In at least 25% of infertile men, no identifiable cause can be attributed to the problem. Because the pathophysiology is ill-defined, this is termed idiopathic infertility. There is a second group of men in whom a cause of infertility may be identified but no specific therapy is available. Both groups of men are candidates for empiric medical therapy. This form of therapy seeks to overcome pathologic conditions that are ill-defined or have no proven treatment. As a rule, it is important to establish a timeline of therapy and decide with the patient when empiric treatment is to be discontinued and other avenues pursued.

A. Clomiphene Citrate
Clomiphene citrate is a synthetic nonsteroidal drug that acts as an antiestrogen and competitively binds to estrogen receptors in the hypothalamus and pituitary. This blocks the action of the normally low levels of estrogen on the male hormone axis and results in increased secretion of GnRH, FSH, and LH. The enhanced output of these hormones increases testosterone production and sperm production. Clomiphene therapy is given for idiopathic low sperm count. It is less effective as a treatment for low motility. The dose is 12.5-50 mg/d either continuously or with a 5-day rest period each month. Serum gonadotropins and testosterone should be monitored at 2-4 weeks and the dose adjusted to keep the testosterone level within the normal range. Higher than normal testosterone levels may result in a decrease in semen quality. Therapy should be discontinued if no semen quality response is observed in 6 months. Although there have been over 30 published trials on clomiphene since 1964, only a few include control arms. In general, there are as many trials showing that clomiphene is equivalent to placebo as there are showing that it improves sperm density and pregnancy rates. Decreased sperm densities have also been observed on this therapy.

B. Tamoxifen
Tamoxifen is commonly used for the treatment of metastatic breast cancer in women. It is also an antiestrogen that works in a manner similar to clomiphene citrate. It may have less estrogenic activity than clomiphene, however. Also indicated for idiopathic oligospermia, the dose of tamoxifen is 10-15 mg twice daily for 3-6 months. Serum testosterone, LH, and FSH should be measured 2-4 weeks after initiating therapy. Semen analyses are taken at 3 months and regularly thereafter.

C. Kallikreins
The kallikrein-kinin system is involved with tissue proliferation, the coagulation cascade, and the complement system. Components of this system are also present in male reproductive tract secretions. They may be involved in induction of sperm motility and stimulation of spermatogenesis. Kallikrein is a pancreatic enzyme that acts on kininogens to release kinins. It has been used for idiopathic oligospermia with the idea that it may enhance sperm metabolism, increase testis blood flow, and stimulate accessory sex gland secretions. For the treatment of low sperm motility, oral porcine pancreatic kallikrein is used in Europe at a dose of 600 IU/d. A recent placebo-controlled clinical trial with 90 subjects showed significant improvements in sperm density, motility, and forward progression in treated men. Pregnancy rates were 38% in the treatment arm and 16% in the placebo arm.

D. Antioxidant Therapy
There is evidence that up to 40% of infertile men have increased levels of reactive oxygen species in the reproductive tract. These species (OH, O2 radicals, and hydrogen peroxide) can cause lipid peroxidation damage to sperm membranes. Treatment with scavengers of these radicals may protect sperm from oxidative damage: glutathione, 600 mg daily for 3-6 months, or vitamin E, 400-1200 U/d. These agents may be useful in a subgroup of infertile men with elevated levels of seminal reactive oxygen species.

E. Growth Hormone
There is emerging evidence that growth hormone- induced insulin-like growth factor-1 may be important for spermatogenesis. In recent European trials of growth hormone in infertile men, individuals with maturation arrest and azoospermia developed sperm counts. The use of growth hormone or its releasing factor may become a new and effective treatment for oligospermia.