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Empiric Medical Therapy of Male Subfertility

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.
A number of agents have been proposed as specific treatment for men with infertility. 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.
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. Although sperm concentration may increase on treatment, little to no effect on sperm motility or pregnancy rates occurs. 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. 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. Dubin and Amelar presented a series of men who underwent adjuvant treatment with hCG (4,000 IU, 2x/week) after varicoceletomy, where pre-varicoceletomy sperm concentration was < 10 x 101 sperm/cc. The pregnancy rate for men undergoing varicoceletomy 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-varicoceletomy 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.
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
potential beneficial effect of prostaglandin inhibition on fertility. With 75 mg/day of indomethacin, increased sperm motility and concentration. 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.
Androgens
Testosterone, many men will achieve and maintain azoospermia for prolonged periods after exogenous testosterone treatment.
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 ( In ternational 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.