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.

Aromatase inhibition causes increased amplitude, but not frequency, of hypothalamic-pituitary output in normal women.

OBJECTIVE: To better understand the site and mode of action of aromatase inhibitors. DESIGN: Prospective study. SETTING: Academic research environment. PATIENT(S): Five eumenorrheic (without polycystic ovary syndrome), early follicular phase women with a normal body mass index (mean: 20.47±0.68 kg/m2), and 12 normal weight, midreproductive aged, early follicular phase women with a normal body mass index (mean: 20.8±1.7 kg/m2) as historical controls. INTERVENTION(S): 2.5 mg letrozole daily for 7 days, with daily urine collection (first morning void), thrice weekly blood sampling, and 4 hours of blood sampling every 10 minutes. MAIN OUTCOME MEASURE(S): Serum luteinizing hormone (LH) measured by a well-characterized immunofluorometric assay with LH pulse characteristics compared between treated and control groups using t tests. RESULT(S): Mean LH and LH pulse amplitude more than doubled in the women who had taken letrozole compared with the controls, but the LH pulse frequency did not differ between the women taking letrozole and the controls. CONCLUSION(S): These results indicate that the release of negative feedback inhibition of estradiol on the hypothalamic-pituitary axis in normal women by aromatase inhibitors creates an amplitude-related increase in endogenous hypothalamic-pituitary drive. The finding that the mean LH and LH pulse amplitude, but not the frequency, increased after letrozole suggests a possible pituitary site of action.

Semen parameters are unrelated to BMI but vary with SSRI use and prior urological surgery.

BACKGROUND: Male infertility affects approximately 6% of reproductive-aged men. It has been suggested that overweight men or men with obese body mass index (BMI) experience prolonged time to pregnancy, though the influence of male BMI on fertility remains understudied. AIMS: We hypothesized that BMI is inversely correlated with fertility, manifested by reduced sperm concentration, motility, and morphology. METHODS: Males of age 18 to 50 with semen analyses and self-reported BMI were included (n = 530). Patient parameters analyzed included age, BMI, smoking, urological, and fertility history. Leutinizing hormone (LH), Follicle-stimulating hormone, testosterone, steroid hormone-binding globulin (SHBG) and free androgen index (FAI) levels (n = 55), and selective serotonin reuptake inhibitor (SSRI) use (n = 12) were also measured. RESULTS: The men in this study had a mean BMI of 28.2 ± 4.9 kg/m(2) (range = 15-60), which is considered overweight, and a mean semen concentration of 55.4 ± 46.8 million/mL, which is in normal range, according to WHO standard. No consistent relationship was observed between increasing BMI and sperm concentration, motility, or morphology, although the testosterone levels trended downward with increasing BMI; there was a suggestion for decreased sperm concentration in current smokers. Men treated with combination SSRI and other psychotropic agent therapy (n = 12) had significantly reduced sperm motility (P = .009). Not unexpectedly, prior urological surgery (n = 77) was associated with lower sperm concentration (P = .0001) and morphology (P = .0008). When in vitro fertilization-embryo transfer (IVF-ET) was used as a treatment modality (n = 121), male BMI was not a significant predictor of clinical pregnancy (P = .06). CONCLUSIONS: In our study, we did not observe a significant association between male BMI and sperm concentration, motility or morphology, or clinical pregnancy following IVF-ET. Significantly, SSRI use may affect sperm parameters negatively.

Replete vitamin D stores predict reproductive success following in vitro fertilization.

OBJECTIVE: To determine whether 25OH-D levels in the follicular fluid (FF) of infertile women undergoing IVF demonstrate a relationship with IVF cycle parameters and outcome, hypothesizing that levels of 25OH-D in body fluids are reflective of vitamin repletion status. DESIGN: Prospective cohort study. SETTING: Academic tertiary care center. PATIENT(S): Eighty-four infertile women undergoing IVF. INTERVENTION(S): Follicular fluid from follicles>or=14 mm; serum (n = 10) and FF levels of 25OH-D. MAIN OUTCOME MEASURE(S): Clinical pregnancy (CP), defined as evidence of intrauterine gestation sac on ultrasound, following IVF; IVF cycle parameters. RESULT(S): Serum and FF levels of 25OH-D were highly correlated (r=0.94). In a predominantly Caucasian population (66%), significantly lower FF 25OH-D levels were noted in Black versus non-Black patients. Significant inverse correlations were seen between FF 25OH-D levels and body mass index (r=-0.25). Significantly higher CP and implantation rates were observed across tertiles of FF25OH-D; patients achieving CP following IVF (n=26) exhibited significantly higher FF levels of 25OH-D. Multivariable logistic regression analysis confirmed FF 25OH-D levels as an independent predictor to success of an IVF cycle; adjusting for age, body mass index, ethnicity, and number of embryos transferred, each ng/mL increase in FF 25OH-D increased the likelihood for achieving CP by 6%. CONCLUSION(S): Our findings that women with higher vitamin D level in their serum and FF are significantly more likely to achieve CP following IVF-embryo transfer are novel. A potential for benefit of vitamin D supplementation on treatment success in infertile patients undergoing IVF is suggested and merits further investigation.

Partial recovery of luteal function after bariatric surgery in obese women.

OBJECTIVE: To determine whether obesity-related reproductive endocrine abnormalities in ovulatory women are reversible with weight loss. DESIGN: Observational cohort study. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Women aged 18-48 years with regular menstrual cycles 21-40 days and a body mass index (BMI) >or=35 kg/m(2) planning to undergo bariatric surgery were recruited. INTERVENTION(S): Twenty-five eumenorrheic (non-polycystic ovary syndrome) women with a mean BMI of 47.3 +/- 5.2 kg/m(2) were sampled with daily menstrual cycle urinary hormones before (n = 25) and 6 months after (n = 9) weight loss surgery resulting in >25% reduction of initial body weight. Daily hormones were compared before and after surgery and with 14 normal-weight control subjects. MAIN OUTCOME MEASURE(S): Metabolites of LH, FSH, E(2), and P were measured daily for one menstrual cycle. Group means were compared using t tests among ovulatory cycles. RESULT(S): Luteal pregnanediol glucuronide (Pdg) increased from 32.8 +/- 10.9 to 73.7 +/- 30.5 microg/mg creatinine (Cr) and whole-cycle LH increased from 168.8 +/- 24.2 to 292.1 +/- 79.6 mIU/mg Cr after surgically induced weight loss. Luteal Pdg remained lower than in normal-weight control subjects (151.7 +/- 111.1 microg/mg Cr). Obese women took longer to attain a postovulatory Pdg rise of >2 microg/mg Cr than control subjects (3.91 +/- 1.51 vs. 1.71 +/- 1.59 days); this improved after surgery (2.4 +/- 1.82 days). Whole-cycle estrone conjugates (E(1c)) was similar to control subjects at baseline, but decreased after weight loss (from 1,026.7 +/- 194.2 to 605.4 +/- 167.1 ng/mg Cr). Follicle-stimulating hormone did not relate to body size in this sample. CONCLUSION(S): Women of very high BMI have deficient luteal LH and Pdg excretion and a delayed ovulatory Pdg rise compared with normal-weight women. Although these parameters improved with weight loss, Pdg did not approach levels seen in normal-weight women. Luteinizing hormone may be less effective in stimulating the corpus luteum in obesity. The large postoperative decrease in E(1c) may reflect the loss of estrone-producing adipose tissue after weight loss.