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Objective To define the live birth rates in a large, population-based study of the most common reproductive-age cancers in women. Design Retrospective cohort study. Setting Population-based study. Patients Female cancer patients diagnosed with cancer at age 18 years old or older between 1952–2014 (n = 17,952) were compared to fertility of non-cancer controls (n = 89,436). Interventions Live births in cancer survivors were compared with those in healthy, age-matched controls. Cases and controls were matched in the ratio of 5:1 for birth year, birthplace (Utah, yes/no), and follow-up time in Utah. Main Outcome Measure Rate of at least one live birth, reported as an incidence rate ratio (IRR). Results Of all cancer survivors, 3,127 (17.4%) had at least 1 live birth after treatment in comparison to 19,405 healthy, age-matched controls (21.7%) with the same amount of time exposure for attempting pregnancy. Breast cancer was the most common cancer type (23.1% of patients in cohort). Compared with age-matched, healthy controls, IRR of live birth was 0.69 (95% confidence interval [CI], 0.67–0.70) for all cancer types, 0.25 (95% CI, 0.20–0.33) for leukemia, 0.40 (95% CI, 0.28–0.59) for gastrointestinal cancers, 0.44 (95% CI, 0.41–0.48) for breast cancer, 0.53 (95% CI, 0.47–0.59) for central nervous system cancers, and 0.57 (95% CI, 0.44–0.73) for soft tissue cancers. With all cancer types stratified by age at diagnosis, IRR for live births in cancer survivors aged >41 years at diagnosis was 0.48 (95% CI, 0.44–0.52); IRR was 0.64 (95% CI, 0.61–0.67) in the group aged 31–40 years and 0.71 (95% CI, 0.69–0.74) in the group aged 18–30 years after their cancer treatment. Conclusions Cancer and its treatment were associated with lower live birth rates when comparing women with cancer vs. age-matched, healthy controls.

Background: Previous Women's Ischemia Syndrome Evaluation (WISE) work demonstrated prior oral contraceptive (OC) use was associated with lower coronary artery disease (CAD) in women with suspected ischemia. The association of prior OC use with longer term all-cause and cardiovascular disease (CVD) mortality is unclear. Materials and Methods: WISE women undergoing coronary angiography for suspected ischemia (enrolled 1996–2001) with prior OC use history and 10-year follow-up data were analyzed. A blinded core laboratory assessed atherosclerotic CAD severity. Kaplan–Meier analyses evaluated prior OC use relative to all-cause and CVD mortality. Cox regression analyses adjusted for baseline differences. Mediation, interaction, and multicollinearity were analyzed. Results: Our 686 women had a mean age 62.5 ± 9.6 years, multiple cardiac risk factors, and 39% previously used OC. Prior OC users were younger, with less lipid-lowering medication use and lower atherosclerotic CAD severity scores (all p

OBJECTIVE: The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS: The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS: This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS: This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

Patients and clinicians alike want to know if stress causes infertility. Stress could impair with reproductive function by a variety of mechanisms, including compromise of ovarian function, spermatogenesis, fertilization, endometrial development, implantation, and placentation. Herein we focus on the pathogenesis and treatment of stress-induced anovulation, which is often termed functional hypothalamic amenorrhea (FHA), with the objective of summarizing the actual knowledge as a clinical guide. FHA is a reversible form of anovulation due to slowing of gonadotropin-releasing hormone pulse frequency that results in insufficient pituitary secretion of gonadotropins to support full folliculogenesis. Importantly, FHA heralds a constellation of neuroendocrine alterations with health concomitants. The activity of the hypothalamic-pituitary-adrenal axis is increased in women with FHA and this observation supports the notion that stress is the cause. The extent of reproductive suppression relates to individual endocrinological and physiological sensitivity to stressors, both metabolic and psychogenic, and chronicity.

Traumatic brain injury (TBI) and can lead to persistent hypogonadotropic hypogonadism (PHH) and poor outcomes. We hypothesized that autoimmune and inflammatory mechanisms contribute to PHH pathogenesis. Men with moderate-to-severe TBI (n = 143) were compared with healthy men (n = 39). The TBI group provided blood samples 1–12 months post-injury (n = 1225). TBI and healthy control (n = 39) samples were assayed for testosterone (T) and luteinizing hormone (LH) to adjudicate PHH status. TBI samples 1–6 months post-injury and control samples were assayed for immunoglobulin M (IgM)/immunoglobulin G (IgG) anti-pituitary autoantibodies (APA) and anti-hypothalamus autoantibodies (AHA). Tissue antigen specificity for APA and AHA was confirmed via immunohistochemistry (IHC). IgM and IgG autoantibodies for glial fibrillary acid protein (GFAP) (AGA) were evaluated to gauge APA and AHA production as a generalized autoimmune response to TBI and to evaluate the specificity of APA and AHA to PHH status. An inflammatory marker panel was used to assess relationships to autoantibody profiles and PHH status. Fifty-one men with TBI (36%) had PHH. An age-related decline in T levels by both TBI and PHH status were observed. Injured men had higher APA IgM, APA IgG, AHA IgM, AHA IgG, AGA IgM, and AGA IgG than controls (p

Context Implantation is a reproductive bottleneck in women, regulated by fluctuations in ovarian steroid hormone concentrations. However, other nuclear receptor ligands are modifiers of endometrial differentiation leading to successful pregnancy. In the present study we analyzed the effects of peroxisome-proliferator-activated receptor β/δ (PPARβ/δ) activation on established cellular biomarkers of human endometrial differentiation (decidualization). Objective The objective of this work is to test the effects of PPARβ/δ ligation on human endometrial cell differentiation. Design Isolated primary human endometrial stromal cells (ESCs) were treated with synthetic (GW0742) or natural (all trans-retinoic acid, RA) ligands of PPARβ/δ, and also with receptor antagonists (GSK0660, PT-S58, and ST247) in the absence or presence of decidualizing hormones (10 nM estradiol, 100 nM progesterone, and 0.5 mM dibutyryl cAMP [3′,5′-cyclic adenosine 5′-monophosphate]). In some cases interleukin (IL)-1β was used as an inflammatory stimulus. Time course and dose-response relationships were evaluated to determine effects on panels of well characterized in vitro biomarkers of decidualization. Results PPARβ/δ, along with estrogen receptor α (ERα) and PR-A and PR-B, were expressed in human endometrial tissue and isolated ESCs. GW0742 treatment enhanced hormone-mediated ESC decidualization in vitro as manifested by upregulation of prolactin, insulin-like growth factor-binding protein 1, IL-11, and vascular endothelial growth factor (VEGF) secretion and also increased expression of ERα, PR-A and PR-B, and connexin 43 (Cx43). RA treatment also increased VEGF, ERα, PR-A, and PR-B and an active, nonphosphorylated isoform of Cx43. IL-1β and PPARβ/δ antagonists inhibited biomarkers of endometrial differentiation. Conclusion Ligands that activate PPARβ/δ augment the in vitro expression of biomarkers of ESC decidualization. By contrast, PPARβ/δ antagonists impaired decidualization markers. Drugs activating these receptors may have therapeutic benefits for embryonic implantation.

Context Human embryonic implantation is regulated by neuroendocrine hormones, ovarian steroids, growth factors, and cytokines. Sympathetic innervation of the uterus also may play a role. Objective We tested the hypothesis that cabergoline (Cb), an agonist of type 2 dopamine receptors (DRD2), could influence endometrial decidualization in vitro. Methods Immunohistochemistry confirmed the presence of catecholaminergic neurons in human uterine tissue. DRD2 mRNA and protein expression in endometrial tissue and cells were validated by quantitative RT-PCR, cDNA microarrays, RNA sequencing, and Western blotting. Isolated human endometrial stromal cells (ESC) were subjected to dose-response and time-course experiments in the absence or presence of decidualizing hormones (10 nM estradiol, 100 nM progesterone, and 0.5 mM dibutyryl cAMP). In some cases, interleukin (IL)-1β (0.1 nM) was used as an inflammatory stimulus. Well-characterized in vitro biomarkers were quantified. Results DRD2 were maximally expressed in vivo in the mid-secretory phase of the cycle and upregulated in ESC in response to decidualizing hormones, as were classical (eg, prolactin) and emerging (eg, VEGF and connexin 43) differentiation biomarkers. Cabergoline treatment more than doubled decidual biomarker expression, whereas risperidone, a dopamine receptor antagonist, inhibited ESC differentiation by >50%. Cabergoline induced characteristic decidual morphology changes and blocked detrimental effects of IL-1β on decidual cytology. Conclusion Our results support the hypothesis that dopaminergic neurons modulate decidualization in situ. We postulate that dopamine agonists, like Cb, could be developed as therapeutic agents to enhance implantation in couples with inflammation-associated infertility.

Polycystic ovary syndrome (PCOS) is a common condition with reproductive and metabolic features. Recent studies confirmed that women with PCOS have multiple genetic allelic variants that are independently associated with hyperandrogenism, gonadotropin regulation, timing of menopause, depression, and metabolic disturbances, including insulin resistance [1]. Of note, the data cited above showed that not all women with PCOS possess the full complement of the 14 genetic variants identified. Genetic heterogeneity results in clinical heterogeneity. We have long recognized that there is a spectrum of clinical presentation, with some women having a more pronounced reproductive phenotype and others presenting primarily with metabolic features. Despite variation related to PCOS genotype and phenotype, however, two long-recognized pathogenic themes remain the same: excess androgen exposure and insulin resistance. Since androgens and insulin modulate of brain architecture and function, it is not surprising that PCOS is associated with a brain phenotype, but also one that presents variably. Building on the notion that the brain is a target of hormones of all classes, in this chapter we characterize the brain phenotype in PCOS and explore the evidence that the brain phenotype is the result of androgen exposure that not only predisposes to anovulation and obesity but also has the potential to skew gender identity and sexual orientation.

Endometriosis is a common gynecological syndrome associated with pain and infertility and characterized by the growth of hormone-responsive endometrial tissue outside the uterine cavity. Three major subtypes of ectopic endometriotic implants are currently recognized, based on their anatomic location: (1) attached to the peritoneal surface, (2) encapsulated within the ovary, or (3) infiltrating the connective tissues of the rectovaginal septum. However, more widely dispersed lesions have been described in the pleura, the cutaneous skin, and even the lacrimal duct [1]. The high prevalence of endometriosis is broadly recognized, and recent population-based estimates put its overall frequency among reproductive-age women at around 11% [2]. This disease is accompanied by pelvic pain in millions of women worldwide, resulting in work absenteeism, social isolation, and high costs of medical and surgical therapies. In the United States, endometriosis is the third commonest indication for hysterectomy, a procedure that can be particularly devastating in women under age 30, because they are likely to experience residual somatic symptoms and a severe psychological sense of loss.

Premenstrual syndrome (PMS) is a recurrent constellation of affective and physical symptoms that begin during the luteal phase of the menstrual cycle and resolve completely or almost completely during the follicular phase. Symptoms range in severity from mild to severe. The pathophysiology of PMS is discussed in this chapter, and potential causes are listed in a table. The diagnosis and differential diagnosis are reviewed. To warrant medical attention, evaluation, and intervention, premenstrual symptoms must be recurrent and sufficiently severe to interfere with daily work and social activities. Mild cases of PMS can be treated with lifestyle modification (e.g., good sleep patterns, regular exercise) and nonpharmacologic therapy (e.g., bright-light therapy, stress management, behavioral therapy). More severe cases warrant aggressive intervention, with pharmacologic therapy and even surgery in women who respond very well to a gonadotropin-releasing hormone (GnRH) agonist and have completed childbearing. This review contains 1 figure, 5 tables and 51 references Key Words: Premenstrual syndrome, premenstrual dysphoric disorder, selective serotonin reuptake inhibitors, anxiogenic progesterone metabolites, estrogen, progesterone.

Perimenopause often represents a physiologically challenging phase in women's lives. The clinical presentation of the perimenopause includes infertility, irregular menstrual cycles, menorrhagia, and new onset of or worsening of mood disorders. Unlike menopause, which is characterized by low levels of estradiol and progesterone, the hallmark of perimenopause is highly variable levels of estradiol and progesterone with abrupt increases and decreases that are often described as a hormonal roller coaster. This chapter invites general gynecologists to understand the hormonal basis of the common complaints of perimenopause and offers information about the physiology of these issues and helpful treatment options.

The neuroendocrinology of reproduction focuses on the neuromodulation of gonadotropin-releasing hormone (GnRH), the ontogeny of the hypothalamic-pituitary-gonadal axis, and common reproductive events and conditions, namely, puberty, the menstrual cycle, and disorders of reproductive function. The core concept underpinning the neuroendocrinology of reproduction is neuroregulation of hypothalamic GnRH drive. In both men and women, reproductive function requires that GnRH input elicit appropriate secretion of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary and that the gonads respond to such input appropriately. Moreover, insufficient GnRH drive causes hypothalamic hypogonadism and secondary insufficiency of gonadal sex steroid hormone synthesis and release in both sexes. Alterations in GnRH drive also reflect gonadal conditions such as dysgenesis, hyperandrogenism, gonadotropin mutations, and aging and loss or absence of oocytes or Sertoli cells. The most common cause of insufficient GnRH drive is functional, that is, due to the endocrine effects of psychologic or behavioral variables. Rarely does reduced GnRH drive reflect organic or congenital causes such as developmental defects, brain tumors, or celiac disease. Despite a common neuropathogenesis the heterogeneity of behavioral variables associated with reduced GnRH drive has resulted in a variety of names, including functional hypothalamic amenorrhea, stress-induced anovulation, and psychogenic amenorrhea.

Severe traumatic brain injury (TBI) activates a robust systemic response that involves inflammatory and other factors, including estradiol (E2), associated with increased deaths. Tumor necrosis factor-alpha (TNFα) is a significant mediator of systemic shock, and it is an extra-gonadal transcription factor for E2 production. The study objectives were to test the hypotheses: (1) a positive feedback relationship exists between acute serum TNFα and E2; and (2) acute concentrations of E2 and TNFα are prognostic indicators of death after severe TBI. This prospective cohort study included N = 157 adults with severe TBI. Serum samples were collected for the first five days post-injury. The TNFα and E2 levels were averaged into two time epochs: first 72 h (T1) and second 72 h post-injury (T2). A cross-lag panel analysis conducted between T1 and T2 TNFα and E2 levels showed significant cross-lag effects: T1 TNFα and T1 E2 were related to T2 E2 and T2 TNFα, respectively. Cox proportional hazards multi variable regression models determined that increases in T1 E2 (hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.15, 2.81), but not T2 E2 (HR = 0.91, 95% CI: 0.56, 1.47), were associated with increased risk of death. Increased T2 TNFα (HR = 2.47, 95% CI: 1.35, 4.53), and T1 TNFα (HR = 1.47, 95% CI: 0.99, 2.19), to a lesser degree, were associated with increased risk of death. Relationships of death with T2 TNFα and T1 E2 were mediated partially by cardiovascular, hepatic, and renal dysfunction. Both E2 and TNFα are systemic, reciprocally related biomarkers that may be indicative of systemic compromise and increased risk of death after severe TBI.

Background: Among premenopausal women presenting with ischemia, hypothalamic hypoestrogenemia (HHE) has been associated with angiographic coronary artery disease (CAD). Further, serum amyloid-alpha (SAA), a marker of systemic inflammation strongly predicts future adverse cardiovascular events. We sought to relate inflammatory markers to HHE and understand if inflammation mediates relations between HHE and CAD. Methods: We assessed premenopausal women not on exogenous hormones undergoing coronary angiography for suspected ischemia. HHE was defined as estradiol Results: Overall, 40 (31%) of the 127 women had HHE with similar age and body mass index compared to no HHE (p=0.48 and p=0.77, respectively). Women with HHE had lower estradiol compared to no HHE (30.4+11.7 vs 112.5+62.4 pg/ml, p Conclusion: Among premenopausal women undergoing coronary angiography for suspected myocardial ischemia, SAA levels were significantly elevated in women with HHE, suggesting that inflammation may serve as a mediator between HHE and CAD. Further investigation relative to inflammation as a treatment target in this cohort may be warranted.

Endometriosis implants are comprised of glandular and stromal elements, macrophages, nerves, and blood vessels and are commonly accompanied by pelvic pain. We propose that activated macrophages are recruited to and infiltrate nascent lesions, where they secrete proinflammatory cytokines, promoting the production of chemokines, neurotrophins, and angiogenic growth factors that sustain an inflammatory microenvironment. Immunohistochemical evaluation of endometriosis lesions reveals in situ colocalization of concentrated macrophages, brain-derived neurotrophic factor (BDNF), and nerve fibers. These observations were coupled with biochemical analyses of primary eutopic endometriosis stromal cell (EESC) cultures, which allowed defining potential pathways leading to the neuroangiogenic phenotype of these lesions. Our findings indicate that IL-1β potently (EC50 = 7 ± 2 ng/mL) stimulates production of EESC BDNF at the mRNA and protein levels in an IL-1 receptor-dependent fashion. Selective kinase inhibitors demonstrate that this IL-1β effect is mediated by c-Jun N-terminal kinase (JNK), NF-κB, and mechanistic target of rapamycin signal transduction pathways. IL-1β regulation of regulated on activation normal T cell expressed and secreted (RANTES), a prominent EESC chemokine, also relies on JNK and NF-κB. An important clinical implication of the study is that interference with BDNF and RANTES production, by selectively targeting the JNK and NF-κB cascades, may offer a tractable therapeutic strategy to mitigate the pain and inflammation associated with endometriosis.

Studies of cigarette use and exposure often rely on either self-report or cotinine assay. In adolescence it is not clear how well assays and self-report correspond, or what effect estrogen exposure has on cotinine.This study sought to identify optimal cut-points for salivary cotinine thresholds for girls with primary, secondary, and no smoke exposure, and whether menarche and hormone contraceptive use are important for interpreting salivary cotinine.This longitudinal prospective study recruited 262 healthy adolescent girls who participated in three annual interviews across 24 months. Salivary cotinine assays and self-report of primary and secondary smoke exposure, menarcheal status, and hormone contraceptive use were collected.No adolescents reported primary smoke exposure without secondary exposure. Optimal cut-points for distinguishing primary smoke exposure from secondary-only and no smoke exposure were 1.05 and 3.01 ng/ml, respectively based on receiver operator curves (ROC); no reliable cut-point for secondary-only versus no smoke exposure was identified. The ideal salivary cotinine cut-point to distinguish primary smoke exposure varied by hormone contraceptive use and was 2.14 ng/ml for those using progesterone contraceptives, higher than that of girls using estrogen contraceptives and those not using hormone contraceptives.This study is the first to examine variance in salivary cotinine cut-points based on hormone exposure for adolescent girls, with findings indicating that hormone contraceptive use in particular may be a key consideration when identifying adolescent smoking. The use of previously recommended salivary cotinine cut-points of 3.85 ng/ml or higher may overestimate nonsmokers.

STUDY QUESTION Do cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA), testosterone (T) and estradiol (E2) differ in women with polycystic ovary syndrome (PCOS) as compared to eumenorrheic, ovulatory women (EW)? SUMMARY ANSWER Women with PCOS displayed higher CSF levels of GABA and E2, and possibly T, than EW. WHAT IS KNOWN ALREADY The chronic anovulation characteristic of PCOS has been attributed to increased central GnRH drive and resulting gonadotropin aberrations. Androgens are thought to regulate GABA, which in turn regulates the neural cascade that modulates GnRH drive. STUDY DESIGN, SIZE, DURATION This cross-sectional observational study included 15 EW and 12 non-obese women with PCOS who consented to a lumbar puncture in addition to 24 h of serum blood collection at 15-min intervals. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 27 women were studied at a the General Clinical Research Center (GCRC) at the University of Pittsburgh. Serum analytes included T, E2 and androstenedione. CSF analytes included GABA, glutamate, glucose, T and E2. MAIN RESULTS AND THE ROLE OF CHANCE Women with PCOS had higher CSF GABA as compared to EW (9.04 versus 7.04 μmol/L, P < 0.05). CSF glucose and glutamate concentrations were similar between the two groups. CSF T was 52% higher (P = 0.1) and CSF E2 was 30% higher (P < 0.01) in women with PCOS compared to EW. Circulating T was 122% higher (P < 0.01) and circulating E2 was 75% higher (P < 0.01) in women with PCOS than in EW. LIMITATIONS REASONS FOR CAUTION The study is limited by its small sample size and the technical limitations of measuring CSF analytes that are pulsatile and have short half-lives. WIDER IMPLICATIONS OF THE FINDINGS Women with PCOS displayed significantly higher circulating levels of T and E2, significantly higher CSF levels of E2, and higher levels of CSF testosterone, although the latter was not statistically significant. A better understanding of the central milieu informs our understanding of the mechanisms mediating increased the GnRH drive in PCOS and lends a new perspective for understanding the presentation, pathogenesis and potential health consequences of PCOS, including gender identity issues. STUDY FUNDING/COMPETING INTEREST(S) No conflicts of interest. The study was funded by NIH grants to SLB (RO1-MH50748, U54-HD08610) and NIH RR-00056 to the General Clinical Research Center of the University of Pittsburgh. TRIAL REGISTRATION NUMBER NCT01674426.

Cosponsoring associations The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. Objective To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA). Participants The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer. Evidence This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus process One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline. Conclusions FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation.

The neuroendocrinology of reproduction focuses on the neuromodulation of gonadotropin-releasing hormone (GnRH), the ontogeny of the hypothalamic-pituitary-gonadal axis, and common reproductive events and conditions, namely, puberty, the menstrual cycle, and disorders of reproductive function. The core concept underpinning the neuroendocrinology of reproduction is neuroregulation of hypothalamic GnRH drive. In both men and women, reproductive function requires that GnRH input elicit appropriate secretion of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary and that the gonads respond to such input appropriately. Moreover, insufficient GnRH drive causes hypothalamic hypogonadism and secondary insufficiency of gonadal sex steroid hormone synthesis and release in both sexes. Alterations in GnRH drive also reflect gonadal conditions such as dysgenesis, hyperandrogenism, gonadotropin mutations, and aging and loss or absence of oocytes or Sertoli cells. The most common cause of insufficient GnRH drive is functional, that is, due to the endocrine effects of psychologic or behavioral variables. Rarely does reduced GnRH drive reflect organic or congenital causes such as developmental defects, brain tumors, or celiac disease. Despite a common neuropathogenesis the heterogeneity of behavioral variables associated with reduced GnRH drive has resulted in a variety of names, including functional hypothalamic amenorrhea, stress-induced anovulation, and psychogenic amenorrhea.

Background Previous studies have reported an association between the timing of menarche and cardiovascular disease ( CVD ). However, emerging studies have not examined the timing of menarche in relation to role of estrogen over a lifetime and major adverse cardiac events ( MACE ). Methods and Results A total of 648 women without surgical menopause undergoing coronary angiography for suspected ischemia in the WISE (Women's Ischemia Syndrome Evaluation) study were evaluated at baseline and followed for 6 years (median) to assess major adverse CVD outcomes. MACE was defined as the first occurrence of all‐cause death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization. Age at menarche was self‐reported and categorized (≤10, 11, 12, 13, 14, ≥15 years) with age 12 as reference. Total estrogen time and supra–total estrogen time were calculated. Cox regression analysis was performed adjusting for CVD risk factors. Baseline age was 57.9 ± 12 years (mean ± SD ), body mass index was 29.5 ± 6.5 kg/m 2 , total estrogen time was 32.2 ± 8.9 years, and supra–total estrogen time was 41.4 ± 8.8 years. MACE occurred in 172 (27%), and its adjusted regression model was J‐shaped. Compared with women with menarche at age 12 years, the adjusted MACE hazard ratio for menarche at ≤10 years was 4.53 (95% CI 2.13‐9.63); and at ≥15 years risk for MACE was 2.58 (95% CI , 1.28‐5.21). Conclusions History of early or late menarche was associated with a higher risk for adverse CVD outcomes. These findings highlight age at menarche as a potential screening tool for women at risk of adverse CVD events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00000554.

Early declines in gonadotropin production, despite elevated serum estradiol, among some individuals with severe traumatic brain injury (TBI) suggests amplified systemic aromatization occurs post-injury. Our previous work identifies estradiol (E2) as a potent mortality marker. Androstenedione (A), a metabolic precursor to E2, estrone (E1), and testosterone (T), is a steroid hormone substrate for aromatization that has not been explored previously as a biomarker in TBI. Here, we evaluated serum A, E1, T, and E2 values for 82 subjects with severe TBI. Daily hormone values were calculated, and E2:A and E1:T ratios were generated and then averaged for days 0–3 post-injury. After data inspection, mean E2:A values were categorized as above (high aromatization) and below (low aromatization) the 50th percentile for 30-day mortality assessment using Kaplan-Meier survival analysis and a multivariable Cox proportional hazard model adjusting for age, and Glasgow Coma Scale (GCS) to predict 30-day mortality status. Daily serum T, E1, and E2 were graphed by E2:A category. Serum E1 and E2 significantly differed over time (p

Extensive pre-clinical studies suggest that sex steroids are neuroprotective in experimental traumatic brain injury (TBI). However, clinical trials involving sex hormone administration have not shown beneficial results, and our observational cohort studies show systemic estradiol (E2) production to be associated with adverse outcomes. Systemic E2 is produced via aromatization of testosterone (T) or reduction of estrone (E1). E1, also produced via aromatization of androstenedione (Andro) and is a marker of T-independent E2 production. We hypothesized that E1 would be (1) associated with TBI-related mortality, (2) the primary intermediate for E2 production, and (3) associated with adipose tissue-specific aromatase transcription. We assessed 100 subjects with severe TBI and 8 healthy controls. Serum levels were measured on days 0–3 post-TBI for key steroidogenic precursors (progesterone), aromatase pathway intermediates (E1, E2, T, Andro), and the adipose tissue-specific aromatase transcription factors cortisol, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). E1 was elevated after TBI versus controls. High E1 was associated with higher progesterone, cortisol, and IL-6 (p

Observational studies have suggested that arterial distensibility decreases during menopause; however, its relationship with hormone therapy use remains controversial. We prospectively studied distensibility and hormone therapy use at different menopause stages.One hundred sixty-one women (aged between 42 and 61 y) without cardiovascular disease underwent carotid artery measurements by ultrasound to calculate distensibility index at baseline and 3 years later. Menopause stage was classified at each visit as premenopausal, perimenopausal, and postmenopausal. Across 3 years of prospective observation, women were classified as remaining premenopausal, remaining postmenopausal, or transitioning (defined as change from premenopausal to perimenopausal, from premenopausal to postmenopausal, from perimenopausal to perimenopausal, or from perimenopausal to postmenopausal).Distensibility declined across time at all menopause stages (P0.0001). Compared with postmenopausal women, premenopausal and transitioning/no hormone therapy women had more than twice the decline in distensibility index (P = 0.06 and P = 0.016, respectively), whereas transitioning/hormone therapy women did not differ in distensibility decline (P = 0.28). In a multivariate model, change in systolic blood pressure (P0.0001) and change in pulse pressure (P = 0.004) were independent predictors of distensibility index change and served as effect modulators. In an adjusted model, women in the premenopausal and transitioning/no hormone therapy groups had a significantly faster decline in distensibility index (P = 0.002 and P = 0.001, respectively) compared with postmenopausal women, whereas the transitioning/hormone therapy group did not (P = 0.21).These findings confirm that the menopausal transition is associated with reduced vascular compliance. Hormone therapy is associated with better arterial distensibility only during the menopausal transition. Additional prospective studies are needed to confirm these findings and to determine whether hormone therapy use beyond the menopausal transition is related to distensibility.

BACKGROUND The purpose of this study was to examine and compare the effects of the first 18 months of anastrozole therapy on cognitive function in women with breast cancer. METHODS This large, longitudinal cohort study was composed of postmenopausal women with early-stage breast cancer who received chemotherapy plus anastrozole (n = 114) or anastrozole alone (n = 173) and a control group (n = 110). Cognitive function was assessed before systemic therapy and 6, 12, and 18 months after therapy initiation and at comparable time points in controls. RESULTS The chemotherapy-anastrozole and anastrozole-alone groups had poorer executive function than the controls at nearly all time points (P 18 months) of anastrozole on cognitive function remain to be determined. Cancer 2015;121:2627–2636. © 2015 American Cancer Society.

Bidirectional communication between the immune and neuroendocrine systems is not well understood in the context of traumatic brain injury (TBI). The purpose of this study was to characterize relationships between cerebrospinal fluid (CSF) cortisol and inflammation after TBI, and to determine how these relationships differ by outcome. CSF samples were collected from 91 subjects with severe TBI during days 0–6 post-injury, analyzed for cortisol and inflammatory markers, and compared to healthy controls (n = 13 cortisol, n = 11 inflammatory markers). Group-based trajectory analysis (TRAJ) delineated subpopulations with similar longitudinal CSF cortisol profiles (high vs. low cortisol). Glasgow Outcome Scale (GOS) scores at 6 months served as the primary outcome measure reflecting global outcome. Inflammatory markers that displayed significant bivariate associations with both GOS and cortisol TRAJ (interleukin [IL]-6, IL-10, soluble Fas [sFas], soluble intracellular adhesion molecule [sICAM]-1, and tumor necrosis factor alpha [TNF]-α) were used to generate a cumulative inflammatory load score (ILS). Subsequent analysis revealed that cortisol TRAJ group membership mediated ILS effects on outcome (indirect effect estimate = −0.253, 95% CI (−0.481, −0.025), p = 0.03). Correlational analysis between mean cortisol levels and ILS were examined separately within each cortisol TRAJ group and by outcome. Within the low cortisol TRAJ group, subjects with unfavorable 6-month outcome displayed a negative correlation between ILS and mean cortisol (r = −0.562, p = 0.045). Conversely, subjects with unfavorable outcome in the high cortisol TRAJ group displayed a positive correlation between ILS and mean cortisol (r = 0.391, p = 0.006). Our results suggest that unfavorable outcome after TBI may result from dysfunctional neuroendocrine–immune communication wherein an adequate immune response is not mounted or, alternatively, neuroinflammation is prolonged. Importantly, the nature of neuroendocrine–immune dysfunction differs between cortisol TRAJ groups. These results present a novel biomarker-based index from which to discriminate outcome and emphasize the need for evaluating tailored treatments targeting inflammation early after injury.

The U.S. National Institutes of Health (NIH) announced last May that steps will be taken to address the over-reliance on male cells and animals in preclinical research. To further address this announcement, in September 2014, scientists with varying perspectives came together at Georgetown University to discuss the following questions. (1) What metrics should the NIH use to assess tangible progress on policy changes designed to address the over-reliance on male cells and animals in preclinical research? (2) How effective can education be in reducing the over-reliance on male cells and animals in preclinical research and what educational initiatives sponsored by the NIH would most likely effect change? (3) What criteria should the NIH use to determine rigorously defined exceptions to the future proposal requirement of a balance of male and female cells and animals in preclinical studies? (4) What additional strategies in addition to proposal requirements should NIH use to reduce the overreliance of male cells and animals in preclinical research? The resulting consensus presented herein includes input from researchers not only from diverse disciplines of basic and translational science including biology, cell and molecular biology, biochemistry, physiology, pharmacology, neuroscience, cardiology, endocrinology, nephrology, psychiatry, and obstetrics and gynecology, but also from recognized experts in publishing, industry, advocacy, science policy, clinical medicine, and population health. We offer our recommendations to aid the NIH as it selects, implements, monitors, and optimizes strategies to correct the over-reliance on male cells and animals in preclinical research.—Sandberg, K., Umans, J. G., Georgetown Consensus Conference Work Group. Recommendations concerning the new U.S. National Institutes of Health initiative to balance the sex of cells and animals in preclinical research.

The cornerstone of female reproduction is the hypothalamic-pituitary-ovarian (HPO) axis. This term is incomplete in that it omits reference to the uterus and endometrium, which are clearly critical to the most important step in reproduction, namely, implantation. Implantation requires that the endometrium become receptive to a healthy blastocyst. Thus, folliculogenesis must result not only in ovulation but also in the secretion of estradiol and progesterone in a pattern that prepares the endometrium for implantation. While implantation failure can be defined as absent hCG production after ovulation that is signaled by menstrual bleeding, the definition also encompasses transient hCG production that is not sustained, which is often called “chemical” pregnancy.

Functional hypothalamic amenorrhea is characterized by anovulation caused by reduced gonadotropin-releasing hormone drive and is associated with hypercortisolemia that has been linked to heightened hypothalamic-pituitary-adrenal reactivity to common psychological and metabolic challenges.We hypothesized that women with functional hypothalamic amenorrhea would display greater cortisol responses to exercise challenge than ovulatory women with eumenorrhea.We completed a cross-sectional comparison of 9 women with functional hypothalamic amenorrhea and 11 women with eumenorrhea who were of reproductive age, who weighed 90-110% ideal body weight, who did not exercise excessively, and who had no formal psychiatric diagnosis. Subjects completed a 20-minute submaximal exercise challenge using a cycle ergometer in a research exercise laboratory. Heart rate and circulatory cortisol, glucose, and lactate were measured at 10-minute intervals before, during, and after the exercise challenge.Baseline (t= -10 minutes) cortisol, glucose, lactate, and heart rate were comparable between groups. Glucose levels rose modestly during exercise by 2.9% in women with eumenorrhea (P=.4) but declined by 10.6% in functional hypothalamic amenorrhea (P.03). The nadir in glucose levels in functional hypothalamic amenorrhea occurred at the end of the 20-minute exercise challenge (t= +20 min). Lactate levels rose comparably in both groups (P.01). Heart rate increased significantly with exercise in both groups (P.01), but the increase was smaller in subjects with functional hypothalamic amenorrhea (P.01). Cortisol levels increased during the exercise challenge in both groups (P.01) and peaked 10 minutes after the exercise ended (t= +30 min). At peak, subjects with functional hypothalamic amenorrhea displayed higher cortisol levels (147±22 [standard error of the mean] ng/mL) than women with eumenorrhea (96±12 ng/mL; P=.05). The mean percent increase over baseline was 62% in women with eumenorrhea and 92% in functional hypothalamic amenorrhea.The heightened cortisol response to exercise in women with functional hypothalamic amenorrhea was associated with a decline in blood glucose level that was not observed in women with eumenorrhea. Women with functional hypothalamic amenorrhea appear to be more reactive at the endocrine level to the metabolic demand of exercise. Submaximal challenge unmasks underlying stress sensitivity in women with functional hypothalamic amenorrhea and highlights the importance of the use of psychological interventions for stress reduction in this population.

Inflammation can interfere with endometrial receptivity. We examined how interleukin 1β (IL-1β) affects expression of the uterine gap junction protein connexin 43 (Cx43), which is known to be critical for embryonic implantation. We used an in vitro model of human endometrial stromal cells (ESCs), Western blotting, and a combination of validated, selective kinase inhibitors to evaluate five canonical IL-1β signaling pathways. Cx43 and two other markers of ESC differentiation (prolactin and VEGF) were inhibited predominantly via IL-1β-activated ERK1/2 and p38 MAP kinase cascades. The findings were corroborated using small interfering RNA to silence critical genes in either pathway. By contrast, upregulation of endogenous pro-IL-1α and pro-IL-1β following recombinant IL-1β treatment was mediated via the Jun N-terminal kinase pathway. The clinicopharmacological significance of our findings is that multiple signaling cascades may need to be neutralized to reverse deleterious effects of IL-1β on human endometrial function.

SUMMARY One of the most dynamic adult human tissues is the endometrium. Through coordinated, cyclical proliferation, differentiation, leukocyte recruitment, apoptosis, and desquamation, the uterine lining is expanded and shed monthly, unless pregnancy is established. Errors in these steps potentially cause endometrial dysfunction, abnormal uterine bleeding, failed embryonic implantation, infertility, or endometrial carcinoma. Our prior studies showed that gap junctions comprised of Gap junction alpha-1 (GJA1) protein, also known as connexin 43 (CX43), subunits are critical to endometrial stromal cell differentiation. The current studies were undertaken to explore the mechanism of endometrial dysfunction when gap junction intercellular communication (GJIC) is disrupted. Gap junction blockade by two distinct GJIC inhibitors, 18α-glycyrrhetinic acid (AGA) and octanol (OcOH), suppressed proliferation and induced apoptosis in endometrial stromal cells, as manifested by reduced biomarkers of cell viability, increased TUNEL staining, caspase-3 activation, sub-G1 chromosomal DNA complement, as well as shortened telomere length. Unexpectedly, we also observed that the chemical inhibitors blocked CX43 gene expression. Moreover, when endometrial stromal cells were induced to undergo hormonal decidualization, following a 7-day exposure to 10 nM 17β-estradiol + 100 nM progesterone + 0.5 mM dibutyryl cAMP, characteristic epithelioid changes in cell shape and secretion of prolactin were blunted in the presence of AGA or OcOH, recapitulating effects of RNA interference of CX43. Our findings indicate that endometrial stromal cell proliferation and maintenance of decidualized endometrial function are GJIC-dependent, and that disruption of gap junctions induces endometrial stromal cell apoptosis. These observations may have important implications for several common clinical endometrial pathologies. Mol. Reprod. Dev. 81: 666–675, 2014. © 2014 Wiley Periodicals, Inc.

Despite significant advances in the management of head trauma, there remains a lack of pharmacological treatment options for traumatic brain injury (TBI). While progesterone clinical trials have shown promise, corticosteroid trials have failed. The purpose of this study was to (1) characterize endogenous cerebrospinal fluid (CSF) progesterone and cortisol levels after TBI, (2) determine relationships between CSF and serum profiles, and (3) assess the utility of these hormones as predictors of long-term outcomes. We evaluated 130 adults with severe TBI. Serum samples (n=538) and CSF samples (n=746) were collected for 6 days post-injury, analyzed for cortisol and progesterone, and compared with healthy controls (n=13). Hormone data were linked with clinical data, including Glasgow Outcome Scale (GOS) scores at 6 and 12 months. Group based trajectory (TRAJ) analysis was used to develop temporal hormone profiles delineating distinct subpopulations. Compared with controls, CSF cortisol levels were significantly and persistently elevated during the first week after TBI, and high CSF cortisol levels were associated with poor outcome. As a precursor to cortisol, progesterone mediated these effects. Serum and CSF levels for both cortisol and progesterone were strongly correlated after TBI relative to controls, possibly because of blood–brain barrier disruption. Also, differentially impaired hormone transport and metabolism mechanisms after TBI, potential de novo synthesis of steroids within the brain, and the complex interplay of cortisol and pro-inflammatory cytokines may explain these acute hormone profiles and, when taken together, may help shed light on why corticosteroid trials have previously failed and why progesterone treatment after TBI may be beneficial.