Male : The Clinical Aspects of Evaluation and Management

J. WILLIAM McROBERTS, M.D.

Division of / Department ofSurgery, University of Kentucky School of Medicine, Lexington, Kentucky

Introduction the number of babies available for adoption have At a time when limiting family size has become been sharply reduced by birth control, liberalized of national interest, increasing numbers of married abortion laws, and an increasing tendency of unwed couples are moving in a different direction-to over­ mothers to keep their babies. come infertility and conceive children. Reasonably Until recently, most physicians were not particu­ reliable statistics indicate that approximately 3 .5 mil­ larly enthusiastic about treating patient infertility. lion couples, or nearly 15% of those of childrearing The reasons for this attitude centered around a gen­ age, are subfertile. If one adds the cases of secondary eral pessimism about being able to help the patient, infertility, in which a pregnancy or a miscarriage has combined with the fact that the physicians' training already occurred in the marriage but is followed by ill-prepared them for evaluating and managing these years of difficulty conceiving another child, the mag­ patients with the result that has prob­ nitude of the infertility problem is indeed impressive. ably been the most misunderstood item since the IRS At the personal level, involuntary childless couples short form. Presently, a more optimistic view is war­ may suffer doubts about their own sexuality and are ranted as therapy is now effective in achieving preg­ often caught in intense emotional, family, and so­ nancy for about 45% of these couples. cietal pressures emanating from their inability to con­ The objective of this article is to present the most ceive. recent information regarding the clinical aspects of Furthermore, the incidence of infertility seems to male infertility and subfertility. The information will be slowly increasing due to a number of factors in­ be practical and directed to understanding both the cluding the increased risk of prolonged anovulation causes of male infertility and the various methods of following the use of birth control pills and to adnexal evaluating and managing male patients with this infections associated with the use of intrauterine de­ problem. vices. Additionally, there is a definite trend by women to delay having children until later in life and thus to bypass the time of their optimal fertility potential Definition of Male Infertility and Subfertility between 22 and 26 years of age. Based on analysis, a precise definition of Whether or not the true incidence of infertility is male infertility and subfertility is difficult because the increasing, there is a definite and substantial increase quality of semen that will achieve a pregnancy for one in the demand for treatment. This reflects a growing couple and not another will vary due to the relative awareness by childless couples that treatment for in­ fecundity of the female partner and the variable inter­ fertility in many instances can be effective and that action of infertility co-factors. In other words, data suggest that there are degrees df fertility for both 1 Correspondence and reprint requests to Dr. 1. William Mc­ sexes, depending on the partner. Nevertheless, given Roberts, Division of Urology, University of Kentucky School of a female partner who is fertile by most standards, Medicine, Lexington , KY 40506 lower limits for semen quality have been established

96 MCV QUARTERLY 14(2): 96-100, 1978 MCROBERTS: EVALUATION AND MANAGEMENT OF MALE INFERTILITY 97 under which a pregnancy is likely to occur.2 - 4 These mately 4.6 cm in greatest diameter (range 3.6-5.5 cm) minimal values are as follows: and 2.6 cm in width (range 2.1-3.2 cm). Because the germinal epithelium comprises about 80% of the.nor­ Total ejaculate volume: 1.5-5.0 ccs mal testicular mass, atrophy of the seminiferous tu­ Sperm count: 20 m/ cc bules will be reflected in a smaller than normal tes­ Sperm motility: 60% motile ticle. On the other hand, normal testicular size does Sperm speed: 2+ (Scale 1-4) not assure normal semen quality. If the patient's Sperm morphology: 60% normal forms body habitus appears abnormal, laboratory investi­ These minimal values must be considered as part gation should be directed at determining any abnor­ of the overall semenogram and may be adjusted if mality of the hypothalmic-pituitary-gonadal axis. one index is of particularly high quality, for example, a patient with a 10 m/ cc sperm density may well be The fertile if his sperm motility is excellent. The semen analysis is without doubt the single most important step in the evaluation of male infer­ History and Physical Examination tility. It is to male infertility what cystoscopy is to Beyond obtaining a basic medical and marital bladder tumors, that is, it is the most critical item in history, the infertility history should be directed at the initial evaluation process and is important in uncovering the specific factors that are known to therapy foll ow-up. contribute to subfertility. These factors can be conve­ The semen analysis, or semenogram, is a study niently divided into four groups: childhood illnesses; of the characteristics of the spermatozoa that are adult illnesses; drugs; and environmental-occupa­ clinically important in assessing fertility. While non­ tional hazards. cellular components of the semen also contribute to Specific childhood illnesses that can adversely fecundity, for clinical purposes the semenogram will effect fertility include cryptorchidism, mumps, sper­ reflect their influence on the spermatozoa! character­ matic cord torsion, direct trauma, and the timing of istics that are decisive in determining fertility poten­ puberty as well as specific surgical procedures includ­ tial, and a separate biochemical analysis of these ing herniorrhaphy, orchiopexy, hypospadias repair, components is neither necessary nor practical. urethroplasty, and Y-V plasty of the bladder neck to Because of its importance, a minimum of two relieve "obstruction." and preferably three semen analyses should be ob­ Adult illnesses that are similarly important in­ tained. Additionally, multiple collections are neces­ clude tuberculosis of the genital tract, mumps, or­ sary because of physiological variations in the same chitis, , , gonorrhea, diabetes, patient and because of technical variations in analyz­ vaginitis in the female partner, and such surgical ing the specimen, for example, acceptable counting procedures as noted under childhood illnesses plus errors vary from 10% to 20% with the same specimen. retroperitoneal surgery (lymphadenectomy, sympa­ Preferably, the semen specimen should be col­ thectomy, and so forth), vasectomy, and prostatic lected by masturbation into a clean, wide-mouthed surgery. glass or plastic container. The container, such as a Drugs that are known to interrupt or alter sper­ standard urine specimen bottle or ointment jar, matogenesis include the nitrofurantoins, amebicides, should be supplied by the physician to avoid facti­ hormones (for example, testosterone, estrogens, cor­ tious results secondary to the container's previous ticosteriods ), as well as most of the anti-cancer contents or cleaning agents. The specimen should be chemotherapeutic drugs. kept warm and delivered to the laboratory for analy­ The patient's occupation may have a bearing on sis within 60-90 minutes. The timing of specimen his fertility status if he is under a great deal of stress collection should reflect the couple's usual coital fre­ or if the are exposed to undue heat or radia­ quency pattern, or if that is variable, an abstinence tion. period of 2-4 days is recommended. Personal or reli­ The physical examination should include a thor­ gious beliefs may require the use of a silastic seminal ough examination of the external genitalia and pros­ fluid collecting device. It is critical that the specimen tate. Testicular size and consistency are particularly represents the entire ejaculate since there are signifi­ important; measurement is facilitated by the use of cant variations in the seminal values from one por­ calipers. The normal adult testis measures approxi- tion to the other with regard to motility, sperm den- 98 MCROBERTS: EVALUATION AND MANAGEMENT OF MALE INFERTILITY sity, and viscosity as compared with the total and ejaculate. Somewhat less than 5% of male infertility pa­ The specific techniques of analyzing the semen tients will present with either aspermia or azoo­ will not be discussed because they are beyond the spermia. In the aspermic patient there is failure of space limitations of this presentation and, addition­ any ejaculate to appear at the time of orgasm. On the ally, are available in recent texts.5 Five principal in­ other hand, the azoospermic patient experiences both dices should be reported on the semen analysis. Rep­ and orgasm, but the ejaculate contains no resentative values for fertile men are as follows: spermatogenic elements. The absence of ejaculation in aspermic patients 1. Total ejaculate volume: 2-5 ccs is generally due to neurogenic causes7 and, less com­ 2. Sperm count (density in millions/cc): greater monly, to . The neurogenic than 50 m /cc causes include pituitary tumors, olfactogenital dys­ 3. Sperm motility(% motile cells): 65% to 85% plasia (Kallman syndrome), and absent contraction 4. Sperm speed (forward progression speed): 3-4 of the and vasa differentia following (scale 0-4) retroperitoneal lymph node dissection for the treat­ 5. Sperm morphology: 60% to 85% normal oval ment of testicular tumors (and not due to retrograde forms as previously thought). The neurogenic causes can be successfully Additionally: The specimen is normally viscous treated in most cases by specific replacement therapy. and opalescent with a grayish-white color. There The common causes of retrograde ejaculation should be no hyperviscosity, pyospermia, or signifi­ include those in which the anatomy of the internal cant sperm agglutination. sphincter is disrupted as in transuretheral resec­ tion (TUR) of the or vesicle neck surgery, Systematic Approach to Male Infertility or where the nerve supply of the internal sphincter A systematic approach to male infertility can be is distrupted as in spinal cord injury, surgical sym­ facilitated with the use of the following diagnostic pathectomy, chemical sympathectomy [guanethidine flow sheet (modified after Lipshultz6 ): (sulfate) (Ismelin)), and diabetes visceral neuropathy. Apart from a history of a previous elective vasec­ tomy, the azoospermic patient's differential diagnosis PHYSICAL SEM EN rests bet ween obstruction or atresia of the epididymal HISTORY 1-----1 EXAMINATION ANALYSIS or vasal ducts and testicular failure as seen in ger­ minal cell aplasia, marked spermatogenic arrest, SEMEN ANALYSIS N ORMAL chromosomal defects, severe peritubular fibrosis, and X3 I Klinefelter syndrome. Evaluate couple The seminal specimens of all azoospermic pa­ ABNORMAL tients should be tested for the presence or absence of fructose: this is quantitatively determined by adding the reducing reagent resorcinol to a small portion of the seminal specimen and bringing it to a boil.5 If ASPERMIA AN D ALL fructose is present, an orange color will appear within AZOOSPERMIA PARAM ETE RS ABNORMAL half a minute of boiling. The presence of fructose, a product of the seminal vesicles, effectively rules out congenital bilateral absence of the vasa as the pres­ PREDOMI NA NCE OF SINGLE ABNORMAL PARAMETER ence of the seminal vesicles depends on the existence of the vasa which embryologically give rise to the former. On the other hand, the presence of fructose The flow sheet is based on the semen analysis only rules out bilateral obstruction of the ejaculatory and the identification of the three broad seminal cate­ ducts but does not assure ductal patency throughout gories of: 1) aspermia and azoospermia, 2) pre­ the vasa and epididymi. Therefore, in a setting of dominance of a single abnormal parameter, and 3) azoospermia and a normal testicular biopsy, vaso­ all parameters abnormal. grams should be obtained to identify the site of ob- MCROBERTS: EVALUATION AND MANAGEMENT OF MALE INFERTILITY 99 struction which can be corrected surgically by micro­ gospermia of less than 20 million/ ml), sperm density surgical techniques, depending on its location. may be improved in about 80% of patients by use of the split-ejaculate technique. To collect a split or Predominence of a Single Abnormal Parameter fractionated ejaculatory specimen, the patient is Approximately a third of subfertile male patients given two collection jars which are numbered #1 and will have a semen analysis characterized by the pre­ #2 and s.ecured together with adhesive tape. The first dominence of a single abnormal parameter, most one third of the ejaculate is collected in jar #1 and the commonly sperm viability/motility. Asthenospermia, remainder in jar #2. In 80% of patients, the sperm a decrease in sperm motility below 60% , can be density will be significantly higher in the first portion caused by a number of factors including sperm im­ of the ejaculate. The more favorable first portion may mobilizing antibodies, infection, endocrinopathy, be delivered to the cervical os by a withdrawal coital varicocele, and epididymal dysfunction. technique (penis withdrawn from the vagina after the It is now widely appreciated that testicular first spurt of ejaculate) or by insemination. In prop­ spermatozoa acquire their fertilizing capacity and erly selected cases, pregnancy results are about 60%. motility as they pass through the . Impor­ tant for these considerations is the fact that testoste­ Diffuse Abnormality of All Seminal Parameters rone is transported, bound to androgen-binding-pro­ The most common (60%) abnormal presentation tein, from the seminiferous tubular fluid to the of the semen analysis is a diffuse abnormality of all epididymis in concentrations about 20 times that of seminal parameters, that is, low sperm density, poor serum. In the epididymis, the antigen-binding-protein sperm viability, and more than 40% abnormal sperm disappears and the free testosterone diffuses into the forms. While nonspecific stress, subclinical endo­ epididymal cell. Therefore, the functional integrity of crinopathy, and epididymal dysfunction or block are the epididymis may be compromised either by failure rare causes of diffuse seminal abnormality, they must of the Leydig cells to produce high enough local nevertheless be considered and treated. concentrations of testosterone, by failure of the Ser­ However, the most common cause of diffuse toli cells to produce adequate amounts of androgen­ seminal abnormality is a varicocele which accounts binding-protein, or by failure of the epididymal epi­ for one third of all cases of male infertility. The thelium to utilize effectively the free testosterone. In varicose enlargement of the veins of the spermatic any event, the end result is a local epididymal envi­ cord (pampiniform plexus) is caused by valvular in­ ronment not optimal for the normal development of competence of the internal spermatic vein with sec­ sperm motility. Therapy is directed at improving the ondary retrograde flow of venous blood from the left local epididymal environment by the administration renal vein into the internal spermatic vein. Because of of gonadotropins which stimulate Leydig cell produc­ the characteristic anatomy of the internal spermatic tion of testosterone and androgen-binding-protein by vein on the left side, varicoceles clinically occur more the Sertoli cells. Therapy has been effective in some­ commonly on that side, that is, 80% left, 19% bilat­ what less than half the patients so treated. Low-dose eral, and 1% right. Even if a varicocele is clinically androgen therapy in the form of fluoxymesterone limited to one side, venous dilatation occurs bilater­ (Halotestin) 2-5 mg, b.i.d., has not been effective. ally due to the liberal cross-venous circulation of Additionally, epididymal dysfunction may be the pampiniform plexus, and the germinal epi­ secondary to complete or partial obstruction, or to thelium of both testes is pathologically affected. changes in the functional integrity of the epididymis Varicoceles are best diagnosed with the patient itself due to such conditions as epididymitis. Treat­ standing erect as recumbency will decompress the ment is directed at the specific disorder and involves varices. Small varicoceles can be more readily appre­ short-circuiting the obstruction by microsurgical ciated by having the patient perform a Valsalva ma­ techniques and by appropriate antibiotic treatment of neuver. The diagnosis of small, subtle, and even sub­ the epididymitis. clinical varicoceles can be facilitated by use of the The most profound manifestation of a viability­ Doppler stethoscope8 ; their diagnosis is equally im­ motility / disorder is which fortunately portant as there is no correlation between the size of is rare as there is no successful treatment. the varicocele and the reduction in spermatogenesis In patients with high ejaculate volumes (>3.5 based on testicular biopsies and semen analyses.9 ml) and a secondary decrease in sperm count ( oli- The mechanism whereby the varicocele causes 100 MCROBERTS: EVALUATION AND MANAGEMENT OF MALE INFERTILITY

the deleterious effect on the germinal epithelium re­ REFERENCES mains unresolved. But of the two principal postulated causes (venous reflux of adrenal "toxins" vs increased I. DERRI CK FC JR , JOHN SON J: Re-examination of " normal" sperm count. Urology 3:99-100, 1974. intrascrotal temperatures secondary to venous stasis), the weight of recent.evidence favors elevated 2. MACLEOD J: Semen quality in one thousand men of known iritrascrotal temperatures as the probable cause of fertility and eight hundred cases of infertile marriage. Fertil depressed spermatogenesis. Steril 2: 115-139, 1951. The treatment of varicoceles is surgical and is directed at preventing retrograde venous flow by in­ 3. AMELAR RD, DUBIN L, SCHO ENFELD C: Semen analysis. terrupting the course of the internal spermatic vein at Urology 2:605-611 , 1973. the level of the inguinal canal (I vanissevich method )10 4. REHA N NE, SOBRERO AJ, FERTIG JW: The semen of fertile 11 or the retroperitoneum (Palomo procedure ). At­ men, statistical analysis of 1,300 men. Fertil Steril 26:492-502, tempts to directly remove the dilated scrotal veins 1975. through a transscrotal incision are to be avoided as they are not effective. 5. AM ELAR RD, DUB IN L, WALSH PC: Male Infertility. Phila­ The overall results of surgery are excellent with delphia, WB Saunders Company, 1977. an improvement in semen quality of 70% and a preg­ nancy rate of 45%. 6. LIPSHULTZ LI , GREE NBERG SH, MALLOY TR: Male infertility, in Garcia CR (ed): The Management of the Infertile Couple. Philadelphia, FA Davis Company, 1978 . Conclusion The prognosis for a previously infertile couple of 7. KJESSLER B, LUN DBERG PO: Dysfunction of the neuro-endo­ achieving a pregnancy has improved substantially crine system in nine males with aspermia. Fertil Steril 25: 1007- over the past 5-8 years. This has been made possible 101 7, 1974. by a variety of diagnostic and therapeutic advances based on a greater understanding of t~sticular and 8. GR EENBERG SH, LIPSH ULTZ LI, MORGA NROTH J, ET AL: The use of the doppler stethoscope in the evaluation of varicoceles. epididymal function and disorder, hypothalamic-pi­ J Ural 117:296-298 , 1977. tuitary-gonadal interrelationships, and reproductive immunological and physiological factors. This 9. AGGER P, JOH NSON SG: Quantitative evaluation of testicular knowledge, combined with a more comprehensive biopsies in varicocele. Fertil Steril 29:52-57, 1978. and systematic approach to the evaluation and man­ agement of the infertile male patient, has made pos­ 10. IVANISS EVI CH 0: Left va ricocele due to reflux, experience with sible the identification of the cause in 80% of patients 4470 operative cases in 42 years. J Int Coll Surg 34:742-757, 1960. as well as effective therapy in approximately 50% of coupfes under the age of 30 and approximately one 11. PALOMO A: Radicai cure of varicocele by a new technique. J third of those who are older. Urol 61:604-607, 1949.