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Female obesity is linked to abnormal menstrual cycles, infertility, reproductive wastage, and deficient LH, FSH, and progesterone secretion.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.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.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; P0.01).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.

The proximate cause of functional hypothalamic amenorrhea (FHA) is reduced GnRH drive. The concomitant increase in circulating cortisol suggests that psychogenic stress plays an etiologic role, but others have argued for a strictly metabolic cause, such as undernutrition or excessive exercise. Indeed, our finding that the cerebrospinal fluid (CSF) concentration of CRH was not elevated in FHA cast doubt about the extent of hypothalamic-pituitary-adrenal activation in FHA and, therefore, we wondered whether central cortisol levels were elevated.We tested the null hypothesis that CSF cortisol levels would be comparable in FHA and eumenorrheic women (EW).The study is a cross-sectional comparison.The study was set in a general clinical research center at an academic medical center.Fifteen women with FHA who were of normal body weight and 14 EW participated.Blood samples were collected at 15-min intervals for 24 h, followed by procurement of 25 ml CSF.Cortisol, cortisol-binding globulin (CBG), and SHBG levels in blood and CSF were the main outcome measures.CSF cortisol concentrations were 30% greater when serum cortisol was 16% higher in FHA compared with EW. Circulating CBG, but not SHBG, was increased in FHA and, thus, the circulating free cortisol index was similar in FHA and EW. Because CBG and SHBG were nil in CSF, the increase in CSF cortisol in FHA was unbound.The hypothalamic-pituitary-adrenal axis is activated in FHA. The maintenance of CRH drive despite increased CSF cortisol indicates resistance to cortisol feedback inhibition. The mechanisms mediating feedback resistance likely involve altered hippocampal corticosteroid reception and serotonergic and GABAergic neuromodulation.

Insulin resistance and dyslipidemia have been described in women with polycystic ovary syndrome (PCOS), a disorder characterized by hyperandrogenism and oligomenorrhea. Although oral contraceptives (OC) are often instituted to regulate menses and suppress HA in women with PCOS, their use has been postulated to cause a deterioration in insulin sensitivity and to adversely affect circulating lipids. To investigate these effects, 9 women with PCOS and 10 age- and weight-matched control women were studied before and during the third month of therapy with a low-dose norethindrone-containing triphasic combination OC using the hyperglycemic clamp technique. At baseline, the PCOS group had higher androgen, triglyceride, and glycosylated hemoglobin concentrations, with a greater insulin response to oral glucose and a lower insulin sensitivity index (ISI) than controls. During OC therapy, a reduction in ISI was observed in both groups, whereas an increase in triglycerides was observed only in controls, removing any observed difference between the two groups in ISI or lipids. In women with PCOS, an increase in insulin concentrations during hyperglycemia accounted for the decline in ISI (P = 0.026), whereas in control women the decrease in ISI was attributable to a decrease in glucose disposal (P = 0.004). In conclusion, PCOS is characterized by insulin resistance in the untreated state. Short-term therapy with a triphasic OC results in a further decline in ISI in women with PCOS, without inducing additional adverse effects on lipids. A more pronounced decline in ISI together with an elevation in triglyceride levels occurs in normal women with OCs. The mechanisms leading to this decrease in ISI are different for each group.

Women with hyperandrogenic anovulation (HAA) have increased circulating levels of LH relative to those of FSH. The cause of this disturbance in gonadotropin secretion is uncertain. Previous investigations have sought to determine if increased GnRH drive is responsible for the excessive LH concentrations. Because previous results have conflicted, we addressed this question by comparing the 24-h secretory patterns of alpha-subunit and LH in women with HAA (n = 9) to those in eumenorrheic women in the midfollicular phase (n = 9). The mean (+/- SEM) pulse frequency was increased in women with HAA compared to that in eumenorrheic women of comparable age and percent ideal body weight for both LH (23.0 +/- 0.7 pulses/24 h vs. 3 17.1 +/- 1.7; P = 0.002) and alpha-subunit (23.0 +/- 0.8 vs. 19.1 +/- 1.2; P = 0.02). LH and alpha-subunit, but not FSH, responses to a submaximal dose of exogenous GnRH were increased in HAA, as were basal LH and alpha-subunit levels (P0.01). The present observations provide evidence for increased GnRH drive, including pulse frequency, in HAA. Although the results confirm the presence of a disturbance in gonadotropin secretion and suggest that its proximate cause may be of hypothalamic origin, they do not exclude the possibility that other factors, perhaps of ovarian origin, play a role in the establishment and/or maintenance of the altered gonadotropin secretory patterns and the chronic anovulation characteristic of HAA.

Plasma melatonin levels were determined by a sensitive RIA at 30 min intervals for 24h in 7 women with functional hypothalamic amenorrhea (HA) and in 7 age and season matched normal cycling women in the early follicular phase (NC). While daytime melatonin concentrations were nondetectable in both groups, the integrated nocturnal levels were 3-fold greater in HA (244 +/- 58 (SE) vs 74 +/- 32 pmol-min/Lx10(3), p less than 0.005). This melatonin increase in HA was due to an elevated peak amplitude (p less than 0.01) and extended duration (p less than 0.05). The latter was mostly due to a significant delay in the offset time of the amplified nocturnal melatonin secretion.