Evidence for a Hypothalamic Site of Action of Clomiphene Citrate in Women*

Abstract

To examine the site of action of clomiphene citrate (CC), LH and FSH pulsatile amplitude, frequency, and responsiveness to GnRH (10 micrograms, iv) were studied in 11 women during the early follicular phase of the menstrual cycle. Six women received CC (150 mg/day) on cycle days 2, 3, and 4, while 5 women received placebo tablets. Blood samples were drawn at 10-min intervals for 8 h before and after the treatment regimen on cycle days 2 and 5, respectively. All women treated with CC had multiple follicular development, as determined by ultrasound. Peripheral levels of estradiol did not change after CC treatment, while progesterone levels decreased slightly. Mean levels of LH increased from 7.5 +/- 0.9 (+/- SEM) to 10.7 +/- 1.4 mIU/ml (P less than 0.05), and FSH increased from 6.7 +/- 0.9 to 10.1 +/- 0.9 mIU/ml (P less than 0.01). After exposure to CC, the pulse frequency of LH during an 8-h period increased significantly (3.3 +/- 0.7 on day 2 vs. 6.8 +/- 0.8 on day 5; P less than 0.01), while the pulse frequency of FSH increased from 3.8 +/- 0.6 to 5 +/- 1.4, as determined by computer pulse analyses. The pulse amplitude of LH and FSH was not significantly altered. In the placebo-treated group, neither pulse amplitude nor pulse frequency changed significantly between cycle days 2 and 5. Pituitary sensitivity to exogenous GnRH did not change after CC treatment. Since the pulsatile frequency of LH is governed by hypothalamic influences, these findings provide compelling evidence for a hypothalamic site of action for CC, probably by inducing an increase in the frequency of GnRH secretion.

Actions of estradiol on discrete attributes of the luteinizing hormone pulse signal in man. Studies in postmenopausal women treated with pure estradiol.

“…Subsequent efforts in the rodent to localize the anatomic sites of exogenous estra, diol's suppressive effects on LH pulse frequency have indicated that only restricted forebrain regions, e.g., the preoptic suprachiasmatic area, are involved (28). Conversely, the use of antiestrogens has provided indirect evidence that endogenous estrogen can tonically suppress LH pulse frequency in man (29)(30)(31).…”

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“…It acts through binding to hypothalamic estrogen receptors, thereby blocking the negative feedback effect of circulating endogenous estrogen. 15 The use of clomiphene is found to be associated with increased incidence of multiple pregnancy. 1 Our patient had spontaneous pregnancy twice after kidney transplant.…”

Efficacy of extended clomifene citrate regimen in comparison with gonadotropins in clomifene citrate-resistant women with polycystic ovary syndrome

“…6 In ovulatory women, CC treatment elevates GnRH pulse frequency. 19 Women with PCOS have an anovulation with abnormally high GnRH pulse frequency. CC treatment, in anovulatory women with PCOS, increases pulse amplitude but not frequency.…”