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.

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.

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.

Menstrual Cycle Hormone Changes in Women Traversing Menopause: Study of Women's Health Across the Nation.

Context: Menstrual cycle hormone patterns in women approaching menopause are inadequately studied. Objective: To describe day-to-day menstrual cycle hormones in women as they approach menopause from the Study of Women's Health Across the Nation Daily Hormone Study (DHS). Design: DHS enrollees collected daily urine for one entire menstrual cycle or up to 50 days, whichever came first, annually, up to the final menstrual period (FMP) or for up to 10 years. Setting: Seven sites across the United States. Participants: A total of 511 premenopausal or early perimenopausal women at enrollment, within 10 years before menopause. Intervention: Time-to-FMP measurement. Main Outcome Measures: Evidence of luteal activity (ELA), determined using objective algorithms. Menstrual cycle/segment length; whole cycle, and segment integrated urinary luteinizing hormone, follicle-stimulating hormone, estrone conjugates, and pregnanediol glucuronide (Pdg) for each year, organized around the FMP. Results: Mean menstrual cycle length was remarkably preserved at 26 to 27 days in ELA cycles; non-ELA cycles had greater variability. The percentage of cycles that were ELA remained high until 5 years before the FMP (87.9%); only 22.8% of cycles within 1 year of the FMP were ELA. Whole cycle hormones remained relatively stable up to 3 years before the FMP, when gonadotropins began to increase. Pdg excretion declined slowly with progress to the FMP, but Pdg patterns of ELA cycles remained distinguishable from non-ELA. Conclusions: Menstrual cycle hormone patterns in perimenopausal women resemble those of midreproductive-aged women until 5 years before menopause, and presumably ovulatory cycles retain a potentially fertile pattern up to the end of reproductive life.

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.

Elderly Female Rhesus Macaques Preserve Lung Alveoli With Estrogen/Progesterone Therapy.

The aging lung is associated with increased susceptibility to chronic inflammatory diseases such as chronic obstructive pulmonary disease where females have been reported to be more susceptible than males. The changes in reproductive hormones due to aging may directly or indirectly affect lung structure and function and little is known on the mechanism of these changes. Twenty female rhesus macaques were divided into four groups. Ovariectomy (OVX) was performed on eight animals with three receiving estrogen/progesterone therapy (HRT) and five animals given implants containing vehicle. The remaining 12 animals represented control groups of ages 10-14 years (n = 6) and ages 20-24 (n = 6). A design-based stereological method was employed to estimate the number of alveoli in the right middle lung lobe along with hormone analysis for possible correlation. A significant decrease was found in the number of alveoli in the vehicle OVX animals compared to intact younger adult females (P < 0.001). A significant increase in alveoli between OVX vehicle animals and those on HRT was also found (P < 0.0001). There was difference in the number of alveoli between younger adult animals and animals on HRT. The loss of ovaries and hormones had a significant effect on alveolar lung morphology. This result mimics what is seen in the aging process and could contribute to gender differences reported in the elderly. Hormone replacement, as reported here, could possibly slow the loss of alveoli due to the aging process or aid in alveolar regeneration through direct or indirect mechanisms. Anat Rec, 299:973-978, 2016. © 2016 Wiley Periodicals, Inc.

Identification of Immunoreactive Luteinizing Hormone Receptors in the Adrenal Cortex of the Female Rhesus Macaque.

Female laboratory macaques were studied under a variety of treatment protocols to determine if immunoreactive luteinizing hormone/gonadal chorionic gonadotropin (LH/CG) receptors were present in the adrenal cortex. All adrenal tissues revealed an absence of immunoreactivity in the in the medulla while staining was present in all three outer zones of the cortex. Increased staining was observed in the zonae reticularis with least staining in the zonae glomerulosa. Moderate and variable staining was found in the zonae fasciculata. These results demonstrate that LH/CG receptors in the adrenal cortex may be more common in higher primates than previously recognized and help explain some aspects of the endocrine changes observed in mid-aged women during the menopausal transition when circulating LH concentrations are rising.

Prenatal and neonatal thyroid stimulating hormone levels and autism spectrum disorders.

Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay (n = 45), and general population controls (GP) (n = 149). Samples were retrieved from prenatal and newborn screening specimen archives. Adjusted logistic regression models showed inverse associations between ASD and log transformed TSH levels in maternal serum samples (ASD vs. GP: OR [95 % CI] 0.33 [0.12-0.91], Early Onset ASD vs. GP: 0.31 [0.10-0.98]). Results for thyroid levels in newborn blood samples were similar though not significant (ASD vs. GP: 0.61 [0.18-2.04]).

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.

Multiple clinically relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys.

Preclinical studies in aged, surgically-menopausal rhesus monkeys have revealed powerful benefits of intermittent estrogen injections on prefrontal cortex-dependent working memory, together with corresponding effects on dendritic spine morphology in the prefrontal cortex. This contrasts with the inconsistent effects of hormone therapy (HT) reported in clinical studies in women. Factors contributing to this discrepancy could include differences in the formulation and sequence of HT regimens, resulting in different neurobiological outcomes. The current study evaluated, in aging surgically menopausal rhesus monkeys, the cognitive effects of 4 HT regimens modeled directly on human clinical practice, including continuous estrogen treatment opposed by progesterone. None of the regimens tested produced any cognitive effect, despite yielding physiologically relevant serum hormone levels, as intended. These findings have implications for the design of regimens that might optimize the benefits of hormone treatment for healthy aging, and suggest that common HT protocols used by women may fail to result in substantial cognitive benefit, at least via direct effects on the prefrontal cortex.

Modulation of higher-primate adrenal androgen secretion with estrogen-alone or estrogen-plus-progesterone intervention.

OBJECTIVE: Circulating adrenal steroids rise during the menopausal transition in most middle-aged women and may contribute to differences in between-women symptoms and ultimate health outcomes. However, the mechanisms for this shift in adrenal steroid production in middle-aged women are not known. This study aims to determine whether hormone therapy (HT) for 1 year can modulate adrenal androgen production. METHODS: Younger (9.8 [0.4] years, n = 20) and older (22.7 [0.4] years, n = 37) female laboratory macaques were ovariectomized, and each group was treated with different regimens of HT for up to 1 year. Changes in adrenal histology and circulating adrenal androgens were monitored after estrogen-alone (E) or estrogen plus progesterone (E + P) treatment, and these changes were compared with the same measures in similarly aged animals given vehicle. RESULTS: Zona reticularis area, serum dehydroepiandrosterone (DHEA), and serum dehydroepiandrosterone sulfate (DHEAS) were higher in younger vehicle-treated animals compared with older vehicle-treated animals (P < 0.02). Both E and E + P treatments decreased circulating DHEAS in the younger group (P < 0.05). Although E treatment also decreased DHEAS in the older group, this was not statistically significant. In contrast, E + P treatment in the older group resulted in a rise in DHEAS over vehicle, which was significantly higher than the results of E treatment (P < 0.01). Circulating concentrations of DHEA exhibited similar trends, but these changes did not reach statistical significance. CONCLUSIONS: These data demonstrate that intervention with ovarian steroids can modulate adrenal androgen production in female higher primates and that both animal age and type of HT regimen determine adrenal response.

Dehydroepiandrosterone sulfate levels reflect endogenous luteinizing hormone production and response to human chorionic gonadotropin challenge in older female macaque (Macaca fascicularis).

OBJECTIVE: We propose that the adrenal gland of an older higher primate female animal model will respond to human chorionic gonadotropin (hCG) hormone challenge by secreting additional dehydroepiandrosterone sulfate (DHEAS). Such a response in surgically and chemically castrated animals will provide proof of concept and a validated animal model for future studies to explore the rise in DHEAS during the menopausal transition of women. METHODS: Twenty-four 18- to 26-year-old female cynomolgus monkeys were screened for ovarian function and then either ovariectomized (n = 4) or treated with a gonadotropin-releasing hormone agonist (GnRHa; n = 20) to block ovarian steroid production. After a recovery period from surgical procedure or down-regulation, a single-dose challenge (1,000 IU/animal, IM) of hCG was then administered to determine if luteinizing hormone (LH)/chorionic gonadotropin could accelerate circulating DHEAS production. Serum DHEAS, bioactive LH, and urinary metabolites of ovarian sex steroids were monitored before, during, and after these treatments. RESULTS: Circulating LH bioactivity and immunoreactive DHEAS concentrations were suppressed in all animals 14 days postadministration of GnRHa. Urinary metabolites of estradiol and progesterone remained low after the surgical procedure or a flare reaction to GnRHa. Circulating DHEAS levels were increased after hCG administration, and the increase in individual animals was proportional to the pretreatment DHEAS at baseline. Circulating DHEAS concentrations were positively correlated to endogenous LH bioactive concentrations prior to hCG challenge and were subsequently further elevated by the hCG challenge while no concomitant change in ovarian steroid hormone excretion was observed. CONCLUSIONS: These data demonstrate a positive adrenal androgen response to LH/chorionic gonadotropin in older female higher primates and suggest a mechanism for the rise in adrenal androgen production during the menopausal transition in women. These results also illustrate that the nonhuman primate animal model can be effectively used to investigate this phenomenon.

Assessment of luteal function in the vervet monkey as a means to develop a model for obesity-related reproductive phenotype.

The objective of the current study was to characterize luteal function in vervet monkeys. Urine from 12 adult female vervets housed at an academic research center was collected for 10 weeks from single-caged monkeys in order to assess evidence of luteal activity (ELA) as determined by urinary excretion of pregnanediol glucuronide (Pdg) and estrone conjugates (E1c). Dual energy X-ray absorptiometry (DXA) was performed on the monkeys to assess body composition, bone density, and fat mass. Menstrual cyclicity was determined using records of vaginal bleeding. ELA was observed in 9 monkeys and was characterized by a late follicular rise in E1c followed by a progressive increase in Pdg excretion. Mean menstrual cycle length was 26.7 ± 3.8 days and the average day of luteal transition was 14 ± 1.8. Three monkeys without ELA had a clearly defined E1c rise (mean 12-fold from nadir) followed by an E1c drop that was not accompanied by Pdg rise and coincided with vaginal bleeding. Among the 9 ELA monkeys, excretion of E1c tended to negatively associate with fat mass, although this finding did not reach statistical significance (r = -0.61, p = 0.08). Similar to women, vervet monkeys experience an increase in E1c late in the follicular phase of the menstrual cycle which is followed by a subsequent luteal Pdg peak. Assessment of urinary reproductive hormones allows for identification of cardinal menstrual cycle events; thus, the similarity of vervet cycles to human menstrual cycles makes them a useful model for obesity-related human reproductive impairment.

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.

Androstenediol complements estrogenic bioactivity during the menopausal transition.

OBJECTIVE: The perimenopausal increase in circulating dehydroepiandrosterone sulfate (DHEAS) levels during the menopausal transition (MT) is accompanied by other adrenal steroids that have the potential to alter estrogen/androgen balance and explain the wide interwoman range of estrogen-related symptoms experienced during the MT. METHODS: Annual serum samples from the Study of Women's Health Across the Nation, which had previously been analyzed for immunoreactive estradiol (E2), testosterone, DHEAS, and sex hormone-binding globulin, were selected based on DHEAS concentration and analyzed for immunoreactive and bioactive estrogens and androgens, including immunoreactive androstenedione, dehydroepiandrosterone, and 5-androstene-3ß,17ß-diol (androstenediol [Adiol]). RESULTS: A two-fold increase in circulating androstenedione and testosterone was found to rise in parallel with the rise in circulating DHEAS, whereas dehydroepiandrosterone and Adiol concentrations rose seven- to eight-fold. Circulating Adiol, which has both androgenic and estrogenic biological activity, was significantly associated (P < 0.02) with circulating estrogen bioactivity only when E2 concentrations were low and Adiol levels were high. CONCLUSIONS: The wide range of circulating levels of Adiol and its contribution to total circulating estrogenicity during the MT is consistent with the observed interwoman difference in symptoms at this time. Therefore, we conclude that Adiol contributes to circulating estrogenicity when E2 production falls at menopause and may contribute significantly to the endocrine changes experienced by midlife women.

Menopausal transition stage-specific changes in circulating adrenal androgens.

OBJECTIVE: It is now recognized that mean circulating dehydroepiandrosterone sulfate (DHEAS) concentrations in most midlife women exhibit a positive inflection starting in early perimenopause, continuing through early postmenopause and returning to early perimenopausal levels by late postmenopause. This rise in mean DHEAS is accompanied by concomitant rises in testosterone (T), dehydroepiandrosteone (DHEA), and androstenedione (Adione) and an equal rise in androstenediol (Adiol). These observations suggest that there is a specific relationship between the circulating levels of steroids emanating from the adrenal glands, declining ovarian function, and the stages of the menopausal transition. This study was designed to test the hypothesis that the menopausal stage-specific change in circulating DHEAS is associated with concomitant changes in the circulating pattern of adrenal steroids and that some of these adrenal androgens could influence the circulating estrogen/androgen balance. METHODS: Stored annual serum samples (N = 120) were first selected to represent four longitudinal DHEAS profiles of individual women to assess and compare changes in the adrenal contribution to circulating steroids. RESULTS: Changes in mean circulating DHEAS levels in midlife women during the menopausal transition is associated with changes in mean circulating T, Adione, and Adiol. Mean Adione and T concentrations changed the least, whereas mean DHEAS and Adiol changed the most. CONCLUSIONS: Changes in circulating steroid hormone emanating from the adrenal during the menopausal transition may be more important than the decline in ovarian function in terms of altering the estrogen/androgen balance.

Dynamic regulation of Wnt7a expression in the primate endometrium: implications for postmenstrual regeneration and secretory transformation.

Despite the vital physiological role of endometrial regeneration during the menstrual cycle and the various pathological implications of abnormal growth of endometrial epithelial cells, the local factors and regulatory mechanisms involved in endometrial regeneration and growth have not been well characterized. Here, we examine the pattern, hormone dependence, and potential functions of Wnt7a (wingless-type MMTV integration site family member 7a), which is known to play a critical role in the formation of the mouse endometrial epithelium during embryonic development, in both human and artificially cycling rhesus macaque endometrium, and using a potent Wnt-antagonist in a mouse model of endometrial regeneration. Wnt7a transcript levels were examined using quantitative real-time PCR and in situ hybridization, and immunohistochemistry was performed to detect Ki-67 and 3,5-bromodeoxyuridine. Stringent, fully conditional Wnt inhibition was achieved by adenoviral expression of Dickkopf-1 during artificial endometrial regeneration in mice. In macaques, Wnt7a expression was confined to the newly formed luminal epithelium (LE) and upper glands during the postmenstrual repair phase. The signal increased in the LE during the proliferative phase but decreased in the upper glands and was undetectable in the glands by the late proliferative phase. Interestingly, Wnt7a was completely suppressed in the LE and remained undetectable in other cell types after 7 d of progesterone treatment. The pattern of Wnt7a expression in the human endometrium was similar to that in macaques. Blockade of Wnt signaling during endometrial regeneration in mice resulted in a dramatic delay in reepithelialization and degeneration of glands and LE. These results strongly suggest, for the first time, a role for Wnt7a in postmenstrual regeneration and proliferation of endometrial glands and LE in primates, and its dramatic suppression by progesterone is likely essential for secretory transformation of the epithelium.