Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Abdominal aortic diameter and vascular atherosclerosis: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES: To gain insight into early mechanisms of aortic widening, we examined associations between the diameter of the abdominal aorta (AD) and cardiovascular disease (CVD) risk factors and biomarkers, as well as measures of subclinical atherosclerosis, in a multi-ethnic population. DESIGN: Cross-sectional cohort. METHODS: A total of 1926 participants (mean age 62, 50% women) underwent chest and abdomen scanning by computed tomography, ultrasound of the carotid arteries, and CVD risk factor assessment. AD was measured 5 cm above and at the bifurcation. RESULTS: In a model containing traditional CVD risk factors, biomarkers and ethnicity, only age (standardized ß = 0.97), male sex (ß = 1.88), body surface area (standardized ß = 0.92), current smoking (ß = 0.42), D-dimer levels (ß = 0.19) and hypertension (ß = 0.53) were independently and significantly associated with increasing AD (in mm) at the bifurcation; use of cholesterol-lowering medications predicted smaller AD (ß = -0.70) (P < 0.01 for all). These findings were similar for AD 5 cm above the bifurcation with one exception: compared to Caucasian-Americans, Americans of Chinese, African and Hispanic descent had significantly smaller AD 5 cm above the bifurcation (ß's = -0.59, -0.49, and -0.52, respectively, all P < 0.01), whereas AD at the bifurcation did not differ by ethnicity. Physical activity, alcohol consumption, diabetes and levels of IL-6, CRP and homocysteine were not independently associated with AD. Higher aortic and coronary artery calcium burden, but not common carotid artery intima-media thickness, were independently, but modestly (ß = 0.11 to 0.19), associated with larger AD. CONCLUSIONS: Incremental widening of the aortic diameter shared some, but not all, risk factors for occlusive vascular disease.

Sex and Age Differences in the Association of Blood Pressure and Hypertension with Cognitive Function in the Elderly: The Rancho Bernardo Study.

OBJECTIVES: This study examines sex and age differences in associations of systolic and diastolic blood pressure (SBP, DBP), pulse pressure and hypertension with cognitive function in a community-dwelling population. DESIGN: Cross-sectional study. SETTING: Research clinic visit in 1988-91. PARTICIPANTS: Participants were 693 men and 1022 women aged 50-97 Measurements: Blood pressure was measured and 12 cognitive function tests were administered. RESULTS: Average age was 73.8±9.9 in men and 73.2±9.3 in women; 62.6% of men and 63.4% of women were hypertensive (SBP≥140 mmHg, DBP≥90 mmHg, or antihypertensive medication use). Each 5-unit increment in SBP, DBP, or pulse pressure and categorical hypertension was associated with significantly increased odds of poor verbal fluency performance in men and poor Trails B performance in women, with strongest associations for hypertension (OR=1.97, CI:1.01,3.85 in men; OR=1.51, CI:1.01,2.26 in women). After age stratification, associations remained statistically significant in younger (<80 years ) but not older (≥80 years) participants. CONCLUSION: Blood pressure as a continuous or categorical variable was associated with poor performance on cognitive function tests, but domains varied by sex and associations were found only in those younger than 80 years. The absent associations in those aged 80 years and older could support the hypothesis that increased blood flow is required to maintain cerebral perfusion with advancing age, or could reflect a survivor effect.

Association between Dietary Sodium Intake and Cognitive Function in Older Adults.

OBJECTIVE: To examine the association of dietary sodium intake with cognitive function in community-dwelling older adults. DESIGN: Cross-sectional study. SETTING: Southern California community. PARTICIPANTS: White men (n=373) and women (n=552), aged 50-96 years from the Rancho Bernardo Study, a longitudinal study of cardiovascular disease risk factors and healthy aging. MEASUREMENTS: During the 1992-1996 research clinic visit, a food frequency questionnaire was used to determine daily sodium intake; cognitive function was assessed with Trails Making Test, part B (Trails B), Mini-Mental State Exam (MMSE), and Verbal Fluency Test (VFT); and medical, clinical and demographic information was obtained. Linear regression was used to assess the association between calorie-adjusted sodium intake and cognitive test scores with adjustment for demographic, behavioral and health measures. Logistic regression examined the odds of having cognitive impairment by sodium intake. RESULTS: Lower sodium intake was associated with poorer performance on Trails B (p=0.008) and MMSE (p=0.003) after controlling for age, sex, and education. Associations did not differ by sex, but there was a significant interaction by age for the Trails B: older (≥80 years), but not younger, adults showed worse performance with lower sodium intake (p=0.03). Associations remained significant after additional adjustment for smoking, alcohol intake, exercise, body weight, cardiovascular risk factors, kidney function, diuretic medication use, and diet quality. Lower daily sodium intake was associated with increased odds of cognitive impairment on the MMSE (score < 26; OR per SD decrease = 1.12, 95% CI 1.08, 1.16). Concluson: Lower sodium intake was associated with worse cognitive function in older community-dwelling adults. For the maintenance of cognitive health, older adults may be advised to avoid very low sodium diets.

Blood pressure trajectories in relation to cardiovascular mortality: The Rancho Bernardo Study.

The added value of blood pressure (BP) trajectories for predicting cardiovascular disease (CVD) is currently unknown. We investigated the association of systolic BP (SBP) trajectories with CVD and all-cause mortality and compared these associations with those of average SBP, taking antihypertensive medication into account. Data from 762 participants of the Rancho Bernardo Study were used. SBP from five examinations (maximum) from 1984 to 2002 was used; mortality data were obtained from 2002 to 2013. SBP trajectories were derived using group-based trajectory modelling. Cox proportional hazards analysis was used to investigate associations of trajectories and average SBP with CVD and all-cause mortality, adjusted for age, sex, cholesterol, smoking, diabetes and antihypertensive medication. Mean baseline age was 65.7 years, and 67% were women. Four trajectories were identified, in which mean SBP increased by 5-12 mm Hg during 10 years. The highest trajectories were associated with two to three times greater CVD mortality and 1.5 times greater all-cause mortality risk, compared with the lowest trajectory. Each 20 mmHg increment in average SBP was associated with 1.4 times greater CVD mortality risk and 1.2 times all-cause mortality risk. Associations were not modified by antihypertensive medication (P-interaction>0.10). SBP trajectories were not superior to average SBP in predicting CVD and all-cause mortality. In the general middle-aged and older population of the Rancho Bernardo study, SBP trajectories provided no added value to average SBP in predicting CVD and all-cause mortality. Long-term average SBP levels and trajectories were significant predictors of CVD and all-cause mortality, irrespective of prescribed antihypertensive medication (which in the 1980s-1990s mainly were diuretics and ß-blockers).

Moderate, Regular Alcohol Consumption is Associated with Higher Cognitive Function in Older Community-Dwelling Adults.

BACKGROUND: Evidence suggests that moderate alcohol consumption may protect against cognitive decline and dementia. However, uncertainty remains over the patterns of drinking that are most beneficial. OBJECTIVE: To examine associations between amount and frequency of alcohol consumption with multiple domains of cognitive function in a well-characterized cohort of older community-dwelling adults in southern California. DESIGN: Observational, cross-sectional cohort study. SETTING: A research visit between 1988-1992 in Rancho Bernardo, California. PARTICIPANTS: 1624 participants of the Rancho Bernardo Study (mean age ± SD = 73.2 ± 9.3 years). Measurements: Participants completed a neuropsychological test battery, self-administered questionnaires on alcohol consumption and lifestyle, and a clinical health evaluation. We classified participants according to average amount of alcohol intake into never, former, moderate, heavy and excessive drinkers, and according to frequency of alcohol intake, into non-drinkers, rare, infrequent, frequent and daily drinkers. We examined the association between alcohol intake and cognitive function, controlling for age, sex, education, exercise, smoking, waist-hip ratio, hypertension and self-assessed health. RESULTS: Amount and frequency of alcohol intake were significantly associated with cognitive function, even after controlling for potentially related health and lifestyle variables. Global and executive function showed positive linear associations with amount and frequency of alcohol intake, whereas visual memory showed an inverted U-shaped association with alcohol intake, with better performance for moderate and infrequent drinkers than for non-drinkers, excessive drinkers or daily drinkers. CONCLUSIONS: In several cognitive domains, moderate, regular alcohol intake was associated with better cognitive function relative to not drinking or drinking less frequently. This suggests that beneficial cognitive effects of alcohol intake may be achieved with low levels of drinking that are unlikely to be associated with adverse effects in an aging population.

Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression.

The nocturnal secretion of plasma melatonin was determined under dim to dark conditions in eight patients with prospectively confirmed premenstrual syndrome and in eight age- and menstrual cycle phase-matched normal control subjects. Plasma samples for melatonin were collected every 30 minutes from 6 PM to 9 AM during the early follicular, late follicular, midluteal and late luteal phases of the menstrual cycle. Compared with normal controls, patients with premenstrual syndrome had an earlier (phase-advanced) offset of melatonin secretion, which contributed to a shorter secretion duration and a decreased area under the curve. No statistically significant differences were found between women with premenstrual syndrome and normal controls for melatonin onset or peak concentration, or for estradiol or progesterone levels. The data demonstrate that women with premenstrual syndrome have chronobiological abnormalities of melatonin secretion. The fact that these patients respond to treatments that affect circadian physiology, such as sleep deprivation and phototherapy, suggests that circadian abnormalities may contribute to the pathogenesis of premenstrual syndrome.

Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies.

Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study.

Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: the Rancho Bernardo Study.

In recent years, adrenal function and aging has been the subject of intense interest. This cross-sectional study examines age and gender differences in plasma levels of cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS), and the molar ratio of cortisol/DHEAS in 50-89-yr-old community-dwelling adults. Plasma hormone levels were assayed in samples obtained between 0730 h and 1100 h from 857 men and 735 nonestrogen-using, postmenopausal women. Hormone levels were stratified by 10-yr age groups and compared by two-factor (gender and age) ANOVA. Overall, age and BMI-adjusted DHEA and DHEAS [collectively DHEA(S)] levels were 40% lower and cortisol levels 10% higher in women than men, resulting in a 1.7-fold higher cortisol/DHEAS molar ratio for women (both, P < 0.001). Cortisol levels increased progressively (20% overall) with age in both men and women (both, P < 0.01). Although DHEA(S) levels declined 60% and the cortisol/DHEAS ratio increased 3-fold across the 40-yr age range for both men and women (all P < 0.001), the pattern of the change differed (all P < 0.01 for interaction). For men, DHEA(S) fell in a curvilinear fashion, with the degree of change decreasing with each decade. In contrast, DHEA(S) levels in women fell 40% from the 50s to 60s, were unvarying from 60-80 yr of age, and declined an additional 18% in the 80s. The cortisol/DHEAS ratio increased in a linear fashion for men, but was flat during the 60-80-yr age range for women. Despite these differences in the effect of aging, levels of DHEA(S) remained lower and cortisol and the cortisol/DHEAS ratio higher, in women than men throughout the 50-89-yr age range. These results were independent of adiposity, smoking, and alcohol consumption. In summary, among older, healthy adults DHEA(S) levels are lower and cortisol levels higher in women than men. The age-related decline in adrenal androgens persists into advanced age for both men and women, but exhibits a sexually dimorphic pattern. In contrast, cortisol levels in men and women show a parallel, linear increase with aging. These findings may have important implications for a host of age-related processes that exhibit gender differences, including brain function, bone metabolism, and cardiovascular disease.

Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea.

The possibility that chronic nutritional deficiency alters leptin regulation and its link to reproductive function was investigated by determining serum leptin levels during a 24-h period with controlled nutrient intake in highly trained athletes with and without menstrual cyclicity and in BMI-matched cycling sedentary controls (n = 8 per group). Our data show that 24th leptin levels were reduced equally (3-fold, P < 0.001) in both cyclic and amenorrheic athletes as compared to controls. Low leptin levels in the athletic groups were consistent with their reduction in body fat (r = 0.91, P < 0.0001) relative to BMI, but were also influenced by the presence of low insulin (r = 0.70, P < 0.001) and elevated cortisol (r = -0.65, P < 0.001) levels. A diurnal pattern of 24h leptin levels, with an approximate 50% rise (P < 0.001) from nadir (0900h) to peak (0100h), was present in normally cycling athletes and controls and was strikingly absent in amenorrheic athletes. The absolute increase in leptin levels from nadir to peak was directly related to insulin excursions in response to meals (r = 0.60, P = .002) and inversely related to the amplitude of the 24h cortisol rhythm (r = -0.70, P = .0002). These findings are consistent with a link between the functionality of adipocytes, nutritional status, and integrity of the reproductive axis in humans.

Nutritional and endocrine-metabolic aberrations in amenorrheic athletes.

Growing evidence suggests that menstrual disturbances in female athletes are related to the metabolic cost of high levels of energy expenditure without compensatory increases in dietary intake. However, the linkage(s) between nutritional deficits and reproductive impairments as a result of slowing of LH pulsatility has not been defined. This study was directed to simultaneously characterize nutritional intake, insulin sensitivity (by rapid iv glucose tolerance test), and 24-h dynamics of insulin/glucose, cortisol, somatotropic [GH/GH-binding protein (GHBP)/insulin-like growth factor I (IGF-I)/IGF-binding proteins (IGFBPs)], and LH axes in highly trained athletes with (cycling athletes; CA) and without (amenorrheic athletes; AA) menstrual cyclicity and in age- and body mass index-matched cycling sedentary controls (CS; n = 8/group). Although daily caloric intake did not differ among the three groups, athletes (CA and AA) consumed less fat and protein than CS. However, the restriction of fat was 50% greater (P < 0.01) in AA than CA and was accompanied by increased carbohydrate (P < 0.05) and fiber (P < 0.01) intake. Athletes, independent of menstrual status, had increased (P < 0.05) insulin sensitivity and reduced insulin levels during the feeding phase of the day. Hypoinsulinemia was more pronounced in AA (P < 0.05) than CA, extending throughout the day, and was accompanied by reduced glucose increments in response to meals (P < 0.05), not seen in CA. Levels of the insulin-dependent IGFBP-1 were markedly elevated (P < 0.001) throughout the diurnal pattern in AA, whereas in CA, a modest elevation (P < 0.001) of IGFBP-1 levels occurred only during the feeding portion of the day. IGFBP-1 levels for the three groups related inversely to 24-h insulin (r = -0.63) and directly to 24-h cortisol (r = 0.69) levels. A 70-80% augmentation (P < 0.001) of 24-h mean GH levels was seen in both groups of athletes, but with distinct pulsatile features. Although pulse amplitude was increased 60% in CA with no change in pulse number, AA displayed more frequent (P < 0.001) pulses, with an elevated (P < 0.01) baseline between pulses. The distorted pattern of GH pulses seen in AA was associated with a 35% decrease in GHBP levels, not seen in CA. Although levels of IGF-I and IGFBP-3 did not differ in either CA or AA, the 2- to 4-fold higher levels of IGFBP-1 in AA than in CA and CS resulted in a 3-fold reduced ratio of IGF-I/IGFBP-1 in AA, which may decrease the bioactivity and hypoglycemic effect of IGF-I. LH pulse frequency was progressively attenuated in the athletes, with a greater (P < 0.001) slowing in AA than CA, unaccompanied by alterations in pulse amplitude or 24-h levels. LH pulse frequency was related positively with insulin (r = 0.65) levels and the ratio of IGF-I/IGFBP-1 (r = 0.69), and negatively with cortisol (r = -0.70) and IGFBP-1 (r = -0.75) concentrations. Stepwise regression analysis suggested that negative influences associated with hypercortisolemia and elevated IGFBP-1 levels predominate in determining GnRH/LH pulsatile activity in these athletes. In sum, although neuroendocrine-metabolic adaptations to the energy cost of exercise training were evident in both groups of athletes, AA displayed alterations distinct from their cycling counterparts, with evidence of a hypometabolic state, including decreased basal body temperature and reduced levels of plasma glucose and serum GHBP, a decrease in the ratio of IGF-I/IGFBP-1, accelerated GH pulse frequency, and elevated interpulse GH levels. Thus, in AA, increased insulin sensitivity, decreased circulating insulin, and a reduced hypoglycemic effect of IGF-I together with elevated GH and cortisol concentrations may comprise a cascade of glucoregulatory adaptations to repartition metabolic fuels for conservation of protein. (ABSTRACT TRUNCATED)

Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women.

Attenuation of the GH and insulin-like growth factor I (IGF-I) axis in aging may be responsible for changes in body composition and metabolism. This relationship has been confirmed by studies of recombinant human GH replacement in aging men and women, but the adverse effects encountered limit its clinical utility. The use of GHRH or its analogs may be an alternative mode for restoring the GH-IGF-I axis in aging individuals. Here we report the endocrine-metabolic changes in response to a GHRH analog in age-advanced men and women. A single blind, randomized, placebo-controlled trial of 5 months duration was conducted. Ten women and 9 men between the ages of 55-71 yr self-injected placebo (saline) s.c. nightly for 4 weeks followed by 16 weeks of [Nle27]GHRH-(1-29)-NH2 at a dose of 10 microg/kg. Subjects underwent 12-h nocturnal (2000-0800 h) frequent blood sampling (10-min intervals) and 24-h urine collection at baseline, after 4 weeks of placebo injections, and after 16 weeks of GHRH analog administration. GH responses to GHRH analog and spontaneous GH pulsatility were assessed. Subjects were also monitored 2, 4, 8, and 12 weeks after commencement of GHRH analog treatment. Blood pressure, body weight, and fasting insulin and glucose levels were recorded at each visit. Serum concentrations of IGF-I, IGF binding protein-1 (IGFBP-1), IGFBP-3, GH-binding protein (GHBP), lipids, and safety laboratory tests (complete blood count and chemistry profile) were measured in fasting samples (0800-0900 h). Body composition was determined by dual energy x-ray absorptiometry scan, and skin thickness was measured at four sites, including the right and left hand and volar forearm, by Harpenden skin calipers. Insulin sensitivity was assessed by a frequently sampled i.v. glucose tolerance test. Quality of life parameters, including sleep, were evaluated through self-administered questionnaires. Nightly GHRH analog administration at 2100 h induced, within 10 min, an acute release of GH, which lasted for 2 h. The GH-releasing effect of GHRH analog was sustained during the course of the study. Compared with placebo, GHRH analog induced a significant increase in 12-h integrated nocturnal GH levels in women (P < 0.01) and men (P < 0.05). This was accompanied, within 2 weeks, by increased serum levels of IGF-I (P < 0.05) and IGFBP-3 (P < 0.001), but not IGFBP-1, which remained elevated for 12 weeks, returning toward baseline by 16 weeks in both genders. Within 4 weeks, GHBP concentrations were significantly increased (P < 0.01) in women, but not in men. Although blood pressure and body weight were unaffected, GHRH analog treatment resulted in a significant increase in skin thickness (P < 0.05) in both genders and increased lean body mass in men only (P < 0.05), with no other changes in body composition or bone mineral density in either gender. There was a trend for a positive nitrogen balance in both genders, which became significant (P = 0.03) when the data were combined. Fasting insulin and glucose levels were unaltered, but a significant increase in insulin sensitivity occurred in men (P < 0.05), but not in women. Assessment of quality of life parameters revealed a significant improvement in general well-being (P < 0.05) and libido (P < 0.01) in men, but not in women, and sleep quality was unaffected in both genders. The only adverse side-effect was transient hyperlipidemia, which resolved by the end of the study. We conclude that nightly administration of GHRH analog for 4 months in age-advanced men and women activated the somatotropic axis. Although an increase in skin thickness was found in both genders, increases in lean body mass, insulin sensitivity, general well-being, and libido occurred in men but not in women. These observations suggest that GHRH analog administration induced anabolic effects favoring men more than women. Further studies are needed to define the gender differences observed in response to GHRH analog administration.

Melatonin rhythms in women with anorexia nervosa and bulimia nervosa.

To discern whether the multiple neuroendocrine-metabolic dysfunctions observed in women with anorexia nervosa (AN) and bulimia nervosa (BN) are associated with altered diurnal variations in serum melatonin profiles, we compared cycling and amenorrheic women with normal weight BN (n = 8) and AN (n = 7) to 21 normal cycling controls. Endogenous depression, which has confounded prior studies of melatonin profiles in women with eating disorders, was excluded in all subjects. Serum samples for melatonin measurements were obtained at frequent intervals (every 20 min) in a controlled light-dark environment, and cycling women were studied in the early follicular phase of the menstrual cycle. Mean (+/- SE) peak melatonin levels were similar in AN, BN, and controls (325 +/- 43, 310 +/- 33, and 334 +/- 30 pmol/L, respectively). The time of melatonin peak, the time of onset and offset of the nocturnal serum melatonin excursion, and the duration of the nocturnal elevation were also similar in the three groups. Analysis of covariance revealed no independent effects of age or time of year on the data. Moreover, when subjects were separated into those with and without menstrual cyclicity, no significant differences in any parameter of melatonin diurnal variation were observed. Taken together, these data suggest that pineal melatonin secretion is unaltered in women with eating disorders, in whom depression is excluded, and that the frequent occurrence of amenorrhea in this population is not mediated by melatonin.

Accelerated 24-hour luteinizing hormone pulsatile activity in adolescent girls with ovarian hyperandrogenism: relevance to the developmental phase of polycystic ovarian syndrome.

A study was initiated to delineate the neuroendocrine characteristics of hyperandrogenic adolescent girls with the aim of discerning features that may relate to the pubertal onset of the polycystic ovarian syndrome. Thirteen 11- to 18-yr-old girls with mild to moderate signs of hyperandrogenism (HA) and increased ovarian volume and 28 age-matched normal girls were recruited for the study. LH pulsatility and FSH levels were analyzed based on serum concentrations measured with sensitive immunofluorometric assays in samples taken at 10-min intervals for 24 h under basal conditions, GnRH antagonist (Nal-Glu) suppression, and dexamethasone suppression. Adrenal and ovarian contributions to serum cortisol, dehydroepiandrosterone, androstenedione, testosterone (T), estrone (E1), estradiol (hourly), 17-hydroxypregnenolone, and 17-hydroxyprogesterone (17PO) concentrations were compared during basal and suppression conditions and after gonadotropin and adrenal stimulations by bolus GnRH (10 micrograms) and CRF (1 microgram/kg). The progression from sleep-augmented pulsatile LH secretion to higher LH levels during wake than sleep observed during normal pubertal development occurred 2 yr earlier in the HA group. The number of LH pulses was significantly higher in the HA group during both sleep and waking, whereas pulse amplitude was higher only during the awake time. Thus, mean LH was 2.0-fold higher during the awake time and only 1.6-fold higher during sleep in the HA group compared to the normal group. The elevation of FSH in HA was small relative to that of LH, resulting in an increased LH/FSH ratio (P < 0.008). The HA group had higher concentrations of 17PO (1.8-fold), androstenedione (1.9-fold), T (2.4-fold), and E1 (1.7-fold) than the normal group (all P < 0.001), with no alteration in circadian rhythm. These elevated steroid levels were significantly correlated with LH levels in the basal state and decreased in proportion to the change in LH during Nal-Glu suppression. During adrenal suppression with dexamethasone, concentrations of cortisol, dehydroepiandrosterone, and 17-hydroxypregnenolone decreased in both groups (P < 0.001), but significant suppression of 17PO, T, and E1 occurred only in the normal girls, indicating the ovarian origin of the increased levels of these steroids with enhanced expression of 17 alpha-hydroxylase activity in HA girls.(ABSTRACT TRUNCATED AT 400 WORDS)

A circadian rhythm of serum follicle-stimulating hormone in women.

While a nocturnal decline in serum LH levels in the early follicular phase of the menstrual cycle has been well established, a diurnal variation in serum FSH levels in women has not been demonstrated. We addressed this issue by determining serum LH and FSH levels at 15-min intervals for 24 h in the early follicular phase (EFP; n = 16) and late follicular phase (LFP; n = 10) of the menstrual cycle and in postmenopausal women (PMW; n = 10). Serum estradiol was simultaneously measured at hourly intervals. As expected, EFP, but not LFP and PMW, women had a 15% nocturnal decline (P less than 0.01) in transverse mean LH levels compared to values in the daytime hours. In contrast, nocturnal FSH transverse mean values were significantly lower than daytime values in all groups studied, demonstrating an 18% decline in EFP (P less than 0.001), a 17% decline in LFP (P less than 0.00001), and a 4.3% decline in PMW (P less than 0.01). Cosinor analysis revealed a circadian rhythm for FSH, with acrophases in the afternoon and nadirs at night in all three groups. The circadian amplitudes were 1.43 +/- 0.22, 1.02 +/- 0.16, and 8.42 +/- 1.31 IU/L for EFP, LFP, and PMW, respectively. The EFP nocturnal decline in LH did not conform to a cosine rhythm. A diurnal variation in estradiol was not present in any of the groups of women. These data constitute the first demonstration of a robust circadian rhythm of serum FSH in women. The comparable timing of the acrophase in all groups of subjects and its presence in the postmenopausal years suggest a central, rather than peripheral, feedback mechanism(s) for the circadian rhythmicity. This observation provides strong evidence for a dissociation in the hypothalamic regulation of pituitary LH and FSH secretion in women. The circadian peak and nadir of circulating FSH may prove to be determining for appropriate follicular development.

Marked augmentation of nocturnal melatonin secretion in amenorrheic athletes, but not in cycling athletes: unaltered by opioidergic or dopaminergic blockade.

Exercise of sufficient intensity during daylight hours has been demonstrated to result in an acute elevation of circulating melatonin levels. The possibility that repeated elevations of daytime melatonin secretion may result in alterations of the nocturnal maxima of the circadian rhythm in highly trained athletic women with and without amenorrhea was investigated. Twenty-four-hour melatonin profiles in matched cyclic sedentary (CS; n = 10) women, cyclic athletic (CA; n = 10) women, and amenorrheic athletic (AA; n = 8) women were compared. The roles of endogenous opioids and dopamine as potential modulators of melatonin secretion were also evaluated by comparing the melatonin profiles during sequential 24-h infusions of saline, followed by either naloxone or metoclopramide (both at 30 micrograms/kg.h). Elevated (P less than 0.05) mean daytime (1000-1700 h) melatonin levels were observed in both groups of athletic women compared to sedentary women. In contrast, nocturnal melatonin levels in sedentary and athletic cycling women were indistinguishable, while amenorrheic athletic women displayed a marked increase in nocturnal peak amplitude (P less than 0.001 vs. CS and CA) and a 2-h delay in offset (P less than 0.001 vs. CS and CA), which yielded a 2-fold amplification of the integrated nocturnal melatonin secretion (P less than 0.001 vs. CS and CA). The onset of the nocturnal rise did not differ among the three groups. Opioidergic and dopaminergic blockade with naloxone and metoclopramide at the doses used did not alter any parameter of melatonin secretion in any of the three groups of women. In conclusion, athleticism in women is associated with an elevation of daytime melatonin levels independent of menstrual status. AA women, but not CA women, display a 2-fold amplification of nocturnal melatonin secretion with a 2-h delay of offset, which does not seem to be linked to athleticism per se. The significance and neuroendocrine basis for the expanded melatonin secretion in athletic amenorrheic women remains to be elucidated.

Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia.

Polycystic ovary syndrome (PCOS) is associated with chronic anovulation, hyperandrogenemia, insulin resistance (IR)/hyperinsulinemia, and a high incidence of obesity. Thus, PCOS serves as a useful model to assess the role of IR and chronic endogenous insulin excess on leptin levels. Thirty-three PCOS and 32 normally cycling (NC) women of similar body mass index (BMI) were studied. Insulin sensitivity (S(I)) was assessed by rapid ivGTT in a subset of 28 PCOS and 29 NC subjects; percent body fat was determined by dual-energy x-ray absorptiometry (DEXA) in 14 PCOS and 17 NC. Fasting (0800 h) and 24-h mean hourly insulin levels were 2-fold higher (P < 0.0001), and S(I) was 50% lower (P = 0.005) in PCOS than in NC, while serum androstenedione (A), testosterone (T), 17-alpha hydroxyprogesterone (17OHP), and estrone (E1) levels were elevated (P < 0.0001), and sex hormone-binding globulin (SHBG) levels were decreased (P < 0.01). Twenty-four hour LH pulse frequency, mean pulse amplitude, and mean LH levels were elevated in PCOS (P < 0.001) as compared with NC. Serum leptin levels for PCOS (24.1 +/- 2.6 ng/mL) did not differ from NC (21.5 +/- 3.5 ng/mL) and were positively correlated with BMI (r = 0.81) and percent body fat (r = 0.91) for the two groups (both P < 0.0001). Leptin levels for PCOS and NC correlated positively with fasting and 24-h mean insulin levels (r = 0.81, P < 0.0001 for both PCOS and NC) and negatively with S(I) and SHBG levels. Leptin concentrations for PCOS, but not NC, correlated positively with 24-h mean glucose levels and inversely with 24-h mean LH levels and 24-h mean LH pulse amplitude. Leptin levels were not correlated with estrogen or androgen levels for either PCOS or NC, although leptin levels were positively related to the ratios of E1/SHBG and E2/SHBG for both PCOS and NC and to the ratio of T/SHBG for PCOS only. In stepwise multivariate regression with forward selection, only 24-h mean insulin levels contributed significantly (P < 0.01) to leptin levels independent of BMI and percent body fat for both PCOS and NC. Given this relationship and the presence of 2-fold higher 24-h mean insulin levels in PCOS, the expected elevation of leptin levels in PCOS was not found. This paradox may be explained by the presence of adipocyte IR specific to PCOS, which may negate the stimulatory impact of hyperinsulinemia on leptin secretion, a proposition requiring further study.

Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity.

In recent years, there has been uncertainty concerning the association of inappropriate gonadotropin secretion (high LH and normal FSH) and the polycystic ovary syndrome (PCOS). In the present study, we ascertained the influence of body composition on LH pulsatile parameters in 33 PCOS and 32 normal cycling (NC) women across a wide range of body mass index (BMI, 19-42 kg/m2). Twenty four-hour pulsatile parameters for serum LH (10-min sampling) and pituitary gonadotropin responses to i.v. bolus GnRH (10 micrograms) were evaluated. Fasting (0800 h) FSH and steroid hormone concentrations and 24-h mean insulin levels were determined. Insulin sensitivity (SI) was assessed by rapid i.v. glucose tolerance test in a subset of 28 PCOS and 29 NC subjects. Our results showed that BMI, an indicator of relative adiposity, had a significant negative impact on 24-h mean LH pulse amplitude (r = -0.63, P < 0.001) and the peak increment of LH in response to GnRH stimulation (r = -0.41; P = 0.02) for PCOS but not NC women. In contrast, 24-h LH pulse frequency was uniformly increased (40%) in PCOS as compared with NC women independent of BMI. In PCOS women, the blunting of pulse amplitude with increasing BMI resulted in a decline in 24-h mean LH levels (r = -0.63, P < 0.001) and the ratio of LH/FSH (r = -0.44, P = 0.02) not seen in NC. With BMI < 30 kg/m2, 24-h mean LH values for PCOS women were greater than the normal range for NC in 95% (18/19) of cases, whereas 24-h LH levels failed to discriminate PCOS from NC women in 43% (6/14) of obese (BMI > 30 kg/m2) PCOS women. Thus, the diagnostic value of LH determinations is retained for PCOS women with BMI < 30 kg/m2. For screening purposes, the mean of two LH values in samples collected at 30-min intervals was found to have a discriminatory power equal to that of the 24-h mean. These findings suggest that 1) BMI negatively influences LH pulse amplitude in PCOS women principally by an effect at the pituitary level; 2) accelerated LH pulse frequency in PCOS women is not influenced by BMI and represents a basic component of hypothalamic dysfunction in PCOS women; and 3) BMI does not influence gonadotropin secretion in normal cycling women. Thus assessments of basal LH levels and the LH/FSH ratio in hyperandrogenic anovulatory women are clinically meaningful when BMI is taken into account. Investigations to define the factor(s) that link adiposity and the attenuation of LH pulse amplitude in PCOS women would add further understanding of this complex neuroendocrine-metabolic disorder.

Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism.

Recently, we reported that hyperandrogenism in adolescent girls is accompanied by augmented LH pulsatility and elevated LH/FSH ratio with increased ovarian volume. Together with higher concentrations of 17-hydroxyprogesterone, androstenedione, testosterone, and estrone that are ovarian in origin, these neuroendocrine features are identical to those seen in adult women with polycystic ovary syndrome. In the present study, we report the metabolic characteristics of these hyperandrogenic adolescent girls. The GH insulin-like growth factor I (IGF-I)-binding protein (BP)-3 axis, insulin sensitivity, and insulin-IGFBP-1/insulin sex hormone binding globulin axes were evaluated in 13 adolescent girls (ages 11-18 yr) with mild to moderate signs of hyperandrogenism (HA) and 28 age-matched normal girls. Insulin sensitivity was assessed by a frequent-sample iv glucose tolerance test (ivGTT, 0.3 g/kg). Twenty-four hour blood samples were obtained at 10-min intervals and were used to determine GH pulsatility (20-min samples), IGFBP-3 levels (0800-0900 h), and fluctuations of insulin, IGFBP-1, and IGF-I (hourly samples) during feeding and fasting phases of the day. In addition, GH responses to GHRH stimulation (1 microgram/kg) were assessed. Fasting insulin concentrations, but not plasma glucose levels, were significantly elevated in the HA group compared with those in the normal group (256 +/- 35 vs. 103 +/- 24 pmol/L, P = 0.0008), as were insulin responses to ivGTT and meals (P < 0.01) and 24-h mean insulin concentrations (P < 0.01). Thus, hyperinsulinemia with normal fasting glucose levels in HA girls may reflect insulin resistance, as suggested by the increased ratio of insulin and glucose (P < 0.001). All measures of insulin were correlated with body mass index (BMI); however, insulin remained significantly higher in the HA group after correcting for BMI, suggesting that decreased insulin sensitivity was related to other factors in addition to BMI. Twenty-four hour IGFBP-1 concentrations showed a diurnal pattern with an inverse relationship to insulin, and 24-h mean concentrations were lower in the HA group (0.35 +/- 0.13 vs. 0.76 +/- 0.09 micrograms/L, P = 0.02). Reduced sex hormone binding globulin levels were also inversely related to insulin levels (P = 0.0007). In contrast, GH pulsatile characteristics and IGF-I/IGFBP-3 levels, as well as GH responses to GHRH, were similar between the groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Gonadotropin-releasing hormone pulse generator activity during pubertal transition in girls: pulsatile and diurnal patterns of circulating gonadotropins.

To delineate the activity of the GnRH pulse generator during pubertal transition, 40 healthy girls 7-18 yr of age were studied. Ten were prepubertal (PP), 7 were in early puberty (EP), and 23 were in late puberty (LP, all postmenarcheal). Serum concentrations of LH and FSH were measured with immunofluorometric assays, which have a sensitivity about 100-fold that of RIA, in samples taken at 10-min intervals for 24 h during basal conditions, during Nal-Glu antagonist suppression, and in response to GnRH stimulation (10 micrograms). Serum levels of androstenedione, testosterone, and estradiol were measured with RIA. A pulsatile pattern of LH and FSH secretion was found in girls of all ages. PP girls had irregular LH pulses with low amplitudes during the daytime, but increased amplitude LH and FSH pulses were evident within 1 h after sleep-onset. Older PP girls had more regular and higher amplitude pulses throughout sleep than younger PP girls. The sleep-related LH and FSH pulses in PP girls were abolished with Nal-Glu GnRH antagonist treatment, reflecting endogenous GnRH pulse activities. The PP group had the most pronounced amplification of LH secretion with sleep yielding a sleep-wake ratio of 4, which decreased to 2 in the EP group and to 1 in the LP group. The emergence of regular daytime LH pulses along with a further amplification of pulsatile activity during sleep was closely related to the onset of breast development. By the age of 16 yr, an LH secretory pattern characteristic of adult women in the early follicular phase, i.e. a decrease in LH concentration during sleep, was established. Mean 24-h LH concentrations increased 40-fold from PP to LP consequent to a 9-fold increase in pulse amplitude and a 4-fold increase in pulse number (both P < 0.0001). Mean FSH concentrations (24 h), which were 20-fold higher than corresponding LH concentrations in the PP group, increased only 3-fold from the PP to the LP group. FSH pulse secretion appears to be predominantly GnRH dependent in PP girls in contrast to girls after ovarian activation, as indicated by the increased FSH responses to both GnRH antagonist suppression and GnRH stimulation in the PP as compared to the EP and LP groups. We conclude that the GnRH pulse generator is functionally active in prepubertal girls with selective expression of LH and FSH pulses after the onset of sleep. The onset of puberty is associated with a greater increase in LH pulse amplitude than frequency.(ABSTRACT TRUNCATED AT 400 WORDS)