Luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight women.

OBJECTIVES: Female obesity is a state of relative hypogonadotrophic hypogonadism. The aim of this study is to examine gonadotrophin secretion and response to gonadotrophin-releasing hormone (GnRH) in the luteal phase of the menstrual cycle and to investigate the pharmacodynamics and pharmacokinetics of endogenous and exogenous luteinizing hormone (LH) in obese women. DESIGN: Participants underwent a luteal phase frequent blood sampling study. Endogenous LH pulsatility was observed, gonadotrophin-releasing hormone (GnRH) was given in two weight-based doses, and GnRH antagonist was administered followed by recombinant LH. PATIENTS: Regularly menstruating obese (n = 10) and normal weight (n = 10) women. MEASUREMENTS: Endogenous hypothalamic-pituitary function (as measured by LH pulsatility), pituitary sensitivity (GnRH-induced LH secretion), pharmacodynamics of endogenous LH and pharmacokinetics of exogenous LH were compared between the obese and normal weight groups. RESULTS: There were no statistically significant differences in endogenous LH pulsatility or pituitary responses to two weight-based doses of GnRH between the obese and normal weight women. There were no differences in the pharmacodynamics of endogenous LH or the pharmacokinetics of exogenous LH between the groups. FSH dynamics did not differ between the groups throughout the study. CONCLUSIONS: The relative hypogonadotrophic hypogonadism of obesity cannot be explained by differences in LH and FSH luteal phase dynamics or differences in endogenous LH pharmacodynamics or exogenous LH pharmacokinetics.

Induction of the LH Surge in Premenarchal Girls Confirms Early Maturation of the Hypothalamic-Pituitary-Ovarian Axis.

PURPOSE: To determine whether premenarchal girls exhibit positive estradiol feedback similar to regularly cycling adult women when given exogenous estradiol. METHODS: This was a prospective clinical cohort study at 2 institutions. Nine girls and 6 women received a 7-day course of transdermal estradiol designed to produce physiologic, mid-cycle circulating estradiol levels. Participants collected daily morning urine for luteinizing hormone (LH), estradiol metabolites (E1c), and progesterone metabolites (Pdg), corrected for creatinine. Main outcomes were percentage increase in LH from nadir to peak and the absolute value of peak LH between the 2 groups, using t testing and linear mixed-effects modeling. RESULTS: All participants exhibited a positive feedback response to estradiol. Adult women had a 532.8% (95% confidence interval [CI]: 253.7-1119) increase in LH after estradiol exposure; premenarchal girls had a 497.9% increase (95% CI: 274.5-903.2; P = .86). The absolute value of the LH surge in women was 9.50 mLU/mgCr (95% CI: 2.59- 43 34.90) and in premenarchal girls was 2.57 mLU/mgCr (95% CI: 0.53-12.49; P = .15). CONCLUSIONS: Premenarchal girls can mount an LH surge proportionally similar to regularly cycling adults. This occurs earlier in puberty than previously believed, in contrast to current dogma that maturation of the hypothalamic-pituitary-ovarian axis occurs after menarche and is the rate-limiting step for the establishment of regular, ovulatory cycles. Failure to achieve regular cycles may instead be due to nutritional or ovarian factors. Young girls who fail to ovulate shortly after menarche may warrant further evaluation for endocrinopathies.

Estradiol Priming Improves Gonadotrope Sensitivity and Pro-Inflammatory Cytokines in Obese Women.

CONTEXT: Obesity is associated with a pro-inflammatory state and relative hypogonadotropic hypogonadism. Estrogen (E2) is a potential link between these phenomena because it exhibits negative feedback on gonadotropin secretion and also inhibits production of pro-inflammatory cytokines. OBJECTIVE: We sought to examine the effect of estrogen priming on the hypothalamic-pituitary-ovarian axis in obesity. DESIGN, SETTING, AND PARTICIPANTS: This was an interventional study at an academic center of 11 obese and 10 normal-weight (NW) women. INTERVENTION: A frequent blood-sampling study and one month of daily urinary collection were performed before and after administration of transdermal estradiol 0.1 mg/d for one entire menstrual cycle. MAIN OUTCOME MEASURES: Serum LH and FSH before and after GnRH stimulation, and urinary estrogen and progesterone metabolites were measured. RESULTS: E2 increased LH pulse amplitude and FSH response to GnRH (P = .048, and P < .03, respectively) in obese but not NW women. After E2 priming, ovulatory obese but not NW women had a 25% increase in luteal progesterone (P = .01). Obese women had significantly higher baseline IL-6, IL-10, TGF-ß, and IL-12 compared with NW (all P < .05); these levels were reduced after E2 (-6% for IL-1ß, -21% for IL-8, -5% for TGF-ß, -5% for IL-12; all P < .05) in obese but not in NW women. CONCLUSIONS: E2 priming seems to improve hypothalamic-pituitary-ovarian axis function and systemic inflammation in ovulatory, obese women. Reducing chronic inflammation at the pituitary level may decrease the burden of obesity on fertility.

Evidence of GnRH antagonist escape in obese women.

CONTEXT: Assisted reproductive technology (ART) cycle cancelation rates are increased among overweight and obese women; however, the reasons for this are not completely clear. Premature luteinization due to inadequate endogenous gonadotropin suppression is a possibility for this higher risk of cancellation. OBJECTIVE: The objective of the study was to investigate the impact of female obesity on the pharmacokinetics of cetrorelix (GnRH antagonist). DESIGN: This was an interventional study. SETTING: The study was conducted at a university clinical and translational research center. PARTICIPANTS: Regularly menstruating obese (n = 10) and normal-weight (n = 10) women participated in the study. INTERVENTIONS: A frequent blood sampling study was performed after a GnRH antagonist was administered, followed by recombinant LH. MAIN OUTCOMES MEASURED: Pharmacokinetics of cetrorelix in obese vs normal weight women were measured. RESULTS: Five of the obese women (50%) and none of the normal-weight women had a rebound of LH (defined as >50% increase in LH level from nadir) over the 14-hour postdose observation period. The obese group had a significantly decreased distributional half-life of cetrorelix compared with the normal-weight group (8.1 ± 1.6 vs 12.7 ± 6.2 hours, P = .02). The obese group exhibited increased clearance of cetrorelix compared with the normal-weight group (25.8 ± 6.8 vs 20.1 ± 8.3 L/h, P = .058). CONCLUSIONS: The altered pharmacokinetics of cetrorelix in obese women may lead to premature ovulation during ART, and this could be one of the mechanisms that results in increased cycle cancelation in this group of women. In accordance with the higher gonadotropin requirements for obese women undergoing ART, weight-based dosing of GnRH antagonists may be required.

Profound reduction of ovarian estrogen by aromatase inhibition in obese women.

OBJECTIVE: It was hypothesized that aromatase inhibitor (AI)-induced interruption of estradiol negative feedback would modulate the reproductive hormone profile of obese women. METHODS: Regularly cycling women aged 18-40 years with a BMI of 18-25 kg/m(2) (normal weight, n = 10) or >30 kg/m(2) (obese; n = 12) were given AI daily for 7 days. Urinary hormone profiles were compared between groups. Fourteen eumenorrheic, normal weight women not receiving AI stimulation served as historical controls. Urinary metabolites for LH, FSH, estradiol (E1c), and progesterone (Pdg) were measured and normalized to a 28-day cycle. Serum estrone and estradiol were measured in the late follicular phase. RESULTS: Whole-cycle LH, FSH, and luteal Pdg excretion did not differ between obese (BMI = 37.1 + 7 kg/m(2) ) and normal weight women treated with AIs, although LH was greater in stimulated compared with unstimulated normal weight women. Whole cycle mean E1c was lower in AI-stimulated obese and normal weight participants compared with nonstimulated normal weight controls, but obese women treated with AI excreted far less E1c (467.7 ± 217.4 µg/mg Cr) than AI-treated normal weight women (911.4 ± 361.8 µg/mg Cr; P = 0.02). Follicular phase serum estrone and estradiol were also lower in AI-treated obese women versus AI-treated normal weight women (61.7 ± 22.8 and 18.3 ± 3.7 pg/ml versus 99.1 ± 30.5 and 37.7 ± 5.9 pg/ml, respectively; P = 0.034 and 0.005). CONCLUSIONS: Normal gonadotropin output and luteal function occur at the expense of reduced E1c excretion in AI-treated women, and this discrepancy is particularly evident in obese women.

The correlation between self-reported and measured height, weight, and BMI in reproductive age women.

This prospective, cross-sectional study of 60 women compares self-reported height, weight, and BMI with measured values. Self-reported BMI (29.0±8.37 kg/m(2)) was slightly lower than measured BMI (29.1±8.38 kg/m(2)) (p=0.4). Eighty percent of participants reported a BMI in the same category in which their BMI was measured. Pearson's correlation coefficient for height (0.96, p<0.001), weight (0.99, p<0.001), and BMI (0.99, p<0.001) were high. Reproductive age women accurately reported their height and weight.