Premature ovarian insufficiency and autoimmune profiles: a prospective case-control study.

OBJECTIVE: Autoimmunity seems to be present in a large proportion of women with spontaneous premature ovarian insufficiency (POI). Whether these women are at increased risk for autoimmune disease has not been determined to date. Therefore, the aim of this study was to investigate a large series of antibodies in order to shed more light into the autoimmune risk of POI women. METHODS: In a prospective case-control study, blood samples from 66 patients with spontaneous POI and 66 healthy controls were analyzed for a series of autoimmune antibodies. RESULTS: POI women revealed significantly increased thyroglobulin antibodies (TGAb) (p = 0.045) and thyroid peroxidase antibodies (TPOAb) (p = 0.002). At least one abnormal autoimmune parameter was present in 37.9% of POI women, compared to 18.2% in healthy controls (p = 0.045). A strong association between POI and increased TGAb (adjusted odds ratio 3.586, p = 0.028), increased TPOAb (adjusted odds ratio 7.496, p = 0.003) and any increased autoimmune parameter (adjusted odds ratio 3.189, p = 0.008) could be demonstrated in a binary logistic regression model. CONCLUSION: A high prevalence of autoimmunity in POI women compared to a healthy young collective could be demonstrated. Thyroid antibodies were significantly increased in POI women. Our data highlight the increased risk for autoimmune diseases, especially for thyroid disorders.

Non-hormonal treatments for managing vulvovaginal atrophy/genitourinary syndrome of menopause.

The demand for non-hormonal therapies for vulvovaginal atrophy (VVA) is increasing due to an increasing number of patients surviving long term post cancer diagnosis, as well as increased public knowledge of the symptoms of menopause and availability of non-hormonal therapies. Treatment options are wide-ranging and encompass different formulations and methods of application. This review summarizes the key characteristics of the main forms of these therapies, as well as considering the current evidence for each of them and where future clinical studies should be directed. Care for VVA may be in primary care, or under gynecology or oncology. Further research requirements include the need for long-term data as well larger randomized controlled trials into alternatives where vaginal estrogen cannot be used as first-line treatment. Widespread education of health-care providers and patients on VVA and the impact on quality of life is urgently needed, as well as increased use of non-hormonal methods in routine clinical practice.

Cardiometabolic health in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is an increasing public health problem with a prevalence now approaching 4%. POI results in adverse effects on the skeleton and central nervous system as well as disturbances of metabolic and cardiological factors that predispose to a major increased risk of cardiovascular disease (CVD). This article reviews the effects of the premature loss of ovarian function on lipids and lipoproteins, glucose and insulin metabolism, body composition, hemostasis and blood pressure, together with effects on the development of metabolic syndrome and diabetes mellitus. The article examines the effects of POI on vascular endothelial function and inflammation that result in arterial disease, and reviews the effects of hormone replacement therapy (HRT) on these various metabolic processes and on cardiovascular outcomes. It is essential that women with POI receive hormonal treatment to help prevent the development of CVD, and that this treatment is continued at least until the normal age of menopause. It appears that HRT has a more favorable effect than the combined oral contraceptive, but larger clinical trials are needed to establish the optimal treatment. Other therapeutic measures may need to be added to correct existing metabolic abnormalities and, in particular, attention to lifestyle factors such as diet and exercise must be encouraged.

Premature ovarian insufficiency: a toolkit for the primary care physician.

Premature ovarian insufficiency (POI) refers to the loss of ovarian activity before the age of 40 years, which leads to hypoestrogenism and amenorrhea. The diagnosis of POI in a young woman has potentially life-changing physical and emotional consequences for both the patient and her family. Therefore, it is very important that the diagnosis is correct and that it is made in a timely manner. Unfortunately, the diagnosis and therefore the effective treatment of POI are often delayed, which underlines the need for education of the broad medical community on the issue. A panel of menopause experts reviewed and critically appraised the literature, and present: (1) the diagnostic approach to POI, (2) the investigation of the etiology of this condition, (3) the therapeutic strategy regarding both hormone replacement therapy and fertility, and (4) the long-term follow-up and management for ensuring quality of life, as well as urogenital, cardiovascular, bone and mental health. The ultimate goal of this article is to provide a complete toolkit for the primary care physician to have easy access to all the information needed for the optimal management of women with POI, in the context of evidence-based and personalized medicine.HIGHLIGHTSPremature ovarian insufficiency occurs in 1% of the female population of reproductive age, yet the diagnosis is often delayed, with severe physical and emotional consequences for the patient.Primary care physicians should be aware of the possibility of premature ovarian insufficiency in young women presenting with menstrual irregularity.Prompt initiation of hormone replacement therapy ensures quality of life and prevents osteoporosis and cardiovascular disease.Women seeking fertility should be referred to specialists to discuss assisted reproduction options.

Vaginal lubricants and moisturizers: a review into use, efficacy, and safety.

Vaginal dryness is common during and after menopause due to declining estrogen. It is one of the symptoms of vulvovaginal atrophy (VVA), which is part of the genitourinary syndrome of menopause. This can be distressing for women and cause pain, discomfort, and dyspareunia. Vaginal dryness affects over 50% of postmenopausal women but is under-reported and thus under-treated due to barriers to seeking help. Estrogen replacement can resolve symptoms, but may be contraindicated or not desired by all women. Over-the-counter vaginal moisturizers and lubricants can ease the symptoms of VVA. However, their chemical composition varies enormously and some are known to cause detrimental effects due to unphysiological pH, osmolality, and additives. The primary purpose of this review is to assess both their efficacy and safety. Women should be directed toward products that are as 'body-similar' as possible to vaginal secretions in terms of pH and osmolality. Products with potentially harmful ingredients should be avoided. Lubricants can be trialed for sexual activity and moisturizers for symptom control, even if topical or systemic menopause hormone therapy is being used.

A direct comparison of women's perceptions and acceptability of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol in the management of young postmenopausal women, under 45 years of age.

OBJECTIVE: To assess the acceptability and perception of postmenopausal women, to two different hormone replacement therapy regimens, in relation to the control of their symptoms and development of adverse effects. STUDY DESIGN: Prospectively recruited postmenopausal women, <45 years, were randomised to one of two treatment arms for 12-months: cyclical micronised progesterone or medroxyprogesterone acetate in combination with transdermal oestradiol. A self-reported questionnaire with matrix rating scales was completed and repeated after 3, 6 and 12-months. MAIN OUTCOME MEASURES: Symptom control and development of adverse effects. RESULTS: Seventy-one individuals were screened, with baseline data available for 67 subjects. A total of 190 questionnaires were returned. The most commonly reported symptoms were low energy levels, vasomotor symptoms and sexual dysfunction. The prevalence of adverse effects ranged between 57.89 and 87.50%, with a reduction seen in the transdermal oestradiol + micronised progesterone arm (73.91% at 3-months, decreasing to 57.89% at 12-months; p = 0.33), compared to the transdermal oestradiol + medroxyprogesterone acetate arm (76.92% at 3-months, increasing to 87.50% at 12-months; p = 0.69). The main reported adverse effects were bloating, weight change and psychological symptoms. A significant difference was documented between the groups after set intervals, with a greater proportion reporting breast tenderness after 3-months (p = 0.01), lower numbers reporting mood swings at 6-months (p = 0.01) and irritability at 12-months (p = 0.03) in the transdermal oestradiol + micronised progesterone arm compared to the transdermal oestradiol + medroxyprogesterone acetate arm. CONCLUSIONS: The acceptability of both regimens was high despite adverse effects, but tolerability of transdermal oestradiol combined with micronised progesterone appeared to be better with fewer women reporting psychological concerns.

Premature ovarian insufficiency: an International Menopause Society White Paper.

The aim of this International Menopause Society White Paper on premature ovarian insufficiency (POI) is to provide the latest information regarding this distressing condition. The impact of POI has far-reaching consequences due to its impact on general, psychological, and sexual quality of life, fertility prospects, and long-term bone, cardiovascular, and cognitive health. Progress in fully understanding the etiology, diagnosis, and optimal management options has been slow thus far due to the complexity of the condition and fragmented research. Recent advances in epidemiological and genetic research have improved our understanding of this condition and randomized prospective trials are being planned to determine the intervention strategies, which will optimize quality of life and long-term well-being. The International Menopause Society has commissioned a number of experts at the forefront of their specialty to define the state of the art in the understanding of this condition, to advise on practical management strategies, and to propose future research strategies. It is hoped that a global task force will subsequently be convened in order to formulate a consensus statement across key societies, to accelerate date collection and analysis of a global POI registry, and to facilitate progress in the key defined areas of research.

Vulvovaginal atrophy in women after cancer.

The number of women surviving longer after a cancer diagnosis is increasing. This means that more awareness regarding their health is required. This review will focus on vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause, one of the most distressing adverse iatrogenic effects of the menopause, secondary to cancer therapies. The cancer therapies themselves, such as radiotherapy, chemotherapy, and surgery, have a direct impact on the lower genital tract which interplays with the ensuing hypoestrogenic state of the menopause. Symptoms of VVA are still under-reported and undertreated as neither clinicians nor patients are forthcoming in discussing the problem, despite its profound negative impact on quality of life. In terms of treatment of VVA, this review will look at the use of various options, including estrogen post cancer diagnosis, as well as considering newer emerging therapies such as dehydroepiandrosterone, ospemifene, and laser. The care of a woman post cancer diagnosis should be a multidisciplinary responsibility. However, further research is required into emerging treatment options as well as long-term safety data, to ensure all health-care providers and women are fully informed and confident to effectively address the impact of VVA post cancer diagnosis.

The European Vulvovaginal Epidemiological Survey (EVES): prevalence, symptoms and impact of vulvovaginal atrophy of menopause.

OBJECTIVES: The primary objective of the European Vulvovaginal Epidemiological Survey (EVES) was to assess, at a country level, the prevalence of postmenopausal women with vulvovaginal atrophy (VVA) confirmed by gynecological clinical assessment among all postmenopausal women attending menopause centers. METHOD: Women aged 45-75 years old with their last menstrual period more than 12 months before and who attended menopause or gynecology centers were included. If they had at least one VVA symptom, women filled a number of questionnaires including the EuroQoL-EQ-5D3L and Day-to-Day Impact of Vaginal Aging (DIVA). Then a gynecological examination was performed to confirm the VVA diagnosis. RESULTS: A total of 2160 evaluable patients were included in the study. VVA was confirmed in 90% of the patients. Compared with patients without confirmed VVA (n = 206), patients with confirmed VVA (n = 1954) were significantly older (p < 0.001), had more severe symptoms (p < 0.001 for vaginal and vulvar symptoms, p < 0.05 for urinary ones) and had a lower quality of life as assessed by EQ-5D3L (p = 0.012) and DIVA (p < 0.001). CONCLUSION: VVA is highly prevalent among postmenopausal women. Gynecological clinical assessment of VVA is associated with severe symptoms and impaired quality of life and therefore should be promoted for appropriate clinical assessment and early therapeutic intervention.

Cardiovascular risk assessment in women - an update.

Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Although it is a disease of aging, vascular disease initiates much earlier in life. Thus, there is a need to be aware of the potential to prevent the development of the disease from an early age and continue this surveillance throughout life. The menopausal period and early menopause present an ideal opportunity to assess cardiovascular risk and plan accordingly. Generally in this period, women will be seen by primary health-care professionals and non-cardiovascular specialists. This review addresses female-specific risk factors that may contribute to the potential development of cardiovascular disease. It is important for all health-care professionals dealing with women in midlife and beyond to be cognisant of these risk factors and to initiate female-specific preventative measures or to refer to a cardiovascular specialist.

2016 IMS Recommendations on women's midlife health and menopause hormone therapy.

The International Menopause Society (IMS) has produced these new 2016 recommendations on women's midlife health and menopause hormone therapy (MHT) to help guide health-care professionals in optimizing their management of women in the menopause transition and beyond. The term MHT has been used to cover therapies including estrogens, progestogens and combined regimens. For the first time, the 2016 IMS recommendations now include grades of recommendations, levels of evidence and 'good practice points', in addition to section-specific references. Where possible, the recommendations are based on and linked to the evidence that supports them, unless good-quality evidence is absent. Particular attention has been paid to published evidence from 2013 onwards, the last time the IMS recommendations were updated. Databases have been extensively searched for relevant publications using key terms specific to each specialist area within menopause physiology and medicine. Information has also been drawn from international consensus statements published by bodies such as the IMS, the European Menopause and Andropause Society and the North American Menopause Society. The recommendations have been produced by experts derived mainly from the IMS, with the assistance of key collaborators where deemed advantageous. In preparing these international recommendations, experts have taken into account geographical variations in medical care, prevalence of diseases, and country-specific attitudes of the public, medical community and health authorities towards menopause management. The variation in availability and licensing of MHT and other products has also been considered.

Vulvar and vaginal atrophy in four European countries: evidence from the European REVIVE Survey.

OBJECTIVES: The aim of the European REVIVE survey was to achieve a better understanding of vulvovaginal atrophy (VVA), a chronic and progressive condition after menopause. We investigated perceptions, experiences and needs in terms of sexual and vaginal health in a sample of European postmenopausal women. METHODS: An online internet based survey was conducted in Italy, Germany, Spain and the UK with a total surveyed sample of 3768 postmenopausal women (age: 45-75 years). RESULTS: The most common VVA symptom was vaginal dryness (70%). VVA has a significant impact on the ability to be intimate (62%), to enjoy sexual intercourse (72%) and to feel sexual spontaneity (66%). Postmenopausal women with VVA are sexually active (51%), but their sexual drive is reduced. Health-care professionals (HCPs) have discussed VVA with postmenopausal women (62%), but they initiated the conversation only in 10% of the cases. The most common treatments for VVA are over-the-counter, non-hormonal, local vaginal products. Thirty-two per cent of postmenopausal women were naïve to any kind of treatment, whereas discussion with the HCP was relevant to be on current treatment (60% of postmenopausal women that discussed VVA with a HCP vs. 23% who did not). The top reasons for poor compliance with vaginal treatments were: not bothersome enough symptoms (18%); vaginal changes not therapeutically reversed (18%); relief from VVA symptoms (17%). Approximately 45% were satisfied with treatment. The most frequent disliked aspects of treatment were the route of administration or the messiness. The fear of hormones was common in postmenopausal women using vaginal prescription products. CONCLUSIONS: The European REVIVE survey confirmed that VVA symptoms are frequent in postmenopausal women and demonstrates a significant impact on quality of life and sexual life. However, the condition is still under-diagnosed and under-treated, with a high rate of dissatisfaction for actual available treatments in the four European countries surveyed. The discussion of symptoms with HCPs seems the most critical factor for diagnosis and treatment of VVA.

Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition?

Vaginal dryness is a common condition that is particularly prevalent during and after the menopause, and is one of the symptoms of vulvovaginal atrophy/genitourinary syndrome of menopause. The impact of vaginal dryness on interpersonal relationships, quality of life, daily activities, and sexual function can be significant, but is frequently underestimated. Furthermore, barriers exist to treatment-seeking, and this condition is often underreported and undertreated. Greater education about vaginal dryness and the range of available treatments is essential to encourage more women to seek help for this condition. Personal lubricants and moisturizers are effective at relieving discomfort and pain during sexual intercourse for women with mild to moderate vaginal dryness, particularly those who have a genuine contraindication to estrogen, or who choose not to use estrogen. However, there is a distinction between lubricants and moisturizers, and notable differences between commercially available products. Women should be advised to choose a product that is optimally balanced in terms of both osmolality and pH, and is physiologically most similar to natural vaginal secretions. A series of recommendations for the use of vaginal lubricants and moisturizers, either on their own or in combination with systemic or topical hormone replacement therapy, is presented.

Genitourinary syndrome of the menopause--dawn of a new era?

Many millions of postmenopausal women continue to suffer in silence from symptoms resulting from estrogen-deficient atrophy of the vulva, vagina and urinary tract whilst the medical profession continues to debate what the condition should be called, how it should be assessed and whether it should be universally treated. It is high time that a unified approach was adopted by all medical societies to reach a consensus on definitions, recognition and management. With the development of the nomenclature for genitourinary syndrome of the menopause (GSM), advances in GSM assessment tools and quality-of-life questionnaires and novel therapeutic interventions, the signs are positive that a new era is finally dawning.

The clinical relevance of the effect of ospemifene on symptoms of vulvar and vaginal atrophy.

OBJECTIVES: To explore clinically relevant differences in severity of vulvar and vaginal atrophy (VVA) in postmenopausal women treated with ospemifene compared with placebo. METHODS: Analysis of two multicenter, randomized, double-blind, 12-week phase-III studies in postmenopausal women (40-80 years, with VVA, treated with ospemifene 60 mg/day or placebo (Study 310 and Study 821)). Severity of vaginal dryness and dyspareunia were evaluated using a four-point scoring system and clinically relevant differences between ospemifene and placebo were analyzed and are presented as improvement (reduction in ≥ 1 unit on four-point scoring system), substantial improvement (reduction in 2-3 units on four-point scoring system) and relief (severity score of mild/none after 12 weeks). RESULTS: In Study 310, significantly more women with a most bothersome symptom of dyspareunia had improvement (68.3% vs. 54.1%; p = 0.0255) or relief (57.5% vs. 41.8%; p = 0.0205) in the severity of dyspareunia from baseline to week 12 with ospemifene compared with placebo. For those with a most bothersome symptom of vaginal dryness, significantly more experienced improvement (74.6% vs. 57.7%; p = 0.0101), substantial improvement (42.4% vs. 26.9%; p = 0.0172) and relief (66.1% vs. 49.0%; p = 0.0140) of vaginal dryness from baseline to week 12 with ospemifene compared with placebo. Proportions of women with improvement/substantial improvement/relief of symptoms of vaginal dryness or dyspareunia were similar in Study 821. Clinically relevant differences were noticeable by week 4. CONCLUSIONS: Treatment with ospemifene was consistently associated with greater improvement, substantial improvement or relief in the severity of the most bothersome symptoms of vaginal dryness or dyspareunia compared with placebo.

Risks and benefits of hormone therapy: has medical dogma now been overturned?

BACKGROUND: In an integrated overview of the benefits and risks of menopausal hormone therapy (HT), the Women's Health Initiative (WHI) investigators have claimed that their 'findings … do not support use of this therapy for chronic disease prevention'. In an accompanying editorial, it was claimed that 'the WHI overturned medical dogma regarding menopausal [HT]'. OBJECTIVES: To evaluate those claims. METHODS: Epidemiological criteria of causation were applied to the evidence. RESULTS: A 'global index' purporting to summarize the overall benefit versus the risk of HT was not valid, and it was biased. For coronary heart disease, an increased risk in users of estrogen plus progestogen (E + P), previously reported by the WHI, was not confirmed. The WHI study did not establish that E+ P increases the risk of breast cancer; the findings suggest that unopposed estrogen therapy (ET) does not increase the risk, and may even reduce it. The findings for stroke and pulmonary embolism were compatible with an increased risk, and among E+ P users there were credible reductions in the risk of colorectal and endometrial cancer. For E+ P and ET users, there were credible reductions in the risk of hip fracture. Under 'worst case' and 'best case' assumptions, the changes in the incidence of the outcomes attributable to HT were minor. CONCLUSIONS: Over-interpretation and misrepresentation of the WHI findings have damaged the health and well-being of menopausal women by convincing them and their health professionals that the risks of HT outweigh the benefits.

Premature ovarian insufficiency: how to improve reproductive outcome?

Premature ovarian insufficiency (POI) is a life-changing condition that affects women in their reproductive age. The condition is not necessarily permanent but is associated with intermittent and unpredictable ovarian activity. Hence, spontaneous pregnancies have been reported to be 5-10%. However, pregnancy in patients with POI is still unlikely and rare. Although, there are reviews on POI in the literature, there is a lack of reports which focus on how to improve the reproductive outcome of these women who wish to conceive spontaneously or use assisted conception with their own oocytes. We found that there is no conclusive evidence of which treatment is optimal for women with POI who wish to conceive using their own gametes. However, one could surmise that it is important to lower gonadotropin levels into the physiological range before embarking on any treatment, even if natural conception is the only choice for the woman/couple. In the future, multi-center, randomized, double-blind, placebo-controlled trials should be carried out, which may entail recruitment of patients from various centers nationally and internationally to increase the sample size and therefore achieve a powered study. This may standardize the treatment of women with POI who wish to conceive and ultimately have their biological child.

Psychosocial adjustment in women with premature menopause: a cross-sectional survey.

OBJECTIVES: Previous studies have found that women with premature menopause often report fertility problems, menopause symptoms and negative experiences of medical services. This study aims to measure the prevalence of these problems and explore whether they have negative impacts on psychosocial adjustment (symptom experience and quality of life). METHODS: A cross-sectional survey was mailed to women who had been diagnosed with premature menopause, recruited from hospital clinics in West London and from a patient support website (the Daisy Network). The survey measured participant characteristics, fertility problems, hot flushes and night sweats, experience of diagnosis, patient satisfaction with medical services, the Women's Health Questionnaire and the General Health Survey SF-36. Responses were described and multiple linear regressions were used to explore predictors of psychosocial functioning and quality of life. RESULTS: A total of 136 women were included in the analysis. Psychosocial functioning was relatively poor compared to typical aged menopausal women. Fertility concerns were prevalent (reported by 71% of the sample), 35% reported experiencing hot flushes and/or nights sweats, and, on average, women were neither satisfied nor unsatisfied with medical services (mean =3.00, standard deviation =0.98). Age, experiencing hot flushes and/or night sweats and patient satisfaction predicted psychosocial functioning, but only explained a small amount of the variance (3-11%). CONCLUSIONS: Women with premature menopause would benefit from interventions that improve psychosocial functioning and quality of life, including improving patient experience and effective treatment of menopause symptoms. Assumptions about treatment needs could not reliably be made based on patient characteristics, suggesting that individually tailored treatments may be more effective.

Randomized placebo- and active-controlled study of desvenlafaxine for menopausal vasomotor symptoms.

OBJECTIVE: To evaluate the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) vs. tibolone and placebo for menopausal vasomotor symptoms and the incidence of uterine bleeding. METHODS: This 12-week, double-blind, randomized, controlled trial was conducted at 35 sites in Europe, two sites in South Africa, and one site in Mexico. Postmenopausal women with ≥50 moderate or severe hot flushes per week (n = 485) were randomized to desvenlafaxine 100 mg/day, tibolone 2.5 mg/day, or placebo. Reduction in the average daily number of moderate and severe hot flushes at weeks 4 and 12 (primary endpoint) was evaluated using analysis of covariance. Safety assessments included incidence of uterine bleeding, adverse events, laboratory values, and vital signs. RESULTS: At week 12, no statistically significant difference was observed in reduction of the average daily number of moderate and severe hot flushes for desvenlafaxine (-5.78) vs. placebo (-5.82; p = 0.921), although time to 50% reduction was significantly less than placebo (13 vs. 26 days, p = 0.006). Hot flush reduction with tibolone (-8.21) was significantly greater than placebo (p < 0.001). Nausea was the most common adverse event with desvenlafaxine, was generally mild to moderate, and resolved within the first 2 weeks. Significantly more subjects experienced bleeding with tibolone (23%) vs. desvenlafaxine (12%; p < 0.024) or placebo (9%; p < 0.001). CONCLUSIONS: Desvenlafaxine did not separate from placebo in reducing the number of moderate to severe hot flushes at week 12, although it did allow women to achieve 50% reduction sooner than placebo. Tibolone did separate from placebo, but with smaller than expected effect. The placebo effect was high (57%). Adverse drug reactions were consistent with the known safety profile of desvenlafaxine, and significantly more women who received tibolone experienced episodes of bleeding compared with women who received desvenlafaxine or placebo.