonadism, GnRH ization of their FSH levels (11 ± 2 IU/l). tion [25], which may neutralise hCG treatment was successful in inducing vi- Similarly, sperm counts of group 1 pla- bioactivity [26–28]. Contraceptive trials rilization and spermatogenesis in men teaued well below the normal range with in women using the effect of antibody with hypothalamically associated idio- 18% remaining azoospermic. The inde- formation against hCG after vaccination pathic hypogonadotropic hypogonadism pendent predictors of outcome of long- (with preparations based on the beta- (IHH) [21]. A small subset of IHH men, term GnRH therapy were: 1.) the pres- subunit of hCG; [29]) have shown that poorly characterized to date, fail to reach ence of some prior pubertal development pregnancies can be prevented at and a normal testicular volume (TV) and (positive predictor; p = 0.003); 2.) a above 50 ng/ml antibody titers [30]). produce sperm on this therapy. To deter- baseline I(B) < 60 pg/ml (negative pre- mine predictors of outcome in terms of dictor; p = 0.009); and 3.) prior crypt- Therapy in men is initiated by adminis- TV and sperm count, authors studied 76 orchidism (negative predictor; p = 0.05). tration of hCG alone, which is given in- IHH men (38% with anosmia) undergo- Conclusion were: a) pulsatile GnRH tramuscularly or subcutaneously. The ing GnRH therapy for 12–24 months. therapy in IHH men is very successful in usual dose is 1500–3000 IU applied The population was stratified according inducing androgen production and sper- twice per week (Monday and Friday) for to the baseline degree of prior pubertal matogenesis; b) normalization of the a period of 8–12 weeks; adjustments development: absent (group 1, n = 52), LH-Leydig cell-T axis is achieved more have to be made to achieve testosterone partial (group 2, n = 18), or complete uniformly than the FSH-Sertoli cell-I(B) levels within the normal range. In some (adult onset HH; group 3, n = 6). Crypt- axis during GnRH therapy; and c) favor- cases sperm can be found in the ejaculate orchidism was recorded in 40% of group able predictors for achieving an adult by then, due to residual FSH secretion 1, 5% of group 2, and none in group 3. testicular size and consequently opti- [11, 31, 32]. Pulsatile GnRH therapy was initiated at mizing spermatogenesis are prior his- 5–25 ng/kg per pulse sc and titrated to tory of sexual maturation, a baseline I(B) Following the induction phase, hMG or attain normal adult male testosterone (T) greater than 60 pg/ml, and absence of rhFSH is administered intramuscularly at levels. LH, FSH, T, and inhibin B (I[B]) cryptorchidism. a dose of 75–150 IU thrice weekly (Mon-

J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 25 Gonadotropin Treatment in Male Infertility day, Wednesday, Friday). Sometimes it pituitarism; complete virilisation was men after a maximal duration of treat- may be necessary to reduce the hCG dose achieved in all patients; in 7 of 8 patients ment of 18 months [40]. due to increasing testosterone levels or willing to provide ejaculates spermato- development of gynecomastia caused by genesis was achieved [34]. The subcuta- Use of Recombinant Human increased levels of testosterone which are neous form of application makes self-ad- LH (rhLH) aromatized to estradiol. A review of 9 pa- ministration feasible: in 60 men with dif- Recombinant hLH is available for stimu- tients with IHH, 9 patients with Kallmann ferent forms of hypogonadotropic hypo- lation purposes in cycles of assisted re- syndrome (group A) and 21 patients with gonadism (16 with Kallmann syndrome, production and used in women to induce (group B) treated with 19 with IHH, 25 with hypopituitarism) ovulation [41]. Whilst hCG is effective this regimen showed appearance of first highly purified urinary FSH (150 IU for 36 hours, rhLH would have to be ad- sperm in the ejaculate after an average thrice/week) and hCG (2500 IU twice/ ministered daily for substitution in men. period of 6 months (1–18 months) in week) were tested for at least 6 months Its use may therefore be limited, but group A, and 4 months (2–16 months) in such a regimen. Results were compa- longer comparative studies in men are in group B. Sperm concentrations were rable to other studies and the treatment lacking. A recent in vitro study suggests 1.2 mill/ml (0.1–9.0 mill/ml) in group A, was well tolerated [1, 35]. that, although human luteinizing hor- and 8.1 mill/ml (0.1–180 mill/ml) in mone (hLH) and chorionic gonadotropin group B [10]. Treatment with hCG/Recombi- (hCG) act on the same receptor, they nant Human FSH (r-hFSH) may nevertheless elicit a different cellu- As mentioned above, duration of therapy rhFSH has advantages over urinary pre- lar and molecular response in COS-7 depends on the initial testicular size and parations in terms of purity, specific ac- and hGL5 cells [42]. the patients’ history of uni- or bilateral tivity, consistent composition and con- maldescensus. Pregnancies were induced stant supply. Multiple dose pharmacoki- Comparison of GnRH and Go- in 5 of 10 patients belonging to group A netics showed an elimination half-life of nadotropin Therapy (time to pregnancy on average 8 months), 48 ± 5 h and proved that serum FSH is There is still some degree of uncertainty and in 17 of 21 patients of group B (time increased in a dose-proportional fashion. regarding the optimal treatment modal- to pregnancy on average 10 months). No intrinsic LH activity was detected ity in patients with hypogonadotropic Testicular size increased from 4.4 ± 2.86 [36]. hypogonadism caused by disorders at to 15.3 ± 7.4 ml (group A), and from the hypothalamic level. Our group re- 14.0 ± 8.7 to 28.3 ± 10.9 ml (group B; Nevertheless, and interestingly, it has ported 42 cases of men with hypogona- [10]). been demonstrated that rhFSH increases dotropic hypogonadism treated for in- testosterone concentrations in spermatic fertility, comprising 24 patients with Treatment with hCG/Highly venous blood. The testosterone produc- IHH or Kallmann syndrome. Six of these Purified Urinary Human FSH tion described in Leydig cells is assumed received pulsatile GnRH treatment, the (Urinary-hFSH) to be increased by a Sertoli cell-released other 18 the conventional hCG/hMG Improved purification methods have nonsteroidal factor [37]. Early case re- regimen. No statistically significant dif- provided highly purified urinary FSH ports suggested its effectiveness in induc- ferences in terms of first appearance of with enhanced specific activity in com- ing spermatogenesis in hypogonadotro- sperm in the ejaculate or time to preg- parison to hMG (10,000 IU/mg of pro- pic hypogonadism [38]. A study includ- nancy were seen, nor was the increment tein vs. 150 IU: mg of protein for hMG). ing ten men with such a diagnosis due to of testicular size significantly different A study including 28 men with hypo- hypothalamic or pituitary disorders pro- [10]. gonadotropic hypogonadism examined vided data concerning the combined the effects of hCG 2000 IU twice weekly therapy with recombinant FSH (150 IU Another study with 36 patients with dis- for 3–6 months followed by 18 months s.c. thrice/week) and hCG (2000 IU 2–3 orders at the hypothalamic level (IHH of additional subcutaneous administra- times/week). Eight men commenced or Kallmann syndrome), divided into tion of highly purified urinary FSH. rhFSH treatment and seven of these initi- groups of 18, reported no significant dif- Twenty-five patients achieved spermato- ated spermatogenesis at a median of ference in effectiveness with respect to genesis, 18 of them with a sperm density 6 months. Five achieved a sperm output sperm counts. With GnRH therapy incre- of more than 1.5 mill/ml. The median of more than 1.5 mill/ml. Mean testicu- ment of testicular volume occurred more time to initiation of spermatogenesis lar volume increased by 4.2 ml. Three rapidly and was significantly more pro- (appearance of sperm in the ejaculate) pregnancies were achieved during FSH nounced than under a gonadotropin regi- was 9 months. Mean testicular volume treatment. Its efficacy is comparable to men. Five patients with the latter therapy increased from 3.6 ± 1.7 to 10.5 ± 4.1 ml. urinary FSH in restoring normal fertility developed gynecomastia, probably due The partner of one patient seeking fertil- in men with gonadotropin deficiency [1, to the significantly higher testosterone ity conceived a child. The effectiveness 39]. concentrations in that group [18]. A 2- was comparable to regimens using hCG year comparison including 16 patients and hMG [33]. A combined analysis of data from 4 stud- showed no advantage of either therapy ies using rFSH/hCG to induce spermato- concerning acceleration and/or enhance- Corroborating results were seen in 14 genesis in men with hypogonadotropic ment of testicular growth, onset of sper- prepubertal males with isolated hypogo- hypogonadism (n = 100) revealed that matogenesis or increment of sperm out- nadotropic hypogonadism or panhypo- spermatogenesis could be achieved in 68 put [17].

26 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) Gonadotropin Treatment in Male Infertility

 Hormonal Treatment of Outlook: Pharmacogenetic Impli- for induction of spermatogenesis in a hypogonadotropic male. cations Fertil Steril 1995; 63: 1326–8. Normogonadotropic Oligo- 6. Gromoll J, Simoni M, Nieschlag E. An activating mutation of asthenotheratozoospermia Recent reports demonstrate that a poly- the follicle-stimulating hormone receptor autonomously sus- morphism in the follicle-stimulating tains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab 1996; 81: 1367–70. Since GnRH and the different gonadotro- hormone beta-subunit promoter (TT-ge- 7. Schaison G, Young J, Pholsena M, et al. Failure of combined pins have proven their benefit in induc- notype vs G/T- or GG-genotype) can be follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypo- tion of spermatogenesis in hypogona- associated with inadequately low FSH gonadotropic hypogonadism. J Clin Endocrinol Metab 1993; dotropic hypogonadism, the application levels and, consequently, lower sperm 77: 1545–9. of these substances was also tested in id- counts [47]. This may present a novel 8. Burris AS, Clark RV, Vantman DJ, Sherins RJ. A low sperm concentration does not preclude fertility in men with isolated iopathic male infertility. While the appli- type of partial hypogonadism, selec- hypogonadotropic hypogonadism after gonadotropin therapy. cation of pulsatile GnRH resulted in a de- tively regarding spermatogenesis and, Fertil Steril 1988; 50: 343–7. crease in FSH levels, no effect on repro- hence, an indication for treatment with 9. Kliesch S, Behre HM, Nieschlag E. High efficacy of gona- dotropin or pulsatile gonadotropin-releasing hormone treat- ductive parameters was seen. There was rFSH in those men with a TT-genotype. ment in hypogonadotropic hypogonadal men. Eur J Endocrinol no evidence for a benefit of this treatment A first trial with rFSH induced a signifi- 1994; 131: 347–54. 10. Büchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile modality [43]. One randomised, con- cantly higher improvement in sperm GnRH or human chorionic gonadotropin:human menopausal trolled study using an hCG/hMG regimen count and quality in TT homozygotes gonadotropin as effective treatment for men with hypogona- dotropic hypogonadism: a review of 42 cases. Eur J Endocrinol for treatment of normogonadotropic regarding carriers of the G allele [48]. 1998; 139: 298–303. oligoasthenoteratozoospermia showed no 11. Burris AS, Rodbard HW, Winters SJ, Sherins RJ. Gonado- significant improvement of sperm para- tropin therapy in men with isolated hypogonadotropic hypogo-  Conclusion nadism: the response to human chorionic gonadotropin is pre- meters or pregnancy rates [44]. dicted by initial testicular size. J Endocrinol Metab 1988; 66: Gonadotropin substitution therapy is 1144–51. A randomised, double-blind, placebo- highly effective in men with hypogona- 12. Saal W, Happ J, Cordes U, Baum RP, Schmidt M. Subcuta- neous gonadotropin therapy in male patients with hypogona- controlled clinical trial using recombi- dotropic hypogonadism to achieve both dotropic hypogonadism. Fertil Steril 1991; 56: 319–24. nant human FSH (daily subcutaneous in- androgenisation and fertility. Up to now, 13. Delemarre-van de Waal H. Induction of testicular growth and spermatogenesis by pulsatile, intravenous administration jections of 150 IU rhFSH) for treatment the use of gonadotropins, especially of gonadotrophin-releasing hormone in patients with hypogo- of idiopathic male infertility in 67 pa- FSH, in normogonadotropic infertile nadotrophic hypogonadism. Clin Endocrinol 1993; 38: 473–80. tients showed significant increases in men cannot be recommended generally. 14. Jones TH, Darne JF. Self-administered subcutaneous hu- man menopausal gonadotropin for the stimulation of testicu- sperm motility in the placebo group and However, clearly predefined patients lar growth and the initiation of spermatogenesis in hypogona- improved sperm DNA condensation in might benefit from this therapy. dotropic hypogonadism. Clin Endocrinol 1993; 38: 203–8. the FSH-treated group. Testicular vol- 15. Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of spermatogenesis and fertility ume increased significantly in the FSH-  Relevancy to Practice during gonadotropin treatment of gonadotropin-deficient infer- treated group compared to the placebo tile men: predictors of fertility outcome. J Clin Endocrinol Metab 2009; 94: 801–8. group. No significant increase in preg- – Secondary hypogonadism can be 16. Happ J, Ditscheid W, Krause U. 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