Influence of Sleep Stage on LH Pulse Initiation in the Normal Late Follicular Phase and in Polycystic Ovary Syndrome.

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.

Insulin Resistance, Hyperinsulinemia, and LH: Relative Roles in Peripubertal Obesity-Associated Hyperandrogenemia.

Context: Peripubertal obesity is associated with variable hyperandrogenemia, but precise mechanisms remain unclear. Objective: To assess insulin resistance, hyperinsulinemia, and LH roles in peripubertal obesity-associated hyperandrogenemia. Design: Cross-sectional analysis. Setting: Academic clinical research unit. Participants: Eleven obese (body mass index for age ≥95%) peripubertal girls. Intervention: Blood samples were taken during a mixed-meal tolerance test (1900 to 2100), overnight (2100 to 0700), while fasting (0700 to 0900), and during an 80 mU/m2/min hyperinsulinemic-euglycemic clamp (0900 to 1100). Main Outcome Measures: The dependent variable was morning free testosterone level; independent variables were insulin sensitivity index (ISI), estimated 24-hour insulin, and estimated 24-hour LH levels. Results: All participants demonstrated insulin resistance and hyperinsulinemia. ISI, but not estimated 24-hour insulin level, correlated positively with morning free testosterone level when correcting for estimated 24-hour LH level and Tanner stage (rs = 0.68, P = 0.046). The correlation between estimated 24-hour LH and free testosterone levels approached significance after adjusting for estimated 24-hour insulin level and Tanner stage (rs = 0.63, P = 0.067). Estimated 24-hour insulin level did not correlate with free testosterone level after adjusting for estimated 24-hour LH level and Tanner stage (rs = 0.47, P = 0.20). Conclusion: 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.

Progesterone has rapid positive feedback actions on LH release but fails to reduce LH pulse frequency within 12 h in estradiol-pretreated women.

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.