the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle. Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin release. (More rapid, lower amplitude pulses of GnRH lead to increased LH and FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH to FSH.) Increased FSH levels cause the growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6 to 7 days after a course of clomifene. In normal men, 50 mg/day clomifene for 8 months has been found to increase testosterone levels by around 870 ng/dL in younger men and by around 490 ng/dL in elderly men. Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men. These findings suggest that the progonadotropic effects of clomifene are stronger in younger men than in older men. In men with hypogonadism, clomifene has been found to increase testosterone levels by 293 to 362 ng/dL and estradiol levels by 5.5 to 13 pg/mL. In a large clinical study of men with low testosterone levels (<400 ng/dL), 25 mg/day clomifene increased testosterone levels from 309 ng/dL to 642 ng/dL after 3 months of therapy. No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly. Other activities Clomifene is an inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase. Concerns about possible induction of desmosterolosis and associated symptoms such as cataracts and ichthyosis with extended exposure precluded the use of clomifene in the treatment of breast cancer. Continuous use of clomifene has been found to increase desmosterol levels by 10% and continuous high doses of clomifene (200 mg/day) have been reported to produce visual disturbances. Pharmacokinetics Clomifene produces N-desmethylclomifene, clomifenoxide (clomifene N-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desmethylclomifene as metabolites. Clomifene is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene, which are the most active of its metabolites. In one study, the peak levels after a single 50 mg dose of clomifene were 20.37 nmol/L for clomifene, 0.95 nmol/L for 4-hydroxyclomifene, and 1.15 nmol/L for 4-hydroxy-N-desmethylclomifene. Clomifene has an onset of action of 5 to 10 days following course of treatment and an elimination half-life