In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.

AE clinical failure portends poor prognosis. Caution should be exercised when considering AE, particularly AE using coils, in patients with a history of anticoagulant, corticosteroid, or vasopressor use.

Short-term metformin use improved biochemical hyperandrogenemia, but did not improve hypothalamic sensitivity to P4 suppression, in adolescent girls.

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.

In women pretreated with estradiol (E2), exogenous progesterone (P4) acutely augments LH and FSH release (P4 positive feedback). Women with PCOS exhibit impaired P4 negative feedback on LH pulse frequency, but it remains unclear whether such women exhibit impaired P4 positive feedback on LH/FSH release. We sought to explore the latter notion as an a priori secondary hypothesis in a study primarily designed to assess whether P4 acutely suppresses LH pulse frequency. We studied 12 women with PCOS and 12 normally-cycling, non-hyperandrogenic controls. After 3 days of transdermal E2 pretreatment (0.2 mg/day), subjects were admitted to the Clinical Research Unit (CRU) for a 24-hour frequent blood sampling protocol starting at 2000 h. (CRU admissions occurred no earlier than cycle day 7 in PCOS and between days 7 and 11 inclusive in controls.) At 0600 h, subjects received either 100 mg oral micronized P4 or placebo (PBO). In a subsequent menstrual cycle, subjects underwent an identical CRU protocol except that P4 was exchanged for PBO or vice versa. LH secretion was analyzed using Autodecon, a deconvolution program that provides estimates of LH pulse frequency, pulsatile LH secretion (amount of LH secreted as pulses), and basal (non-pulsatile) LH secretion. Results were analyzed using 2-period crossover design analysis of covariance. In both groups, neither LH pulse frequency nor basal LH secretion changed significantly with P4 (compared to changes with PBO). Mean LH increased with P4 in both groups—3.1-fold (95% CI, 2.4–4.0) in controls and 2.7-fold (95% CI, 2.1–3.5) in PCOS; in both groups, P4-related changes were significantly greater than PBO-related changes (Bonferroni-corrected p=0.012 and 0.010, respectively). In controls, pulsatile LH secretion increased 3.5-fold (95% CI, 2.3–5.2) with P4—significantly more than with PBO (p=0.029); while in PCOS, a 2.6-fold (95% CI, 1.8–3.9) increase with P4 was not significantly different from changes with PBO (p=0.911). In controls, mean FSH increased 2.0-fold (95% CI, 1.7–2.3) with P4—significantly more than with PBO (p=0.004); but in PCOS, a 1.5-fold (95% CI, 1.3–1.8) increase was not significantly different from changes with PBO (p=0.072). Despite the above, between-group (PCOS vs. controls) differences in P4-induced changes in pulsatile LH secretion and mean FSH were not formally (statistically) demonstrable. Between-group differences representing potential confounders included age (median 25.5 vs. 19.0 y; p=0.029), body mass index (29.9 vs. 21.8 kg/m2; p=0.006), and cycle day of CRU admissions (day 45.0 vs. 10.4 for P4 admissions; 30.0 vs. 10.0 for PBO admissions). In summary, these data suggest that P4-induced increases in pulsatile LH secretion and mean FSH may be blunted in PCOS compared to controls, which could contribute to ovulatory dysfunction in PCOS. However, our results do not confirm this possibility, and further study is needed.