Clomiphene citrate, 50–400 rag/day for 2–12 months (median 7 months), stimulated the pituitary-gonadal axis in 13 normal men as evidenced by increased urinary excretion of hormones. Urinary total gonadotropins were increased by 80–400%, urinary ICSH 160–1200%, urinary estrogens by 150–680%, and urinary testosterone by 140–250%. In each individual the increase in ICSH was greater than the increase in total gonadotropins. No dose relationship was observed in any of these hormonal parameters. Sperm concentration was dosage related: low dosages of clomiphene (50 mg/day) caused an increase; intermediate dosages (100 and 200 mg/day) caused an increase, decrease, or no change; and high doses caused precipitous decreases. One subject given 3 doses showed 3 responses in sperm counts from an increase with a low dosage to azoospermia with a high dosage. It is inferred that the effect of the increase in gonadotropins and testosterone stimulates spermatogenesis at the spermatogonial level, causing an increase in sperm count; and that the stimulatory effect is obliterated at higher clomiphene dose levels by the direct damaging action of clomiphene upon spermatids, thus causing oligospermia or azoospermia.
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Heller et al. (1969) studied this question.