Clinically relevant hormone treatments fail to induce spinogenesis in prefrontal cortex of aged female rhesus monkeys.

Preclinical animal models have provided strong evidence that estrogen (E) therapy (ET) enhances cognition and induces spinogenesis in neuronal circuits. However, clinical studies have been inconsistent, with some studies revealing adverse effects of ET, including an increased risk of dementia. In an effort to bridge this disconnect between the preclinical and clinical data, we have developed a nonhuman primate (NHP) model of ET combined with high-resolution dendritic spine analysis of dorsolateral prefrontal cortical (dlPFC) neurons. Previously, we reported cyclic ET in aged, ovariectomized NHPs increased spine density on dlPFC neurons. Here, we report that monkeys treated with cyclic E treatment paired with cyclic progesterone (P), continuous E combined with P (either cyclic or continuous), or unopposed continuous E failed to increase spines on dlPFC neurons. Given that the most prevalent form of ET prescribed to women is a combined and continuous E and P, these data bring into convergence the human neuropsychological findings and preclinical neurobiological evidence that standard hormone therapy in women is unlikely to yield the synaptic benefit presumed to underlie the cognitive enhancement reported in animal models.

Early exposure to wildfire smoke can lead to birth defects.

The results of two previously published reports of the events and impacts of the Campfire wildfire smoke exposure that occurred in California in 2018 are amplified from the point of view of the potential toxic mechanism involved. The Campfire wildfire led to the exposure of a breeding colony of macaque monkeys (Macaca mulatta) during the peak of their breeding season in 2018-2019. Considering the timing, adverse effects, and endocrine implications reported, the cumulative evidence points to an early toxic sensitive period that can lead to birth defects in higher primates and human pregnancies. This deeper inspection of the published observations provides important caveats and useful guidance for future investigators. The unique higher primate placental-adrenal-brain axis may limit the use of many traditional toxicologic approaches. Retrospective neurological evaluations of human fetuses exposed to air pollutants during organogenesis and subsequent retrospective characterization of air samples using in vitro and animal models may be the best procedures to follow.

Costs and consequences of cellular compartmentalization and substrate competition among human enzymes involved in androgen and estrogen synthesis.

The impact of compartmental expression of steroidogenic enzymes and of changes in flux through delta5 and delta4 metabolism on sex steroid synthesis was investigated by rebuilding pathways using recombinant enzyme expression by infection of insect cells with recombinant baculovirus constructs. Human cytochromes 17alpha-hydroxylase/17,20-lyase (P450c17) and aromatase (P450arom), always coexpressed with their redox partner NADPH-P450 oxidoreductase (CPR) and 3beta-hydroxysteroid dehydrogenase/delta5-4 isomerase (3betaHSD; types 1 or 2), were compartmentally expressed in different cell populations or coexpressed together with pregnenolone (100 nM) as substrate. Estrone was compared among cell compartments expressing different enzyme combinations or in cells coexpressing all enzymes (experiment 1). Additionally, P450c17, 3betaHSD, and CPR were all coexpressed, and androstenedione was measured in cells with different 3betaHSD expression levels or activity using an inhibitor, trilostane (experiment 2). Steroids were measured by immunoassay and mass spectrometry. In experiment 1, partitioning of P450c17, P450arom, and 3betaHSD markedly decreased estrone synthesis in comparison to cells coexpressing enzymes in different combinations. However, partitioning P450arom with 3betaHSD from P450c17 in different cell populations resulted in more estrone than either of the other two-cell compartment models. In experiment 2 (cells coexpressing P450c17, 3betaHSD, and CPR), androstenedione secretion was (paradoxically) higher at lower levels of 3betaHSD, and partial inhibition of 3betaHSD by trilostane also increased androstenedione when 3betaHSD expression was high. We conclude 1) that tissue or cell-specific, partitioned expression of sex steroid synthesizing enzymes limits rather than maximizes estrogen synthesis and 2) that limiting metabolism by 3betaHSD can paradoxically promote androgen synthesis when 3betaHSD expression is high by promoting delta5-steroid flux.

Adverse biobehavioral effects in infants resulting from pregnant rhesus macaques' exposure to wildfire smoke.

As wildfires across the world increase in number, size, and intensity, exposure to wildfire smoke (WFS) is a growing health problem. To date, however, little is known for any species on what might be the behavioral or physiological consequences of prenatal exposure to WFS. Here we show that infant rhesus monkeys exposed to WFS in the first third of gestation (n = 52) from the Camp Fire (California, November, 2018) show greater inflammation, blunted cortisol, more passive behavior, and memory impairment compared to animals conceived after smoke had dissipated (n = 37). Parallel analyses, performed on a historical control cohort (n = 2490), did not support the alternative hypothesis that conception timing alone could explain the results. We conclude that WFS may have a teratogenic effect on the developing fetus and speculate on mechanisms by which WFS might affect neural development.

Effects of the 2018 Camp Fire on birth outcomes in non-human primates: Case-control study.

The November 2018 Camp Fire, a devastating wildfire in Northern California, occurred during the peak of breeding season for field monkeys at the California National Primate Research Center (CNPRC). Effects of environmental stressors, such as wildfires, on birth outcomes in primates, and in humans, are poorly understood. Additionally, wildfires are of growing concern due to their increasing frequency and severity. The objective was to examine the impact of wildfire smoke on fertility, timing of birth, and pregnancy loss for field monkeys. A unique case-control study to investigate birth outcomes in rhesus macaques (Macaca mulatta) was conducted at the CNPRC. All females in the study were maintained in outdoor fields during a period of elevated ambient wildfire smoke from November 8-22, 2018. In addition to ambient air quality evaluations, the effects on fertility, timing to birth, and pregnancy loss were documented. Archival records of approximately 5,000 conceptions from the previous nine years served as control data. During the Camp Fire, ambient fine particulate (PM 2.5) levels exceeded the 24 -h National Ambient Air Quality Standard (35 µg/m 3) of the United States Environmental Protection Agency, reaching levels as high as 185 µg/m 3. A statistically significant association was observed between birth loss and the 2018-2019 CNPRC breeding season. As this wildfire event occurred during various stages of early pregnancy, an association can be inferred between early gestational exposure and increased risk of pregnancy loss.

Lowered progesterone metabolite excretion and a variable LH excretion pattern are associated with vasomotor symptoms but not negative mood in the early perimenopausal transition: Study of Women's Health Across the Nation.

OBJECTIVE: The menopausal transition is characterized by progressive changes in ovarian function and increasing circulating levels of gonadotropins, with some women having irregular menstrual cycles well before their final menstrual period. These observations indicate a progressive breakdown of the hypothalamic-pituitary-ovarian axis often associated with an increase in menopausal symptoms. Relationships between vasomotor symptoms (VMS) and depressed mood and sleep as well as a bidirectional association between VMS and depressed mood in mid-life women have been reported, but the endocrine foundations and hormone profiles associated with these symptoms have not been well described. Our objective was to determine the relationship between daily urinary hormone profiles and daily logs of affect and VMS during the early perimenopausal transition. STUDY DESIGN: SWAN, the Study of Women's Health Across the Nation, is a large, mutli-ethnic, multisite cohort study of 3302 women aged 42-52 at baseline, designed to examine predictors of health and disease in women as they traversed the menopause. Inclusion criteria were: an intact uterus and at least one ovary present, at least one menstrual period in the previous three months, no use of sex steroid hormones in the previous three months, and not pregnant or lactating. A subset (n = 849) of women aged 43-53 years from all study sites in the first Daily Hormone Study collection were evaluated for this substudy. OUTCOME MEASURES: We measured daily VMS, and urinary hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), pregnanediol glucuronide (PdG) and estradiol (estrone conjugate, E1C). RESULTS: A variable pattern of LH and negative LH feedback were the hormone patterns most strongly associated with increased VMS. In contrast, no hormone pattern was significantly related to negative mood. CONCLUSION: Fluctuations of LH associated with low progesterone production were associated with VMS but not negative mood, suggesting different endocrine patterns may be related to increased negative mood than to the occurrence of VMS.

Impact of adrenal hormones, reproductive aging, and major depression on memory circuitry decline in early midlife.

Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen that is, in part, aromatized to estradiol. It continues to be produced after menopause and provides estrogenicity after depletion of ovarian hormones. Estradiol depletion contributes to memory circuitry changes over menopause, including changes in hippocampal (HIPP) and dorsolateral- and ventrolateral-prefrontal cortex (DLPFC; VLPFC) function. Further, major depressive disorder (MDD) patients have, in general, lower levels of estradiol and lower DHEAS than healthy controls, thus potentially a higher risk of adverse menopausal outcomes. We investigated whether higher DHEAS levels after menopause is associated with better memory circuitry function, especially in women with MDD. 212 adults (ages 45-55, 50% women) underwent clinical and fMRI testing. Participants performed a working memory (WM) N-back task and an episodic memory verbal encoding (VE) task during fMRI scanning. DHEAS levels were significantly associated with memory circuitry function, specifically in MDD postmenopausal women. On the WM task, lower DHEAS levels were associated with increased HIPP activity. On the VE task, lower DHEAS levels were associated with decreased activity in the HIPP and VLPFC. In contrast, there was no association between DHEAS levels and memory circuitry function in MDD pre/perimenopausal women, men, and non-MDD participants regardless of sex and reproductive status. In fact, MDD postmenopausal women with higher levels of DHEAS were similar to MDD pre/perimenopausal women and men. Thus, memory circuitry deficits associated with MDD and a lower ability of the adrenal gland to produce DHEAS after menopause may contribute to a lower ability to maintain intact memory function with age.

Triclocarban enhances testosterone action: a new type of endocrine disruptor?

Many xenobiotics have been associated with endocrine effects in a wide range of biological systems. These associations are usually between small nonsteroid molecules and steroid receptor signaling systems. In this report, triclocarban (TCC; 3,4,4'-trichlorocarbanilide), a common ingredient in personal care products that is used as an antimicrobial agent was evaluated and found to represent a new category of endocrine-disrupting substance. A cell-based androgen receptor-mediated bioassay was used to demonstrate that TCC and other urea compounds with a similar structure, which have little or no endocrine activity when tested alone, act to enhance testosterone (T)-induced androgen receptor-mediated transcriptional activity in vitro. This amplification effect of TCC was also apparent in vivo when 0.25% TCC was added to the diet of castrated male rats that were supported by exogenous testosterone treatment for 10 d. All male sex accessory organs increased significantly in size after the T+TCC treatment, compared with T or TCC treatments alone. The data presented here suggest that the bioactivity of endogenous hormones may be amplified by exposure to commercial personal care products containing sufficient levels of TCC.

Sex Differences in the Prenatal Programming of Adult Metabolic Syndrome by Maternal Androgens.

Context: Growing preclinical evidence suggests that hormonal programming by androgens in utero may contribute to cardiovascular disease risk in adult offspring. However, the effect of prenatal androgens on cardiometabolic outcomes in the human population, especially their potential differential impact on male vs female offspring, has not been well studied. Design: Adult offspring (n = 274) of mothers enrolled in the New England birth cohorts of the Collaborative Perinatal Project were assessed at ages 39 to 50. Androgen bioactivity was measured in maternal serum during the third trimester using a receptor-mediated luciferase expression bioassay. Metabolic syndrome (MetS) using Adult Treatment Panel III criteria was assessed in adult offspring. Bioactive androgens were analyzed as quartiles, with the lowest quartile (Q1) defined as the reference. Generalized estimating equations were used to evaluate the relationship of maternal bioactive androgens on offspring MetS risk overall and by sex, controlling for potential confounders and intrafamilial correlation. Results: Mean age and body mass index of adult offspring were 44.7 ± 2.6 years and 29.7 ± 6.7 kg/m2, respectively. Participants born to mothers with the highest quartile (Q4) compared with Q1 of bioactive androgens had higher risk for MetS [adjusted odds ratio (aOR): 2.53(1.07 to 6.02)]. Stratified by sex, this association was found to be significant among women [Q4 vs Q1; aOR: 4.06 (1.10 to 14.93)] but not men [Q4 vs Q1; aOR: 1.67 (0.53 to 5.26)]. Women born to mothers with the highest levels of maternal bioactive androgens also demonstrated a 4.84-fold increased odds for having hypertension [Q4 vs Q1; aOR: 4.84 (1.12 to 20.85)]. Conclusion: Higher levels of maternal androgens were associated with increased risk for incident MetS in adult offspring, an effect that was significant in women but not men.

Sex-hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN).

BACKGROUND: Recent clinical trials have shifted attention away from estrogens and toward androgens and sex hormone-binding globulin (SHBG) as potential mediators of increasing cardiovascular (CV) risk in women at midlife. METHODS AND RESULTS: The correlation between reproductive hormones and CV risk factors was evaluated in a multiethnic (white, black, Hispanic, Chinese, and Japanese) sample of 3297 premenopausal and perimenopausal women. Testosterone and estradiol (E2) were evaluated along with SHBG and the free androgen index (FAI), the amount of testosterone not bound by SHBG. Low SHBG and high FAI were strongly and consistently related to elevated CV risk factors (higher insulin, glucose, and hemostatic and inflammatory markers and adverse lipids) even after controlling for body mass index (P<0.001 for all). Low levels of E2 were associated with elevated CV risk factors to a lesser degree. These observations were consistent across the 5 ethnic groups. Compared with whites, blacks had higher levels of SHBG and lower levels of FAI, and Chinese had lower levels of SHBG and higher levels of FAI. CONCLUSIONS: Low SHBG and high FAI are strongly associated with CV risk factors in racially diverse women, and thus, androgens likely play a role in the CV risk profile of perimenopausal women.

Circulating bioactive androgens in midlife women.

CONTEXT: It is important to characterize the biological activity of circulating androgenic steroid hormones during the menopausal transition because these appear to impact the metabolic and cardiovascular health risk factors of women. OBJECTIVE: The objective of the study was to develop and characterize a cell-based bioassay that measures the androgen receptor-mediated signal transduction in serum. DESIGN: This was a clinically relevant experimental study nested in a sample population of a longitudinal cohort study. SETTING: The study was conducted at a university laboratory. METHODS: A receptor-mediated luciferase expression bioassay based on HEK 293 cells that were stably cotransfected with plasmids containing the human androgen receptor and luciferase gene was developed. In 49 samples from menstruating women aged 42-52 yr, total testosterone (T) and SHBG concentrations were measured by immunoassay; free T concentrations were calculated from the total T and SHBG concentrations. RESULTS: Mean total T concentration of the sample was 1.15 nm (sd 0.46, range 0.57-3.86 nm). The mean bioactive androgen detected was 1.00 nm (sd 0.24, range 0.53-1.60 nm). Calculated free T (mean 0.0156 nm) was significantly lower than the levels of bioactive androgens measured by receptor-mediated bioassay. There was significant positive correlation between bioactive androgen levels and total T values in young women and polycystic ovarian disorder patients, whereas no correlation was found between the two values in middle-aged women. CONCLUSIONS: An androgen receptor-mediated bioassay can provide additional information in the evaluation of total bioactive androgens in midlife women. Our data suggest that levels of circulating SHBG may have a significant impact on the levels of total circulating bioavailable androgens.

Granulosa cell tumors of the equine ovary.

The granulosa cell tumor is the most common ovarian tumor in mares. A clinical diagnosis can be made based on the presence ofa unilaterally enlarged ovary and a small inactive contralateral ovary. Endocrine testing may be beneficial to confirm a diagnosis. Surgical removal of the tumor eliminates the adverse effect on pituitary function and results in resumption of follicular development and ovulation in the opposite ovary over time.

Characterizing the trajectories of vasomotor symptoms across the menopausal transition.

OBJECTIVE: The aim of the study was to investigate the heterogeneity of temporal patterns of vasomotor symptoms (VMS) over the menopausal transition and identify factors associated with these patterns in a diverse sample of women. METHODS: The Study of Women's Health Across the Nation is a multisite longitudinal study of women from five racial/ethnic groups transitioning through the menopause. The analytic sample included 1,455 women with nonsurgical menopause and a median follow-up of 15.4 years. Temporal patterns of VMS and associations with serum estradiol and follicle-stimulating hormone, race/ethnicity, body mass index, and demographic and psychosocial factors were examined using group-based trajectory modeling. RESULTS: Four distinct trajectories of VMS were found: onset early (11 years before the final menstrual period) with decline after menopause (early onset, 18.4%), onset near the final menstrual period with later decline (late onset, 29.0%), onset early with persistently high frequency (high, 25.6%), and persistently low frequency (low, 27.0%). Relative to women with persistently low frequency of VMS, women with persistently high and early onset VMS had a more adverse psychosocial and health profile. Black women were overrepresented in the late onset and high VMS subgroups relative to white women. Obese women were underrepresented in the late onset subgroup. In multivariable models, the pattern of estradiol over the menopause was significantly associated with the VMS trajectory. CONCLUSIONS: These data distinctly demonstrate heterogeneous patterns of menopausal symptoms that are associated with race/ethnicity, reproductive hormones, premenopause body mass index, and psychosocial characteristics. Early targeted intervention may have a meaningful impact on long-term VMS.

Cellular expression and hormonal regulation of neuropilin-1 and -2 messenger ribonucleic Acid in the human and rhesus macaque endometrium.

Although much is known about the biology of vascular endothelial growth factor (VEGF) and its cognate receptors (VEGFRs), VEGFR1 and VEGFR2, little is known about the roles of the VEGFRs neuropilin (NP)-1 and NP-2 in the primate endometrium. In this study, we investigated the cellular localization and hormonal regulation of NP-1 and NP-2 mRNA by in situ hybridization in the endometrium of ovariectomized, hormonally cycled rhesus macaques and women during the natural menstrual cycle. NP-1 mRNA was highly expressed in vascular endothelium and in stromal cells, but in these cells, NP-1 expression did not change during the menstrual cycle. However, NP-1 mRNA was also expressed in the luminal epithelium (not the glands), and its expression in these cells was elevated during the mid- to late proliferative phase and completely suppressed during the secretory phase. The increase in NP-1 level in the luminal epithelium was estradiol dependent because such expression was not detectable in the absence of estradiol in ovariectomized, hormone-deprived animals. Moreover, NP-1 expression in the luminal epithelium was highly correlated with the degree of proliferation in these cells. A recent study showed that blockade of VEGF action can inhibit luminal epithelial cell proliferation, but there is no evidence of VEGFR1 and VEGFR2 expression in these cells. Therefore, NP-1 may be the relevant VEGFR that mediates proliferation in this epithelium. NP-2 mRNA, unlike NP-1, was expressed only by the endothelium of veins, and in these cells, its expression was hormonally regulated in the converse manner: it was very low during the proliferative phase and high during the secretory phase. The increased permeability and edema observed during the secretory phase in the primate endometrium may be mediated in part by VEGF-NP-2 interaction. In the human endometrium, the pattern of expression and cellular localization of both NP-1 and NP-2 during the menstrual cycle were essentially identical with that seen in the rhesus macaque endometrium. These are the first data to specify the hormonal regulation and cell-specific expression of NP-1 and NP-2 mRNA in the endometrium of both women and nonhuman primates. The findings extend our understanding of VEGF action in the primate endometrium.

Cigarette smoking and effects on hormone function in premenopausal women.

Cigarette smoke contains compounds that are suspected to cause reproductive damage and possibly affect hormone activity; therefore, we examined hormone metabolite patterns in relation to validated smoking status. We previously conducted a prospective study of women of reproductive age (n = 403) recruited from a large health maintenance organization, who collected urine daily during an average of three to four menstrual cycles. Data on covariates and daily smoking habits were obtained from a baseline interview and daily diary, and smoking status was validated by cotinine assay. Urinary metabolite levels of estrogen and progesterone were measured daily throughout the cycles. For the present study, we measured urinary levels of the pituitary hormone follicle-stimulating hormone (FSH) in a subset of about 300 menstrual cycles, selected by smoking status, with the time of transition between two cycles being of primary interest. Compared with nonsmokers, moderate to heavy smokers (>/= 10 cigarettes/day) had baseline levels (e.g., early follicular phase) of both steroid metabolites that were 25-35% higher, and heavy smokers (>/= 20 cigarettes/day) had lower luteal-phase progesterone metabolite levels. The mean daily urinary FSH levels around the cycle transition were increased at least 30-35% with moderate smoking, even after adjustment. These patterns suggest that chemicals in tobacco smoke alter endocrine function, perhaps at the level of the ovary, which in turn effects release of the pituitary hormones. This endocrine disruption likely contributes to the reported associations of smoking with adverse reproductive outcomes, including menstrual dysfunction, infertility, and earlier menopause.

Alcohol consumption and serum hormone levels during pregnancy.

Factors that change sex hormone levels during pregnancy may have long-term health consequences for the offspring, including changes in breast cancer risk. A cross-sectional analysis of alcohol consumption and hormone levels in 339 pregnant women sampled from the Child Health and Development Study cohort was undertaken. Alcohol intake was queried from 1959 to 1966, long before any hazards of drinking during pregnancy were publicized. Third trimester serum hormone levels including estradiol and testosterone were analyzed. Among 339 pregnant women, 196 reported some alcohol consumption during pregnancy. The drinkers were divided into three groups with intake levels of 0.2-0.5, 0.6-2.0, and 2.1-12.5 ounces of ethanol per week. The second group corresponds to a median intake of approximately 2 drinks per week, and the last group corresponds to a median intake of approximately 1 drink per day, which is considered "light" to "moderate" drinking. Maternal estradiol levels were not associated with alcohol intake during pregnancy. However, serum testosterone was significantly lower, by 12.2%, in the latter two groups of drinking pregnant women, [confidence interval (CI)=-3.0 to 25.2] and 25.6% (CI=9.2-39.5), respectively. The alcohol intakes reported are far below those shown to cause fetal alcohol syndrome, or any of the fetal alcohol effects so far studied. Light alcohol intake during pregnancy is associated with lower maternal testosterone. The health implications are uncertain, but may include an increased breast density in the daughters of drinking mothers.

Early life triclocarban exposure during lactation affects neonate rat survival.

Triclocarban (3,4,4'-trichlorocarbanilide; TCC), an antimicrobial used in bar soaps, affects endocrine function in vitro and in vivo. This study investigates whether TCC exposure during early life affects the trajectory of fetal and/or neonatal development. Sprague Dawley rats were provided control, 0.2% weight/weight (w/w), or 0.5% w/w TCC-supplemented chow through a series of 3 experiments that limited exposure to critical growth periods: gestation, gestation and lactation, or lactation only (cross-fostering) to determine the susceptible windows of exposure for developmental consequences. Reduced offspring survival occurred when offspring were exposed to TCC at concentrations of 0.2% w/w and 0.5% w/w during lactation, in which only 13% of offspring raised by 0.2% w/w TCC dams survived beyond weaning and no offspring raised by 0.5% w/w TCC dams survived to this period. In utero exposure status had no effect on survival, as all pups nursed by control dams survived regardless of their in utero exposure status. Microscopic evaluation of dam mammary tissue revealed involution to be a secondary outcome of TCC exposure rather than a primary effect of compound administration. The average concentration of TCC in the milk was almost 4 times that of the corresponding maternal serum levels. The results demonstrate that gestational TCC exposure does not affect the ability of dams to carry offspring to term but TCC exposure during lactation has adverse consequences on the survival of offspring although the mechanism of reduced survival is currently unknown. This information highlights the importance of evaluating the safety of TCC application in personal care products and the impacts during early life exposure.

Metabolic and endocrine effects of a polyunsaturated fatty acid-rich diet in polycystic ovary syndrome.

Effects of a polyunsaturated fatty acid (PUFA)-rich diet were investigated in 17 polycystic ovary syndrome (PCOS) patients. After a 3-month habitual diet period, dietary fats were partly replaced with PUFAs for another 3 months. The PUFA-rich diet increased plasma linoleic acid from 28.36 +/- 1.00% to 33.76 +/- 1.08% (P < 0.002) and alpha-linolenic acid from 0.52 +/- 0.03% to 1.06 +/- 0.10% (P < 0.0001). Fasting glucose increased from 76 +/- 3 to 95 +/- 3 mg/dl (4.2 +/- 0.2 to 5.30.2 mmol/liter; P < 0.0001), and the area under the curve for glucose during oral glucose tolerance test increased from 421 +/- 34 to 503 +/- 31 mg/dl (23.4 +/- 1.9 to 27.9 +/- 1.7 mmol/liter; P < 0.001). Plasma insulin did not change either at fasting or during oral glucose tolerance test. Fasting plasma free fatty acids decreased from 0.596 +/- 0.048 to 0.445 +/- 0.058 mg/dl (P = 0.037), and ketone bodies decreased from 9.14 +/- 1.57 to 3.63 +/- 0.62 mg/dl (895 +/- 154 to 356 +/- 61 micromol/liter; P < 0.003). Plasma 15-deoxyprostaglandin J(2) tended to decrease (from 239 +/- 65 to 171 +/- 60 ng/ml; P = 0.053). Plasma testosterone, free testosterone, SHBG, dehydroepiandrosterone sulfate, LH, FSH, and urinary estrogen conjugates did not change. Urinary pregnanediol 3-glucuronide increased from 18.6 +/- 2.2 to 31.0 +/- 5.7 micro g/mg creatinine (P = 0.038). In conclusion, increased dietary PUFA intake can exert significant metabolic and endocrine effects in women with PCOS.

Luteal phase deficiency in recreational runners: evidence for a hypometabolic state.

Exercising women with amenorrhea exhibit a hypometabolic state. The purpose of this study was to evaluate the relationship of luteal phase deficient (LPD) menstrual cycles to metabolic hormones, including thyroid, insulin, human GH (hGH), leptin, and IGF-I and its binding protein levels in recreational runners. Menstrual cycle status was determined for three consecutive cycles in sedentary and moderately active women. Menstrual status was defined as ovulatory or LPD. Subjects were either sedentary (n = 10) or moderately active (n = 20) and were matched for age (27.7 +/- 1.2 yr), body mass (60.2 +/- 3.3 kg), menstrual cycle length (28.4 +/- 0.9 d), and reproductive age (14.4 +/- 1.2 yr). Daily urine samples for the determination of estrone conjugates, pregnanediol 3-glucuronide, and urinary levels of LH were collected. Blood was collected on a single day during the follicular phase (d 2-6) of each menstrual cycle for analysis of TSH, insulin, total T3, total T4, free T4, leptin, hGH, IGF-I, and IGF binding protein (IGFBP)-1 and IGFBP-3. Among the 10 sedentary subjects, 28 of 31 menstrual cycles were categorized as ovulatory (SedOvul). Among the 20 exercising subjects, 24 menstrual cycles were included in the ovulatory category (ExOvul), and 21 menstrual cycles were included in the LPD category (ExLPD). TSH, total T4, and free T4 levels were not significantly different among the three categories of cycles. Total T3 was suppressed (P = 0.035) in the ExLPD (1.63 +/- 0.07 nmol/liter) and the ExOvul categories of cycles (1.75 +/- 0.8 nmol/liter) compared with the SedOvul category of cycles (2.15 +/- 0.1 nmol/liter). Leptin levels were lower (P < 0.001) in both the ExOvul (5.2 +/- 0.4 microg/liter) and the ExLPD categories of cycles (5.1 +/- 0.4 microg/liter) when compared with the SedOvul category of cycles (13.7 +/- 1.7 microg/liter). Insulin was lower (P = 0.009) only in the ExLPD category of cycles (31.9 +/- 2.8 pmol/liter) compared with the SedOvul (60.4 +/- 8.3 pmol/liter) and ExOvul (61.8 +/- 10.4 pmol/liter) categories of cycles. IGF-I, IGFBP-1, IGFBP-3, IGF-I/IGFBP-1, IGF-I/IGFBP-3, and hGH were comparable among the different categories of cycles. These data suggest that exercising women with LPD menstrual cycles exhibit hormonal alterations consistent with a hypometabolic state that is similar to that observed in amenorrheic athletes and other energy-deprived states, although not as comprehensive. These alterations may represent a metabolic adaptation to an intermittent short-term negative energy balance.

The relationship of circulating dehydroepiandrosterone, testosterone, and estradiol to stages of the menopausal transition and ethnicity.

In this report, 3029 women between the ages of 42 and 54 yr from five ethnic groups were studied for 2 yr. Log circulating dehydroepiandrosterone sulfate (DHEAS) concentrations were highest among Chinese and Japanese and lowest among African Americans and Hispanics, and this pattern persisted after adjustment for age, smoking, and log body mass index (BMI). With the exception of Japanese women, log BMI was negatively related to log circulating DHEAS. The magnitude of this association varied by ethnic group, and the decline in log circulating DHEAS levels with higher log BMI was steepest for Chinese and least steep for Hispanics. The relationship between log DHEAS and log BMI was positive for Japanese. DHEAS levels did not decline at a steady rate during the menopausal transition and transiently increased in some women and increased, on average, during the transition to late perimenopause. These increases tended to be larger for Chinese, Hispanic, and Japanese than for African Americans and Caucasians, although the interactions were not statistically significant. Changes in circulating testosterone and, to a lesser extent, estradiol were correlated to changes in DHEAS. These data have importance in understanding the endocrinology of the menopausal transition, defining the relationship of adrenal steroid production during declining ovarian function and determining a rationale regarding DHEAS supplementation for older women.