Nanette Santoro

Menopausal hormone therapy and menopausal symptoms

A majority of women will experience bothersome symptoms related to declining and/or fluctuating levels of estrogen during their menopausal transition. Vasomotor symptoms, vaginal dryness, poor sleep, and depressed mood have all been found to worsen during the menopausal transition. While vasomotor symptoms gradually improve after menopause, the time course can be many years. Vaginal dryness does not improve without treatment, while the long-term course of sleep and mood deterioration is not clearly defined at this time. A small minority of women have vasomotor symptoms that persist throughout the remainder of their lives. These common menopausal symptoms all improve with estrogen treatment. Over the last 10 years, we have witnessed a dramatic reduction in enthusiasm for menopausal hormone therapy, despite its high efficacy relative to other treatments. We have also seen the emergence of sound, evidence-based clinical trials of non-hormonal alternatives that can control the common menopausal symptoms. Understanding the natural history of menopausal symptoms, and the risks and benefits of both hormonal and non-hormonal alternatives, helps the clinician individualize management plans to improve quality of life.

Endometrial Shedding Effect on Conception and Live Birth in Women With Polycystic Ovary Syndrome

OBJECTIVE: To estimate whether progestin-induced endometrial shedding, before ovulation induction with clomiphene citrate, metformin, or a combination of both, affects ovulation, conception, and live birth rates in women with polycystic ovary syndrome (PCOS). METHODS: A secondary analysis of the data from 626 women with PCOS from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network trial was performed. Women had been randomized to up to six cycles of clomiphene citrate alone, metformin alone, or clomiphene citrate plus metformin. Women were assessed for occurrence of ovulation, conception, and live birth in relation to prior bleeding episodes (after either ovulation or exogenous progestin-induced withdrawal bleed). RESULTS: Although ovulation rates were higher in cycles preceded by spontaneous endometrial shedding than after anovulatory cycles (with or without prior progestin withdrawal), both conception and live birth rates were significantly higher after anovulatory cycles without progestin-induced withdrawal bleeding (live births per cycle: spontaneous menses 2.2%; anovulatory with progestin withdrawal 1.6%; anovulatory without progestin withdrawal 5.3%; P<.001). The difference was more marked when rate was calculated per ovulation (live births per ovulation: spontaneous menses 3.0%; anovulatory with progestin withdrawal 5.4%; anovulatory without progestin withdrawal 19.7%; P<.001). CONCLUSION: Conception and live birth rates are lower in women with PCOS after a spontaneous menses or progestin-induced withdrawal bleeding as compared with anovulatory cycles without progestin withdrawal. The common clinical practice of inducing endometrial shedding with progestin before ovarian stimulation may have an adverse effect on rates of conception and live birth in anovulatory women with PCOS. LEVEL OF EVIDENCE: II

Trajectories of estradiol and follicle-stimulating hormone over the menopause transition and early markers of atherosclerosis after menopause.

Aim The purpose of this study was to assess associations between distinct patterns of circulating estradiol (E2) and follicle-stimulating hormone (FSH) over the menopause transition (MT) and subclinical measures of atherosclerosis after menopause. Methods and results Four temporal patterns of E2 decline (Low: low before and after final menstrual period (FMP); Medium: medium before and high after FMP; High-early decline: high prior to FMP and early decline thereafter; High-late decline: high prior to FMP and late decline thereafter) and three of FSH rise (Low, Medium, High) over 9.6 years across FMP were identified and linked to carotid intima-media-thickness (IMT), adventitial diameter (AD), and presence of carotid plaque (cPlaque) measured after menopause at the 12th annual visit (visit 12). Participants were 856 women (age at visit 12u2009=u200959.5u2009±u20092.7 years) from the Study of Womens Health Across the Nation (SWAN), who never reported a stroke or a heart attack. In models adjusted for visit 12 or baseline cardiovascular disease (CVD) risk factors, odds of having any cPlaque were ∼43% lower among women with the High-early decline E2 trajectory compared to women with the Low E2 trajectory. In contrast, women with the Medium E2 trajectory had significantly higher IMT than those with the Low E2 trajectory adjusting for visit 12 CVD risk factors. Interestingly, adjusting for baseline CVD risk factors attenuated this association. The Low FSH group had lower IMT than the Medium and High FSH groups (pu2009≤u20090.05) in all models. Conclusion During MT, women are subjected to hormonal alterations that could potentially increase their risk of developing CVD after menopause.

The relationship of circulating proteins in early pregnancy with preterm birth

BACKGROUNDnPreterm birth (PTB) (< 37 completed weeks gestation) is a pathological outcome of pregnancy and a major global health problem. Babies born preterm have an elevated risk for long-term adverse medical and neurodevelopmental sequelae. Substantial evidence implicates intrauterine infection and/or inflammation in PTB. However, these are often relatively late findings in the process, when PTB is inevitable. Identification of earlier markers of PTB may make successful intervention possible. Although select proteins, notably those related to thexa0inflammatory pathways, have been associated with PTB, there has been a lack of research into the role of other protein pathways in the development of PTB. The purpose of this study was to investigate, using a previously described biomarker discovery approach, a subset of circulating proteins and their association with PTB focusing on samples from early pregnancy.nnnOBJECTIVESnThe objectives of the study were as follows: (1) to perform a large-scale biomarker discovery, utilizing an innovative platform to identify proteins associated with preterm birth in plasma taken between 10 and 15 weeks gestation and, (2) to determine which protein pathways are most strongly associated with preterm birth. To address these aims, we measured 1129 proteins in a plasma sample from early pregnancy using a multiplexed aptamer-based proteomic technology developed in Colorado by SomaLogic.nnnSTUDY DESIGNnUsing a nested case-control approach, we measured proteins at a single time point in early pregnancy in 41 women who subsequently delivered preterm and 88 women who had term uncomplicated deliveries. We measured 1129 proteins using a multiplexed aptamer-based proteomic technology developed by SomaLogic. Logistic regressions and random forests were used to compare protein levels.nnnRESULTSnThe complement factors B and H and the coagulation factors IX and IX ab were the highest-ranking proteins distinguishing cases of preterm birth from term controls. The top 3 pathways associated with preterm birth were the complement cascade, the immune system, and the clotting cascade.nnnCONCLUSIONnUsing a discovery approach, these data provide further confirmation that there is an association of immune- and coagulation-related events in early pregnancy with preterm birth. Thus, plasma protein profiles at 10-15 weeks of gestation are related to the development of preterm birth later in pregnancy.

Luteal Phase Dynamics of Follicle Stimulating and Luteinizing Hormones in Obese and Normal Weight Women

Female obesity is a state of relative hypogonadotrophic hypogonadism. The aim of this study is to examine gonadotrophin secretion and response to gonadotrophin‐releasing hormone (GnRH) in the luteal phase of the menstrual cycle and to investigate the pharmacodynamics and pharmacokinetics of endogenous and exogenous luteinizing hormone (LH) in obese women.

Vitamin D Deficiency is Associated with Poor Ovarian Stimulation Outcome in PCOS but not Unexplained Infertility

ContextnThe impact of vitamin D deficiency on the success of ovarian stimulation according to underlying infertility diagnosis has not been investigated.nnnObjectivenTo evaluate the relationship between vitamin D deficiency and reproductive outcomes after ovarian stimulation in women with either polycystic ovary syndrome (PCOS) or unexplained infertility.nnnDesignnRetrospective cohort study.nnnSettingnAnalysis of randomized controlled trial (RCT) data.nnnParticipantsnParticipants from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) RCT (n = 607); participants from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) RCT of unexplained infertility (n = 647).nnnInterventionsnSerum 25(OH)D levels measured in banked sera.nnnMain Outcome MeasuresnPrimary: live birth; secondary: ovulation (PPCOS II), pregnancy, and early pregnancy loss.nnnResultsnIn PPCOS II, subjects with vitamin D deficiency [25(OH)D < 20 ng/mL or 50 nmol/L] were less likely to ovulate (adjusted OR, 0.82; 95% CI, 0.68 to 0.99; P = 0.04) and experienced a 40% lower chance of live birth (adjusted OR, 0.63; 95% CI, 0.41 to 0.98; P = 0.04) than those not deficient. In AMIGOS, no significant association between vitamin D deficiency and live birth was noted. In pregnant subjects from both studies, vitamin D deficiency was associated with elevated risk of early pregnancy loss (OR, 1.6; 95% CI, 1.0 to 2.6; P = 0.05).nnnConclusionsnIn this investigation of women pursuing ovarian stimulation, the association between vitamin D deficiency and diminished live birth relied on carrying the diagnosis of PCOS and was not observed in unexplained infertility. Given the generally modest success of ovarian stimulation, addressing vitamin D deficiency may prove an important treatment adjunct for many infertile women.

Age‐stratified thresholds of anti‐Müllerian hormone improve prediction of polycystic ovary syndrome over a population‐based threshold

Due to its consistent elevation in polycystic ovary syndrome (PCOS) and correlation with polycystic ovarian morphology (PCOM), anti‐Mullerian hormone (AMH) has been proposed as a marker of the syndrome. However, prior studies reporting thresholds of AMH for a PCOS diagnosis have been limited by small sample size, inappropriate controls, and heterogeneous AMH assays. We sought to evaluate the suitability of a standardized AMH assay as a biomarker of PCOS.

Identifying the Critical Gaps in Research on Sex Differences in Metabolism Across the Life Span

The National Institutes of Health (NIH) Office of Research in Womens Health now functions under a mandate calling for the systematic inclusion of both female and male cells, animals, and human subjects in all types of research, so that sex as a biological variable is understood in health and disease. Sex-specific data can improve disease prevention, diagnosis, and treatment as well as reduce inequities. Inclusion of women in research studies has modestly improved over the last 20 years, yet preclinical research is still primarily done using male animal models and male-derived cells, with the result that many conclusions are made based on incomplete and sex-biased data. There are important, yet poorly studied, sex differences in cardiometabolic disease. To begin to address these sex differences, the Center for Womens Health Research at the University of Colorado held its inaugural National Conference, Sex Differences Across the Lifespan: A Focus on Metabolism, in September 2016 (cwhr@ucdenver.edu). Research to address the important goal of understanding key sex differences in cardiometabolic disease across the life span is lacking. The goal of this article is to discuss the current state of research addressing sex differences in cardiometabolic health across the life span, to outline critical research gaps that must be addressed in response to NIH mandates, and, importantly, to develop strategies to address sex as a biological variable to understand disease mechanisms as well as develop diagnostic and therapeutic modalities.

The Role of Body Weight in Menstrual Disturbances and Amenorrhea

In normal weight women, a 10–15% reduction from ideal body weight (IBW) is associated with amenorrhea [1, 2]. There is considerable interindividual variation in the menstrual cycle manifestations that may occur in association with low body weight. It is likely that the key element involved in eating disorders or low weight related amenorrhea is stress. It appears that the adaptation to the chronic stress involved in food restriction plays a major role. Additives to the low body weight are excessive exercise and a somewhat “driven” personality style. These attributes lead to chronic activation of the adrenocorticotrophic axis and elevated cortisol and corticotrophin releasing factor (CRF) [3]. The end result is functional hypothalamic amenorrhea (FHA), although less severe conditions appear to exist. For example, women who undergo rapid, intense exercise training, and mild dietary restriction will develop a luteal phase defect cycle phenotype, with lengthening of the menstrual cycle, but eventual folliculogenesis and ovulation (albeit with low levels of luteal progesterone secretion and a shortened luteal phase [4]). In many clinical scenarios, it is impossible to separate the relative contributions of body weight, body fat, perceived stress, and exercise to the amenorrhea or menstrual disturbances. This chapter focuses primarily on body weight and body fat as determinants of normal reproductive function.

Nutrition and Reproduction

Abstract There appears to a be an optimal window of nutritional sufficiency to allow for reproduction to occur in males and females. The male hypothalamic pituitary (HP) axis is relatively static and therefore is more resistant to nutritional perturbations than is the female HP axis. However, accumulating data indicate that both under- and overnutrition have consequences on the pace of sexual maturation in humans and on subsequent reproductive function. This chapter will review current knowledge of this field.