Empiric Medical Therapy of Male Subfertility

Introduction

When an infertile man presents for evaluation, but no specific abnormalities are found to account for this problem, then the patient has idiopathic infertility. It is predictable that patients would expect a medical therapy to improve sperm production or quality, given the number and varieties of treatment that are now available for various medical problems. In my experience, patients frequently request, and are surprised by, the paucity of effective nonspecific medical treatments for male infertility.

A number of agents have been proposed as specific treatment for men with infertility. In each of the following sections, we will present the rationale behind treatment with these drugs, results of treatment and clinically important caveats to treatment. It is important to remember that dramatic natural variation in sperm quality can occur in men with male infertility. Therefore, infertile men empirically treated must be compared to other men treated with placebo. Otherwise, selection of men with impaired sperm quality for treatment who will have spontaneous improvement in semen parameters may artificially suggest a remarkable effect of an ineffective drug.

Anti-estrogens

Both clomiphene citrate and tamoxifen are estrogen receptor blockers that have been suggested as empiric treatments for male infertility. By preventing the important negative feedback of estrogens to the pituitary and hypothalamus, LH/FSH pulsatile release and GnRH stimuli are augmented. Since FSH is important for spermatogenesis, it is possible that increased FSH release may further enhance sperm production. Increased LH release also results in higher serum testosterone levels that are converted peripherally as well as in the liver to estrogens. Since men with idiopathic infertility have normal testosterone levels, by definition, the increased FSH, LH and testosterone that result from clomiphene or tamoxifen treatment may boost testosterone and estrogen levels above normal levels. This increased estrogen production may be detrimental to normal sperm production and should be avoided. Therefore, all patients considered for empiric therapy should be counselled to have early and frequent testosterone and estradiol levels to monitor treatment.

More importantly, the effect of anti-estrogens on fertility for men with idiopathic subfertility are unimpressive. A partial list of series of patients treated in controlled series with clomiphene citrate is presented below. Although sperm concentration may increase on treatment, little to no effect on sperm motility or pregnancy rates occurs. A significant number of patients may have a dramatic decline in sperm production on empiric therapy. Patients should be aware of these minimal benefits and possible risks prior to treatment. Common side effects of clomiphene citrate include visual disturbances, weight gain or loss, changes in libido, gastrointestinal or neurological disturbances as well as skin changes. Initial doses should probably be only 12.5-25 mg/day if this treatment is chosen, to avoid excessive serum testosterone levels.

Aromatase Inhibitors

Aromatase inhibitors block the conversion of testosterone to estrogen. Treatment with an aromatase inhibitor decreases estrogen levels, which leads to increased LH and FSH release from the pituitary, with a subsequent increase in testicular stimulation and serum testosterone levels without the usual increase in estrogen levels seen for anti-estrogens. Although one uncontrolled study suggested an increase in sperm concentration for nearly all patients treated (89%), other well-designed placebo-controlled studies have demonstrated no significant improvement in pregnancy rates for treated patients. Although many patients will have increased sperm concentration, no improvement in sperm motility was seen in these studies.

Gonadotropins

Exogenous gonadotropins (usually given as hCG or hMG, although newer recombinant human FSH is now available) have been applied for the treatment of men with idiopathic infertility. It is theoretically possible that infertile men could have defective or inefficient production of bioactive LH or FSH that could be specifically treated with exogenous hCG or hMG. However, a syndrome of defective FSH production in men has not been described, as it has been for women.

Dubin and Amelar presented a series of men who underwent adjuvant treatment with hCG (4,000 IU, 2x/week) after varicocelectomy, where pre-varicocelectomy sperm concentration was < 10 x 101 sperm/cc. The pregnancy rate for men undergoing varicocelectomy with adjuvant hCG was 44 %, compared to 23 % for men not receiving hCG. Similar results were reported by Mehan and Cheval. However, the documentation of pre- and post-varicocelectomy serum testosterone levels was not well documented; it is possible that some patients with initially low testosterone levels were also treated.

Exogenous FSH has also been administered to men whose sperm failed to achieve normal fertilization rates during IVF by Acosta et al. Despite a lack of changes in serum FSH or semen parameters, treated patients had a dramatic improvement in fertilization rates and pregnancies. Given the known high fertilization and pregnancy rates for couples with idiopathic failure to fertilize who undergo another IVF cycle without treatment, there remains little rationale to treat men with expensive exogenous FSH for idiopathic infertility until randomized studies support its use. GnRH has also been used as a treatment for idiopathic male infertility. Since GnRH is normally released in a pulsatile fashion, it is difficult to ascertain what an optimum dose should be, unless continuous pulsatile treatment was administered & LH pulses monitored. Excess exogenous GnRH can also lead to down-regulation of pituitary GNRH receptors and LH responsiveness. The one controlled study in medical literature does not demonstrate a benefit of GNRH over placebo.

Kallikrein

Kallikrein is a protein that has proteolytic activity, cleaving kininogen to produce kinins (e.g., bradykinin and kallidin) that can act locally in the inflammatory response. The kallikrein-kinin system has in vitro activity in the regulation of sperm motility. Schill has reported improved semen parameters and a 20% increase in pregnancy (18 to 38%) for men treated over 60 days with 600 kU/day of kallikrein in a double-blind cross-over study with placebo controls. However, other investigators have demonstrated a decrease in semen parameters with kallikrein treatment. In addition, pre-existing epididymal or prostatic inflammatory conditions may be exacerbated by kallikrein treatment.

Indomethacin

Prostaglandins have an inhibitory effect on testicular steroidogenesis and spermatogenesis in vivo, as well as on sperm motility in vitro. These observations suggest a negative regulatory effect of Prostaglandins on testicular and spermatozoal function. This would suggest a potential beneficial effect of prostaglandin inhibition on fertility.

One controlled study by Barkay and associates has suggested an increase in FSH, LH and testosterone levels in men treated with indomethacin or ketoprofen. With 75 mg/day of indomethacin, increased sperm motility and concentration was observed, with a pregnancy rate of 35%. Optimal treatment regimens have yet to be determined, and which patients are most suitable for this treatment has not yet been worked out. Gastritis is common in susceptible individuals and treatment should be avoided for any patient with known sensitivity to aspirin or other nonsteroidal anti-inflammatory agents.

Phosphodiesterase Inhibitors

Pentoxifylline and other methylxanthines can increase sperm motility in vitro with possible improvements in fertilization rates. However, systemic administration of these agents has not shown a reliable response in sperm production or function.

Low Dose Corticosteroids

Based on chronic inflammatory infiltrates on testis biopsy and the known action of antisperm antibodies on fertility, low dose corticosteroids have been advocated for treatment of idiopathic infertility, without demonstrable benefit. Even low doses of corticosteroids may have significant side effects, including gastritis, sleeplessness & mood changes, as well as alterations in bone vascularity, such as with aseptic necrosis of the hip.

Androgens

Testosterone rebound, a phenomenon of increased sperm concentration after suppression of testicular function by exogenous testosterone, has historically been applied to infertile men with occasional reports of success. However, many men will achieve and maintain azoospermia for prolonged periods after exogenous testosterone treatment. Therefore, this treatment is best avoided and relegated to historic importance only. Low dose oral androgens (methyltestosterone 10-50 mg/day, or fluoxymesterone 5-20 mg/day) have been used to theoretically improve epididymal function and improve sperm motility. This approach has not been shown to be efficacious.

Zinc

Prostatic secretions, and therefore semen, are normally rich in zinc. Administration of exogenous systemic zinc to malnourished men can improve sperm production. However, in the absence of zinc deficiency, exogenous zinc administration is probably of little benefit and has been shown at high doses to be detrimental to sperm function.

Vitamins C, E, A, and Other Antioxidants

Vitamins C and E, as well as other agents such as pentoxifylline and allopurinol are known to have antioxidant activity. Reactive oxygen species are found at high levels in up to 40% of infertile men, whereas they are virtually never found in the semen of fertile men. Seminal fluid is known to be very rich in antioxidants, and removal of seminal fluid has an adverse action on sperm viability. In addition, vitamin C can decrease endogenous oxidative damage to sperm DNA after systemic administration to men. This activity was optimally seen at 250 mg/day of Vitamin C (the highest dose tested) and 400 IU (International Units) of Vatamin E, and especially in men who are predisposed to having low seminal fluid ascorbic acid levels, such as smokers.

However, low levels of superoxide anion may be critically important to fertilization related events in sperm, including the acrosome reaction. The adverse activity of some antioxidants, including pentox, on egg function may further support the physiologic action of low levels of some reactive oxygen species during fertilization. In addition, no controlled studies have demonstrated a benefit of systemic administration of antioxidants on male fertility. Indeed, one antioxidant, allopurinol, has been shown to have a specific drug-related effect on sperm function in a hamster-egg penetration test.

High dose administration of antioxidants has theoretical adverse as well as potential beneficial effects on male fertility. Use of these agents at pharmacologic doses should not be advocated until data exist to support their benefits in male infertility, although low or moderate doses of vitamins C or E could have some benefit.

No individual agent or agents can predictably improve sperm function or fertility for men with idiopathic subfertility. Prior to considering such non-specific treatment, side effects, potential detrimental effects, and the paucity of documented benefit should be carefully presented to patients. Based on these data, I generally recommend against empiric therapy to the infertility patients that I see, except for low dose vitamin supplementation. Instead, specific interventions such as assisted reproduction that have a quantifiable benefit are suggested to the couple with idiopathic male infertility.