In women, progesterone suppresses luteinizing hormone (LH) (gonadotropin‐releasing hormone) pulse frequency, but how rapidly this occurs is unknown. In estradiol‐pretreated women in the late follicular phase, progesterone administration at 1800 did not slow sleep‐associated LH pulse frequency. However, mechanisms controlling LH pulse frequency may differ according to sleep status; and we thus hypothesized that progesterone acutely suppresses waking LH pulse frequency. This was a randomized, double‐blind, crossover study of LH secretory responses to progesterone versus placebo administered at 0600. We studied 12 normal women in the late follicular phase (cycle days 7–11), pretreated with 3 days of transdermal estradiol (0.2 mg/day). Subjects underwent a 24‐h blood sampling protocol (starting at 2000) and received either 100 mg oral micronized progesterone or placebo at 0600. In a subsequent menstrual cycle, subjects underwent an identical protocol except that oral progesterone was exchanged for placebo or vice versa. Changes in 10‐h LH pulse frequency were similar between progesterone and placebo. However, mean LH, LH pulse amplitude, and mean follicle‐stimulating hormone exhibited significantly greater increases with progesterone. Compared to our previous study (progesterone administered at 1800), progesterone administration at 0600 was associated with a similar increase in mean LH, but a less pronounced increase in LH pulse amplitude. We conclude that, in estradiol‐pretreated women in the late follicular phase, a single dose of progesterone does not suppress waking LH pulse frequency within 12 h, but it acutely amplifies mean LH and LH pulse amplitude – an effect that may be influenced by sleep status and/or time of day.

In insulin-resistant obese girls with hyperinsulinemia, free testosterone levels correlated positively with insulin sensitivity and, likely, circulating LH concentrations but not with circulating insulin levels. In the setting of relatively uniform hyperinsulinemia, variable steroidogenic-cell insulin sensitivity may correlate with metabolic insulin sensitivity and contribute to variable free testosterone concentrations.

Objective: During the early follicular phase, sleep-related luteinizing hormone (LH) pulse initiation is positively associated with brief awakenings but negatively associated with rapid eye movement (REM) sleep. The relationship between sleep architecture and LH pulse initiation has not been assessed in other cycle stages or in women with polycystic ovary syndrome (PCOS). Design and Methods: We performed concomitant frequent blood sampling (LH pulse analysis) and polysomnography on 8 normal women (cycle day 7–11) and 7 women with PCOS (at least cycle day 7). Results: In the normal women, the 5 min preceding LH pulses contained more wake epochs and fewer REM epochs than the 5 min preceding randomly determined time points (wake: 22.3 vs. 9.1%, p = 0.0111; REM: 4.4 vs. 18.8%, p = 0.0162). However, LH pulse initiation was not related to wake or REM epochs in PCOS; instead, the 5 min preceding LH pulses contained more slow-wave sleep (SWS) than the 5 min before random time points (20.9 vs. 6.7%, p = 0.0089). Compared to the normal subjects, the women with PCOS exhibited a higher REM-associated LH pulse frequency (p = 0.0443) and a lower proportion of wake epochs 0–5 min before LH pulses (p = 0.0205). Conclusions: Sleep-related inhibition of LH pulse generation during the later follicular phase is normally weakened by brief awakenings and strengthened by REM sleep. In women with PCOS, LH pulse initiation is not appropriately discouraged by REM sleep and may be encouraged by SWS; these abnormalities may contribute to a high sleep-related LH pulse frequency in PCOS.

Polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance. Adolescent hyperandrogenemia (HA) may precede adult PCOS. Androgen production in females occurs in both the adrenals and the ovaries, but the relative contribution of each to adolescent HA is unknown. Both luteinizing hormone (LH) and insulin contribute to HA in adult PCOS, and both correlate with HA in obese girls, but detailed assessments of LH and insulin in combination with ovarian and adrenal androgen responses to stimulation (in the same individual) have not been described. To assess the relative roles of stimulatory factors (LH and insulin) and end organ (adrenal, ovarian) responsiveness to stimulation, we have studied 16 girls with obesity: age 13.4 (10.5–15.9) y (median [range]); Tanner 5 (2 girls 2-3; 14 girls 4-5); BMI Z 2.2 (1.7–2.7); free testosterone (T) 17.7 (6.6–88.3) pmol/L. Subjects underwent a detailed study including (a) frequent blood sampling for LH (6p–9a), to estimate mean 24-h LH; (b) sampling for insulin from 1 h before to 2 h after a standardized mixed meal (7p) and while fasting (7a–9a), to estimate mean 24-h insulin; (c) an adrenal stimulation protocol (dexamethasone [DEX] given at 10p, with 17-OHProgesterone [17OHP], T, and androstenedione (∆4A) drawn before plus 30 and 60 min after synthetic ACTH [250 mcg iv] given at 7a); and (d) an ovarian stimulation protocol (after the 8a sample above, recombinant hCG [r-hCG, 25 mcg iv] given, DEX given at 10p, with 17OHP, T, and ∆4A drawn the next morning at 8a). Responses to ACTH and r-hCG stimulation were defined as the mean value 30 and 60 min post-ACTH and the value 24 h post-hCG, respectively, minus the post-DEX morning value. Relationships between such responses and estimated mean 24-h LH and 24-h insulin were assessed using Spearman partial correlation (correcting for differences in 24-h insulin and 24-h LH, respectively). Estimated 24-h LH was 3.7 (1.8–21.5) mIU/mL in the group, while estimated 24-h insulin was 61.4 (23.2–175) uIU/mL. After correcting for differences in 24-h insulin, estimated 24-h LH predicted hCG-stimulated changes in T (r = 0.61, p = 0.02), but did not predict ACTH-stimulated changes in T. When corrected for 24-h LH, there were no significant relationships between estimated 24-h insulin and T responses to either r-hCG or ACTH. Estimated 24-h LH and 24-h insulin were not correlated with ACTH- or hCG-stimulated changes in either 17OHP or ∆4A. These data suggest that, in pubertal girls with obesity, either that ovarian T responses to stimulation are influenced by ambient LH concentrations, but not by insulin, or that ovarian hyperresponsiveness leads to increased LH. Similar relationships with 17OHP or ∆4A were not evident, for either ambient LH or insulin. Simultaneous detailed assessments of LH, insulin, and end organ (adrenal, ovarian) responsiveness to stimulation may help discriminate the determinants of HA in girls with obesity.