Management of unscheduled bleeding on HRT: A joint guideline on behalf of the British Menopause Society, Royal College Obstetricians and Gynaecologists, British Gynaecological Cancer Society, British Society for Gynaecological Endoscopy, Faculty of Sexual and Reproductive Health, Royal College of General Practitioners and Getting it Right First Time.

Unscheduled bleeding on hormone replacement therapy (HRT) can affect up to 40% of users. In parallel with the increase in HRT prescribing in the UK, there has been an associated increase in referrals to the urgent suspicion of cancer pathway for unscheduled bleeding. On behalf of the British Menopause Society (BMS) an expert review panel was established, including primary and secondary care clinicians with expertise in the management of menopause, with representatives from key related organisations, including the Royal College of Obstetricians & Gynaecologists, the British Gynaecological Cancer Society, British Society for Gynaecological Endoscopy, Royal College of General Practitioners and Faculty of Sexual and Reproductive Health, and service development partners from NHS England and GIRFT (Getting it Right First Time). For each topic, a focused literature review was completed to develop evidence led recommendations, where available, which were ratified by consensus review within the panel and by guideline groups.

EMAS position statement: Vitamin D and menopausal health.

INTRODUCTION: There is increasing evidence that vitamin D has widespread tissue effects. In addition to osteoporosis, vitamin D deficiency has been associated with cardiovascular disease, diabetes, cancer, infections and neurodegenerative disease. However, the effect of vitamin D supplementation on non-skeletal outcomes requires clarification, especially in postmenopausal women. AIM: This position statement provides an evidence-based overview of the role of vitamin D in the health of postmenopausal women based on observational and interventional studies. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Vitamin D status is determined by measuring serum 25-hydroxyvitamin D levels. Concentrations <20 ng/ml (<50 nmol/l) and <10 ng/ml (<25 nmol/l) are considered to constitute vitamin D deficiency and severe deficiency, respectively. Observational data suggest an association between vitamin D deficiency and adverse health outcomes in postmenopausal women, although they cannot establish causality. The evidence from randomized controlled trials concerning vitamin D supplementation is not robust, since many studies did not consider whether people were deficient at baseline. Moreover, high heterogeneity exists in terms of the population studied, vitamin D dosage, calcium co-administration and duration of intervention. Concerning skeletal health, vitamin D deficiency is associated with low bone mass and an increased risk of fractures. Vitamin D supplementation at maintenance doses of 800-2000 IU/day (20-50 µg/day), after repletion of vitamin D status with higher weekly or daily doses, may be of benefit only when co-administered with calcium (1000-1200 mg/day), especially in the elderly populations and those with severe vitamin D deficiency. Concerning cardiovascular disease, vitamin D deficiency is associated with an increased prevalence of cardiovascular risk factors, mainly metabolic syndrome, type 2 diabetes mellitus and dyslipidemia. Vitamin D deficiency, especially its severe form, is associated with an increased risk of cardiovascular events (coronary heart disease, stroke, mortality), independently of traditional risk factors. Vitamin D supplementation may have a modestly beneficial effect on lipid profile and glucose homeostasis, especially in obese individuals or those ≥60 years old and at doses of ≥2000 IU/day (≥50 µg/day). However, it has no effect on the incidence of cardiovascular events. Concerning cancer, vitamin D deficiency is associated with increased incidence of and mortality from several types of cancer, such as colorectal, lung and breast cancer. However, the data on other types of gynecological cancer are inconsistent. Vitamin D supplementation has no effect on cancer incidence, although a modest reduction in cancer-related mortality has been observed. Concerning infections, vitamin D deficiency has been associated with acute respiratory tract infections, including coronavirus disease 2019 (COVID-19). Vitamin D supplementation may decrease the risk of acute respiratory tract infections and the severity of COVID-19 (not the risk of infection). Concerning menopausal symptomatology, vitamin D deficiency may have a negative impact on some aspects, such as sleep disturbances, depression, sexual function and joint pains. However, vitamin D supplementation has no effect on these, except for vulvovaginal atrophy, at relatively high doses, i.e., 40,000-60,000 IU/week (1000-1500 IU/week) orally or 1000 IU/day (25 µg/day) as a vaginal suppository.

Impact of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol on cardiovascular markers in women diagnosed with premature ovarian insufficiency or an early menopause: a randomised pilot trial.

OBJECTIVE: To compare the difference between micronised progesterone (MP) and medroxyprogesterone acetate (MPA) in combination with transdermal oestradiol (t-E2) on cardiovascular disease (CVD) risk markers in women diagnosed with an early menopause and premature ovarian insufficiency (EMPOI). BACKGROUND: The European Society for Cardiology has identified carotid femoral pulse wave velocity (cfPWV) as the gold standard cardiogenic biomarker for risk stratification of arterial disease. Menopause has been shown to augment the age-dependent increase in arterial stiffness, with hormone replacement therapy (HRT) being the mainstay of management of women diagnosed with EMPOI. STUDY DESIGN: A pilot randomised prospective open-label trial. Women were randomised to either cyclical MP (Utrogestan® 200mg) or MPA (Provera® 10mg) in conjunction with t-E2 (Evorel® Patches 50mcg/day) for 12 months. Seventy-one subjects were screened, and baseline data are available for 57 subjects. MAIN OUTCOME MEASURE: Carotid-femoral pulse wave velocity (cfPWV). RESULTS: PWV did not significantly change from baseline in either treatment arm. MP + t-E2 demonstrated a positive effect on traditional CVD markers, with a significant improvement seen in cardiac output (CO) (0.71±1.01mL/min, 95% CI 0.20 to 1.21) and reduction in diastolic blood pressure (DBP) (-3.43±6.31mmHg, 95% Cl -6.57 to -0.29) and total peripheral resistance (TPR) (-0.15±0.19mmHg⋅min⋅mL-1, 95% CI -0.24 to -0.05) after 12 months. MPA + t-E2, in contrast, did not demonstrate significant changes from baseline in traditional haemodynamic parameters. CONCLUSION: The positive changes in traditional markers were not reflected in the cardiogenic biomarker, cfPWV, which has demonstrated a higher positive predictive value for cardiovascular events than traditional measurements.

Menopause, wellbeing and health: A care pathway from the European Menopause and Andropause Society.

This care pathway from the European Menopause and Andropause Society (EMAS) provides an updated pathway for monitoring and guidance of women at midlife, focusing on those approaching the end of the reproductive life-cycle, going through the menopausal transition and beyond. The care pathway is written by professionals involved in women's health and provides a stepwise individualized approach, stratified according to needs, symptoms and reproductive stage. Furthermore, the pathway provides details on screening for chronic diseases related to menopause and ageing. Treatment options for climacteric symptoms range from menopausal hormone therapy to non-hormonal alternatives and lifestyle modifications. Therapy should be tailored to personal needs and wishes. The pathway aims to offer a holistic, balanced approach for monitoring middle-aged women, aiming to control health problems effectively and ensure healthy ageing.

The effect of micronized progesterone and medroxyprogesterone acetate in combination with transdermal estradiol on hemostatic biomarkers in postmenopausal women diagnosed with POI and early menopause: a randomized trial.

OBJECTIVE: To compare the impact of micronized progesterone (MP) or medroxyprogesterone acetate (MPA) in combination with transdermal estradiol (t-E2) on traditional coagulation factors and thrombin generation parameters in postmenopausal women diagnosed with premature ovarian insufficiency or early menopause. METHOD: Randomized prospective trial conducted in women diagnosed with premature ovarian insufficiency or early menopause and an intact uterus, recruited over 28 months. All participants were prescribed t-E2 and randomized to either cyclical MP or MPA using a web-based computer randomization software, Graph Pad. Thrombin generation parameters were measured at baseline and repeated after 3-months. Traditional hemostatic biomarkers were measured at baseline and repeated after 3, 6, and 12-months. Seventy-one participants were screened for the study, of whom 66 met the inclusion criteria. In total, 57 participants were randomized: 44 completed the thrombin generation assessment arm of the study, whilst 32 completed 12-months of the traditional coagulation factor screening component of the trial. RESULTS: Thrombin generation parameters did not significantly change from baseline after 3-months duration for either progestogen component when combined with t-E2, unlike the traditional coagulation factors. Protein C activity, free Protein S, and Antithrombin III levels decreased with time in both treatment arms. CONCLUSION: Fluctuations in traditional hemostatic biomarkers were not reproduced by parallel changes in thrombin generation parameters that remained neutral in both groups compared with baseline. The absence of statistically significant changes in thrombin generation for the first 3-months of hormone therapy use is reassuring and would suggest a neutral effect of both progestogens on the global coagulation assay.

British Menopause Society tools for clinicians: Progestogens and endometrial protection.

Progestogen administration is required to oppose naturally produced or administered estrogens to provide endometrial protection. Within HRT regimens, this should be delivered for at least the same duration as that produced during the luteal phase of the monthly cycle and in the recommended doses to protect against the risk of endometrial hyperplasia and endometrial cancer. This includes progestogens administered for 12-14 days a month in sequential regimens and continuous daily intake in continuous combined HRT regimens. Shorter durations and lower doses of progestogen intake are likely to be associated with an increased risk of breakthrough bleeding, endometrial hyperplasia, and endometrial cancer.

A cross-sectional national questionnaire survey assessing the views of members of the British Menopause Society on the management of patients with unscheduled bleeding on hormone replacement therapy.

OBJECTIVE: To explore the views of members of the British Menopause Society on the management of women with unscheduled bleeding on hormone replacement therapy. STUDY DESIGN: An electronic cross-sectional questionnaire survey. MAIN OUTCOME MEASURES: Investigations, treatment options and preferences for the management of women with unscheduled bleeding on hormone replacement therapy. RESULTS: A total of 91/178 (51%) clinicians investigate patients with unscheduled bleeding within three to six months of starting sequential hormone replacement therapy (seq-HRT) versus 83/178 (47%) for continuous combined hormone replacement therapy (con-HRT). A total of 52/178 (29%) versus 54/178 (30%) would investigate unscheduled bleeding continuing beyond six months while 18/178 (10%) versus 26/178 (15%) would investigate within three months. Assessment is requested as urgent by 88/176 (50%) clinicians, routine by 47/176 (27%) and a two-week-wait-suspected cancer referral by 41/176 (23%). A total of 97/178 (55%) clinicians would continue seq-HRT and refer versus 117/178 (66%) for con-HRT. A total of 46/178 (26%) clinicians would change the progestogen preparation in women with unscheduled bleeding on seq-HRT. For women on con-HRT, 12/178 (7%) clinicians would change to seq-HRT and 8/178 (5%) to the Mirena IUS. The Mirena IUS is the preferred progestogen for 81/178 (45%) of clinicians when prescribing hormone replacement therapy. CONCLUSIONS: There is a varied approach in the practise amongst British Menopause Society members to managing women with unscheduled bleeding on hormone replacement therapy. Further research is needed to determine the optimal assessment pathways for women with unscheduled bleeding on hormone replacement therapy.

Vision for menopause care in the UK.

Menopause is a major life event affecting all women in a variety of ways, both short and long term. All women should have access to accurate information, available in all forms and through all recognised sources. All healthcare professionals should have a basic understanding of the menopause and know where to signpost women for advice, support and treatment whenever appropriate. Every primary care team should have at least one nominated healthcare professional with a special interest and knowledge in menopause. All healthcare professionals with a special interest in menopause should have access to British Menopause Society Menopause Specialists for advice, support, onward referral and leadership of multidisciplinary education. With the introduction of the comprehensive British Menopause Society Principles and Practice of Menopause Care programme, the society is recognised throughout the UK as the leading provider of certificated menopause and post reproductive health education and training for healthcare professionals. Restrictions imposed by the coronavirus pandemic have been a springboard for the British Menopause Society to bring innovations to the services provided for our membership and for healthcare professionals throughout the UK.

A Randomized Trial of Endometrial Scratching before In Vitro Fertilization.

BACKGROUND: Endometrial scratching (with the use of a pipelle biopsy) is a technique proposed to facilitate embryo implantation and increase the probability of pregnancy in women undergoing in vitro fertilization (IVF). METHODS: We conducted a pragmatic, multicenter, open-label, randomized, controlled trial. Eligible women were undergoing IVF (fresh-embryo or frozen-embryo transfer), with no recent exposure to disruptive intrauterine instrumentation (e.g., hysteroscopy). Participants were randomly assigned in a 1:1 ratio to either endometrial scratching (by pipelle biopsy between day 3 of the cycle preceding the embryo-transfer cycle and day 3 of the embryo-transfer cycle) or no intervention. The primary outcome was live birth. RESULTS: A total of 1364 women underwent randomization. The frequency of live birth was 180 of 690 women (26.1%) in the endometrial-scratch group and 176 of 674 women (26.1%) in the control group (adjusted odds ratio, 1.00; 95% confidence interval, 0.78 to 1.27). There were no significant between-group differences in the rates of ongoing pregnancy, clinical pregnancy, multiple pregnancy, ectopic pregnancy, or miscarriage. The median score for pain from endometrial scratching (on a scale of 0 to 10, with higher scores indicating worse pain) was 3.5 (interquartile range, 1.9 to 6.0). CONCLUSIONS: Endometrial scratching did not result in a higher rate of live birth than no intervention among women undergoing IVF. (Funded by the University of Auckland and others; PIP Australian New Zealand Clinical Trials Registry number, ACTRN12614000626662 .).

Outpatient management of severe ovarian hyperstimulation syndrome: a systematic review and a review of existing guidelines.

Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of assisted reproductive treatment. Management of women with severe OHSS has traditionally included hospitalisation for close monitoring and supportive treatment. The aim of this review is to assess the evidence for safety and efficacy of outpatient management of severe OHSS. A systematic review of studies describing outpatient management options was performed. Current guidance from advisory bodies was also reviewed. Outpatient management has been found in observational studies to be safe and cost-effective compared to inpatient management. Paracentesis of ascitic fluid seems to be effective treatment for severe OHSS along with supportive management including maintenance of fluid balance and preventative measures against thrombo-embolism. GnRH antagonist was shown in few studies to be effective in treatment of early severe OHSS although further research is required to assess its role in this context. Appropriate outpatient set up and protocols are essential to provide safe outpatient management for women with severe OHSS.

Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis.

OBJECTIVE: To systematically review and summarize the existing evidence related to the efficacy and safety of transdermal T in postmenopausal women for the treatment of hypoactive sexual desire disorder (HSDD). DESIGN: Systematic reviews and meta-analysis. SETTING: Not applicable. PATIENT(S): Seven randomized controlled trials enrolled 3,035 participants; 1,350 women were randomized to treatment with T patch, and 1,379 women were randomized to placebo. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome: satisfying sexual episodes. SECONDARY OUTCOMES: sexual activity, orgasm, Profile of Female Sexual Function domains (desire), personal distress score, adverse events, acne, increased hair growth, facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction, total adverse events, serious adverse events, withdrawal from study, and follow-up rate. RESULT(S): The T group had significantly more satisfying sexual episodes, sexual activity, orgasms, desire, significant change in Personal Distress Scale score, androgenic adverse events, acne, and hair growth compared with the placebo group. There was no significant difference between the two groups in increase in facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction to the patch, total adverse events, serious adverse events, reasons for withdrawal from the study, and the number of women who completed the study. CONCLUSION(S): The short-term efficacy in terms of improvement of sexual function and safety of transdermal T in naturally and surgically menopausal women affected by HSDD either on or not on estrogen progestin hormone therapy is evident from this systematic review. The use of transdermal T is associated with increase in androgenic adverse events such as acne but is not associated with any serious adverse events.

Fertility desires, choice of hormone replacement and the effect of length of time since menopause on bone density in women with premature ovarian insufficiency: a review of 223 consecutive new referrals to a tertiary centre.

Premature ovarian insufficiency can have significant implications for the affected women. This review assesses the fertility desires, choice of hormone replacement, and the effect of time since menopause on the bone density of these women. This is a retrospective analysis of 223 consecutive new referrals. The average age (mean [± standard deviation]) of the women was 37.35 (± 5.88) years, with 24.1% (n = 19/79) presenting within 12 months of the onset of symptoms, most commonly, vasomotor type symptoms (n = 98/223; 43.9%). Of the women included, 58.7% (n = 131/223) took hormone replacement therapy (HRT), most commonly, an oral (n = 90/131; 68.7%) sequential preparation (n = 91/131; 69.5%), with a significant number of women >40 years of age preferring the transdermal route (n = 26/54; 48.1%; p<0.01). A total of 37.7% (n = 84/223) of the women expressed concerns regarding their future fertility, more notable in women ≤ 40 years (n = 72/142; 50.7%; p < 0.01). Of these, 41.7% (n = 35/84) took HRT, most commonly, a sequential regimen (n = 26/35; 74.3%) with oral estradiol (n = 30/35; 85.7%); 69.5% (n = 155/223) of the women had had a bone densitometry scan performed, with 66.5% (n = 103/155) showing normal bone mineral density (BMD), but a greater likelihood of having reduced BMD the greater the time delay in presentation. No difference was seen for the three broad categories of BMD when further analysed for the cause of premature ovarian insufficiency, but a significant difference was noted for the spinal Z-scores, whereby women who underwent a surgically induced menopause were noted to have lower BMD compared with the other causes (p < 0.01). These findings can be useful in counselling women and guiding clinicians in their management of women with premature ovarian insufficiency.

A randomised controlled trial comparing the effects of micronized progesterone to medroxyprogesterone acetate on cardiovascular health, lipid metabolism and the coagulation cascade in women with premature ovarian insufficiency: study protocol and review of the literature.

Premature ovarian insufficiency (POI) can have significant health implications for the affected patient population, but remains a largely under researched area. There is lack of evidence from randomised controlled trials to guide clinical practice, regarding the optimal hormone replacement therapy regimens, dose and route of administration. Furthermore, little research has addressed the effect of the various progestogens used on health parameters in women with POI. Here we describe an ongoing randomised clinical trial looking at the effects of micronized progesterone and medroxyprogesterone acetate, both used in combination with transdermal oestradiol on the cardiovascular system, lipid profile and coagulation cascade in women with POI as a step towards better understanding of the implications of hormone treatment in this cohort of women.

Medical and surgical options for induced abortion in first trimester.

Medical abortion has been shown to be an effective alternative to surgery for termination of pregnancy in the late as well as the early first trimester of pregnancy. This review discusses the development, application and the current issues with medical and surgical abortion in the first trimester. Studies comparing the two approaches are also assessed as well as potential research directions in this area.

Fatal pulmonary embolus after uterine artery fibroid embolisation.

We report a 44-year-old woman who developed a fatal pulmonary embolus after uterine artery fibroid embolisation (UAE). Bilateral UAE was carried out through a single right-femoral artery puncture. The largest fibroid in the anterior fundal wall measured 4.5 cm, and the largest fibroid in the posterior fundal wall measured 6 cm. The appearances after UAE were satisfactory, and the procedure was apparently uneventful. No immediate complications were noted. The patient developed sudden-onset shortness of breath and went into cardiac arrest 19 h after the procedure. Postmortem autopsy confirmed that the cause of a death was a pulmonary embolism. To our knowledge this is the first reported case in the United Kingdom in which death occurred from a pulmonary embolus after UAE.

Psychological sequelae of medical and surgical abortion at 10-13 weeks gestation.

BACKGROUND: Although not much research comparing the emotional distress following medical and surgical abortion is available, few studies have compared psychological sequelae following both methods of abortion early in the first trimester of pregnancy. The aim of this review was to assess the psychological sequelae and emotional distress following medical and surgical abortion at 10-13 weeks gestation. METHODS: Partially randomized patient preference trial in a Scottish Teaching Hospital was conducted. The hospital anxiety and depression scales were used to assess emotional distress. Anxiety levels were also assessed using visual analog scales while semantic differential rating scales were used to measure self-esteem. A total of 368 women were randomized, while 77 entered the preference cohort. RESULTS: There were no significant differences in hospital anxiety and depression scales scores for anxiety or depression between the groups. Visual analog scales showed higher anxiety levels in women randomized to surgery prior to abortion (P < 0.0001), while women randomized to surgical treatment were less anxious after abortion (P < 0.0001). Semantic differential rating scores showed a fall in self-esteem in the randomized medical group compared to those undergoing surgery (P = 0.02). CONCLUSIONS: Medical abortion at 10-13 weeks is effective and does not increase psychological morbidity compared to surgical vacuum aspiration and hence should be made available to all women undergoing abortion at these gestations.