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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

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

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.

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.

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.

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.

Vulvar and vaginal atrophy (VVA) is a chronic, progressive medical condition prevalent among postmenopausal women, which produces symptoms such as dyspareunia, vaginal dryness, and vaginal irritation. Currently, the only prescription options are systemic and vaginal estrogen therapies that may be limited by concerns about long-term safety and breast cancer risk. Ospemifene is a tissue-selective estrogen agonist/antagonist (a selective estrogen receptor modulator) recently approved by the US Food and Drug Administration for treatment of dyspareunia, a symptom of VVA, due to menopause. Ospemifene, the first nonestrogen oral treatment for this indication, may provide an alternative to treatment with estrogen. Animal models with ospemifene suggest an inhibitory effect on growth of malignant breast tissue, but animal data cannot necessarily be extrapolated to humans. Clinical trials, including 3 long-term studies assessing the overall safety of ospemifene, support that ospemifene is generally well tolerated, with beneficial effects on the vagina, neutral effects on the breast, and minimal effects on the endometrium.

Clinical Opinion www. AJOG .org GENERAL GYNECOLOGY A statement on abortion by 100 professors of obstetrics: 40 years later One Hundred Professors of Obstetrics and Gynecology F orty years ago, leaders in obstetrics and gynecology published a com- pelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. 1 They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. 1 They wrote to ex- press their concern for women’s health in a new legal and medical era of re- productive control and to define the responsibilities of academic obstetrician- gynecologists. Since then, we have advanced the fields of reproduction and family planning. Thanks to these developments, women can now prevent pregnancy with safer and more effective forms of contracep- tion (most recently long-acting revers- ible methods), with simple and sensitive hormonal and sonographic methods to determine pregnancy status and dura- tion, and with new methods of infer- tility treatment and prenatal testing that rely on the option of terminating inten- ded pregnancies that are diagnosed as abnormal. To terminate pregnancies, cli- nicians now use misoprostol and mife- pristone for “medical abortion” (which in 2009 accounted for 16.5% of termina- tions in the United States and can be office-based) and use sonographic guid- ance of intrauterine procedures along with new methods for inducing cervical dilation and uterine contraction; patients From the 100 Professors (Appendix). Received Dec. 3, 2012; revised Jan. 23, 2013; accepted March 7, 2013. The author reports no conflict of interest. Reprints not available from the authors. a 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.03.007 In this Journal in 1972, 100 leaders in obstetrics and gynecology published a compelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. They wrote to express their concern for women’s health in a new legal and medical era of reproductive control and to define the responsibilities of academic obstetrician-gynecologists. Forty years later, 100 professors examine the statement of their predecessors in light of medical advances and legal changes and suggest a further course of action for obstetrician gynecologists. Key words: abortion, law, teaching hospital benefit from innovations in counseling and new approaches to pain control. 2-6 Studies of abortion practice and out- comes are also much more sophisticated than they were 40 years ago. 7,8 We have had 40 years of medical progress but have witnessed political regression that the 100 professors did not anticipate. In 2011 alone, 24 states passed 92 legislative restrictions on abortion. 9 Waiting periods after consent are now law in 26 states. Alabama, Arizona, Florida, Kansas, Louisiana, North Car- olina, Oklahoma and Texas require pa- tients to view ultrasound images and, in Arizona, Louisiana, Mississippi and Texas, to listen to fetal heart beats. 10 Laws in 27 states force physicians to provide deceptive counseling including false statements about risks of breast cancer, infertility and mental health. They include laws to limit second-trimester abortion under the guise of protecting the fetus from pain (Alabama, Idaho, Indiana, Kansas, Louisiana, Nebraska, and Oklahoma). 11 Laws directed specif- ically at medical education in Arizona, Kansas, and Texas prohibit abortion training in public institutions and another 7 states ban abortion in public hospitals, precluding training in them. 12 What vision of the future of legalized abortion did the 100 professors have? How accurately did they estimate the need for safe, legal abortion and antici- pate their colleagues’ willingness and commitment to meeting it? They wrote, “In view of the impending change in abortion practices generated by new state legislation and federal court de- cisions, we believe it helpful to [respond] to this increasingly liberal course of events.by contributing to the solution of an imminent problem.” 1 Forty years later, the change is not liberal. Its effects will threaten, not improve, women’s health and already obstruct physicians’ evidence-based and patient-centered practices. We review our predecessors’ 1972 statement and judge how it com- ports with what actually occurred and with legislation that has been adopted over the 40 years since their writing and the passage of Roe v Wade. The 100 professors were remarkably prescient in anticipating the need for 1 million legal abortions and today’s abortion rate of 1 in 4 pregnancies. 13,14 They predicted that teaching hospitals with specialized outpatient facilities could meet the demand and believed that abortions were the responsibility of hospitals. But today, 90% of abortions, which include the 10% that are in the second trimester, are done away from hospitals. 15 Many hospitals enforce fetal and maternal health restrictions that are not based in the law but are MONTH 2013 American Journal of Obstetrics & Gynecology FLA 5.1.0 DTD ! YMOB9193_proof ! 15 April 2013 ! 10:46 am ! ce

Clinical Opinion www. AJOG .org GENERAL GYNECOLOGY A statement on abortion by 100 professors of obstetrics: 40 years later One Hundred Professors of Obstetrics and Gynecology F orty years ago, leaders in obstetrics and gynecology published a com- pelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade (Supplementary Data available at www.AJOG.org). 1 They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. 1 They wrote to ex- press their concern for women’s health in a new legal and medical era of re- productive control and to define the responsibilities of academic obstetrician- gynecologists. Since then, we have advanced the fields of reproduction and family planning. Thanks to these developments, women can now prevent pregnancy with safer and more effective forms of contracep- tion (most recently long-acting revers- ible methods), with simple and sensitive hormonal and sonographic methods to determine pregnancy status and dura- tion, and with new methods of infer- tility treatment and prenatal testing that rely on the option of terminating inten- ded pregnancies that are diagnosed as abnormal. To terminate pregnancies, cli- nicians now use misoprostol and mife- pristone for “medical abortion” (which in 2009 accounted for 16.5% of termina- tions in the United States and can be office-based) and use sonographic guid- ance of intrauterine procedures along with new methods for inducing cervical From the 100 Professors (Appendix). Received Dec. 3, 2012; revised Jan. 23, 2013; accepted March 7, 2013. The author reports no conflict of interest. Reprints not available from the authors. a 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.03.007 In this Journal in 1972, 100 leaders in obstetrics and gynecology published a compelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. They wrote to express their concern for women’s health in a new legal and medical era of reproductive control and to define the responsibilities of academic obstetrician-gynecologists. Forty years later, 100 professors examine the statement of their predecessors in light of medical advances and legal changes and suggest a further course of action for obstetrician gynecologists. Key words: abortion, law, teaching hospital dilation and uterine contraction; patients benefit from innovations in counseling and new approaches to pain control. 2-6 Studies of abortion practice and out- comes are also much more sophisticated than they were 40 years ago. 7,8 We have had 40 years of medical progress but have witnessed political regression that the 100 professors did not anticipate. In 2011 alone, 24 states passed 92 legislative restrictions on abortion. 9 Waiting periods after consent are now law in 26 states. Alabama, Arizona, Florida, Kansas, Louisiana, North Car- olina, Oklahoma, and Texas require pa- tients to view ultrasound images and, in Arizona, Louisiana, Mississippi, and Texas, to listen to fetal heart beats. 10 Laws in 27 states force physicians to provide deceptive counseling including false statements about risks of breast cancer, infertility, and mental health. They include laws to limit second-trimester abortion under the guise of protecting the fetus from pain (Alabama, Idaho, Indiana, Kansas, Louisiana, Nebraska, and Oklahoma). 11 Laws directed specif- ically at medical education in Arizona, Kansas, and Texas prohibit abortion training in public institutions and another 7 states ban abortion in public hospitals, precluding training in them. 12 What vision of the future of legalized abortion did the 100 professors have? How accurately did they estimate the need for safe, legal abortion and antici- pate their colleagues’ willingness and commitment to meeting it? They wrote, “In view of the impending change in abortion practices generated by new state legislation and federal court de- cisions, we believe it helpful to [respond] to this increasingly liberal course of events.by contributing to the solution of an imminent problem.” 1 Forty years later, the change is not liberal. Its effects will threaten, not improve, women’s health and already obstruct physicians’ evidence-based and patient-centered practices. We review our predecessors’ 1972 statement and judge how it com- ports with what actually occurred and with legislation that has been adopted over the 40 years since their writing and the passage of Roe v Wade. The 100 professors were remarkably prescient in anticipating the need for 1 million legal abortions and today’s abortion rate of 1 in 4 pregnancies. 13,14 They predicted that teaching hospitals with specialized outpatient facilities could meet the demand and believed that abortions were the responsibility of hospitals. But today, 90% of abortions, which include the 10% that are in the second trimester, are done away from hospitals. 15 Many hospitals enforce fetal and maternal health restrictions that SEPTEMBER 2013 American Journal of Obstetrics & Gynecology

Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality (p=0.019) and better GOS-6 scores (p=0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone (p≤0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores (p≤0.05, all comparisons), and those with>1 risk SNP variant had a higher risk for poor outcome, compared with those with ≤1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI.

Modern methods of diagnosis have made the distinction between hypothalamic failure and ovarian failure routine. Failure of the orderly progression of hypothalamic gonadotrophin-releasing hormone (GnRH) → pituitary gonadotrophins → ovarian steroids and inhibin → hypothalamus/pituitary results in anovulation/amenorrhea. The hypothalamic connections that regulate the pattern and amplitude of GnRH pulses are plastic and respond to external/psychological conditions and internal/metabolic factors that may affect the hypothalamic substrate on which estrogen levels can act. We trace the neuroendocrine regulation of the ovarian cycle, concentrating on hypothalamic connections that underlie negative and positive feedback control of GnRH and the complementary role of the adenohypophysis. The main hormone regulating this "central axis" and the development of the endometrium is estradiol which is exported from the developing ovarian follicles and thereby closes the feedback loop with follicle development. Progesterone and inhibin are also involved. Neuroendocrine responses to internal and external factors can cause anovulation and amenorrhea. Generally, these are accompanied by abnormal negative feedback between estradiol and the gonadotrophins; coexistence of low estradiol and luteinizing hormone/follicle-stimulating hormone. There are three main causes: (1) genetic diseases that interfere with the migration of GnRH cells into the brain or result in misfolding of GnRH; (2) input from the brain that interrupts normal feedback (e.g. stress and weight loss amenorrhea); and (3) the effect of agents which alter central neurotransmission and hypothalamic function (e.g. elevated prolactin and psychotropic medications). All types of hypothalamic insufficiency result in insufficient stimulation of the ovaries. In addition to amenorrhea, this central alteration also results in other complications (downstream disease) that make hypothalamic amenorrhea of greater consequence than simply reproductive failure. Thus, there may be more at stake in the diagnosis and treatment of hypothalamic failure than brings the patient to her caregiver.

There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20-80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [(11)C]WAY100635 and [(18)F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (V(T)) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age(2), sex, and hormone concentrations, with post hoc regional significance set at p0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004-0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05-0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03-0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex-hormone-serotonin receptor relationships.

Athletic women are at risk for developing ovulatory dysfunction, which presents variably as menstrual irregularity or absence. Initially characterized as an isolated disruption of hypothalamic gonadotropin-releasing hormone (GnRH) release, athletic amenorrhea, a form of hypogonadotropic hypogonadism, is invariably accompanied by additional neuroendocrine aberrations, including activation of adrenal and suppression of thyroidal axes. Exercise may elicit intermittent or chronic metabolic stress owing to increased energy expenditure and/or insufficient or imbalanced nutrient intake. In addition, athletic activities are motivated by or serve as psychogenic stressors. Prior studies dichotomized stressors as metabolic or psychogenic. Not only is this a false dichotomy because all stressors have both a metabolic and a psychogenic component, but also stressors act synergistically rather than in isolation to compromise GnRH drive and endocrine homeostasis. To ameliorate reproductive and endocrine consequences of stress, then, requires identification and amelioration of all relevant stressors. Formal psychosocial support helps individuals to develop better coping strategies and make appropriate lifestyle changes. Our research has shown that cognitive behavior therapy restores reproductive and endocrine balance.

It has been suggested that both endogenous reproductive hormones and hormone therapy may play a protective role against coronary artery disease (CAD). However, recent clinical trials have failed to demonstrate the benefit of a variety of forms of hormone therapy. The observational data on the role of endogenous reproductive hormones, using surrogate measures such as number of birth, age at menarche, and age at menopause are inconsistent. In addition, the longer-term associations have not been evaluated. The aim of this study was to evaluate the relationships between detailed measurements of endogenous and exogenous estrogen exposure time with angiographic CAD and major adverse cardiovascular events.We assessed total estrogen exposure time, quantitative CAD by a core angiography laboratory, and prospectively measured major adverse cardiovascular events in 646 postmenopausal women undergoing coronary angiography for evaluation for suspected ischemia in the Women's Ischemia Syndrome Evaluation (WISE) study.Timing of postmenopausal exogenous hormone therapy (HT) use was associated with reduced CAD. Two summarized total estrogen time scores (TET and sTET) were not related to angiographic CAD after accounting for HT use. In addition, these scores were not related to cardiovascular events over a median of 6.0 years of follow-up.There was no independent relation of estrogen exposure time to angiographic CAD or major adverse cardiovascular events in a contemporary cohort of postmenopausal women evaluated for suspected ischemia. Our results suggest that the paradigm of estrogen protection from CAD in women may be more complex than estrogen exposure duration alone.

Sex steroids modulate brain function at all developmental stages of life. This article focuses on the role of sex steroids after menopause with the intent of addressing the question whether or to what extent sex steroids, particularly estrogenic agents, are neuroprotective for the aging brain of women. The rationale for delving into this complicated topic is that the information and perspective so acquired will aid physicians in counseling surgically and naturally menopausal women about their therapeutic options. Whereas we review and synthesize relevant data from monkey, other animal, cellular, and molecular studies, the emphasis is on human studies and reconciling the disparate evidence. Although the knowledge gaps are considerable, available evidence suggests that extended use of non-oral estradiol is a reasonable course of action if the woman to be treated has a relatively low risk for cardiovascular disease and venous thromboembolism or a high concern about developing dementia. It is important to emphasize that estradiol may negatively impact an already unhealthy individual and yet synergize other health-promoting behaviors such as good nutrition, exercise, and stress reduction in a relatively healthy individual.

Feedback inhibition of the amygdala via medial prefrontal cortex (mPFC) is an important component in the regulation of complex emotional behaviors. The functional dynamics of this corticolimbic circuitry are, in part, modulated by serotonin (5-HT). Serotonin 2A (5-HT(2A)) receptors within the mPFC represent a potential molecular mechanism through which 5-HT can modulate this corticolimbic circuitry. We employed a multimodal neuroimaging strategy to explore the relationship between threat-related amygdala reactivity, assessed using blood oxygen level-dependent functional magnetic resonance imaging, and mPFC 5-HT(2A) density, assessed using [(18)F]altanserin positron emission tomography in 35 healthy adult volunteers. We observed a significant inverse relationship wherein greater mPFC 5-HT(2A) density was associated with reduced threat-related right amygdala reactivity. Remarkably, 25-37% of the variability in amygdala reactivity was explained by mPFC 5-HT(2A) density. We also observed a positive correlation between mPFC 5-HT(2A) density and the magnitude of right amygdala habituation. Furthermore, functional coupling between the amygdala and mPFC was positively correlated with 5-HT(2A) density suggesting that effective integration of emotionally salient information within this corticolimbic circuitry may be modulated, at least in part, by mPFC 5-HT(2A). Collectively, our results indicate that mPFC 5-HT(2A) is strongly associated with threat-related amygdala reactivity as well as its temporal habituation and functional coupling with prefrontal regulatory regions.

Bacterial contamination may cause loss or damage to cultured oocytes or embryos, resulting in cancelation or delaying of a fresh embryo transfer. While live births have been reported following the transfer of embryos contaminated with yeast, very little information is available on how to handle embryos with bacterial contamination. We report two cases of successful pregnancy in patients with bacterial contamination of embryo culture dishes.We retrospectively reviewed 878 oocyte retrievals performed between January 2011 and December 2014. Bacterial contamination was recorded in two split IVF/ICSI cases, where contamination occurred in embryo culture drops containing embryos from conventional insemination but not from ICSI on day 3.To minimize the adverse effects of bacterial contamination on transfer outcomes, we removed the zona pellucida of contaminated frozen blastocysts and successfully obtained clinical pregnancies following transfer of zona-free blastocysts that were previously contaminated during IVF culture.Removal of the zona pellucida is an appropriate approach to handle blastocysts contaminated with bacteria during in vitro culture.

Behaviors that chronically activate the hypothalamic-pituitary-adrenal (HPA) axis and/or suppress the hypothalamic-pituitary-thyroidal (HPT) axis disrupt the hypothalamic-pituitary-gonadal axis in women and men. Individuals with functional hypothalamic hypogonadism typically engage in a combination of behaviors that concomitantly heighten psychogenic stress and increase energy demand. Although it is not widely recognized clinically, functional forms of hypothalamic hypogonadism are more than an isolated disruption of gonadotropin-releasing hormone (GnRH) drive and reproductive compromise. Indeed, women with functional hypothalamic amenorrhea display a constellation of neuroendocrine aberrations that reflect allostatic adjustments to chronic stress. Given these considerations, we have suggested that complete neuroendocrine recovery would involve more than reproductive recovery. Hormone replacement strategies have limited benefit because they do not ameliorate allostatic endocrine adjustments, particularly the activation of the adrenal and the suppression of the thyroidal axes. Indeed, the rationale for the use of sex steroid replacement is based on the erroneous assumption that functional forms of hypothalamic hypogonadism represent only or primarily an alteration in the hypothalamic-pituitary-gonadal axis. Potential health consequences of functional hypothalamic amenorrhea, often termed stress-induced anovulation, may include an increased risk of cardiovascular disease, osteoporosis, depression, other psychiatric conditions, and dementia. Although fertility can be restored with exogenous administration of gonadotropins or pulsatile GnRH, fertility management alone will not permit recovery of the adrenal and thyroidal axes. Initiating pregnancy with exogenous means without reversing the hormonal milieu induced by chronic stress may increase the likelihood of poor obstetrical, fetal, or neonatal outcomes. In contrast, behavioral and psychological interventions that address problematic behaviors and attitudes, such as cognitive behavior therapy (CBT), have the potential to permit resumption of full ovarian function along with recovery of the adrenal, thyroidal, and other neuroendocrine aberrations. Full endocrine recovery potentially offers better individual, maternal, and child health.

The purpose of this study was to determine whether cognitive function changes over time in women with breast cancer who received adjuvant therapy as compared to women with breast cancer who received no adjuvant therapy. Three groups of women (n=46) were studied; groups 1 and 2 consisted of women with stage I or II breast cancer. Group 1 received chemotherapy and group 2 received chemotherapy plus tamoxifen. Group 3 consisted of women with ductal carcinoma in situ who received no chemotherapy or tamoxifen. Cognitive function was evaluated at three timepoints. Time 1 occurred after surgery and before chemotherapy initiation in groups 1 and 2. Time 1 for group 3 occurred post-surgery. Time 2 occurred within 1 week after the conclusion of chemotherapy for groups 1 and 2 and at a comparable time for group 3. Time 3 occurred 1 year after Time 2. Women who received chemotherapy plus tamoxifen exhibited deterioration on measures of visual memory and verbal working memory and reported more memory complaints. Women who received chemotherapy alone also exhibited deteriorations in verbal working memory. Conversely, cognitive function scores improved in women who received no therapy, indicating practice effects. In conclusion, adjuvant chemotherapy in women with breast cancer can be associated with deteriorations in memory and this may persist over time. The addition of tamoxifen may lead to more widespread memory deficits. Copyright © 2005 John Wiley & Sons, Ltd.

Objective To evaluate past oral contraceptive use and angiographic coronary artery disease in women. Setting Academic medical centers. Patient(s) Six hundred seventy-two postmenopausal women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia. Intervention(s) Past oral contraceptive use, assessed by reproductive questionnaire. Main Outcome Measure(s) Quantitative coronary artery disease, assessed by a core angiography laboratory. Result(s) Past oral contraceptive use was associated with a lower mean coronary artery disease severity index score (mean ± SD: 11.8 ± 10.3 vs. 18.7 ± 17.3) compared with non–prior users, despite age adjustment. Past oral contraceptive use remained a significant independent negative predictor of coronary artery disease severity when adjusting for coronary risk factors, including age, diabetes mellitus, triglycerides, low-density lipoprotein cholesterol, smoking, aspirin use, and lipid-lowering medication (model R 2 = 0.19). The modeling indicated that past oral contraceptive use was associated with a 2.44 lower coronary artery disease severity score index. There was no apparent relationship between duration of past oral contraceptive use and the coronary artery disease severity index score. Conclusion(s) Past oral contraceptive use is associated with less coronary artery disease, measured by quantitative coronary angiography, among postmenopausal women with suspected myocardial ischemia. These findings suggest that a prospective study should address the hypothesis that past oral contraceptive use during the premenopausal years might offer women protection from atherosclerotic coronary disease later in life.

Purpose To conduct a clinical trial to determine if an educational intervention and a nutritional intervention could enhance physical and psychological functioning among younger women completing treatment for early-stage breast cancer. Patients and Methods Younger women (50 years of age or younger, N = 252), within 2 months of having completed active nonhormonal adjuvant therapy, diagnosed with stage 0, I, or II breast cancer with 10 or fewer positive lymph nodes were randomly assigned to a three-arm clinical trial. Women in the control arm of the trial received standard medical care. Women in the two active arms received either an educational intervention, designed to provide information about their illness and enhance adjustment, or a nutritional intervention, designed to promote a more healthy diet. Primary end points included mental functioning, physical functioning, and depressive symptoms. Women were assessed before random assignment, 4 months later (immediately postintervention), and 13 months later (9 months postintervention). Results Participants assigned to the two active treatment arms had significantly less depressive symptomatology and better physical functioning by 13-month follow-up (differences between the two active arms were nonsignificant). These effects were primarily accounted for by changes in intrusive thoughts, concerns regarding cancer recurrence and mortality, self-concept perceptions, and self-efficacy expectations. Conclusion Tailored psychosocial interventions can be effectively designed to enhance adjustment among younger women who are completing nonhormonal adjuvant therapy.

Epidemiological and psychophysiological data suggest that groups that differ in reproductive hormones and stress responses also differ in risk for cardiovascular disease. To evaluate the effects of hormone therapy on women's cardiovascular responses to laboratory stressors, 89 healthy postmenopausal women were tested twice, before and after exposure for about 8 weeks to one of the five conditions: placebo, Estratab (primarily estrone), Estratab plus Prometrium (micronized progesterone), Estratab plus Provera (synthetic progestin), and Estratest (same estrogen as in Estratab plus methyltestosterone). Results showed that women assigned to Estratab plus Prometrium and Estratest had diminished systolic blood pressure responses to stress upon retesting, whereas the other groups did not change in the level of their responses. Women assigned to Estratab plus Prometrium had diminished diastolic blood pressure responses during a speech stressor upon retesting, whereas women assigned to Estratab plus Provera increased. Our findings show that hormone therapy does affect women's stress responses, but they do not provide a simple explanation as to why groups at high and low risk for cardiovascular disease differ in reproductive hormones and stress responses.

Accurate classification of menopausal status is important to epidemiological research evaluating the role of reproductive hormones in disease processes. Algorithms relying on repeat hormone assays are unfeasible in large epidemiological studies. This paper summarizes the development of the Women's Ischemia Syndrome Evaluation (WISE) Hormonal menopausal status algorithm for determining premenopausal, perimenopausal, and postmenopausal status using menstrual and reproductive history and reproductive hormone levels obtained at a single clinic visit.The authors compared the accuracy of this algorithm with two currently used self-report algorithms: Menstrual, based only on months since last menstrual period, and Historical, which adds age and surgical history.The study population consisted of 515 women (329 clearly postmenopausal) enrolled in the WISE study who were undergoing coronary angiography for suspected ischemia. A subgroup of 186, not clearly postmenopausal, was classified by these three algorithms. Results were evaluated against individualized expert consensus classification. The Menstrual and Historical classifications differed significantly (p0.0001) from expert consensus, with 32%-26% discordant classifications, respectively. For the WISE Hormonal classification, discordance was 4%.The authors conclude that inaccurate classifications of menopausal status occur frequently in self-report algorithms. Use of the relatively simple WISE algorithm can improve the accuracy of menopausal status classification for epidemiological research.

OBJECTIVE—To evaluate menstrual cycle histories among women with type 1 diabetes, their sisters, and unrelated control subjects without diabetes across all reproductive ages. RESEARCH DESIGN AND METHODS—Menstrual and reproductive histories were obtained by questionnaire from 143 women with type 1 diabetes, 186 sisters without diabetes, and 158 unrelated control subjects without diabetes participating in the Familial Autoimmune and Diabetes study. RESULTS—Women with type 1 diabetes had more menstrual problems (long cycles, long menstruation, and heavy menstruation) before age 30 years than sisters and control subjects. These differences were all statistically significant, except for heavy menstruation at age CONCLUSIONS—The results suggest that type 1 diabetes is an independent risk factor for menstrual disturbances in young adults. Future studies may determine whether addressing menstrual disturbances improves quality of life and health for these women.

OBJECTIVES We sought to evaluate hypoestrogenemia of hypothalamic origin and its association with angiographic coronary artery disease (CAD) in premenopausal women. BACKGROUND Coronary artery disease in premenopausal women appears to have a particularly poor prognosis. Primate animal data suggest that premenopausal CAD is strongly determined by psychosocial stress-induced central disruption of ovulatory cycling and resulting hypoestrogenemia. METHODS We assessed reproductive hormone blood levels and angiographic CAD using core laboratories in 95 premenopausal women with coronary risk factors who were enrolled in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation and were undergoing coronary angiography for evaluation for suspected ischemia. RESULTS Premenopausal women with angiographic CAD (n = 13) had significantly lower estradiol, bioavailable estradiol, and follicle-stimulating hormone (FSH) (all p < 0.05) than women without angiographic CAD (n = 82), even after controlling for age. Hypoestrogenemia of hypothalamic origin, defined as estradiol

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.

Two experiments were conducted to understand the influence of estrogen exposure on cardiovascular responses to acute stress measured by impedance cardiography. Study I compared stress responses of 29 postmenopausal women who used postmenopausal hormone replacement therapy (HRT) and 29 who did not use HRT. Women who did not use HRT had higher systolic blood pressure and pulse pressure responses to the tasks relative to HRT users. Study 2 compared stress responses of 38 healthy postmenopausal women not initially on HRT who were randomly assigned to transdermal estradiol or placebo treatment for 6-8 weeks. HRT assignment did not influence substantially women's cardiovascular responses to stress. Characteristics correlated with HRT use, not HRT itself, or differences in type, duration, and dosage may account for the discrepancy in results.

Objective To assess the impact of increased consumption of milk, without other dietary advice, on older adults' energy and nutrient intakes, weight, cardiovascular risk factors (blood pressure, plasma lipid levels), and quality of life. Subjects/setting Two hundred four healthy men and women, aged 55 to 85 years, who consumed fewer than 1.5 dairy servings per day were chosen from six US academic health centers. Design Randomized, controlled open trial. Intervention Advice to increase skim or 1% milk intake by 3 cups per day (n=101) or to maintain usual diet (n=103) for 12 weeks after a 4-week baseline period. Main outcome measures Changes in energy and nutrient intake assessed from 3-day food records, body weight, blood pressure, and plasma lipid levels. Statistical analyses performed Group-by-time analysis of variance with repeated-measures, χ 2 test. Results Compliance with the intervention was good. Compared with controls, participants in the milk-supplemented group significantly increased energy, protein, cholesterol, vitamins A, D, and B-12, riboflavin, pantothen ate, calcium, phosphorus, magnesium, zinc, and potassium intakes. Prevalence of nutrient inadequacy, assessed for nutrients with Estimated Average Requirements, decreased among women in the milk group for magnesium (40% .at baseline vs 13% at 12 weeks, P P P P P =.002). Quality of life scores were high at baseline and remained high throughout. Applications/conclusions Older adults can successfully increase milk intake, thereby meaningfully improving their nutrient intakes. Dietitians can play a key role in disseminating this advice. J Am Diet Assoc. 2000; 100:810-817 .

Women with polycystic ovary syndrome come to the gynecologist with a variety of symptoms, including menstrual irregularities, hirsutism, acne, weight gain, obesity, and infertility. An accurate diagnosis requires both confirmation of signs and symptoms of polycystic ovary syndrome and exclusion of other disorders. Once the diagnosis of polycystic ovary syndrome has been established, the presence of concomitant conditions, such as hypertension, dyslipidemia, and diabetes, must be assessed. Because the cause of polycystic ovary syndrome is not clear, treatment options have focused on symptom management. Such treatment options include oral contraceptives, gonadotropin-releasing hormone analogs with “add-back” hormone regimens, antiandrogens, ovulation-inducing agents, electrolysis, nutritional and weight loss counseling, exercise, laparoscopic ovarian drilling, and glucocorticoids. Pathogenic considerations, risk factor assessments, and treatment objectives combine to determine the choice of therapies. It is not clear whether insulin resistance is clinically important or causal in polycystic ovary syndrome symptom complex in all affected women. Polycystic ovary syndrome may be the final common expression of a variety of metabolic or neuroendocrine perturbations. If insulin resistance is a universal feature, it would make sense to treat with an insulin-sensitizing agent in the expectation that symptoms would resolve or improve. If insulin resistance is not the main etiologic factor, however, then insulin-sensitizing agents would be useful as adjunctive agents only for women with clinically important insulin resistance (eg, patients with polycystic ovary syndrome in whom insulin resistance causes hyperglycemia). In such cases an insulin-sensitizing agent could be instituted along with a program of weight loss and exercise. (Am J Obstet Gynecol 1998;179:S109-13.)

Women with hyperandrogenic anovulation (HAA) exhibit increased GnRH drive, as evidenced by a faster LH pulse frequency that slows in response to progestin-induced opioidergic tone. To determine whether increased GnRH-LH drive in HAA reflects altered sex steroid exposure caused by chronic anovulation or is an intrinsic hypothalamic attribute, we compared the pulsatile LH response to oral contraceptive (OC)-induced suppression in seven women with HAA, with that of seven eumenorrheic women (EW). LH levels were determined at 10-min intervals for 12 h after 19–21 days of OC use and 5–7 days after cessation. Testosterone, androstenedione, estradiol, FSH, and LH levels were determined at weekly intervals before, during, and after OC use. LH pulse number/12 h was higher (P < 0.001) in HAA during and after OCs, when compared with that of EW. Mean LH was increased in HAA before, during, and after OCs. Testosterone, androstenedione, and estradiol levels were higher in HAA before OCs, but they decreased to similar levels during OC use in both groups. FSH concentrations were similar before and during OCs but rose more after cessation of OCs in EW. These findings indicate that GnRH drive in HAA is resistant to OC-induced suppression and, therefore, could be an intrinsic hypothalamic attribute.

Many forms of stress, including psychosocial stress, may be associated with reproductive dysfunction. Women seeking treatment for infertility often have been subjected to multiple stressors. The authors have developed an experimental primate model of hypothalamic amenorrhea. Combining mild psychosocial stress with a mild diet and moderate exercise suppresses reproductive function in this model. Because serotonergic activity is decreased in persons who are inordinately sensitive to stress, a study was planned to determine whether differences in endogenous function of the central serotonergic system can be found in stress-sensitive and stress-resistant female cynomolgus macaques. Sedated monkeys previously categorized as highly stress-resistant (HSR, normal menstrual cyclicity through 2 stress cycles), medium stress-resistant (MSR, ovulatory in only the first cycle), or stress-sensitive (SS, anovulatory when first exposed to stress) were challenged with an intravenous dose of 5 mg/kg of the serotonin-releasing drug fenfluramine. The hypothesis was that SS animals would have lower levels of central serotonergic activity. Thyrotropin-releasing hormone (TRH) was administered to control for differences in pituitary stores of prolactin or corticotropin-releasing factor (CRF) to control for low levels of ACTH. Release of prolactin in response to fenfluramine was significantly greater in the HSR animals than in the MSR and SS groups. Cortisol responses to fenfluramine were higher in the SS group than in either group of stress-resistant animals. Similar responses to fenfluramine were no longer evident after stimulation with TRH combined with CRF. These studies in macaques indicate differing reproductive hormone responses to moderate stress. Stress sensitivity correlates with prolactin secretion in response to fenfluramine, which promotes the release of serotonin. Highly stress-resistant animals have higher endogenous serotonin levels than do stress-sensitive animals in the absence of stress. Whether this reflects secretion of ovarian steroids, social status, or genetic predisposition remains to be determined.

Advances in our understanding of the physiological mechanisms subserving reproduction and those mediating responses to stress now permit us to understand in detail at least one mechanism by which stress compromises fertility. In women, stress, as evidenced by an increase in cortisol secretion, suppresses hypothalamic gonadotropin-releasing hormone (GnRH) input to the pituitary-ovarian axis. If the decrement in GnRH drive is chronic, anovulation results. Episodic decrements in the GnRH pulse generator likely result in luteal inadequacy or oligo-ovulation. The more complete the suppression of GnRH, the more likely is the reproductive compromise to be clinically recognizable. Profound and persistent loss of GnRH input manifests as amenorrhea, whereas episodic or less profound interruptions in GnRH secretion can be clinically occult and present only as decrements in luteal phase progesterone secretion by the corpus luteum in the face of preserved menstrual cycle intervals, i.e., so-called luteal phase defects. Recognition of stress-induced compromise of ovarian function expands therapeutic options because, at least in theory, stress management and reduction will lead to return of GnRH drive, resumption of ovulation and menses, and restoration of fertility.

Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general and brain aging in particular. Functional hypothalamic amenorrhea, a phenotypically recognizable form of stress, is due to stress-induced suppression of endogenous gonadotropin-releasing hormone secretion. Reversal of functional hypothalamic amenorrhea includes restoration of ovulatory ovarian function and fertility and amelioration of hypercortisolism and hypothyroidism. Taken together, recovery from functional hypothalamic amenorrhea putatively offers neuroprotection and ameliorates stress-induced premature brain aging and possibly syndromic Alzheimer's disease. Amenorrhea may be viewed as a sentinel indicator of stress. Hypothalamic hypogonadism is less clinically evident in men and the diagnosis is difficult to establish. Whether there are other sex differences in the impact of stress on brain aging remains to be better investigated, but it is likely that both low estradiol from stress-induced anovulation and low testosterone from stress-induced hypogonadism compromise brain health.

A standard infertility evaluation consists of a semen analysis, hysterosalpingogram, post-coital test, endometrial biopsy and laparoscopy. Although these tests are well grounded in clinical experience, information on their ability to discriminate between fertile and infertile couples is limited. In this study, we performed standard infertility tests plus two others--sperm antibodies and cervical culture for Mycoplasma hominis and Ureaplasma urealyticum--on fertile and infertile couples. Women in the fertile group were selected from those who had delivered a child within the previous 2 years and who were scheduled for a laparoscopic tubal ligation. Women in the infertile group were selected from those presenting for an infertility evaluation (mean duration of infertility 4.2 years), and they were matched by age (+/- 3 years) and race with fertile subjects. Subjects were recruited from both private and clinic patients. A total of 64 couples (32 matched pairs) completed the evaluation. At least one 'abnormal' infertility test was found in 69% of fertile and 84% of infertile couples. With the exception of tubal damage and endometriosis, which as expected were more common in infertile couples, no significant differences between groups for remaining infertility factors could be demonstrated. Despite the small size of the current study, these results confirm the feasibility and importance of comparisons of the prevalence of infertility factors in fertile and infertile couples.

Celiac disease occurs in roughly 1% of all humans. It is an autoimmune condition initially caused by hypersensitivity and hyperimmunity to a class of proteins, called gliadins, which are found in the outer husk of common grains such as wheat, barley, rye, and oats.

The suppression of melatonin by bright light is probably mediated by the suprachiasmatic nucleus (SCN) in humans. In animals, SCN cells have broad visual receptive fields, suggesting that peripheral bright light could be effective for melatonin suppression. Twelve healthy subjects were subjected to 1000 lux illumination for 2 hr from 0100 to 0300 on two occasions: once lighting the central visual field 5 degrees from the center of gaze and once lighting the peripheral visual field 60 degrees lateral to the direction of gaze. Six subjects were observed on a third occasion in dim light. The three conditions differed significantly, with less melatonin secreted in 1000 lux, but melatonin levels with central and peripheral illumination did not differ. This suggests that phototherapy using bright light in the visual periphery may be effective.