There is a great deal of pessimism concerning the potential for significant therapy in the male. The reason, I believe, is that therapy in the past has often been limited to the male with marked oligospermia (i.e., sperm count less than 20 million/ml). At these low levels the condition is usually irreversible. Influenced by MacLeod and Gold’s report, therapists considered the subfertile male, with 20 to 40 million/ml, as “normal” or “fertile,” and treatment was often withheld from this group. If, however, one accepts the concept of the couple as a unit, and that a sperm count of 20 to 40 million/ml cc represents subfertility, treatment of this subfertile male could be meaningful as far as the couple is concerned. Ironically, this is the group of males for whom the most can be done, and yet who often go without treatment.

The salutary effect of various regimens and medications on spermatogenesis can be overemphasized and undoubtedly have been in many reports published over the past 35 years. Even after a careful reading of a report, one is usually uncertain as to the efficacy of the recommended medication or program. This is often due to the failure to use controls, although this may be difficult when it comes to therapy. Other pitfalls are present; first, the natural variation in sperm count that may vary spontaneously by 20 to 30 million. When reporting results in terms of improved semen quality, most authors do not take this variation into sufficient consideration. Another factor is the spontaneous pregnancy rate, even with sperm counts of less than 20 million/ml. Table “Frequency Distributions of Sperm Counts Found in 2000 Allegedly Fertile Men Requesting Vasectomy Compared with Previous Reports” is a composite of three studies of fertile populations of men. Within these fertile populations, 5% to 21% had sperm counts of less than 20 million/ml, and between 12% and 31% had counts ranging between 20 and 40 million/ml. Too often the issue is clouded when therapists include males in both groups of sperm counts and do not statistically compare the results with the known fertility rates in these groups. This does not mean that the regimens proposed are not without merit, but the therapist should use them in the light of the present state of infertility knowledge and its limitations.

Table Frequency Distributions of Sperm Counts Found in 2000 Allegedly Fertile Men Requesting Vasectomy Compared with Previous Reports

Sperm count (millions/ml) MacLeod and Gold (%) Nelson and Bunge (%) Rehan et al. (%)
<10.1 2 4.7 2
10.1-20.0 3 15.5 5
20.1-40.0 12 30.8 16
40.1-60.0 12 21.0 18
60.1-80.0 14 14.3 21
80.1-100.0 13 6.7 13
>100.0 44 7.0 24
Number of subjects 1000 386 1300
Source of patients Prenatal clinic Vasectomy clinic Vasectomy clinic

Hormone Therapy

In the past, approaches to hormone therapy have mainly been attempts to administer exogenous hormones to stimulate spermatogenesis. Since, in the majority of cases, subfertility and oligospermia are not associated with any hormonal deficiency, or at least a demonstrable one, it is not surprising that the results have not been too promising. However, there are times when hormone therapy is indicated, or can at least be utilized as a last resort.

Androgens

In 1950, studies by Heller and co-workers showed that, if spermatogenesis was depressed by testosterone administration, there was a rebound of spermatogenesis to levels “significantly” higher than those before treatment. When high doses of testosterone propionate or long-acting testosterone are administered over a 10-week period, if a rebound occurs it will usually appear within 3 to 6 months.

In Rowley and Heller’s follow-up report, 110 of 163 courses of therapy resulted in a rise in sperm concentration. In 41% of the couples, conception followed therapy. These are promising figures, but the expected variation in sperm count, the natural fertility in oligospermic males, and the failure to break down the results by various levels of count make the work difficult to interpret. A few other investigators also cautiously reported success, but the fact that this treatment has failed to become firmly established after 35 years speaks for its questionable nature. One drawback is that in a small number of individuals — 2% in one series —there is a permanent decrease in spermatogenesis. One should therefore be cautious about utilizing this therapy in men with subfertile specimens (20 to 40 million) where there is a significant spontaneous conception rate until all other approaches have been exhausted.

The use of low-dose androgens has also been recommended. Since exogenous testosterone will reduce the production of testosterone by the testicles through hypothalamic pituitary inhibition, this form of therapy does not appear to have any scientific rationale. Rowley and Heller pointed out that it required, on the average, 11.2 g of exogenous testosterone daily to result in direct stimulation of the testes. Nevertheless, reports on its use persist, and a recent report states that it may help sperm motility when other parameters are not effective.

Clomiphene Citrate

The reports considering the effectiveness of clomiphene citrate in improving sperm quantity and quality are also conflicting. As in most studies, the number of cases is small and the definitions of oligospermia are variable. Medical treatment in the male has the additional problem of requiring long courses of treatment to note improvement in spermatogenesis, and this is not always followed. In Mellinger and Thompson’s preliminary report, improvements in counts in 10 of 13 oligospermic males were noted, but conception did not occur. The study of Wieland and co-workers revealed variable results in 11 men who were treated with cisclomiphene. Schellen and Beck treated 101 patients with clomiphene for 40, 60, or 90 days. Ozoospermic patients gave no response, although some with oligospermia showed improvement. There were 19 pregnancies.

Paulson and Wacksman believe that the best candidates for clomiphene therapy are those men with oligospermia and normal follicle-stimulating hormone levels but who show some evidence of spermatic hypoplasia on testicular biopsy. The suggested regimen is 25 mg daily, with 5-day rest periods and with therapy maintained for up to 9 months. Heller and his co-workers have summarized their conclusions concerning clomiphene: while low doses (25 to 50 mg daily) stimulate sperm production in normal men, higher doses have a higher toxic effect on spermatogenesis. Recent studies utilizing placebos as a control failed to show any improvement with clomiphene on semen parameters, the sperm penetration test, or the occurrence of pregnancy.

Human Chorionic Gonadotropin

The ability of human chorionic gonadotropin (HCG) to bring about improved spermatogenesis in individuals with hypogonadotropic hypogonadism is well accepted. The same ability for improved spermatogenesis in relation to oligospermia in eugonadotropic males is controversial. Table “Results with Human Chorionic Gonadotropin in the Treatment of Male Infertility” summarizes some of the reports over the past 30 years. A critical evaluation of these papers reveals that some of the patients had initial sperm counts of more than 30 million, and a few of more than 40 million, making one wish that the authors had been more selective. In this group, the improvement in pregnancies that occurs in oligospermia (), make it difficult to establish the reliability of these reports.

Despite a cursory view suggesting improvement, Rowley and Heller conclude that HCG does not stimulate spermatogenesis in normal men. It should also be noted in these studies that there is often an initial depression of spermatogenesis followed in 2 to 4 months by a rebound or “overproduction.” There is general agreement that when the initial sperm count is less than 10 million, there is universal failure. It would appear that the HCG can be given as a last resort, provided that expectations for significant improvement are not high.

Human Menopausal Gonadotropin

The results of human menopausal gonadotropin (HMG), are similar to those for HCG. For those few patients in whom there is oligospermia, or azoospermia, due to pituitary failure (hypopituitary hypogonadism), HMG provides a significant replacement therapy. Even then, for good results, it is best combined with chorionic gonadotropin.

Various reports on the use of HMG in oligospermia accompanied by normal pituitary function are summarized in Table “Effect of Human Menopausal Gonadotropin in the Treatment of Male Infertility”, but the small number of cases in each report and the difficulty in differentiating between increasing sperm count due to therapy or only that seen as the normal variation makes them difficult to interpret. The report by Danezis and Batrinos was the most optimistic, with 5 of 11 cases showing improvement in sperm count, and improved motility noted in 7.

Table Effect of Human Menopausal Gonadotropin in the Treatment of Male Infertility

Study Number of cases Initial sperm count (million) Number of cases improved Pregnancies
Lytton and Mroueh 16 rare to 21 3 2
Polishuk et al. 23 0 to 21 4 1
Danezis and Batrinos 11 1 to 22 5 2
Mroueh et al. 8 rare to 33 1 Not reported
Schwartzstein 12 rare to 20 5 Not reported

In view of the expense and prolonged therapy involved, more conservative approaches should be attempted before resorting to gonadotropin therapy for oligospermia associated with normal pituitary gonadotropin levels.

Gonadotropin-Releasing Hormone

A few reports are now available concerning the clinical use of gonadotropin-releasing hormone (GnRH) in normal gonadotropin oligospermic males. Initially, injections were given two or three times daily over a lengthy period of time. In one study, three of six subjects, and in another study two of four subjects with oligospermia, showed an increase in sperm count. Despite these somewhat optimistic preliminary reports, the multiplicity of injections, as well as other pitfalls of evaluation, still make this a questionable approach; this is further complicated by a recent report of antibody formation to releasing hormones after prolonged administration required in the male. More recently, a study utilizing a pulsatile infusion pump demonstrated that this approach was more effective than multiple injections.

Other Hormones

Stewart postulated that cortisone may be of value in the treatment of selected cases of male infertility, particularly in patients with congenital or acquired adrenal-genital syndrome. It is recommended, therefore, that when there is a good sperm count with low motility, dehydroepiandrosterone-sulfate be measured. To find actual adrenal hyperplasia in the male is quite rare, so this kind of treatment is not often indicated. Indeed, there are reports of suppression of spermatogenesis by corticosteroid administration.

Therapy is effective in true hypothyroidism, but this, too, is rare. The use of triiodothyronine, 25 to 50 |xg daily, seems to be of some empirical value when there is lowered motility in association with a normal sperm count.

Treatment of Environmental Factors

The most promising approach to therapy for the male factor is to modify the male’s environmental status. In many instances the subfertile male (with a sperm count of 20 to 40 million) plays a significant etiologic role in the couple’s infertility. Treating the subfertile male helps the couple because primarily the subfertile male, and not the infertile one, will respond to modification of environmental factors.

The adverse effects of heat on spermatogenesis has been appreciated for some time. Therefore, avoidance of skin-tight underwear, prolonged sitting, hot baths, whirlpool baths, or saunas have been shown to result in improvement of seminal characteristics. Specialized cooling supports have also resulted in significant improvement.

Excellent studies have now demonstrated the harmful effects of tobacco and alcohol on spermatogenesis, and these should be avoided. The role of caffeine is being investigated. Recent in vitro studies have shown that caffeine stimulated ejaculated human spermatozoa, but this has not been carried over to in vitro studies. At present, there is no evidence to indicate that vitamins significantly enhance semen quality.

Surgical Treatment

Varicocele Llgation

The efficacy of varicocele ligation remains controversial (). Since the optimistic reports from Great Britain in the 1950s, enthusiasm over the effectiveness of this procedure has continued. In the United States, Charny initially reported a 64% improvement in semen quality; he restricted his therapy to include only men with sperm counts of less than 20 million. In 36 patients, 14 pregnancies resulted—a significant success rate. In 1970, Dubin and Amelar reported an 81% improvement in sperm quality and a 48% pregnancy rate in 111 cases. In their study, the size of the varicocele appeared to have no influence on the outcome of the therapy. Other reports have not only demonstrated that this is one of the most promising treatments for the male (with significant improvement in semen quality even in patients with counts less than 10 million/ml), but have recommended ligating the left spermatic vein when oligospermia exists even without clinical evidence of varicocele. In contrast to these optimistic reports, one more recent study failed to demonstrate a significant improvement from internal spermatic reinligation and called for a large-scale prospective study.

The technique is to ligate the internal spermatic vein just above the internal inguinal ring through an incision just above, and parallel to, Poupart’s ligament. If there are multiple branches, these are ligated as well. Care must be taken to avoid damage to the spermatic artery. Hydrocele is an occasional complication, but this should not affect fertility.

Epididymovasostomy

When there is complete azoospermia and a biopsy shows normal sper-matogenesis, obstruction is diagnosed, and an operation to reestablish continuity can be considered. The technique has been thoroughly described by Amelar. For the operation to be successful, there has to be normal sperm production, the obstruction must be in a relatively small segment of the vas distal to the epididymis, and the vas must be otherwise normal. Only problems of azoospermia fall into this category. Once these criteria have been satisfied, the operation itself is technically successful in only 20% of patients, and thus, yield in pregnancies is not great. Balanced against this is the relative innocu-ousness of the procedure. The recent introduction of microsurgery, less reactive suture material, and constant irrigation may improve results.

Vasovasostomy

Along with the increased use of vasectomy for contraception has also come an increase in the number of men requesting reanastomosis. Where in the past this was an operation of a limited success, modern techniques using microsurgery, a nylon stent, and fine sutures produce some improvement in results.

Retrograde Ejaculation

Retrograde ejaculation is associated with disruption of the physiologic closure of the proximal end of the posterior urethra concomitant with emission. By employing the sequence of emptying the bladder, ejaculation, and immediate catheterization to remove the ejaculate followed by insemination of the female partner, conception becomes a distinct possibility. Recently, the addition of specialized buffers and the use of intrauterine insemination have increased the effectiveness of treatment of this relatively rare condition.

Assisted Reproductive Technology

The techniques and medications described above are utilized, for the most part, in an attempt to improve the quantity and quality of sperm delivered by the male. Unfortunately, the results of such treatments are not always effective, and we must turn to techniques of concentration and improved delivery that will further increase the chances of conception. The new techniques of assisted reproductive technology (intrauterine insemination, gamete intrafallopian transfer, and in vitro fertilization) are now widely used and will be described in the following chapters. These approaches are more exotic. It is hoped that the young therapists of today will not foresake the less exciting therapeutic approaches as described in this chapter, and that add their small part to the improvement of sperm quality.

 

Selections from the book: “Infertility: A Clinician’s Guide to Diagnosis and Treatment”. Edited by Melvin L. Taymor, M.D., 1990.

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