Stimulatory effects of stress on gonadotropin secretion in estrogen-treated women

Although stress is known to inhibit the hypothalamic-pituitary-gonadal axis, recent studies in the monkey show that, under certain conditions, in the presence of estrogen, stress may actually stimulate LH release. We investigated the effects of a mild inflammatory stress (2.0-3.0 ng/kg endotoxin) on LH release in five postmenopausal women with and without transdermal estradiol (E2, 0.1 mg) replacement. In another five E2-treated women, LH release was studied when the adrenal was stimulated directly by a 3-h ACTH infusion (Cortrosyn, 50 microg/h). Mean E2 levels were less than 12 pg/mL in the unreplaced subjects and were 86 +/- 10 pg/mL and 102 +/- 18 pg/mL in the two groups of E2-replaced subjects. Blood was sampled every 15-20 min for 2 h before and for 7 h after endotoxin or ACTH injection. Mean cortisol and progesterone levels increased in all three groups over time (P < 0.001). In the women without E2 replacement, basal LH was 26.8 +/- 5.3 mIU/mL and did not change significantly, over time, after endotoxin (P = 0.58). In the same women on E2, however, a significant increase in LH occurred after endotoxin (P = 0.02), from a mean hourly baseline of 15.3 +/- 5.4 mIU/mL to a peak of 50.0 +/- 25.2 mIU/mL. During the ACTH infusion, there was a significant stimulation of LH release in the E2-replaced subjects (P < 0.001), from a mean hourly baseline of 13.3 +/- 3.0 mIU/mL to a peak of 44.1 +/- 11.7 mIU/mL. In both groups, this increase occurred 2-4 h after the initial rise in progesterone and persisted to the end. We conclude that, in the presence of sufficient estrogen, activation of the hypothalamic-pituitary-adrenal axis leads to a stimulation of LH release. This is likely related to a rise in adrenal progesterone and its known stimulatory effect on LH release in the presence of E2. These studies provide a potential mechanism in the human by which an acute stress during the follicular phase of the menstrual cycle might lead to a premature LH surge and thereby interfere with follicular maturation and ovulation.