Liver, visceral and subcutaneous fat in men and women of South Asian and white European descent: a systematic review and meta-analysis of new and published data.

AIMS/HYPOTHESIS: South Asians have a two- to fivefold higher risk of developing type 2 diabetes than those of white European descent. Greater central adiposity and storage of fat in deeper or ectopic depots are potential contributing mechanisms. We collated existing and new data on the amount of subcutaneous (SAT), visceral (VAT) and liver fat in adults of South Asian and white European descent to provide a robust assessment of potential ethnic differences in these factors. METHODS: We performed a systematic review of the Embase and PubMed databases from inception to August 2021. Unpublished imaging data were also included. The weighted standardised mean difference (SMD) for each adiposity measure was estimated using random-effects models. The quality of the studies was assessed using the ROBINS-E tool for risk of bias and overall certainty of the evidence was assessed using the GRADE approach. The study was pre-registered with the OSF Registries ( https://osf.io/w5bf9 ). RESULTS: We summarised imaging data on SAT, VAT and liver fat from eight published and three previously unpublished datasets, including a total of 1156 South Asian and 2891 white European men, and 697 South Asian and 2271 white European women. Despite South Asian men having a mean BMI approximately 0.5-0.7 kg/m2 lower than white European men (depending on the comparison), nine studies showed 0.34 SMD (95% CI 0.12, 0.55; I2=83%) more SAT and seven studies showed 0.56 SMD (95% CI 0.14, 0.98; I2=93%) more liver fat, but nine studies had similar VAT (-0.03 SMD; 95% CI -0.24, 0.19; I2=85%) compared with their white European counterparts. South Asian women had an approximately 0.9 kg/m2 lower BMI but 0.31 SMD (95% CI 0.14, 0.48; I2=53%) more liver fat than their white European counterparts in five studies. Subcutaneous fat levels (0.03 SMD; 95% CI -0.17, 0.23; I2=72%) and VAT levels (0.04 SMD; 95% CI -0.16, 0.24; I2=71%) did not differ significantly between ethnic groups in eight studies of women. CONCLUSIONS/INTERPRETATION: South Asian men and women appear to store more ectopic fat in the liver compared with their white European counterparts with similar BMI levels. Given the emerging understanding of the importance of liver fat in diabetes pathogenesis, these findings help explain the greater diabetes risks in South Asians. FUNDING: There was no primary direct funding for undertaking the systematic review and meta-analysis.

Uterine-Artery Embolization or Myomectomy for Uterine Fibroids.

BACKGROUND: Uterine fibroids, the most common type of tumor among women of reproductive age, are associated with heavy menstrual bleeding, abdominal discomfort, subfertility, and a reduced quality of life. For women who wish to preserve their uterus and who have not had a response to medical treatment, myomectomy and uterine-artery embolization are therapeutic options. METHODS: We conducted a multicenter, randomized, open-label trial to evaluate myomectomy, as compared with uterine-artery embolization, in women who had symptomatic uterine fibroids and did not want to undergo hysterectomy. Procedural options included open abdominal, laparoscopic, or hysteroscopic myomectomy. The primary outcome was fibroid-related quality of life, as assessed by the score on the health-related quality-of-life domain of the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire (scores range from 0 to 100, with higher scores indicating a better quality of life) at 2 years; adjustment was made for the baseline score. RESULTS: A total of 254 women, recruited at 29 hospitals in the United Kingdom, were randomly assigned: 127 to the myomectomy group (of whom 105 underwent myomectomy) and 127 to the uterine-artery embolization group (of whom 98 underwent embolization). Data on the primary outcome were available for 206 women (81%). In the intention-to-treat analysis, the mean (±SD) score on the health-related quality-of-life domain of the UFS-QOL questionnaire at 2 years was 84.6±21.5 in the myomectomy group and 80.0±22.0 in the uterine-artery embolization group (mean adjusted difference with complete case analysis, 8.0 points; 95% confidence interval [CI], 1.8 to 14.1; P = 0.01; mean adjusted difference with missing responses imputed, 6.5 points; 95% CI, 1.1 to 11.9). Perioperative and postoperative complications from all initial procedures, irrespective of adherence to the assigned procedure, occurred in 29% of the women in the myomectomy group and in 24% of the women in the uterine-artery embolization group. CONCLUSIONS: Among women with symptomatic uterine fibroids, those who underwent myomectomy had a better fibroid-related quality of life at 2 years than those who underwent uterine-artery embolization. (Funded by the National Institute for Health Research Health Technology Assessment program; FEMME Current Controlled Trials number, ISRCTN70772394.).

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy.

BACKGROUND: Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS: A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS: Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).

Menopausal hormone therapy and women's health: An umbrella review.

BACKGROUND: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412). CONCLUSIONS: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

Association of the functional ovarian reserve with serum metabolomic profiling by nuclear magnetic resonance spectroscopy: a cross-sectional study of ~ 400 women.

BACKGROUND: Women with diminished ovarian reserve are known to have increased cardiovascular risk, whether there is a continuous association between the ovarian reserve biomarkers; anti-Müllerian hormone (AMH), antral follicle count (AFC) and cardio-metabolic risk factors are unknown. METHODS: A cross-sectional study of 398 women intending to undergo IVF with pre-treatment early follicular AMH and AFC measurements. Serum lipids, lipoprotein subclasses and low-molecular-weight metabolites were quantified by NMR spectroscopy (155 metabolic measures). Associations were analysed using multivariable regression. RESULTS: Participants were mean 35.5 (SD 4.43) years old and had a median AMH of 16 pmol/l (IQR 8.8, 28.0 pmol/l) and a median AFC of 12 (IQR 7.16). AMH showed positive associations with HDL, omega-6 and polyunsaturated fatty acids and the amino acids isoleucine, leucine and tyrosine, with effects ranging from 0.11 (95%CI 0.004 to 0.21) for total lipids in small HDL to 0.16 (0.06 to 0.26) for isoleucine, for a mean difference of one SD of metabolite per one SD increment in AMH, and negatively with acetate: - 0.31(- 0.22, - 0.004) SD per 1 SD AMH. AFC was positively associated with alanine, glutamine and glycine. Results were consistent, though less precisely estimated, when restricted to those women who were preparing for treatment because of their partner's infertility. CONCLUSIONS: In women intending to have IVF, AMH and AFC were not associated with traditional lipid measured but were associated with a number of novel cardiovascular risk factors. Prospective studies will be required for replication, determination of causality and confirmation that ovarian reserve is impacting on metabolism rather than variation in metabolism is influencing ovarian reserve.

Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence.

Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.

Oestrogen replacement in postmenopausal women.

Menopausal symptoms can disrupt a woman's personal and social life. Vasomotor symptoms (hot flushes and night sweats) are the most common symptoms and can be treated very effectively with oestrogen-based hormone therapy. The decision to use oestrogen (often simply termed hormone therapy or hormone replacement therapy or HT) therapy involves balancing the potential benefits against the potential risks. Most agree that short-term oestrogen therapy, using the lowest effective dose, is a reasonable option for recently menopausal women with moderate-to-severe symptoms who are in good cardiovascular health (Martin and Manson. 2008. J. Clin. Endocrinol. Metab. 93, 4567-75). Whilst effective and safe in most instances, HT is not suitable for all women or for all menopause-related symptoms when alternatives are available. The role of HRT in chronic disease prevention is also discussed.

Therapeutic options for the management of abnormal uterine bleeding.

Just as the investigation of abnormal uterine bleeding (AUB) is approached systematically using the two FIGO systems for AUB in the reproductive years, treatment options can be considered similarly. Therapeutic options fall into two categories-medical and surgical-and while medical management is typically regarded as first-line therapy, there are several exceptions defined by the presenting cause or causes, mainly when infertility is a concurrent issue. In the early 1990s, up to 60% of women underwent a hysterectomy for the symptom of heavy menstrual bleeding (HMB), but this figure has decreased. The number of women undergoing a hysterectomy for benign disorders continues to decline, along with an increase in hysterectomies performed using minimally invasive techniques. Discussions about therapeutic options are tailored to the individual patient, and we include the risks and benefits of each option, including no management, to enable the patient to make an informed choice. The different types of treatment options and the factors affecting decision-making are considered in this article.

Anti-Müllerian hormone for the diagnosis and prediction of menopause: a systematic review.

BACKGROUND: The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman's circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles remaining in the ovary and declines towards the menopause, serum AMH may be of value in the early diagnosis and prediction of age at menopause. OBJECTIVE AND RATIONALE: This systematic review was undertaken to determine whether there is evidence to support the use of AMH alone, or in conjunction with other markers, to diagnose menopause, to predict menopause, or to predict and/or diagnose premature ovarian insufficiency (POI). SEARCH METHODS: A systematic literature search for publications reporting on AMH in relation to menopause or POI was conducted in PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials up to 31 May 2022. Data were extracted and synthesized using the Synthesis Without Meta-analysis for diagnosis of menopause, prediction of menopause, prediction of menopause with a single/repeat measurement of AMH, validation of prediction models, short-term prediction in perimenopausal women, and diagnosis and prediction of POI. Risk-of-bias was evaluated using the Tool to Assess Risk of Bias in Cohort Studies protocol and studies at high risk of bias were excluded. OUTCOMES: A total of 3207 studies were identified, and 41, including 28 858 women, were deemed relevant and included. Of the three studies that assessed AMH for the diagnosis of menopause, one showed that undetectable AMH had equivalent diagnostic accuracy to elevated FSH (>22.3 mIU/ml). No study assessed whether AMH could be used to shorten the 12 months of amenorrhoea required for a formal diagnosis of menopause. Studies assessing AMH with the onset of menopause (27 publications [n = 23 835 women]) generally indicated that lower age-specific AMH concentrations are associated with an earlier age at menopause. However, AMH alone could not be used to predict age at menopause with precision (with estimates and CIs ranging from 2 to 12 years for women aged <40 years). The predictive value of AMH increased with age, as the interval of prediction (time to menopause) shortened. There was evidence that undetectable, or extremely low AMH, may aid early diagnosis of POI in young women with a family history of POI, and women presenting with primary or secondary amenorrhoea (11 studies [n = 4537]). WIDER IMPLICATIONS: The findings of this systematic review support the use of serum AMH to study the age of menopause in population studies. The increased sensitivity of current AMH assays provides improved accuracy for the prediction of imminent menopause, but diagnostic use for individual patients has not been rigorously examined. Prediction of age at menopause remains imprecise when it is not imminent, although the finding of very low AMH values in young women is both of clinical value in indicating an increased risk of developing POI and may facilitate timely diagnosis.

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Approach to the Patient With New-Onset Secondary Amenorrhea: Is This Primary Ovarian Insufficiency?

Menstrual cyclicity is a marker of health for reproductively mature women. Absent menses, or amenorrhea, is often the initial sign of pregnancy-an indication that the system is functioning appropriately and capable of generating the intended evolutionary outcome. Perturbations of menstrual regularity in the absence of pregnancy provide a marker for physiological or pathological disruption of this well-orchestrated process. New-onset amenorrhea with duration of 3 to 6 months should be promptly evaluated. Secondary amenorrhea can reflect structural or functional disturbances occurring from higher centers in the hypothalamus to the pituitary, the ovary, and finally, the uterus. Amenorrhea can also be a manifestation of systemic disorders resulting in compensatory inhibition of reproduction. Identifying the point of the breakdown is essential to restoring reproductive homeostasis to maintain future fertility and reestablish reproductive hormonal integrity. Among the most challenging disorders contributing to secondary amenorrhea is primary ovarian insufficiency (POI). This diagnosis stems from a number of possible etiologies, including autoimmune, genetic, metabolic, toxic, iatrogenic, and idiopathic, each with associated conditions and attendant medical concerns. The dual assaults of unanticipated compromised fertility concurrently with depletion of the normal reproductive hormonal milieu yield multiple management challenges. Fertility restoration is an area of active research, while optimal management of estrogen deficiency symptoms and the anticipated preventive benefits of hormone replacement for bone, cardiovascular, and neurocognitive health remain understudied. The state of the evidence for an optimal, individualized, clinical management approach to women with POI is discussed along with priorities for additional research in this population.

Uterine artery embolization or myomectomy for women with uterine fibroids: Four-year follow-up of a randomised controlled trial.

OBJECTIVE: To examine the quality of life experienced by women with symptomatic uterine fibroids who had been treated with UAE in comparison to myomectomy. We report the four-year follow-up of the FEMME randomised trial. Two-year follow-up data has been previously reported. STUDY DESIGN: Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolization were recruited from 29 UK hospitals. Women were excluded if they had significant adenomyosis, any malignancy, pelvic inflammatory disease or had had a previous open myomectomy or uterine artery embolization.Participants were randomised to myomectomy or embolization in a 1:1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic, according to clinician preference. Embolization of the uterine arteries was performed according to local practice, under fluoroscopic guidance.The primary outcome measure was the Uterine Fibroid Symptom Quality of Life questionnaire, adjusted for baseline score and reported here at four years post-randomisation. Subsequent procedures for fibroids, pregnancy and outcome were amongst secondary outcomes.Trial registration ISRCTN70772394 https://doi.org/10.1186/ISRCTN70772394. RESULTS: 254 women were randomized, 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolization (98 underwent embolization). At four years, 67 (53%) and 81 (64%) completed UFS-QoL quality of life scores. Mean difference in the UFS-QoL at 4 years was 5.0 points (95% CI -1.4 to 11.5; p = 0.13) in favour of myomectomy. There were 15 pregnancies in the UAE group and 7 in the myomectomy group, with a cumulative pregnancy rate to four years of 15% and 6% respectively (hazard ratio: 0.48; 95% CI 0.18-1.28). The cumulative repeat procedure rate to four years was 24% in the UAE group and 13% in the myomectomy group (hazard ratio: 0.53; 95% CI 0.27-1.05). CONCLUSIONS: Myomectomy resulted in greater improvement in quality of life compared with uterine artery embolization, although by four years, this difference was not statistically significant. Missing data may limit the generalisability of this result. The numbers of women becoming pregnant were too small draw a conclusion on the effect of the procedures on fertility.

Uterine artery embolisation versus myomectomy for premenopausal women with uterine fibroids wishing to avoid hysterectomy: the FEMME RCT.

BACKGROUND: Uterine fibroids are the most common tumour in women of reproductive age and are associated with heavy menstrual bleeding, abdominal discomfort, subfertility and reduced quality of life. For women wishing to retain their uterus and who do not respond to medical treatment, myomectomy and uterine artery embolisation are therapeutic options. OBJECTIVES: We examined the clinical effectiveness and cost-effectiveness of uterine artery embolisation compared with myomectomy in the treatment of symptomatic fibroids. DESIGN: A multicentre, open, randomised trial with a parallel economic evaluation. SETTING: Twenty-nine UK hospitals. PARTICIPANTS: Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolisation were recruited. Women were excluded if they had significant adenomyosis, any malignancy or pelvic inflammatory disease or if they had already had a previous open myomectomy or uterine artery embolisation. INTERVENTIONS: Participants were randomised to myomectomy or embolisation in a 1 : 1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic. Embolisation of the uterine arteries was performed under fluoroscopic guidance. MAIN OUTCOME MEASURES: The primary outcome was the Uterine Fibroid Symptom Quality of Life questionnaire (with scores ranging from 0 to 100 and a higher score indicating better quality of life) at 2 years, adjusted for baseline score. The economic evaluation estimated quality-adjusted life-years (derived from EuroQol-5 Dimensions, three-level version, and costs from the NHS perspective). RESULTS: A total of 254 women were randomised - 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolisation (98 underwent embolisation). Information on the primary outcome at 2 years was available for 81% (n = 206) of women. Primary outcome scores at 2 years were 84.6 (standard deviation 21.5) in the myomectomy group and 80.0 (standard deviation 22.0) in the uterine artery embolisation group (intention-to-treat complete-case analysis mean adjusted difference 8.0, 95% confidence interval 1.8 to 14.1, p = 0.01; mean adjusted difference using multiple imputation for missing responses 6.5, 95% confidence interval 1.1 to 11.9). The mean difference in the primary outcome at the 4-year follow-up time point was 5.0 (95% CI -1.4 to 11.5; p = 0.13) in favour of myomectomy. Perioperative and postoperative complications from all initial procedures occurred in similar percentages of women in both groups (29% in the myomectomy group vs. 24% in the UAE group). Twelve women in the uterine embolisation group and six women in the myomectomy group reported pregnancies over 4 years, resulting in seven and five live births, respectively (hazard ratio 0.48, 95% confidence interval 0.18 to 1.28). Over a 2-year time horizon, uterine artery embolisation was associated with higher costs than myomectomy (mean cost £7958, 95% confidence interval £6304 to £9612, vs. mean cost £7314, 95% confidence interval £5854 to £8773), but with fewer quality-adjusted life-years gained (0.74, 95% confidence interval 0.70 to 0.78, vs. 0.83, 95% confidence interval 0.79 to 0.87). The differences in costs (difference £645, 95% confidence interval -£1381 to £2580) and quality-adjusted life-years (difference -0.09, 95% confidence interval -0.11 to -0.04) were small. Similar results were observed over the 4-year time horizon. At a threshold of willingness to pay for a gain of 1 QALY of £20,000, the probability of myomectomy being cost-effective is 98% at 2 years and 96% at 4 years. LIMITATIONS: There were a substantial number of women who were not recruited because of their preference for a particular treatment option. CONCLUSIONS: Among women with symptomatic uterine fibroids, myomectomy resulted in greater improvement in quality of life than did uterine artery embolisation. The differences in costs and quality-adjusted life-years are very small. Future research should involve women who are desiring pregnancy. TRIAL REGISTRATION: This trial is registered as ISRCTN70772394. FUNDING: This study was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 22. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Uterine fibroids are the most common non-cancerous tumour in women of childbearing age. Uterine fibroids are associated with heavy bleeding, lower chances of having children and reduced quality of life. Traditional surgical options were either to remove the fibroids (via myomectomy) or to completely remove the womb. A newer approach, known as uterine artery embolisation, involves blocking the blood supply to the fibroids in the womb. WHAT DID WE PLAN TO DO?: We compared myomectomy with uterine artery embolisation in women with fibroids who wanted to keep their womb. We wanted to see which treatment improved quality of life, was associated with the fewest complications and was the best value for money for the NHS. We also wanted to see if either treatment had an impact on women's ability to get pregnant and give birth. We included 254 women in a clinical trial. Women were assigned to have myomectomy or uterine artery embolisation at random to ensure a fair comparison. Women completed questionnaires about their symptoms and quality of life at intervals up to 4 years after treatment. WHAT DID WE FIND?: We found that myomectomy improved women's quality of life more than uterine artery embolisation. Complications from the treatments occurred in a similar proportion of women. There appeared to be no difference on reproductive hormone levels between treatments. Too few women in the trial got pregnant for any difference in the numbers of women having children to be seen. The differences in costs and overall disease burden were small. WHAT DOES THIS MEAN?: Both treatments improve quality of life and cost about the same to the NHS but, on average, myomectomy will provide greater benefit to women. There is no evidence to suggest that either treatment is unsuitable for women wanting to get pregnant, but more research is needed in younger women.

Predictive validity of the personal qualities assessment for selection of medical students in Scotland.

BACKGROUND: The Personal Qualities Assessment (PQA) was developed to enhance medical student selection by measuring a range of non-cognitive attributes in the applicants to medical school. Applicants to the five Scottish medical schools were invited to pilot the test in 2001 and 2002. AIMS: To evaluate the predictive validity of PQA for selecting medical students. METHODS: A longitudinal cohort study was conducted in which PQA scores were compared with senior year medical school performance. RESULTS: Consent to access performance markers was obtained from 626 students (61.6% of 1017 entrants in 2002-2003). Linkable Foundation Year (4th) rankings were available for 411 (66%) students and objective structured clinical examination (OSCE) rankings for 335 (54%) of those consenting. Both samples were representative of the original cohort. No significant correlations were detected between separate elements of the PQA assessment and student performance. However, using the algorithm advocated by Powis et al. those defined as 'non-extreme' (<±1.5 SD from the cohort mean scores; SD, standard deviation) character types on the involved-detached and on the libertarian-communitarian moral orientation scales were ranked higher in OSCEs (average of 7.5% or 25 out of 335, p = 0.049). CONCLUSIONS: This study was limited by high attrition and basic outcome markers which are insensitive to relevant non-cognitive characteristics. However, it is the largest currently available study of predictive validity for the PQA assessment. There was one finding of significance: that those students who were identified by PQA as 'not extreme' on the two personal characteristics scales performed better in an OSCE measure of professionalism. Futures studies are required since psychometric testing for both cognitive and non-cognitive attributes are increasingly used in admission process and these should include more and better measures of professionalism against which to correlate non-cognitive traits.

Spousal associations of serum metabolomic profiles by nuclear magnetic resonance spectroscopy.

Phenotype-based assortative mating is well established in humans, with the potential for further convergence through a shared environment. To assess the correlation within infertile couples of physical, social, and behavioural characteristics and 155 circulating metabolic measures. Cross sectional study at a tertiary medical center of 326 couples undertaking IVF. Serum lipids, lipoprotein subclasses, and low-molecular weight metabolites as quantified by NMR spectroscopy (155 metabolic measures). Multivariable and quantile regression correlations within couples of metabolite profiles. Couples exhibited statistical correlations of varying strength for most physical, social, and behavioural characteristics including age, height, alcohol consumption, education, smoking status, physical activity, family history and ethnicity, with correlation coefficients ranging from 0.22 to 0.73. There was no evidence of within couple associations for BMI and weight, where the correlation coefficients were - 0.03 (95% CI - 0.14, 0.08) and 0.01 (95% CI - 0.10, 0.12), respectively. Within spousal associations of the metabolite measurements were all positive but with weak to modest magnitudes, with the median correlation coefficient across all 155 measures being 0.12 (range 0.01-0.37 and interquartile range 0.10-0.18). With just four having associations stronger than 0.3: docosahexaenoic acid (0.37, 95% CI 0.22, 0.52), omega-3 fatty acids (0.32, 95% CI 0.20, 0.43) histidine (0.32, 95% CI 0.23, 0.41) and pyruvate (0.32, 95% CI 0.22, 0.43). Infertile couples exhibit spousal similarities for a range of demographic and serum metabolite measures, supporting initial assortative mating, with diet-derived metabolites suggesting possible subsequent convergence of their individual metabolic profile.

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 amenorrhoea. 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 (HRT) 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 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.

A core outcome set for vasomotor symptoms associated with menopause: the COMMA (Core Outcomes in Menopause) global initiative.

OBJECTIVE: Vasomotor symptoms (VMS) (hot flashes and night sweats) affect most women over the menopause transition. Comparing the safety and effectiveness of treatments for vasomotor symptoms is limited by the use of inconsistent outcome measures, and uncertainty as to which outcomes are most important to symptomatic women. To address this, we have developed a Core Outcome Set (COS) for use in clinical trials of treatments for VMS. METHODS: We systematically reviewed the primary outcomes measured in randomized controlled trials of treatments for VMS. These were refined and entered into a two-round modified Delphi survey completed by clinicians, researchers, and postmenopausal women between November 2019 and March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." Two international consensus meetings were held to finalize the COS. RESULTS: Based on the systematic review, 13 separate outcomes were included in the Delphi process. This was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to categorize importance scores obtained during Round 2 of the Delphi survey. These informed discussions at the consensus meetings which were attended by 56 participants from 28 countries. The final COS includes six outcomes: 1) frequency of VMS, 2) severity of VMS, 3) distress, bother or interference caused by VMS, 4) impact on sleep, 5) satisfaction with treatment, and 6) side-effects of treatment. CONCLUSION: Implementation of this COS will: better enable research studies to accurately reflect the joint priorities of postmenopausal women, clinicians and researchers, standardize outcome reporting, and facilitate combining and comparing results from different studies, and ultimately improve outcomes for women with bothersome VMS.

Video Summary:http://links.lww.com/MENO/A763 .

A core outcome set for genitourinary symptoms associated with menopause: the COMMA (Core Outcomes in Menopause) global initiative.

OBJECTIVE: Genitourinary symptoms, such as vaginal dryness and pain with sex, are commonly experienced by postmenopausal women. Comparing treatments for these genitourinary symptoms are restricted by the use of different outcome measures in clinical trials and the omission of outcomes, which may be relevant to women. The aim of this project was to develop a Core Outcome Set (COS) to be reported in clinical trials of treatments for genitourinary symptoms associated with menopause. METHODS: We performed a systematic review of randomized controlled trials of treatments for genitourinary symptoms associated with menopause and extracted their outcomes. This list was refined and entered into a two-round modified Delphi survey, which was open to clinicians, researchers, and postmenopausal women from November 2019 to March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." The final COS was determined following two international consensus meetings. RESULTS: A total of 26 unique outcomes were included in the Delphi process, which was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to the Delphi scores to categorize outcomes by importance, which informed the e consensus meetings, attended by 43 participants from 21 countries. The final COS includes eight outcomes: (1) pain with sex, (2) vulvovaginal dryness, (3) vulvovaginal discomfort or irritation, (4) discomfort or pain when urinating, (5) change in most bothersome symptom, (6) distress, bother or interference of genitourinary symptoms, (7) satisfaction with treatment, (8) side effects of treatment. CONCLUSION: These eight core outcomes reflect the joint priorities of postmenopausal women, clinicians, and researchers internationally. Standardized collection and reporting of these outcomes in clinical trials will facilitate the comparison of different treatments for genitourinary symptoms, advance clinical practice, and ultimately improve outcomes for symptomatic women.

Video Summary:http://links.lww.com/MENO/A765 .