Using advanced analytics to help identify women who are more likely to have a severe subjective experience of vulvovaginal atrophy: a modeling study.

OBJECTIVE: To develop a model to identify women likely to be severely impacted by vulvovaginal atrophy (VVA), based on their experience of symptoms and non-clinical factors. METHODS: Multivariate statistics and machine-learning algorithms were used to develop models using data from a cross-sectional, observational, multinational European survey. A set of independent variables were chosen to assess subjective VVA severity and its impact on daily activities. RESULTS: A final composite model was selected that included three categories of variables: clinical severity, patient demographics/clinical characteristics and Day-to-Day Impact of Vaginal Aging (DIVA) variables related to emotion/mood, impact on lifestyle and frequency of sex. The model accurately classified 71% of women. Three DIVA variables (feeling bad about yourself, desire/interest in sex, physical comfort related to sitting) explained much of the variation in the dependent variable of the model. Over 90% of the impact of VVA relates to certain psychosocial and behavioral aspects that can be identified without the need to consider physical signs/symptoms. CONCLUSION: Non-clinical factors can contribute significantly to the overall VVA burden.Questions used in developing the composite model could form the basis of an instrument to help screen women prior to clinical consultation and improve VVA management.

Hormone replacement therapy prescribing in menopausal women in the UK: a descriptive study.

BACKGROUND: Recent studies on the prescribing of hormone replacement therapy (HRT) medicines to treat symptoms of menopause are lacking. AIM: To describe the prescribing of HRT in a cohort of UK menopausal women. DESIGN & SETTING: Population-based drug utilisation study using IQVIA Medical Research Database (IMRD-UK). METHOD: Primary care data of women with recorded menopause and/or aged ≥50 years between January 2010 and November 2021 were extracted from the database. The incidence rate of women who received their first prescription for HRT was calculated annually using person-years-at-risk (PYAR) as the denominator. Incidence rates of HRT were estimated by type and route of administration. Relative changes in annual incidence rates were expressed as percentages and the average percentage change was assessed using linear regression. Annual prescribing prevalence per 100 women was calculated using mid-year menopausal population estimates. RESULTS: The incidence rate of prescribing of HRT increased from 5.01 in 2010 to 18.16 per 1000 PYAR in 2021, a relative increase of 13.64% (95% confidence interval [CI] = 6.97 to 20.30) per year. The incidence rate of fixed combinations of HRT increased from 3.33 to 12.23 per 1000 PYAR in 2010 and 2021, respectively. Transdermal formulations of HRT increased from 1.48 to 14.55 per 1000 PYAR in 2010 and 2021, respectively. The overall proportion of women in receipt of a prescription for HRT changed from 7.89% in 2010 to 6.86% in 2020. CONCLUSION: This study shows a steady increase in the number of women receiving their first prescription for HRT during the study period, which suggests regained acceptance of HRT medicines.

Reflections on a specialist HIV menopause service: Experiences of managing menopause in women living with HIV: Experiences of managing menopause in women living with HIV.

OBJECTIVES: We describe here characteristics and clinical outcomes of women living with HIV attending an HIV menopause service. METHODS: This was a retrospective case note review of women attending the monthly HIV menopause clinic from January 2015 to July 2018. RESULTS: In all, 55 women attended the service. The overall mean age was 49 years; 50% were black and 20% had a previous AIDS-defining condition. All were on antiretroviral therapy (ART); the median CD4 count was 678 cells/µL; 93% had a viral load < 50 copies/mL; 7% had previous hepatitis C infection; 27% had a history of smoking; 45% had risk factors or existing cardiovascular disease; 24% had a mental health condition. The median duration of symptoms before clinic attendance was 18 months. Vasomotor symptoms (84%), menstrual cycle changes (62%), psychological (56%) and urogenital symptoms (29%) were reported. Twenty-two per cent had early menopause or premature ovarian insufficiency. The mean age at attendance of women diagnosed with menopause (n = 24) was 52 years. However, their average duration of symptoms prior to review was 28 months. A total of 61% had osteopenia/osteoporosis, 73% received menopausal hormone therapy (MHT), and 73% had symptomatic improvement, although 58% of these required higher doses of MHT. Median time on MHT was 10 months. Five patients had their ART modified. No serious MHT adverse effects were observed. CONCLUSIONS: Menopausal hormone therapy uptake was high, with most women observing an improvement in symptoms. Comorbidities were common, highlighting the need for integrated care based on a woman's needs. The long delay from initial symptoms to treatment demonstrates the need for better access to specialist advice for women experiencing menopause.

Alternative and non-hormonal treatments to symptoms of menopause.

Ovarian function can start to decline a few years before the eventual cessation of the menstrual cycle. The average age of menopause in the UK is 51 years, and it is a retrospective diagnosis after 12 months of amenorrhoea. Women can experience many symptoms such as vasomotor and vulvovaginal symptoms that impact them physically, psychologically, sexually and thus their overall wellbeing. Women may have medical contraindications to hormonal therapy or may prefer non-hormonal or alternative treatments. This review looks at the evidence, efficacy, and safety of a range of complementary or alternative treatments and non-hormonal pharmacological treatments for the treatment of vasomotor symptoms and vulvovaginal atrophy of menopause.

No increase in incidence or risk of recurrence of breast cancer in ospemifene-treated patients with vulvovaginal atrophy (VVA).

OBJECTIVE: To estimate the incidence and recurrence of breast cancer (BC) in patients with vulvovaginal atrophy (VVA) treated with ospemifene and matched untreated VVA patients using real-world data. STUDY DESIGN: Retrospective matched cohort study. MAIN OUTCOME MEASURES: VVA patients were identified from the 2011-2018 US MarketScan® insurance claims database. For incidence, ospemifene-treated VVA patients without evidence of BC prior to index treatment were matched to two untreated VVA controls similarly without history of BC on age, index VVA year, geographic region, Charlson Comorbidity categories, and follow-up time. BC after the index treatment was identified by BC diagnosis codes, mastectomy, chemotherapy, or radiation procedure. Incidence rate, rate ratio (RR) and their 95 % confidence intervals (CI) were calculated. The process was repeated to estimate BC recurrence in patients with a history of BC in 1:1, 1:2 and 1:3 matches. RESULTS: 1728 ospemifene users and 3456 untreated patients met the inclusion and matching criteria for assessing incidence. The average number of days for which ospemifene was supplied was 314 (standard deviation [SD] = 340). Average follow-up time from index treatment was 937 days (SD = 392) for treated patients and 915 days (SD = 396) for controls. BC incidence rates per 1000 person-years was 2.03 (95 % CI: 1.06-3.91) for treated patients and 3.53 (95 % CI: 2.49-4.99) for controls (RR = 0.58, 95 % CI: 0.28-1.21). No difference in recurrence was observed between ospemifene-treated and matched untreated patients. Ten (32.3 %) treated vs. 25 (40.3 %) controls in the 1:2 matched analysis had a recurrence. CONCLUSION: No differences were observed in the BC incidence and recurrence rates in ospemifene users compared with matched controls.

Global Consensus Position Statement on the Use of Testosterone Therapy for Women.

This Statement is being simultaneously published in the journals Climacteric, Maturitas, Journal of Sexual Medicine, and Journal of Clinical Endocrinology and Metabolism on behalf of the International Menopause Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, and The Endocrine Society, respectively. This Position Statement has been endorsed by the International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynaecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Global Consensus Position Statement on the Use of Testosterone Therapy for Women.

This Position Statement has been endorsed by the International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynecologists.

Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action.

OBJECTIVE: Seventy percent of postmenopausal women experience vasomotor symptoms, which can be highly disruptive and persist for years. Hormone therapy and other treatments have variable efficacy and/or side effects. Neurokinin B signaling increases in response to estrogen deficiency and has been implicated in hot flash (HF) etiology. We recently reported that a neurokinin 3 receptor (NK3R) antagonist reduces HF in postmenopausal women after 4 weeks of treatment. In this article we report novel data from that study, which shows the detailed time course of this effect. METHODS: Randomized, double-blind, placebo-controlled, single-center, crossover trial of an oral NK3R antagonist (MLE4901) for vasomotor symptoms in women aged 40 to 62 years, experiencing ≥7 HF/24 hours some of which were reported as bothersome or severe (Clinicaltrials.gov NCT02668185). Thirty-seven women were randomized and included in an intention-to-treat analysis. To ascertain the therapeutic profile of MLE4901, a post hoc time course analysis was completed. RESULTS: By day 3 of treatment with MLE4901, HF frequency reduced by 72% (95% CI, -81.3 to -63.3%) compared with baseline (51 percentage point reduction compared with placebo, P < 0.0001); this effect size persisted throughout the 4-week dosing period. HF severity reduced by 38% compared with baseline by day 3 (95% CI, -46.1 to -29.1%) (P < 0.0001 compared with placebo), bother by 39% (95% CI, -47.5 to -30.1%) (P < 0.0001 compared with placebo), and interference by 61% (95% CI, -79.1 to -43.0%) (P = 0.0006 compared with placebo); all continued to improve throughout the 4-week dosing period (to -44%, -50%, and -70%, respectively by day 28, all P < 0.0001 compared with placebo). CONCLUSIONS: NK3R antagonism rapidly relieves vasomotor symptoms without the need for estrogen exposure.

Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Hot flushes affect 70% of menopausal women and often severely impact physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but is not without risk. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes. METHODS: This phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants were healthy women aged 40-62 years, having seven or more hot flushes in every 24 h of which some were reported as being severe or bothersome, who had not had a menstrual period for at least 12 months, and who had not been taking any medication shown to improve menopausal flushes in the preceding 8 weeks. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and placebo (orally, twice daily) in random order separated by a 2 week washout period. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. The primary outcome was the total number of hot flushes during the final week of both treatment periods. Analyses were by intention to treat and per protocol using generalised linear mixed models and standard crossover analysis. All analyses were prespecified in the study protocol. The trial is registered at ClinicalTrials.gov, number NCT02668185. FINDINGS: 68 women were screened between Feb 3 and Oct 10, 2016, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22-67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81-58·56] vs MLE4901 19·35 [15·99-23·42]; adjusted estimate of difference 29·66 [17·39-42·87], p<0·0001). Treatment was well tolerated. Three participants developed a transaminase rise (alanine aminotransferase 4·5-5·9 times the upper limit of normal) with a normal bilirubin 28 days after starting MLE4901, which normalised within 90 days. INTERPRETATION: Treatment with a neurokinin 3 receptor antagonist (MLE4901) could be practice changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure. Larger scale studies of longer duration are now indicated. FUNDING: UK Medical Research Council and National Institute for Health Research.

Fourth consensus of the International Society for Premenstrual Disorders (ISPMD): auditable standards for diagnosis and management of premenstrual disorder.

Whilst professional bodies such as the Royal College and the American College of Obstetricians and Gynecologists have well-established standards for audit of management for most gynaecology disorders, such standards for premenstrual disorders (PMDs) have yet to be developed. The International Society of Premenstrual Disorders (ISPMD) has already published three consensus papers on PMDs covering areas that include definition, classification/quantification, clinical trial design and management (American College Obstetricians and Gynecologists 2011; Brown et al. in Cochrane Database Syst Rev 2:CD001396, 2009; Dickerson et al. in Am Fam Physician 67(8):1743-1752, 2003). In this fourth consensus of ISPMD, we aim to create a set of auditable standards for the clinical management of PMDs. All members of the original ISPMD consensus group were invited to submit one or more auditable standards to be eligible in the inclusion of the consensus. Ninety-five percent of members (18/19) responded with at least one auditable standard. A total of 66 auditable standards were received, which were returned to all group members who then ranked the standards in order of priority, before the results were collated. Proposed standards related to the diagnosis of PMDs identified the importance of obtaining an accurate history, that a symptom diary should be kept for 2 months prior to diagnosis and that symptom reporting demonstrates symptoms in the premenstrual phase of the menstrual cycle and relieved by menstruation. Regarding treatment, the most important standards were the use of selective serotonin reuptake inhibitors (SSRIs) as a first line treatment, an evidence-based approach to treatment and that SSRI side effects are properly explained to patients. A set of comprehensive standards to be used in the diagnosis and treatment of PMD has been established, for which PMD management can be audited against for standardised and improved care.

Oral estradiol and dydrogesterone combination therapy in postmenopausal women: review of efficacy and safety.

HRT is known to be effective for the relief of menopausal symptoms and prevention of osteoporosis. HRT should be tailored to the woman, enhancing the beneficial effects of the treatment while minimizing the risks. It is difficult to evaluate data on particular preparations of HRT and the different dosages in isolation. The purpose of this review is to highlight the efficacy and safety specific to oral estradiol and dydrogesterone combinations of four different dose strengths. A systematic literature search using Medline was carried out to identify studies containing efficacy or safety data. The findings of the retrieved publications confirm that estradiol and dydrogesterone combinations give very effective menopausal symptom relief and prevention of osteoporosis whilst maintaining a good safety profile. Data also show that these combinations of HRT give additional benefit to certain metabolic parameters including lipids, insulin, glucose and body fat distribution. By selecting the treatment and dose most suitable for each individual woman at her particular stage of menopause, the benefits can be optimized whilst mitigating the risks. HRT plays an important role in improving and maintaining women's health when used appropriately.

ISPMD consensus on the management of premenstrual disorders.

The second consensus meeting of the International Society for Premenstrual Disorders (ISPMD) took place in London during March 2011. The primary goal was to evaluate the published evidence and consider the expert opinions of the ISPMD members to reach a consensus on advice for the management of premenstrual disorders. Gynaecologists, psychiatrists, psychologists and pharmacologists each formally presented the evidence within their area of expertise; this was followed by an in-depth discussion leading to consensus recommendations. This article provides a comprehensive review of the outcomes from the meeting. The group discussed and agreed that careful diagnosis based on the recommendations and classification derived from the first ISPMD consensus conference is essential and should underlie the appropriate management strategy. Options for the management of premenstrual disorders fall under two broad categories, (a) those influencing central nervous activity, particularly the modulation of the neurotransmitter serotonin and (b) those that suppress ovulation. Psychotropic medication, such as selective serotonin reuptake inhibitors, probably acts by dampening the influence of sex steroids on the brain. Oral contraceptives, gonadotropin-releasing hormone agonists, danazol and estradiol all most likely function by ovulation suppression. The role of oophorectomy was also considered in this respect. Alternative therapies are also addressed, with, e.g. cognitive behavioural therapy, calcium supplements and Vitex agnus castus warranting further exploration.

Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus.

Premenstrual disorders (PMD) are characterised by a cluster of somatic and psychological symptoms of varying severity that occur during the luteal phase of the menstrual cycle and resolve during menses (Freeman and Sondheimer, Prim Care Companion J Clin Psychiatry 5:30-39, 2003; Halbreich, Gynecol Endocrinol 19:320-334, 2004). Although PMD have been widely recognised for many decades, their precise cause is still unknown and there are no definitive, universally accepted diagnostic criteria. To consider this issue, an international multidisciplinary group of experts met at a face-to-face consensus meeting to review current definitions and diagnostic criteria for PMD. This was followed by extensive correspondence. The consensus group formally became established as the International Society for Premenstrual Disorders (ISPMD). The inaugural meeting of the ISPMD was held in Montreal in September 2008. The primary aim was to provide a unified approach for the diagnostic criteria of PMD, their quantification and guidelines on clinical trial design. This report summarises their recommendations. It is hoped that the criteria proposed here will inform discussions of the next edition of the World Health Organisation's International Classification of Diseases (ICD-11), and the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) criteria that are currently under consideration. It is also hoped that the proposed definitions and guidelines could be used by all clinicians and investigators to provide a consistent approach to the diagnosis and treatment of PMD and to aid scientific and clinical research in this field.

Cyclical dydrogesterone in secondary amenorrhea: results of a double-blind, placebo-controlled, randomized study.

Secondary amenorrhea in women with normal estrogen levels increases the risk of endometrial carcinoma. Cyclical dydrogesterone induces regular withdrawal bleeding and effectively protects the endometrium of postmenopausal women receiving estrogens. In order to assess the efficacy of dydrogesterone in inducing regular withdrawal bleeds in premenopausal women with secondary amenorrhea or oligomenorrhea and normal estrogen levels, a double-blind, randomized, placebo-controlled, multicenter study was conducted in 104 women using cyclical dydrogesterone as is used for estrogen replacement therapy. Treatment consisted of dydrogesterone (10 mg/day on days 1-14 followed by placebo on days 15-28 of each cycle) given for six cycles of 28 days. The control group received placebo throughout the six cycles. Bleeding was documented by the patient on diary cards. The number of women with withdrawal bleeding during the first cycle was twice as high in the dydrogesterone group as in the placebo group (65.4% vs. 30.8%; p = 0.0004). Superiority of dydrogesterone was also observed for regularity of bleeding over the six cycles (p < 0.0001), although endometrial thickness after six cycles did not differ between the groups. In conclusion, dydrogesterone is significantly superior to placebo in inducing withdrawal bleeding, and maintaining regular bleeding, in women with secondary amenorrhea and normal estrogen levels.