Impact of estetrol (E4) on hemostasis, metabolism and bone turnover in postmenopausal women.

OBJECTIVE: This study aimed to determine the effects of estetrol (E4) on hemostasis, lipids, carbohydrate metabolism and bone turnover in postmenopausal women. METHODS: This study was a multicenter, randomized, double-blind placebo-controlled phase 2 trial. Participants (n = 180, age 43-64 years) received E4 2.5 mg, 5 mg, 10 mg and 15 mg or placebo once daily for 12 weeks. Changes from baseline at week 12 were evaluated versus placebo for hemostasis parameters, sex hormone binding globulin (SHBG), lipids, carbohydrate metabolism and bone markers. RESULTS: Changes for hemostasis parameters were minimal with a small increase only in the normalized activated protein C sensitivity ratio in the E4 15 mg group versus placebo. SHBG increased in the E4 5 mg, 10 mg and 15 mg groups versus placebo. High-density lipoprotein cholesterol increased in all E4 groups; changes were not consistent for other lipids. Significant decreases versus placebo were seen for insulin resistance (E4 10 mg group), hemoglobin A1c (E4 15 mg group) and type 1 collagen C-terminal telopeptide (E4 10 mg and 15 mg groups). Small decreases in osteocalcin in the E4 5 mg, 10 mg and 15 mg groups were significant versus the increase observed in placebo. CONCLUSION: E4 had limited impact on hemostasis and potentially beneficial effects on lipids, carbohydrate metabolism and bone turnover.

Hormone replacement therapy - where are we now?

Hormone replacement therapy (HRT) was the standard of care for menopause management until 2002, when perceptions changed following release of the initial results from the Women's Health Initiative (WHI) trial. Fears of breast cancer and heart attacks engendered by that report were not supported by the data, especially for recently menopausal women. Clinically, HRT is usually initiated near menopause. The WHI tested something different - the effects of HRT started a decade or more after menopause. As it turned out, age at starting HRT is critical in determining benefit/risk. HRT use plummeted following the WHI in 2002 and has remained low, prompting strong interest in alternative treatments. None provide the range of benefits across multiple organ systems offered by estrogen. Most have concerning adverse effects in their own right. HRT can provide effective relief for a wide range of health conditions, potentially avoiding the need for multiple treatments for separate problems. Unfortunately, among many women and clinicians, the perception of HRT benefit/risk is distorted, and its use avoided, leading to unnecessary distress. Following the WHI, many clinicians have not received adequate training to feel comfortable prescribing HRT. When initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementias.

Metabolic and cardiovascular effects of TX-001HR in menopausal women with vasomotor symptoms.

Objective: This study aimed to evaluate the effects of TX-001HR (17ß-estradiol [E2] and progesterone [P4] in a single oral capsule) on cardiometabolic markers and outcomes. Methods: Four E2/P4 doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) were compared with placebo in menopausal women with vasomotor symptoms (VMS) and a uterus in the phase 3 REPLENISH (ClinicalTrials.gov, NCT01942668) trial. Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months as well as cardiovascular events are summarized. Results: A total of 1835 participants took ≥1 capsule of daily E2/P4; 1684 received E2/P4 and 151 received placebo. No clinically significant changes in lipid parameters, coagulation factors, or glucose were observed between treatment groups. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1-4%, 6-11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). One episode of deep venous thrombosis and three cases of cardiovascular disease were observed, similar to expected rates of these events in the general population. Conclusions: In the REPLENISH trial, postmenopausal women with VMS treated with E2/P4 had no clinically meaningful effects on lipids, glucose, or coagulation parameters compared with placebo.

Factors associated with short interpregnancy interval among women treated with in vitro fertilization.

PURPOSE: To evaluate factors associated with interpregnancy interval (IPI) among women treated with in vitro fertilization (IVF). METHODS: Women with at least two cycles of IVF between 2004 and 2013 were identified from the SART CORS database and grouped by age at first cycle, infertility diagnosis, IVF treatment parameters, and cycle 1 outcome (singleton or multiple live birth or no live birth, length of gestation, and birthweight). The distributions of IPIs (in months, 0-5, 6-11, 12-17, 18-23, and ≥ 24) were compared across these factors. IPI was fit as a function of these factors by a general linear model, separately for singleton and multiple live births and no live births at cycle 1. RESULTS: The study included 93,546 women with two consecutive IVF cycles where the first cycle resulted in a clinical intrauterine pregnancy or a live birth. Among women with a live birth in cycle 1, there was a general pattern of longer IPI for younger women compared to older women. Women with a multiple birth waited longer before initiating a second cycle than women with a singleton birth. For women with no live birth in the first cycle, nearly three fourths initiated cycle 2 within 6 months, regardless of their age. Short (0-5 months) IPI was associated with preterm delivery, older maternal age, and use of donor oocytes. CONCLUSIONS: Age of the mother, outcome of the first pregnancy, and treatment factors affect the length of the interpregnancy interval. Because short IPI has been associated with poor outcomes, women who are at risk for short IPI should be counseled about these outcome risks.

Correction to: Factors associated with short interpregnancy interval among women treated with in vitro fertilization.

The original version of this article unfortunately contained a mistake. The name of an investigator was incorrectly listed as M. B. Morton, instead of M. B. Brown.

Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.

The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF.

What the future holds for women after menopause: where we have been, where we are, and where we want to go.

With an increasing world population of postmenopausal women, providers of health care need to focus on improving the quality of life as well as the longevity of women. This review emphasizes the importance of health care for postmenopausal women, particularly the role of menopausal hormonal therapy (MHT), from the perspective of where we have been, where we are now, and where we can expect to be in the future. Use of MHT increased dramatically in the 1980s and then fell very abruptly in the early 2000s with the publications of various randomized hormonal trials, including the Women's Health Initiative (WHI). The recent publications from the WHI with 13 years of follow-up are different from the initial reports and do not show an increase in cardiovascular risk in any age group (with the exception of venous thrombosis). Breast cancer risk increased marginally with estrogen/progestogen therapy, related to duration of use, but with estrogen-alone therapy, breast cancer risk decreased significantly, as did mortality. For younger women receiving estrogen alone, there is great consistency between all randomized trials, including the WHI and observational data showing a coronary benefit and a decrease in all-cause mortality. Recent data also confirm the 'timing hypothesis', suggesting that younger women benefit from MHT, while older women do not exhibit this effect. In the future, we will have many more genetic and molecular tools to guide therapy and risk assessment, as we move into an era of personalized medicine. An important opportunity presents at the onset of menopause to prevent diseases which usually occur some 10 years later. Part of this preventative strategy may involve MHT.

Prevention of diseases after menopause.

Women may expect to spend more than a third of their lives after menopause. Beginning in the sixth decade, many chronic diseases will begin to emerge, which will affect both the quality and quantity of a woman's life. Thus, the onset of menopause heralds an opportunity for prevention strategies to improve the quality of life and enhance longevity. Obesity, metabolic syndrome and diabetes, cardiovascular disease, osteoporosis and osteoarthritis, cognitive decline, dementia and depression, and cancer are the major diseases of concern. Prevention strategies at menopause have to begin with screening and careful assessment for risk factors, which should also include molecular and genetic diagnostics, as these become available. Identification of certain risks will then allow directed therapy. Evidence-based prevention for the diseases noted above include lifestyle management, cessation of smoking, curtailing excessive alcohol consumption, a healthy diet and moderate exercise, as well as mentally stimulating activities. Although the most recent publications from the follow-up studies of the Women's Health Initiative do not recommend menopause hormonal therapy as a prevention strategy, these conclusions may not be fully valid for midlife women, on the basis of the existing data. For healthy women aged 50-59 years, estrogen therapy decreases coronary heart disease and all-cause mortality; this interpretation is entirely consistent with results from other randomized, controlled trials and observational studies. Thus. as part of a comprehensive strategy to prevent chronic disease after menopause, menopausal hormone therapy, particularly estrogen therapy may be considered as part of the armamentarium.

Emergence of ovulatory cycles with aging in women with polycystic ovary syndrome (PCOS) alters the trajectory of cardiovascular and metabolic risk factors.

STUDY QUESTION: What alters cardiovascular and metabolic risk factors with aging in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Lipid parameters, mainly low-density lipoprotein (LDL) cholesterol, increase with aging, but not in women who attain ovulatory cycles. WHAT IS KNOWN ALREADY: Cardiovascular and metabolic parameters tend to increase with aging, but this has not been shown in a prospective longitudinal study in women with PCOS. Correlates of these changes have not been identified. STUDY DESIGN: A prospective cohort of 118 hyperandrogenic women with PCOS who were followed from the age of 20-25 years at 5 year intervals for 20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty-five age-matched controls and another 35 age-matched controls in their 40s, 20 years later. Longitudinal measurements of body mass index (BMI), waist circumference, fasting serum steroids, glucose, insulin, lipids, prevalence of metabolic syndrome and ovulatory status. MAIN RESULTS AND THE ROLE OF CHANCE: After 20 years, in the entire group, waist circumference increased as did glucose, total cholesterol (C), high-density lipoprotein-C (HDL-C), LDL-C and non-HDL-C. The prevalence of metabolic syndrome was 7% at the beginning and 6% at the end. Fifty-one women with PCOS were found to be ovulatory and 67 remained anovulatory after 20 years. Anovulatory women had higher insulin, lower QUICKI and higher total C, LDL-C, non-HDL-C and lower HDL-C. In ovulatory women there were no alterations in lipids or glucose and minor changes in insulin and QUICKI compared with controls. None of the parameters were influenced by BMI or waist circumference. LIMITATIONS, REASONS FOR CAUTION: Inability to follow controls for 20 years. Associations observed between ovulatory function and lowered cardiovascular and metabolic risks cannot imply cause and effect. WIDER IMPLICATIONS OF THE FINDINGS: Phenotypic variability, particularly ovulatory function, in women diagnosed to have PCOS appears to influence cardiovascular and metabolic risks. It is unclear if these data pertain to other populations and ethnicities of women. STUDY FUNDING/COMPETING INTERESTS: Self-funded; no conflicts of interest.

Global consensus statement on menopausal hormone therapy.

The following Consensus Statement is endorsed by The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society.

Hormone therapy and the risk of stroke: perspectives 10 years after the Women's Health Initiative trials.

Principal findings on stroke from the Women's Health Initiative (WHI) clinical trials of hormone therapy indicate that estrogen, alone or with a progestogen, increases a woman's risk of stroke. These results were not unexpected, and research during the past decade has tended to support these findings. Consistent evidence from clinical trials and observational research indicates that standard-dose hormone therapy increases stroke risk for postmenopausal women by about one-third; increased risk may be limited to ischemic stroke. Risk is not modified by age of hormone initiation or use, or by temporal proximity to menopause, and risk is similar for estrogen plus progestogen and for unopposed estrogen. Limited evidence implies that lower doses of transdermal estradiol (≤50 µg/day) may not alter stroke risk. For women less than 60 years of age, the absolute risk of stroke from standard-dose hormone therapy is rare, about two additional strokes per 10 000 person-years of use; the absolute risk is considerably greater for older women. Other hormonally active compounds - including raloxifene, tamoxifen, and tibolone - can also affect stroke risk.

Potential amelioration of morbidity in patients with chromosomal anomalies: relevance to Bardet-Biedl syndrome.

Given the genetic basis of their disease, children with major chromosomal abnormalities including Bardet-Biedl syndrome (BBS) are generally considered to have a guarded prognosis with persistence or progression of disease manifestations. Although various therapeutic interventions are commonly used to control signs and symptoms of illness, parents of BBS children are usually cautioned against hoping for sustained improvement. A case of a 21-month-old girl, diagnosed with BBS, manifesting signs of worsening visual impairment, obesity, irascible and disordered behaviour, as well as developmental delay, is presented. After initial evaluation suggested specific biochemical deficiencies, nutritional status correction was undertaken and the patient's signs and symptoms subsequently resolved over the course of several months. To the authors' knowledge, this is the first case report of sustained resolution of all disease manifestations in the face of previously deteriorating health in a young child with this major chromosomal abnormality. It appears that biochemical imbalances and insufficiencies resulting from abnormal metabolism and excretion are potentially amenable to extraordinary dietary supplementation, with partial or complete resolution of clinical abnormalities. It is recommended that all children with chromosomal abnormalities have biochemical and nutritional status evaluation with correction of disordered biochemistry as is possible.

HRT and breast cancer risk: a realistic perspective.

A new analysis from the Women's Health Initiative included data on breast cancer incidence over a 11-year period from the randomized trial of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) and a subsequent observational follow-up. The conclusions were that CEE/MPA use was associated with an increase in both breast cancer incidence and mortality. We have concerns over the validity of their statistical analyses, as adjustments for baseline characteristics or for multiple comparisons demonstrate no significant differences in incidence between those allocated to CEE/MPA or placebo. We suspect that the apparent increase in mortality is the result of surveillance and detection bias rather than a true cause and effect. Even if such an effect were true, mortality from breast cancer would still be a very rare event. We also question the clinical relevance and applicability of their findings. The data over the 11 years show no increased risk of breast cancer with CEE/MPA in women who had not previously used hormone replacement therapy (HRT), and the vast majority of women on HRT would not be prior users at initiation. It should be remembered that women using CEE alone showed a significant decrease in breast cancer risk in the WHI trial and follow-up. Even if combined estrogen?progestogen HRT did cause an increase in breast cancer risk, and this is not proven, the magnitude of that risk is small, and less than that risk seen with many lifestyle factors. HRT is a benefit, not a risk, for those women requiring it.

Menopausal hot flushes and night sweats: where are we now?

OBJECTIVE: An overview of the current knowledge on the etiology and treatment of vasomotor symptoms in postmenopausal women. MATERIALS AND METHODS: Acknowledged experts in the field contributed a brief assessment of their areas of interest which were combined and edited into the final manuscript. RESULTS: Women around the world experience vasomotor symptoms as they enter and complete the menopause transition. Vasomotor symptoms, specifically hot flushes, are caused by a narrowing of the thermoneutral zone in the brain. This effect, although related to estrogen withdrawal, is most likely related to changes in central nervous system neurotransmitters. Peripheral vascular reactivity is also altered in symptomatic women. Estrogen replacement therapy is the most effective treatment for hot flushes. Of the other interventions investigated, selective serotonin and selective norepinephrine reuptake inhibitors and gabapentin show efficacy greater than placebo. Objective monitoring of hot flushes indicates a robust improvement with hormone replacement therapy but little to no change with placebo. These data suggest that the subjective assessment of responses to therapy for vasomotor symptom results in inaccurate data. Hot flushes have recently been associated with increased cardiovascular risks and a lower incidence of breast cancer, but these data require confirmation. CONCLUSIONS: Vasomotor symptoms are experienced by women of all ethnic groups. They are caused by changes in the central nervous system associated with estrogen withdrawal and are best treated with estrogen replacement therapy. Objective monitoring of hot flushes indicates that placebo has little to no effect on their improvement. Subjective assessments of hot flushes in clinical trials may be inaccurate based on objective measurement of the frequency of hot flushes. Based on preliminary reports, women experiencing hot flushes have an increased risk of cardiovascular disease and a reduced incidence of breast cancer.

The risk of stroke in postmenopausal women receiving hormonal therapy.

Stroke affects one in five women and is the third leading cause of death in the United States. The incidence increases with age, and the number of females experiencing a stroke is similar to the number of men, unlike in coronary disease, where the number of females suffering from the disease is lower before menopause and then slowly becomes equal to the number of men. There are multiple risk factors for stroke, but the most significant ones influencing the relationship between hormones and stroke are obesity, hypertension and smoking. There have been multiple studies looking at the relationship between hormones and stroke. Among observational studies, 21 have shown no effect, while six have shown a decreased risk and four studies, an increased risk. It is clear that the risk of stroke with hormones is only for ischemic and not hemorrhagic stroke. Among randomized trials, the Women's Health Initiative data, because of the study's size, have provided the greatest weight in meta-analytic reviews. Overall, an increase of 20-40% has been found, and, because of various confounding factors, it has been difficult to determine whether this is statistically significant, although several studies have confirmed this for all postmenopausal women treated. However, in younger women, aged 50-59 years, there is little evidence that the risk is significantly increased, and the overall background prevalence is low: 6-8/10 000 women/year. Recent studies have suggested the risk is not increased significantly with transdermal therapy and with lower doses, although use of progestogen does not appear to influence the risk assessment. There is lack of consistent data on whether early age of initiation of therapy affects the risk. Because this risk may pertain to younger postmenopausal women, and there is a very small risk of stroke reported for young women taking oral contraceptives, it is suggested that the small risk in younger women is through an inflammatory/thrombosis mechanism in susceptible women, rather than one of atherosclerosis, as with coronary disease. Nevertheless, in younger postmenopausal women, with a lower baseline prevalence rate, even if there is a 40% increased risk, the attributable risk would result in 1-2 additional cases/10 000 women/year, which would be considered a very rare event.

Postmenopausal oral estrogen therapy affects hemostatic factors, but does not account for reduction in the progression of subclinical atherosclerosis.

BACKGROUND: Hemostatic factors influenced by postmenopausal hormone therapy may contribute to atherosclerosis. The Estrogen in the Prevention of Atherosclerosis Trial (EPAT), a 2-year, randomized, double-blind, placebo-controlled trial, demonstrated reduced subclinical atherosclerosis progression measured by change in common carotid artery intima-media thickness (CIMT) with unopposed oral 17beta-estradiol. OBJECTIVES: To assess the effect of postmenopausal hormone therapy on the levels of several hemostatic factors, and the relationship between these factors and the progression of subclinical atherosclerosis. PATIENTS AND METHODS: We measured tissue plasminogen activator (t-PA) antigen, factor (F) VII, D-dimer and albumin longitudinally, and plasminogen activator inhibitor type 1 (PAI-1) and fibrinogen at trial-end, in 186 postmenopausal women. RESULTS: Estradiol vs. placebo was associated with greater FVII and lower t-PA, albumin, PAI-1 and fibrinogen (all P < or = 0.001), with no estradiol effect on D-dimer (P = 0.42). Only mean on-trial t-PA was positively associated with the absolute level of CIMT on-trial (r = 0.29, P < 0.0001), but this was attenuated with age and body mass index adjustment. No longitudinally measured hemostatic factor was associated with CIMT progression. However, higher CIMT during the trial was significantly related to increases in t-PA. CONCLUSIONS: These results confirm previous findings regarding estrogen's effect on hemostatic factors and show that albumin is negatively associated with estrogen therapy. These hemostatic factors did not account for the reduction of CIMT progression with 17beta-estradiol seen in EPAT. Atherosclerosis itself may affect levels of hemostatic factors (reverse causality), with subsequent involvement in atherosclerosis-associated thrombosis.

Prevalence and metabolic characteristics of adrenal androgen excess in hyperandrogenic women with different phenotypes.

BACKGROUND: Serum DHEAS has been found to be elevated in some women with polycystic ovary syndrome (PCOS). We wished to determine whether this prevalence is different in women with androgen excess who have different phenotypes and to correlate these findings with various cardiovascular and metabolic parameters. METHODS: Two hundred and thirty-eight young hyperandrogenic women categorized into various diagnostic groups were evaluated for elevations in serum DHEAS, testosterone, glucose, insulin, quantitative insulin-sensitivity check index (QUICKI), cholesterol, HDL-C, LDL-C, triglycerides and C-reactive protein (CRP). Data were stratified based on elevations in DHEAS. RESULTS: Serum DHEAS was elevated in 39.5% for the entire group [36.7% in PCOS and 48.3% in idiopathic hyperandrogenism (IHA)]. In classic (C)-PCOS, the prevalence was 39.6% and in ovulatory (OV) PCOS it was 29.1%. These differences were not statistically significant. Women with elevated DHEAS had higher testosterone but lower insulin, higher QUICKI, lower total and LDL-cholesterol and higher HDL-cholesterol, p<0.01. Triglycerides and CRP were not different. This trend was greatest in women with C-PCOS. CONCLUSIONS: The prevalence of adrenal hyperandrogenism, as determined by elevations in DHEAS, appears to be statistically similar in IHA, C-PCOS and compared to OV-PCOS. Metabolic and cardiovascular parameters were noted to be more favorable in those women who have higher DHEAS levels.

Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis of PCOS.

OBJECTIVE: Metabolic syndrome (MBS) is a common disorder and is thought to be extremely prevalent in polycystic ovary syndrome (PCOS). In the USA the prevalence of MBS in PCOS has been reported to be as high as 43-46% using Adult Treatment Panel III (ATP-III) criteria. Because of differences in diet, lifestyle and genetic factors, we postulated that the prevalence of MBS might not be as high in Italian women. This study sought to determine the prevalence of MBS in Italian women using both the ATP-III and the World Health Organization (WHO) criteria and to determine whether the prevalence is influenced by the way in which PCOS is diagnosed. DESIGN: Assessment of the prevalence of MBS in 282 women with PCOS, aged 18-40 years, living in western Sicily. Eighty-five age- and weight-matched normal women served as controls. METHODS: Patients were divided into those with chronic anovulation and hyperandrogenism (classic PCOS; n = 225) and others with hyperandrogenism and polycystic ovaries but who were ovulatory (ovulatory PCOS; n = 57). A 75 g oral glucose tolerance test was carried out, as were lipid determinations; insulin resistance was assessed by the Quantitative Insulin-Sensitivity Check Index (QUICKI). We used ATP-III and WHO criteria to diagnose MBS. RESULTS: Using ATP-III criteria, the prevalence of MBS was 8.2% and using WHO criteria it was 16% in Italian women with PCOS. In controls, the prevalence was 2.4% using both methods. In classic PCOS patients, MBS was higher (8.9% by ATP-III, 17.3% by WHO) than in ovulatory PCOS (5% and 10.6% respectively). Body weight significantly modified prevalence rates. CONCLUSION: MBS is substantially higher in women with PCOS than in the general population, and the prevalence is higher in those women diagnosed by classic criteria. However, the prevalence of MBS in PCOS appears to be much lower in Italy than in the USA.