Longitudinal Evaluation of Reproductive Endocrine Function in Men with ACTH-Dependent Cushing Syndrome.

CONTEXT: Hypogonadism may be caused by Cushing syndrome (CS) and may intensify its adverse consequences. OBJECTIVE: To determine the frequency of male hypogonadism before and after curative surgery for CS, and its cause. DESIGN: Post-hoc analyses of prospective cohort studies. SETTING: Clinical research center. PATIENTS: Men with ACTH-dependent CS. Cohort 1 (C1) (n=8, age 32.5±12 y; studied 1985-1989); Cohort 2 (C2) (n=44, 42.7 ± 15.1 y; studied 1989-2021). INTERVENTIONS: C1: Every 20-minute blood sampling for 24h before and 1-40 months after surgical cure. Three subjects underwent GnRH stimulation tests pre- and post-surgery. C2: Hormone measurements at baseline and 6 and 12 months (M) post-cure. MAIN OUTCOME MEASURES: C1: LH, FSH, LH pulse frequency and LH response to GnRH. C2: LH, FSH, testosterone (T), free T, fT4, T3, TSH and UFC levels and frequency of hypogonadism pre- and post-surgery. RESULTS: C1: mean LH and LH pulse frequency increased after surgery (p < 0.05) without changes in LH pulse amplitude, mean FSH, or peak gonadotropin response to GnRH. C2: 82% had baseline hypogonadism (total T 205 ± 28 ng/dL). Thyroid hormone levels varied inversely with UFC and cortisol. LH, total and free T, and SHBG increased at 6M and 12M post surgery, but hypogonadism persisted in 51% at 6M and in 26% at 12M. CONCLUSION: Hypogonadism in men with CS is widely prevalent but reversible in ∼75% of patients one year after surgical cure and appears to be mediated through suppression of hypothalamic GnRH secretion, and modulated by thyroid hormones.

Predicting nutrition and environmental factors associated with female reproductive disorders using a knowledge graph and random forests.

OBJECTIVE: Female reproductive disorders (FRDs) are common health conditions that may present with significant symptoms. Diet and environment are potential areas for FRD interventions. We utilized a knowledge graph (KG) method to predict factors associated with common FRDs (for example, endometriosis, ovarian cyst, and uterine fibroids). MATERIALS AND METHODS: We harmonized survey data from the Personalized Environment and Genes Study (PEGS) on internal and external environmental exposures and health conditions with biomedical ontology content. We merged the harmonized data and ontologies with supplemental nutrient and agricultural chemical data to create a KG. We analyzed the KG by embedding edges and applying a random forest for edge prediction to identify variables potentially associated with FRDs. We also conducted logistic regression analysis for comparison. RESULTS: Across 9765 PEGS respondents, the KG analysis resulted in 8535 significant or suggestive predicted links between FRDs and chemicals, phenotypes, and diseases. Amongst these links, 32 were exact matches when compared with the logistic regression results, including comorbidities, medications, foods, and occupational exposures. DISCUSSION: Mechanistic underpinnings of predicted links documented in the literature may support some of our findings. Our KG methods are useful for predicting possible associations in large, survey-based datasets with added information on directionality and magnitude of effect from logistic regression. These results should not be construed as causal but can support hypothesis generation. CONCLUSION: This investigation enabled the generation of hypotheses on a variety of potential links between FRDs and exposures. Future investigations should prospectively evaluate the variables hypothesized to impact FRDs.

Questionnaire-based exposome-wide association studies for common diseases in the Personalized Environment and Genes Study.

The exposome collectively refers to all exposures, beginning in utero and continuing throughout life, and comprises not only standard environmental exposures such as point source pollution and ozone levels but also exposures from diet, medication, lifestyle factors, stress, and occupation. The exposome interacts with individual genetic and epigenetic characteristics to affect human health and disease, but large-scale studies that characterize the exposome and its relationships with human disease are limited. To address this gap, we used extensive questionnaire data from the diverse North Carolina-based Personalized Environment and Genes Study (PEGS, n = 9, 429) to evaluate exposure associations in relation to common diseases. We performed an exposome-wide association study (ExWAS) to examine single exposure models and their associations with 11 common complex diseases, namely allergic rhinitis, asthma, bone loss, fibroids, high cholesterol, hypertension, iron-deficient anemia, ovarian cysts, lower GI polyps, migraines, and type 2 diabetes. Across diseases, we found associations with lifestyle factors and socioeconomic status as well as asbestos, various dust types, biohazardous material, and textile-related exposures. We also found disease-specific associations such as fishing with lead weights and migraines. To differentiate between a replicated result and a novel finding, we used an AI-based literature search and database tool that allowed us to examine the current literature. We found both replicated findings, especially for lifestyle factors such as sleep and smoking across diseases, and novel findings, especially for occupational exposures and multiple diseases.

Application of machine learning and artificial intelligence in the diagnosis and classification of polycystic ovarian syndrome: a systematic review.

Introduction: Polycystic Ovarian Syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and remains widely underdiagnosed leading to significant morbidity. Artificial intelligence (AI) and machine learning (ML) hold promise in improving diagnostics. Thus, we performed a systematic review of literature to identify the utility of AI/ML in the diagnosis or classification of PCOS. Methods: We applied a search strategy using the following databases MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Web of Science, and the IEEE Xplore Digital Library using relevant keywords. Eligible studies were identified, and results were extracted for their synthesis from inception until January 1, 2022. Results: 135 studies were screened and ultimately, 31 studies were included in this study. Data sources used by the AI/ML interventions included clinical data, electronic health records, and genetic and proteomic data. Ten studies (32%) employed standardized criteria (NIH, Rotterdam, or Revised International PCOS classification), while 17 (55%) used clinical information with/without imaging. The most common AI techniques employed were support vector machine (42% studies), K-nearest neighbor (26%), and regression models (23%) were the commonest AI/ML. Receiver operating curves (ROC) were employed to compare AI/ML with clinical diagnosis. Area under the ROC ranged from 73% to 100% (n=7 studies), diagnostic accuracy from 89% to 100% (n=4 studies), sensitivity from 41% to 100% (n=10 studies), specificity from 75% to 100% (n=10 studies), positive predictive value (PPV) from 68% to 95% (n=4 studies), and negative predictive value (NPV) from 94% to 99% (n=2 studies). Conclusion: Artificial intelligence and machine learning provide a high diagnostic and classification performance in detecting PCOS, thereby providing an avenue for early diagnosis of this disorder. However, AI-based studies should use standardized PCOS diagnostic criteria to enhance the clinical applicability of AI/ML in PCOS and improve adherence to methodological and reporting guidelines for maximum diagnostic utility. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022295287.

Predicting nutrition and environmental factors associated with female reproductive disorders using a knowledge graph and random forests.

Objective: Female reproductive disorders (FRDs) are common health conditions that may present with significant symptoms. Diet and environment are potential areas for FRD interventions. We utilized a knowledge graph (KG) method to predict factors associated with common FRDs (e.g., endometriosis, ovarian cyst, and uterine fibroids). Materials and Methods: We harmonized survey data from the Personalized Environment and Genes Study on internal and external environmental exposures and health conditions with biomedical ontology content. We merged the harmonized data and ontologies with supplemental nutrient and agricultural chemical data to create a KG. We analyzed the KG by embedding edges and applying a random forest for edge prediction to identify variables potentially associated with FRDs. We also conducted logistic regression analysis for comparison. Results: Across 9765 PEGS respondents, the KG analysis resulted in 8535 significant predicted links between FRDs and chemicals, phenotypes, and diseases. Amongst these links, 32 were exact matches when compared with the logistic regression results, including comorbidities, medications, foods, and occupational exposures. Discussion: Mechanistic underpinnings of predicted links documented in the literature may support some of our findings. Our KG methods are useful for predicting possible associations in large, survey-based datasets with added information on directionality and magnitude of effect from logistic regression. These results should not be construed as causal, but can support hypothesis generation. Conclusion: This investigation enabled the generation of hypotheses on a variety of potential links between FRDs and exposures. Future investigations should prospectively evaluate the variables hypothesized to impact FRDs.

The Thyroid Hormone Axis and Female Reproduction.

Thyroid function affects multiple sites of the female hypothalamic-pituitary gonadal (HPG) axis. Disruption of thyroid function has been linked to reproductive dysfunction in women and is associated with menstrual irregularity, infertility, poor pregnancy outcomes, and gynecological conditions such as premature ovarian insufficiency and polycystic ovarian syndrome. Thus, the complex molecular interplay between hormones involved in thyroid and reproductive functions is further compounded by the association of certain common autoimmune states with disorders of the thyroid and the HPG axes. Furthermore, in prepartum and intrapartum states, even relatively minor disruptions have been shown to adversely impact maternal and fetal outcomes, with some differences of opinion in the management of these conditions. In this review, we provide readers with a foundational understanding of the physiology and pathophysiology of thyroid hormone interactions with the female HPG axis. We also share clinical insights into the management of thyroid dysfunction in reproductive-aged women.

The skin is no barrier to mixtures: Air pollutant mixtures and reported psoriasis or eczema in the Personalized Environment and Genes Study (PEGS).

BACKGROUND: Autoimmune (AI) diseases appear to be a product of genetic predisposition and environmental triggers. Disruption of the skin barrier causes exacerbation of psoriasis/eczema. Oxidative stress is a mechanistic pathway for pathogenesis of the disease and is also a primary mechanism for the detrimental effects of air pollution. METHODS: We evaluated the association between autoimmune skin diseases (psoriasis or eczema) and air pollutant mixtures in 9060 subjects from the Personalized Environment and Genes Study (PEGS) cohort. Pollutant exposure data on six criteria air pollutants are publicly available from the Center for Air, Climate, and Energy Solutions and the Atmospheric Composition Analysis Group. For increased spatial resolution, we included spatially cumulative exposure to volatile organic compounds from sites in the United States Environmental Protection Agency Toxic Release Inventory and the density of major roads within a 5 km radius of a participant's address from the United States Geological Survey. We applied logistic regression with quantile g-computation, adjusting for age, sex, diagnosis with an autoimmune disease in family or self, and smoking history to evaluate the relationship between self-reported diagnosis of an AI skin condition and air pollution mixtures. RESULTS: Only one air pollution variable, sulfate, was significant individually (OR = 1.06, p = 3.99E-2); however, the conditional odds ratio for the combined mixture components of PM2.5 (black carbon, sulfate, sea salt, and soil), CO, SO2, benzene, toluene, and ethylbenzene is 1.10 (p-value = 5.4E-3). SIGNIFICANCE: While the etiology of autoimmune skin disorders is not clear, this study provides evidence that air pollutants are associated with an increased prevalence of these disorders. The results provide further evidence of potential health impacts of air pollution exposures on life-altering diseases. SIGNIFICANCE AND IMPACT STATEMENT: The impact of air pollution on non-pulmonary and cardiovascular diseases is understudied and under-reported. We find that air pollution significantly increased the odds of psoriasis or eczema in our cohort and the magnitude is comparable to the risk associated with smoking exposure. Autoimmune diseases like psoriasis and eczema are likely impacted by air pollution, particularly complex mixtures and our study underscores the importance of quantifying air pollution-associated risks in autoimmune disease.

Determination of Half-lives of Circulating FSH and LH Glycoforms in Women During GnRH Receptor Blockade.

CONTEXT: Both FSH and LH circulate as 2 glycoforms, differing in number of glycans: low-N-glycosylated glycoforms, FSHtri and LHdi, and fully N-glycosylated glycoforms, FSHtetra and LHtri. OBJECTIVES: To determine the half-lives of endogenous circulating gonadotropin glycoforms in women during GnRH receptor blockade. DESIGN/PARTICIPANTS: Serum samples were collected in 8 healthy women before and up to 20 hours after administration of the NAL-GLU GnRH antagonist. Three women were in early follicular phase, 2 at mid-cycle phase, and 3 were postmenopausal. MAIN OUTCOME MEASURES: The half-life of each glycoform was estimated by monoexponential decay for FSH (n = 8) and LH (n = 5). Data were analyzed using paired t tests. RESULTS: Half-lives in the circulation of low-N-glycosylated glycoforms of both FSH and LH were shorter than those of the fully N-glycosylated glycoforms (mean; range, FSHtri 343; 116-686 minutes vs FSHtetra 757; 436-1038, minutes, P = 0.0003; LHdi 125, 84-198 minutes vs LHtri 164, 107-235 minutes, P = 0.004). The half-lives of low-and fully N-glycosylated forms of LH were shorter than the corresponding half-lives of FSH glycoforms, P = 0.0008. CONCLUSIONS: For both FSH and LH, low-N-glycosylated glycoforms disappeared from the circulation faster than the fully N-glycosylated. The half-lives of low and fully N-glycosylated forms of LH were shorter than the corresponding half-lives of FSH. The estimated values for half-life in the circulation of total FSH and total LH will depend on the relative amounts of the 2 glycoforms of each hormone and their individual disappearance rates in circulation.

Questionnaire-based exposome-wide association studies (ExWAS) reveal expected and novel risk factors associated with cardiovascular outcomes in the Personalized Environment and Genes Study.

While multiple factors are associated with cardiovascular disease (CVD), many environmental exposures that may contribute to CVD have not been examined. To understand environmental effects on cardiovascular health, we performed an exposome-wide association study (ExWAS), a hypothesis-free approach, using survey data on endogenous and exogenous exposures at home and work and data from health and medical histories from the North Carolina-based Personalized Environment and Genes Study (PEGS) (n = 5015). We performed ExWAS analyses separately on six cardiovascular outcomes (cardiac arrhythmia, congestive heart failure, coronary artery disease, heart attack, stroke, and a combined atherogenic-related outcome comprising angina, angioplasty, atherosclerosis, coronary artery disease, heart attack, and stroke) using logistic regression and a false discovery rate of 5%. For each CVD outcome, we tested 502 single exposures and built multi-exposure models using the deletion-substitution-addition (DSA) algorithm. To evaluate complex nonlinear relationships, we employed the knockoff boosted tree (KOBT) algorithm. We adjusted all analyses for age, sex, race, BMI, and annual household income. ExWAS analyses revealed novel associations that include blood type A (Rh-) with heart attack (OR[95%CI] = 8.2[2.2:29.7]); paint exposures with stroke (paint related chemicals: 6.1[2.2:16.0], acrylic paint: 8.1[2.6:22.9], primer: 6.7[2.2:18.6]); biohazardous materials exposure with arrhythmia (1.8[1.5:2.3]); and higher paternal education level with reduced risk of multiple CVD outcomes (stroke, heart attack, coronary artery disease, and combined atherogenic outcome). In multi-exposure models, trouble sleeping and smoking remained important risk factors. KOBT identified significant nonlinear effects of sleep disorder, regular intake of grapefruit, and a family history of blood clotting problems for multiple CVD outcomes (combined atherogenic outcome, congestive heart failure, and coronary artery disease). In conclusion, using statistics and machine learning, these findings identify novel potential risk factors for CVD, enable hypothesis generation, provide insights into the complex relationships between risk factors and CVD, and highlight the importance of considering multiple exposures when examining CVD outcomes.

Prevalence of Hirsutism Among Reproductive-Aged African American Women.

Background: Hirsutism is the most common clinical symptom of hyperandrogenism, but racial and ethnic-specific thresholds have not been established. Our objective was to characterize hirsutism using self-report of hair growth in a large sample of African American women. Materials and Methods: The Study of Environment, Lifestyle, and Fibroids is a prospective community-based cohort study of African American women (23-34 at recruitment). A total of 1568 participants received the modified Ferriman-Gallwey (mFG) pictorial assessment and were asked if they were ever bothered by excess hair. We estimated the prevalence of hirsutism (mFG score ≥8) and associations of acne, polycystic ovary syndrome (PCOS), and menstrual cycle characteristics with hirsutism. We also explored hirsutism defined by the 95th percentile of scores in our cohort (mFG = 11) and a newly recommended criterion, mFG = 4. Results: We could determine hirsutism status in 1556 women. Thirty-seven percent reported being bothered by excess hair, and 10% met the mFG criterion for hirsutism. History of severe facial acne was positively associated with hirsutism (prevalence ratio: 1.90; 95% confidence interval [CI]: 1.30-2.76), as was physician-diagnosed PCOS (2.22, 95% CI: 1.30-3.81). Women with irregular menstrual cycles were also more likely to report hirsutism (1.78, 95% CI: 1.00-3.18). Results were similar using mFG ≥11 and attenuated using mFG ≥4. Conclusions: Hirsutism prevalence was 10% in this community sample of African American women and was associated with PCOS, severe acne, and irregular menstrual cycles suggesting this represented hirsutism caused by hyperandrogenism. Ethnically diverse, population-based studies assessing the association between mFG score and androgen levels are needed to better understand the hirsutism threshold as a clinical marker of hyperandrogenism.

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants.

PURPOSE: SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders. METHODS: Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population. RESULTS: Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD. CONCLUSION: SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.

CONTEXT: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. OBJECTIVE: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. DESIGN: We compared patients with HA to control women. SETTING: The study was conducted at secondary referral centers. PATIENTS AND OTHER PARTICIPANTS: Women with HA (n = 106) and control women (ClinSeq study; n = 468). INTERVENTIONS: We performed exome sequencing in all patients and controls. MAIN OUTCOME MEASURE(S): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. RESULTS: RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). CONCLUSIONS: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.

Cadmium Exposure and Ovarian Reserve in Women Aged 35-49 Years: The Impact on Results From the Creatinine Adjustment Approach Used to Correct for Urinary Dilution.

Cadmium is toxic to the ovaries in animal studies, but its association with diminished ovarian reserve in women is not established. We investigated urinary cadmium, a biomarker of long-term exposure, in relation to diminished ovarian reserve, as indicated by elevated serum follicle-stimulating hormone concentrations (≥10 IU/L), in women aged 35-49 years (unweighted n = 1,681). Using data from the Third National Health and Nutrition Examination Survey (1988-1994), we conducted Poisson regression to estimate adjusted relative risks and 95% confidence intervals. Because the best approach to correcting for urinary dilution in spot samples with creatinine remains controversial, we employed 3 approaches: standardization, covariate adjustment, and covariate-adjusted standardization. Our data suggested a modest association with standardization (highest quartile vs. lowest: relative risk (RR) = 1.3, 95% confidence interval (CI): 0.8, 1.9; P for trend = 0.06) and covariate-adjusted standardization (highest quartile vs. lowest: RR = 1.3, 95% CI: 0.9, 1.9; P for trend = 0.05) and a stronger association with covariate adjustment (highest quartile vs. lowest: RR = 1.8, 95% CI: 1.2, 2.9; P for trend = 0.01). The stronger association with covariate adjustment may reflect bias from conditioning on urinary creatinine, a collider in the hypothesized causal pathway. We conclude that cadmium may contribute to ovarian aging in women and that careful consideration of the creatinine adjustment approach is needed to minimize bias.

Environmental Factors Involved in Maternal Morbidity and Mortality.

Nongenetic, environmental factors contribute to maternal morbidity and mortality through chemical exposures via air, water, soil, food, and consumer products. Pregnancy represents a particularly sensitive window of susceptibility during which physiological changes to every major organ system increase sensitivity to chemicals that can impact a woman's long-term health. Nonchemical stressors, such as low socioeconomic status, may exacerbate the effects of chemical exposures on maternal health. Racial/ethnic minorities are exposed disproportionately to both chemicals and nonchemical stressors, which likely contribute to the observed health disparities for maternal morbidities and mortality. Epidemiological studies linking exposures to adverse maternal health outcomes underscore the importance of environmental health impacts, and mechanistic studies in model systems reveal how chemicals perturb biological pathways and processes. Environmental stressors are associated with a variety of immediate maternal health impacts, including hypertensive disorders of pregnancy, fibroids, and infertility, as well as long-term maternal health impacts, such as higher risk of breast cancer and metabolic disorders. Identifying and reducing a pregnant woman's environmental exposures is not only beneficial to her offspring but also important to preserve her short- and long-term health.

Depot Medroxyprogesterone Acetate Use and Blood Lead Levels in a Cohort of Young Women.

BACKGROUND: Injectable contraceptive use is common, with 74 million users worldwide. Use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA) is associated with bone mineral density loss. We hypothesize that increased bone resorption with DMPA use allows for mobilization of the toxic metal lead stored in bone to blood, presenting users with increased systemic exposure to lead. OBJECTIVE: The objective of our study was to investigate the association between current DMPA use and blood lead concentrations. METHODS: We conducted a cross-sectional analysis using enrollment data from the Study of Environment, Lifestyle & Fibroids (SELF), a cohort of 1,693 African-American women who were 23-35 years of age. Data on DMPA use were collected by computer-assisted telephone interview. Blood lead concentrations were measured in whole blood samples among 1,548 participants (91% of cohort). We estimated the adjusted percent difference in blood lead concentrations and 95% confidence intervals (CI) between current DMPA users and nonusers using multivariable linear regression. RESULTS: Geometric mean blood lead concentration was 0.69µg/dL (95% CI: 0.67, 0.71). After adjustment, current DMPA users (7% of cohort) had blood lead concentrations that were 18% higher than those of nonusers (95% CI: 8%, 29%). Similar associations were observed with additional analyses to assess for potential bias from smoking, DMPA-induced amenorrhea, use of estrogen-containing contraceptives, having given birth in the prior year, and history of medical conditions or current medication use associated with bone loss. DISCUSSION: Our results indicate that current DMPA use is associated with increased blood lead concentrations. Further research, particularly in populations highly exposed to lead, is warranted to consider tradeoffs between the adverse effects of lead on human health and the importance of DMPA as a contraceptive option to prevent unintended pregnancy. https://doi.org/10.1289/EHP7017.

The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action.

The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health.

Long-Term Follow-Up and Treatment of a Female With Complete Estrogen Insensitivity.

CONTEXT: We previously reported the first female with a causative ESR1 gene variant, who exhibited absent puberty and high estrogens. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown. OBJECTIVE: The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment. DESIGN: We have characterized gonadotropin pulsatility and followed this patient's endocrine profile and bone density over 8 years. Seventy-five different compounds were tested for transactivation of the variant receptor. A personalized medicine approach was tailored to our patient. SETTING: Academic medical center. PATIENT OR OTHER PARTICIPANTS: A 24-year-old adopted white female with CEI. INTERVENTION(S): The patient was treated with diethylstilbestrol (DES) for approximately 2.5 years. MAIN OUTCOME MEASURE(S): Induction of secondary sexual characteristics. RESULTS: Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH, and mildly elevated mean follicle-stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the variant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient. CONCLUSIONS: Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. OBJECTIVE: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

Impact of Estradiol Variability and Progesterone on Mood in Perimenopausal Women With Depressive Symptoms.

CONTEXT: Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated. OBJECTIVE: To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology. DESIGN AND INTERVENTION: Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models. SETTING: Academic medical center. PATIENTS: Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3). MAIN OUTCOME MEASURE: Depressive symptoms (MADRS score). RESULTS: During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (ß = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; ß = -2.62 [95% CI, -4.52 to -0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events. CONCLUSIONS: Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.

Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling.

CONTEXT: Kisspeptin-neurokinin B (NKB)-dynorphin neurons are critical regulators of the hypothalamic-pituitary-gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear. OBJECTIVE: To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB. DESIGN: Case/control. SETTING: Academic medical center. PARTICIPANTS: Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice. INTERVENTIONS: Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin. MAIN OUTCOME MEASURES: LH pulse characteristics. RESULTS: Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin. CONCLUSION: The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.