Enhanced hypothalamic-pituitary sensitivity to estrogen in premenopausal women with diminished ovarian reserve compared with older perimenopausal controls.

OBJECTIVE: We have previously characterized the reproductive hormone profile in infertile women with diminished ovarian reserve (DOR) as being distinct from that seen in age-comparable healthy controls. Hypothesizing that DOR reflects accelerated reproductive aging, we herein compare urinary reproductive hormone dynamics between young women with DOR and a population of chronologically older perimenopausal controls. METHODS: In this prospective observational study, urinary levels of pituitary gonadotropins (follicle-stimulating hormone and luteinizing hormone) and metabolites of estrogen (estrone conjugate) and progesterone were assessed in daily morning urine samples collected in a spontaneous menstrual cycle in 8 infertile premenopausal women with DOR and in 11 perimenopausal controls. Areas under the curves were calculated for the respective measured hormones, and comparisons were made using the Mann-Whitney U test. RESULTS: Urinary estrone conjugate levels were significantly attenuated in premenopausal women with DOR compared with the older perimenopausal cohort. Despite the relatively lower estrogen, a significantly more pronounced luteinizing hormone surge was evident in the younger population. Early follicle-stimulating hormone was lower in women with DOR, but luteal urinary progesterone excretion was comparable in the two groups. CONCLUSIONS: Our data suggest distinctions in functioning of the central (hypothalamic-pituitary) and peripheral (ovarian) components of the hypothalamic-pituitary-ovarian axis in premenopausal women with DOR compared with chronologically older perimenopausal controls. Increased hypothalamic-pituitary sensitivity to estrogen positive feedback is suggested in premenopausal women with DOR. Our observations identify DOR as a distinct entity in the paradigm of reproductive senescence.

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.

Characterizing the reproductive hormone milieu in infertile women with diminished ovarian reserve.

OBJECTIVE: To elucidate the reproductive hormone profiles in association with a diagnosis of diminished ovarian reserve (DOR). DESIGN: Prospective observational study. SETTING: Academic tertiary care infertility practice. PATIENT(S): Eight regularly cycling infertile women diagnosed with DOR as the underlying contributor to infertility and 14 age-comparable healthy controls. INTERVENTION(S): Daily morning urine voids were collected during one menstrual cycle. MAIN OUTCOME MEASURE(S): Urinary excretion of gonadotropins (FSH, LH) and metabolites of estrogen (E; estrone conjugate) and P (pregnanediol 3 glucoronide) during an entire menstrual cycle in women with DOR and healthy controls. RESULT(S): Women with DOR demonstrated significantly higher urinary FSH levels in the early follicular phase, exaggerated amplitudes, significantly protracted durations of LH, concomitant FSH surges, and significantly impaired luteal phase urinary excretions of estrone conjugate and pregnanediol 3 glucoronide compared with the controls. CONCLUSION(S): Women with DOR demonstrate reproductive hormone profiles that are distinct from age-comparable controls, share similarities with profiles previously described during menopause transition, as well as exhibit unique features not previously recognized in the context of reproductive aging.

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.

Low serum osteoprotegerin levels in premenopausal infertile women with low bone density: an association of relevance?

OBJECTIVE: To evaluate if the levels of the central regulators of osteoclast activity, osteoprotegerin (OPG) and receptor activator for nuclear factor kappaB-ligand (RANk-L), correlate with bone mineral density (BMD) parameters in premenopausal infertile women. DESIGN: Cross-sectional study. SETTING: Academic infertility practice. PATIENT(S): 82 Infertile, but otherwise healthy, premenopausal women< 42 years age presenting for routine care. INTERVENTION(S): BMD assessment; serum samples (cycle days 1 to 3), questionnaire addressing demographics, medical, social, family, and personal histories. MAIN OUTCOME MEASURE(S): BMD categorized as "Low" (Z -1.0); Biomarkers of bone metabolism (BAP, TRAP, NTX, OPG, RANK-L) and ovarian reserve (FSH, estradiol). RESULT(S): The prevalence of low BMD was 23% (19/82). Significantly lower levels of OPG were observed in association with low BMD compared with normal BMD (1.37 +/- 0.57 versus 2.0 +/- 1.05 pMol/L). Multivariable logistic regression analyses revealed low OPG levels as independent predictors of low BMD after adjusting for parameters known to influence bone density. CONCLUSION(S): We demonstrate an independent relationship between low circulating levels of OPG and low BMD in premenopausal healthy, albeit infertile, women.

Implications of diminished ovarian reserve (DOR) extend well beyond reproductive concerns.

OBJECTIVES: To investigate whether a diagnosis of diminished ovarian reserve (DOR) in premenopausal years has adverse implications for skeletal health and quality of life. DESIGN: This was a cross-sectional study of infertile, albeit healthy, mid-reproductive-age women (younger than 42 y) attending an academic infertility practice. RESULTS: Eighty-nine women with varying causes of infertility were prospectively enrolled. Serum (cycle d 1-3) was collected for markers of ovarian reserve, bone metabolism, testosterone, and free androgen index. Bone mineral density (BMD) was assessed and categorized as low if the Z score was less than -1.0). Infertile women with DOR (n = 28) demonstrated significantly higher serum follicle-stimulating hormone levels (P < 0.001), lower müllerian-inhibiting substance (MIS) levels (P < 0.001), smaller ovarian dimensions (P < 0.05), lower testosterone levels (P = 0.035), lower free androgen index (P = 0.019), and enhanced bone metabolism (P = 0.003); although the prevalence of low BMD was higher in women with DOR who were younger than 41, this relationship was not of statistical significance (P = 0.106). Women younger than 41 years of age with DOR were significantly more likely to manifest disturbed sleep (P = 0.049) and acknowledge dissatisfaction with sexual intimacy (P = 0.004) compared with those with infertility and normal ovarian reserve. After adjustment for potential confounders, a diagnosis of DOR was significantly associated with low BMD, increased bone turnover, sexual dissatisfaction, and disturbed sleep. CONCLUSIONS: Our data suggest that DOR unmasked in the context of infertility evaluation has adverse implications for a woman's well-being that extend well beyond the thus far appreciated reproductive concerns. A decline in ovarian hormones, specifically estrogen and testosterone, concomitant with DOR may be hypothesized as a mechanism that can explain the observed multisystem ramifications of DOR including increased bone turnover, low BMD, sexual distress, and disturbed sleep.

Onset of ovulation after menarche in girls: a longitudinal study.

INTRODUCTION: Hypothalamic-pituitary axis maturity has been believed to be the rate-limiting step in the development of ovulatory menstrual cycles. We hypothesized that, given current nutritional conditions, hypothalamic-pituitary axis maturation would be relatively rapid in menarcheal girls. METHODS: Daily urine and menstrual records were collected for 2 yr each from 10 girls aged 11-13 yr at study entry. Urinary excretion of LH, FSH, estradiol (E1c), and progesterone (Pdg) metabolites was measured using established ELISAs. An objective algorithm detected rises of LH, FSH, E1c, and Pdg consistent with follicular maturation and/or ovulation. RESULTS: Nine of 10 girls enrolled into the study experienced the onset of menarche prior to or during the 2-yr collection period. LH and FSH surges, as well as small amplitude Pdg increments, were observed prior to menarche. Regular, ovulatory-appearing cycles with LH surges and gradually increasing and more sustained Pdg rises were observed over time after menarche, although duration of Pdg elevations remained shorter than in adult women (8.9 +/- 1.0 vs. 12.1 +/- 0.8 d, P = 0.043). E1c levels leading to LH/FSH surges were lower in perimenarcheal girls than adult controls, and bleeding episodes did not uniformly correlate with hormone patterns. Progressive increases in FSH and Pdg, but not LH or E1c, were observed in association with menarche. CONCLUSION: Mature hormone patterns are established within several months of and even prior to menarche in normal-weight perimenarcheal girls. Factors determining menstrual bleeding in perimenarcheal girls may not be solely dependent on reproductive hormones or the neuroendocrine axis.

Vasomotor symptoms in infertile premenopausal women: a hitherto unappreciated risk for low bone mineral density.

OBJECTIVE: To identify the prevalence of vasomotor symptoms (VMS) in a population of premenopausal infertile women and to determine whether VMS is associated with enhanced bone turnover and low bone mineral density (BMD). DESIGN: Cross-sectional study. SETTING: Academic infertility practice. PATIENT(S): Eighty-two premenopausal infertile, but otherwise healthy, women attending for routine infertility care. INTERVENTION(S): Bone mineral density testing, general health and Profile of Mood States questionnaires, and serum samples (cycle d 1-3). MAIN OUTCOME MEASURE(S): Vasomotor symptoms, specifically hot flashes (HF) and night sweats (NS); BMD z score, BMD categorized as low (Z -1.0); ovarian reserve assessment (biochemical and ovarian dimensions on transvaginal ultrasound); and serum markers of bone turnover (collagen N-terminal telo-peptide, tartrate-resistant acid phosphatase, and bone-specific alkaline phosphatase) and ovarian reserve (FSH, E(2), and inhibin B). Multivariable regression analyses determined the associations between VMS, BMD, and bone turnover (individual markers and composite turnover score). RESULT(S): The prevalence of VMS was 12% in this relatively young population (mean [+/- SD] age [years], 34.53 +/- 4.32). Symptomatic women were statistically significantly more likely to report sleep disturbances and to exhibit evidence of low BMD, as well as to exhibit enhanced bone turnover and poorer ovarian reserve parameters. Multivariable logistic regression analyses confirmed the statistical significance of both HF and NS as independent correlates to low BMD after adjusting for age, body mass index, smoking status, menstrual regularity, and ovarian reserve status. Multivariable linear regression analyses demonstrated that NS, but not HF, predicted higher bone turnover at a statistically significant level after adjusting for age, smoking, menstrual regularity, and ovarian reserve. CONCLUSION(S): We demonstrate, in a premenopausal population of infertile women, evidence of morbid accompaniments to VMS, including sleep disturbances and evidence of low BMD. Our data further suggest a state of enhanced bone turnover in association with VMS, specifically in those experiencing NS. Declining ovarian reserve may be the common pathophysiological mechanism underlying VMS and low BMD in the symptomatic population and merits further investigation.

Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women.

CONTEXT: Female obesity is linked to abnormal menstrual cycles, infertility, reproductive wastage, and deficient LH, FSH, and progesterone secretion. OBJECTIVE AND DESIGN: To elucidate the reproductive defects associated with obesity, we sampled 18 eumenorrheic (nonpolycystic ovary syndrome) women with a mean +/- sem body mass index of 48.6 +/- 1.4 kg/m2 with daily, first morning voided urine collections, seven of whom also had early follicular phase 12-h, every 10-min blood sampling to assess LH pulses. Daily hormones were compared with 11 eumenorrheic, normal-weight controls. A separate control group of 12 eumenorrheic, normal-weight women was used for the LH pulse studies. MAIN OUTCOME MEASURES: Assays for LH (serum and urine) and FSH, and estradiol and progesterone metabolites (estrone conjugate and pregnanediol glucuronide; urine) were performed. Daily hormones were meaned and normalized to a 28-d cycle length. LH pulsations were determined using two objective methods. Group means were compared using t tests. RESULTS: Reduced whole-cycle mean, normalized pregnanediol glucuronide was observed in obese (38.2 +/- 2.1 microg/mg creatine) compared with normal-weight women (181.3 +/- 35.1 microg/mg creatine; P = 0.002), without significant differences in LH, FSH, or estrone conjugate. Early follicular phase LH pulse frequency did not differ from normal-weight women, but both amplitude and mean LH were dramatically reduced in obese women (0.8 +/- 0.1 and 2.0 +/- 0.3 IU/liter) compared with controls (1.6 +/- 0.2 and 3.4 +/- 0.2 IU/liter; P < 0.01). CONCLUSIONS: A novel defect in the amplitude but not the frequency of LH pulsations appears to underlie the reproductive phenotype of obesity. The deficit in pregnanediol glucuronide appears to exceed the deficit in LH. The patterns of hypothalamic-pituitary-ovarian axis function unique to the obese state differ from other abnormal reproductive states.

Factors affecting reproductive hormones in HIV-infected, substance-using middle-aged women.

OBJECTIVE: To determine whether reproductive hormone levels are affected by human immunodeficiency virus (HIV) and drug use. DESIGN: HIV-infected and uninfected women (N=429), median age 45, were interviewed on menstrual frequency, demographic and psychosocial characteristics, and drug use behaviors. Serum was obtained on cycle days 1 to 5 in women reporting regular menses. Premenopausal-, early menopausal, and late menopausal transition and postmenopausal stages were assigned based on menstrual history. Serum was assayed for follicle-stimulating hormone (FSH), estradiol (E2), luteinizing hormone (LH), prolactin, thyroid-stimulating hormone, and inhibin B. Body mass index, HIV serostatus, and CD4+ counts were measured. Factors associated with hormone concentrations were assessed using uni- and multivariable analyses. Hormone concentrations were compared within menstrual status categories using nonparametric comparisons of means. RESULTS: In this cross-sectional analysis, LH and FSH increased, and E2 and inhibin B were significantly lower in women of older age and more advanced menopausal status. Increased body mass index was strongly associated with decreased LH. Opiate use was significantly associated with lower inhibin B and E2 and increased prolactin. Poorer self-rated health was statistically significantly associated with lower LH and FSH, but increased education was associated with higher LH and FSH. Among HIV-seropositive women, opiate users had detectably lower FSH and LH than nonusers, and use of highly active antiretroviral therapy was significantly related to higher LH, FSH, and E2, whereas cocaine use was associated with lower E2. CONCLUSIONS: Age and menopausal status are strongly related to reproductive hormones. Body mass index and use of opiates, cocaine, and highly active antiretroviral therapy as well as educational attainment and perceived health can significantly modify reproductive hormones during the menopausal transition and need to be considered when interpreting hormone levels in middle-aged women.