Recommended measurement instruments for genitourinary symptoms associated with menopause: the COMMA (Core outcomes in menopause) consortium.

OBJECTIVE: The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects. METHODS: We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome. RESULTS: A total of 87 publications reporting on 34 PROMs were identified from 21,207 publications screened. Of these 34 PROMs, 29 were not considered to sufficiently map onto the core outcomes, and 26 of these also had insufficient measurement properties. Therefore, only five PROMs corresponding to two core outcomes were considered for recommendation. We recommend the PROMIS Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity to measure the outcome of "pain with sexual activity" and the Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire to measure "distress, bother or interference" from genitourinary symptoms. Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events in study participants, which is a requirement of Good Clinical Practice. CONCLUSIONS: Suitable PROMs and definitions were identified to measure three of eight core outcomes. Because of the lack of existing measures, which align with the core outcomes and have evidence of high-quality measurement properties, future work will focus on developing or validating PROMs for the remaining five core outcomes.

Recommended measurement instruments for menopausal vasomotor symptoms: the COMMA (Core Outcomes in Menopause) consortium.

OBJECTIVE: The aim of the study is to identify suitable definitions and patient-reported outcome measures (PROMs) to assess each of the six core outcomes previously identified through the COMMA (Core Outcomes in Menopause) global consensus process relating to vasomotor symptoms: frequency, severity, distress/bother/interference, impact on sleep, satisfaction with treatment, and side effects. METHODS: A systematic review was conducted to identify relevant definitions for the outcome of side-effects and PROMs with acceptable measurement properties for the remaining five core outcomes. The consensus process, involving 36 participants from 16 countries, was conducted to review definitions and PROMs and make final recommendations for the measurement of each core outcome. RESULTS: A total of 21,207 publications were screened from which 119 reporting on 40 PROMs were identified. Of these 40 PROMs, 36 either did not adequately map onto the core outcomes or lacked sufficient measurement properties. Therefore, only four PROMs corresponding to two of the six core outcomes were considered for recommendation. We recommend the Hot Flash Related Daily Interference Scale to measure the domain of distress, bother, or interference of vasomotor symptoms and to capture impact on sleep (one item in the Hot Flash Related Daily Interference Scale captures interference with sleep). Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events, which is a requirement of Good Clinical Practice. CONCLUSIONS: We identified suitable definitions and PROMs for only three of the six core outcomes. No suitable PROMs were found for the remaining three outcomes (frequency and severity of vasomotor symptoms and satisfaction with treatment). Future studies should develop and validate PROMs for these outcomes.

Genome-wide association study identifies genetic regulation of oestrone concentrations and association with endometrial cancer risk in postmenopausal women.

BACKGROUND: Oestrone, predominantly made in fat, is the main circulating oestrogen and important for target tissue oestradiol production in women after menopause. The present study was undertaken to determine the genetic regulation of blood oestrone, measured with precision, in postmenopausal women and to explore associations between the identified genetic loci and endometrial cancer in a large, independent cohort. METHODS: A genome-wide association study (GWAS) was undertaken in women aged at least 70 years to identify genetic associations with blood oestrone concentrations measured by liquid chromatography and tandem mass spectrometry. The GWAS included participants from the Sex Hormones in Older Women (SHOW) study, a sub-study of the longitudinal ASPREE (ASPirin in Reducing Events in the Elderly) randomised trial. Of the 6358 women providing a biobank sample at enrolment, 4951 unrelated women of European ancestry, not taking sex hormones, anti-oestrogens, anti-androgens or systemic glucocorticoids were included in the GWAS. Single nucleotide polymorphisms (SNPs) from loci identified below the genome-wide significance threshold were then tested in an independent cohort (the UK Biobank) for association with endometrial cancer risk, using logistic regression and adjusting for age, body mass index (BMI) and the top 10 genetic principal components. FINDINGS: The median age of the 4951 women included in the GWAS was 75.9 years (range 70-94.8 years). The GWAS identified four independent SNPs associated with oestrone concentrations (p < 5 × 10-8). Among them, the effect (minor) alleles rs34670419-T, rs2846729-T and rs2414098-T were associated with lower oestrone concentrations. Carrying these effect alleles was associated with lower oestrone concentrations in a dose-dependent manner. The effect allele rs56400819-A was associated with higher oestrone concentrations. When applied to UK Biobank, carrier status for rs2414098-T associated with the CYP19A1 gene which encodes the aromatase enzyme required for oestrogen synthesis was significantly associated with lower endometrial cancer risk (adjusted odd ratio [aOR] 0.87 [95% CI 0.82-0.93]; p = 6.69 × 10-5 for women across all ages and aOR 0.89 [95% CI 0.83-0.96]; p = 0.003 for postmenopausal women). None of the models that included age, body mass index (BMI), the top 10 genetic principal components, parity and diabetes mellitus explained more than 7.6% of the variation in risk. INTERPRETATION: We have shown genetic regulation of oestrone concentrations in postmenopausal women, and that SNPs associated with oestrone were also associated with endometrial cancer risk, independent of BMI, parity and diabetes mellitus. Although the apparent contribution was modest, the biological influence of oestrone concentrations may be greater through conversion to oestradiol in endometrial tissue. FUNDING: The ASPREE trial was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (Grant U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (Grant 34047, 1127060); Monash University (Australia); and the Victorian Cancer Agency (Australia). The ASPREE Healthy Ageing Biobank was funded by the CSIRO (Flagship Grant), the National Cancer Institute (Grant U01 AG029824) and Monash University. This analysis of sex hormones was funded by an NHMRC of Australia Project Grant (No. 1105305). SRD holds an NHMRC Investigator Grant (2016627). PL is supported by a National Heart Foundation Future Leader Fellowship (102604).

Performance of artificial intelligence in 7533 consecutive prevalent screening mammograms from the BreastScreen Australia program.

OBJECTIVES: To assess the performance of an artificial intelligence (AI) algorithm in the Australian mammography screening program which routinely uses two independent readers with arbitration of discordant results. METHODS: A total of 7533 prevalent round mammograms from 2017 were available for analysis. The AI program classified mammograms into deciles on the basis of breast cancer (BC) risk. BC diagnoses, including invasive BC (IBC) and ductal carcinoma in situ (DCIS), included those from the prevalent round, interval cancers, and cancers identified in the subsequent screening round two years later. Performance was assessed by sensitivity, specificity, positive and negative predictive values, and the proportion of women recalled by the radiologists and identified as higher risk by AI. RESULTS: Radiologists identified 54 women with IBC and 13 with DCIS with a recall rate of 9.7%. In contrast, 51 of 54 of the IBCs and 12/13 cases of DCIS were within the higher AI score group (score 10), a recall equivalent of 10.6% (a difference of 0.9% (CI -0.03 to 1.89%, p = 0.06). When IBCs were identified in the 2017 round, interval cancers classified as false negatives or with minimal signs in 2017, and cancers from the 2019 round were combined, the radiologists identified 54/67 and 59/67 were in the highest risk AI category (sensitivity 80.6% and 88.06 % respectively, a difference that was not different statistically). CONCLUSIONS: As the performance of AI was comparable to that of expert radiologists, future AI roles in screening could include replacing one reader and supporting arbitration, reducing workload and false positive results. CLINICAL RELEVANCE STATEMENT: AI analysis of consecutive prevalent screening mammograms from the Australian BreastScreen program demonstrated the algorithm's ability to match the cancer detection of experienced radiologists, additionally identifying five interval cancers (false negatives), and the majority of the false positive recalls. KEY POINTS: • The AI program was almost as sensitive as the radiologists in terms of identifying prevalent lesions (51/54 for invasive breast cancer, 63/67 when including ductal carcinoma in situ). • If selected interval cancers and cancers identified in the subsequent screening round were included, the AI program identified more cancers than the radiologists (59/67 compared with 54/67, sensitivity 88.06 % and 80.6% respectively p = 0.24). • The high negative predictive value of a score of 1-9 would indicate a role for AI as a triage tool to reduce the recall rate (specifically false positives).

Dysmenorrhea, Workability, and Absenteeism in Australian Women.

Background: This study determined the prevalence of bothersome menstrual symptoms and their association with workability in naturally menstruating women not using hormonal contraception. Materials and Methods: A representative sample of community-dwelling Australian women aged 18-39 years selected from two large national electronic databases responded to a survey on general health. This study focuses on self-reported dysmenorrhea and menstrual bleeding and their association with workability and absenteeism in working women, assessed by the Workability Index. Results: Of 3,555 women, 1,573 (44.2% [95% CI: 42.6%-45.9%]) reported moderate to severe dysmenorrhea and 774 (21.8% [95% CI: 20.4%-23.2%]) reported heavy to very heavy bleeding. Women with dysmenorrhea were 50% more likely to report poorer work performance and twice as likely to report more days of sick leave in the past year (absenteeism) than other women. Conclusions: Despite the availability of safe and effective management options, Australian working women aged 18-39 years continue to experience bothersome dysmenorrhea and menstrual bleeding. Dysmenorrhea is associated with increased absenteeism and poorer workability. Therefore, awareness needs to be raised among women and health care providers of ways to manage dysmenorrhea and heavy bleeding and the unmet need for intervention in the community, respectively.

Associations between low sex hormone concentrations and depression in older women: An observational study.

OBJECTIVE: We investigated whether low sex hormone concentrations are associated with depression in older women. STUDY DESIGN: This was a cross-sectional study of Australian women, aged at least 70 years, not taking medications modulating sex hormone levels. Associations between hormones, measured by liquid chromatography-tandem mass spectrometry, and depression were examined by logistic regression adjusted for potential confounders. MAIN OUTCOME MEASURES: The primary outcome was a Center for Epidemiologic Studies Depression score >10, designated as 'depression', with an expanded definition that included anti-depressant use as a secondary outcome. RESULTS: For the 5535 participants in the analysis, median age 74.0 years (interquartile range 71.7-77.7), depression prevalence was 5.8 % (95 % CI 5.2-6.4 %). In the adjusted models, a statistically significantly greater likelihood of depression was seen for women with testosterone and oestrone blood concentrations in quartile 1 compared with quartiles 2-4 (odds ratio 1.33, 95 % CI 1.04 to 1.70, p = 0.022; and 1.37, 95 % CI 1.06 to 1.78, p = 0.017, respectively). For the expanded definition, the odds ratios for the lowest testosterone and oestrone quartile compared with other quartiles were 1.47 (95 % CI 1.24 to 1.75, p < 0.001) and 1.31 (95 % CI 1.09 to 1.58, p < 0.001), respectively. A significant association for low DHEA was seen only for the expanded definition of depression (1.36, 95 % CI 1.13 to 1.64, p = 0.001). Receiver operating characteristic curves showed that the contribution of each sex hormone to the likelihood of depression was small. CONCLUSIONS: Amongst older women not taking medications that influence sex hormone concentrations, low testosterone and oestrone levels are associated with a greater likelihood of depression, but the effects are small. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and clinicaltrials.gov (NCT01038583).

A brief intervention for improving alcohol literacy and reducing harmful alcohol use by women attending a breast screening service: a randomised controlled trial.

OBJECTIVES: To assess the effectiveness of a brief alcohol intervention for improving awareness of alcohol as a breast cancer risk factor, improving alcohol literacy, and reducing alcohol consumption by women attending routine breast screening. DESIGN: Single-site, double-blinded randomised controlled trial. SETTING: Maroondah BreastScreen (Eastern Health, Melbourne), part of the national breast cancer screening program. PARTICIPANTS: Women aged 40 years or more, with or without a history of breast cancer and reporting any alcohol consumption, who attended the clinic for routine mammography during 5 February - 27 August 2021. INTERVENTION: Active arm: animation including brief alcohol intervention (four minutes) and lifestyle health promotion (three minutes). CONTROL ARM: lifestyle health promotion only. MAJOR OUTCOME MEASURE: Change in proportion of women who identified alcohol use as a clear risk factor for breast cancer (scaled response measure). RESULTS: The mean age of the 557 participants was 60.3 years (standard deviation, 7.7 years; range, 40-87 years); 455 had recently consumed alcohol (82%). The proportions of participants aware that alcohol use increased the risk of breast cancer were larger at four weeks than at baseline for both the active intervention (65% v 20%; odds ratio [OR], 41; 95% confidence interval [CI], 18-97) and control arms of the study (38% v 20%; OR, 4.9; 95% CI, 2.8-8.8), but the change over time was greater for the active intervention arm (arm × time: P < 0.001). Alcohol literacy also increased to a greater extent in the active than the control arm, but alcohol consumption did not significantly change in either arm. CONCLUSION: A tailored brief alcohol intervention for women attending breast screening was effective for improving awareness of the increased breast cancer risk associated with alcohol use and alcohol literacy more broadly. Such interventions are particularly important given the rising prevalence of risky drinking among middle-aged and older women and evidence that even very light alcohol consumption increases breast cancer risk. REGISTRATION: ClinicalTrials.gov, NCT04715516 (prospective; 20 January 2021).

Risky alcohol consumption among women in Australia attending breast screening services: an exploratory cross-sectional study.

BACKGROUND AND AIMS: Alcohol is a major modifiable risk factor for female breast cancer, with breast cancer risk now associated with substantially lower consumption levels than those previously deemed safe. This study sought to measure risky drinking among women attending breast screening services in Australia according to new national alcohol guidelines and to compare daily, weekly and recent (past 12 months) consumption to Australian gender and age population norms. DESIGN, SETTING AND PARTICIPANTS: This study was a retrospective analysis of cross-sectional data from the Lifepool Project (collected October 2011-January 2016) in Victoria, Australia, comprising a convenience sample of women attending breast screening services aged 40+ years. MEASUREMENTS: Typical and heavy alcohol consumption patterns over the previous 12 months (frequency, quantity), socio-demographic (e.g. age, education) and health-related (e.g. menopause status, breast cancer history) characteristics. Primary outcomes were the proportion of women drinking at a level exceeding new guidelines for weekly and daily alcohol consumption. FINDINGS: Of 49 240 women, mean age was 59.94 years (standard deviation = 7.14, range = 40-94 years). Most women had consumed alcohol during the past 12 months [41 628, 85.48%, 95% confidence interval (CI) = 85.16, 85.79]. One in five women (8464, 18.34%, 95% CI = 17.99, 18.69) were drinking at a level exceeding new national guidelines for weekly consumption (i.e. greater than 10 standard drinks per week), and one in six (7446, 15.60%, 95% CI = 15.28, 15.93) were exceeding new guidelines for consumption on a single day (i.e. greater than four standard drinks on any 1 day, more than once per month). The proportion of women in this sample drinking daily (4.21-11.19%), weekly (34.73-50.71%) and in the past 12 months (74.96-90.81%) was significantly greater among nearly all age groups (by decade), compared with Australian gender and age norms [drinking daily (3.4-9.1%), weekly (27.1-37.6%) and in the past 12 months (64.4-81.9%)]. CONCLUSIONS: There appears to be a high prevalence of risky alcohol consumption among a large convenience sample of breast screening service clients in Australia using new national alcohol guidelines introduced in December 2020.

The impact of endometriosis on work ability in young Australian women.

BACKGROUND: Whereas symptomatic endometriosis may affect work performance, the impact of endometriosis in the general community is not known. AIMS: The associations between endometriosis and each of sick leave and work ability, were investigated in a large sample of non-healthcare seeking women. MATERIALS AND METHODS: This community-based, cross-sectional study recruited 6986 women, aged 18-39 years, from three eastern states of Australia between 11 November 2016 and 21 July 2017. Women were identified as having endometriosis if they had undergone a pelvic ultrasound and reported a diagnosis of endometriosis. Working women completed the Work Ability Index. RESULTS: Participants were predominantly of European ancestry (73.1%) and 46.8% were overweight or had obesity. The prevalence of endometriosis was 5.4% (95%CI 4.9-6.0%) with the highest prevalence of 7.7% (95%CI 6.5 to 9.1%) for women aged 35-39 years. Among the 4618 working women, those with endometriosis had significantly more sick days from work (33.6% reported ≥10 days vs 13.5%, overall χ2 P < 0.001). Endometriosis was associated with a greater likelihood of poor to moderate work ability, after adjusting for age, body mass index, ethnicity, relationship status, student status, insecure housing, being a carer for another person, parity, ever use of assisted reproductive technologies, and depressed mood (odds ratio 1.90, 95%CI 1.40-2.58, P < 0.001). CONCLUSIONS: This study provides new evidence that the negative impact of endometriosis on work attendance and work ability is not limited to women with prevalent symptoms and severe disease, but appears to encompass women across a broader spectrum of this condition in the community.

A Brief Intervention for Improving Alcohol Literacy and Addressing Harmful Alcohol Use Among Women Attending an Australian Breast Screening Service (Health4her): Protocol for a Hybrid Effectiveness-Implementation Trial.

BACKGROUND: Alcohol consumption is a major modifiable risk factor for female breast cancer, even in small amounts. However, awareness of this risk remains low. National breast screening programs are uniquely positioned to provide timely and targeted health information and behavior change strategies to improve alcohol literacy and reduce consumption. A breast screening service is a novel health care setting for brief alcohol intervention, with the potential for extensive reach. OBJECTIVE: This study aimed to conduct a formative evaluation with breast screening service consumers to understand the need for, and acceptability of, brief alcohol intervention in the breast screening setting and collaboratively design a brief alcohol intervention (Health4Her); to test the effectiveness of Health4Her in improving knowledge of alcohol as a breast cancer risk factor (primary outcome), improving alcohol literacy, and reducing consumption among women attending a breast screening service; and to examine the implementation strategy through process evaluation. METHODS: This was a hybrid type II effectiveness-implementation trial comprising a randomized controlled trial (RCT) alongside a mixed methods program evaluation guided by applicable elements of the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework and Consolidated Framework for Implementation Research. Formative evaluation comprised a retrospective analysis of alcohol consumption data (n=49,240), a web-based survey (n=391), and focus groups and interviews (n=31) with breast screening service consumers. Women attending routine mammography, drinking at any level, were recruited to the single-site, double-blind RCT (n=558), and completed a baseline assessment before randomization (1:1) to receive Health4Her (alcohol brief intervention + lifestyle information) or control (lifestyle information) via animation on an iPad. Follow-up assessments were performed 4 and 12 weeks after randomization. The process evaluation included evaluation of trial administrative data, participant quantitative (n=497) and qualitative feedback (n=30), and site staff qualitative feedback (n=11). RESULTS: This research was funded in March and May 2019. Data collection for the formative evaluation and trial recruitment occurred between January and April 2020 and February and August 2021, respectively, with finalization of follow-up data collection in December 2021. Quantitative process evaluation data were collected during trial implementation, and collection of participant and staff feedback was finalized in December 2021. Results of the retrospective analysis of alcohol consumption data from breast screening service consumers is anticipated to be published in March 2023 and the results of the RCT to be published in March 2023. CONCLUSIONS: This study is anticipated to generate new substantial knowledge on the alcohol consumption and literacy needs of women attending breast screening and the extent to which these can be addressed using a novel, tailored brief alcohol intervention. The study design permits the evaluation of the effectiveness and implementation of Health4Her to predict and facilitate uptake in breast screening services. TRIAL REGISTRATION: ClinicalTrials.gov NCT04715516; https://clinicaltrials.gov/ct2/show/NCT04715516. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/44867.

The association between sex hormones and the change in brain-predicted age difference in older women.

OBJECTIVE: The role of circulating sex hormones on structural brain ageing is yet to be established. This study explored whether concentrations of circulating sex hormones in older women are associated with the baseline and longitudinal changes in structural brain ageing, defined by the brain-predicted age difference (brain-PAD). DESIGN: Prospective cohort study using data from NEURO and Sex Hormones in Older Women; substudies of the ASPirin in Reducing Events in the Elderly clinical trial. PATIENTS: Community-dwelling older women (aged 70+ years). MEASUREMENTS: Oestrone, testosterone, dehydroepiandrosterone (DHEA), and sex-hormone binding globulin (SHBG) were quantified from plasma samples collected at baseline. T1-weighted magnetic resonance imaging was performed at baseline, 1 and 3 years. Brain age was derived from whole brain volume using a validated algorithm. RESULTS: The sample comprised of 207 women not taking medications known to influence sex hormone concentrations. A statistically higher baseline brain-PAD (older brain age relative to chronological age) was seen for women in the highest DHEA tertile compared with the lowest in the unadjusted analysis (p = .04). This was not significant when adjusted for chronological age, and potential confounding health and behavioural factors. Oestrone, testosterone and SHBG were not associated with brain-PAD cross-sectionally, nor were any of the examined sex hormones or SHBG associated with brain-PAD longitudinally. CONCLUSION: No strong evidence of an association between circulating sex hormones and brain-PAD. Given there is prior evidence to suggests sex hormones may be important for brain ageing, further studies of circulating sex hormones and brain health in postmenopausal women are warranted.

Endogenous dehydroepiandrosterone and depression in postmenopausal women: a systematic review of observational studies.

IMPORTANCE: The associations between endogenous dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), and depression in older women are uncertain. However, DHEA supplements are widely available over the counter in some countries, and some people may be taking DHEA with the hope of positive mood effects. OBJECTIVE: This systematic review aimed to investigate the association between endogenous DHEA/DHEAS blood concentrations and depression/depressive symptoms in community-dwelling postmenopausal women.Evidence Review: Searches were conducted in Ovid MEDLINE, EMBASE, PsycINFO, and Web of Science databases for observational studies with at least 100 community-dwelling participants until March 9, 2022. The bibliographies of retrieved articles were manually searched. The studies published in English and meeting the inclusion criteria were included in the review. The risk of bias was assessed with the modified Hoy tool for cross-sectional designs and the Joanna Briggs Institute modified critical appraisal checklist for cohort studies. FINDINGS: Of the 30 articles retrieved for full-text review, 14 met the criteria for inclusion. Seven studies were cross-sectional, six were longitudinal, and one had both cross-sectional and longitudinal data. Five of eight cross-sectional studies found no association between DHEAS and depression, whereas three studies reported an inverse association. Similarly, most of the studies (n = 4) with longitudinal data reported no association, whereas two studies reported either an inverse association or mixed results for DHEAS and depression severity. No association between DHEA and depression was found irrespective of the study design. Heterogeneity of design was a barrier to meta-analysis and between study comparison. The majority of studies were limited by high risk of bias in at least one assessed domain. CONCLUSION AND RELEVANCE: This systematic review does not support an association between endogenous DHEA/DHEAS and depression in postmenopausal women.

The association between testosterone and depression in postmenopausal women: A systematic review of observational studies.

OBJECTIVE: The contribution of testosterone to depression in older women is uncertain. This review was conducted to investigate the association between endogenous testosterone blood concentrations and depression in postmenopausal women. METHODS: We searched Ovid MEDLINE, EMBASE, PsycINFO, and Web of Science databases for observational studies with at least 100 community-dwelling participants. The results were categorised by study design, and the reporting of total, bioavailable and free testosterone findings is narrative. RESULTS: The search strategy retrieved 28 articles for full-text review, of which eight met the criteria for inclusion; these described 6 cross-sectional and 2 longitudinal studies. Testosterone was measured by immunoassay in all of the included studies. No association was seen between total testosterone or free testosterone and depression in either the cross-sectional or the longitudinal studies. A significant association between bioavailable testosterone and incident depressive symptoms was limited to women at least 21 years postmenopause in one study. Most of the cross-sectional studies were not representative of national populations and lacked random selection. CONCLUSIONS: This systematic review does not support an association between testosterone and depression in postmenopausal women. However, as the included studies had substantial methodological limitations, studies of community-based samples, employing validated instruments for depression and precise measurement of blood testosterone, are needed to address this knowledge gap.

Endogenous testosterone concentrations and muscle mass, strength and performance in women, a systematic review of observational studies.

OBJECTIVE: To explore the associations between endogenous testosterone blood concentrations and muscle mass, strength and performance in community dwelling women. DESIGN, PATIENTS AND MEASUREMENTS: Online databases, including Ovid MEDLINE, EMBASE and Web of Science, were searched for observational studies, with at least 100 female participants, reporting associations between endogenous testosterone blood concentrations and muscle mass, strength and performance. The findings were synthesized in a narrative review. Heterogeneity in study design and analysis precluded a meta-analysis. RESULTS: Of the 36 articles retrieved for full-text review, 10 met the inclusion criteria. Eight studies were cross-sectional, 1 longitudinal and 1 provided both cross-sectional and longitudinal data. Testosterone was measured by liquid chromatography-tandem mass spectrometry in two studies and by immunoassay in 8. An association between total testosterone and muscle mass, strength or performance in women was not found. The studies of calculated free or bioavailable testosterone and lean muscle mass reported a positive association, but no association was reported for muscle strength or performance. Each included study was limited by a high risk of bias in at least one assessed domain. CONCLUSIONS: This review does not support an association between testosterone and muscle mass, strength or performance in women. This, together with the reported associations between free or bioavailable testosterone and muscle mass should be interpreted cautiously due to the predominant use of immunoassay and the inaccuracy of calculated variables. Additionally, biological significance of nonprotein bound testosterone has not been established. Further studies examining the relationship between precisely measured testosterone and muscle mass and function in women are required.

Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.

BACKGROUND: Blood testosterone concentrations in women decline during the reproductive years and reach a nadir in the seventh decade, after which concentrations increase and are restored to those of reproductive-aged women early in the eighth decade. We aimed to establish the association between the concentration of testosterone in the blood and risk of major adverse cardiovascular events (MACE) and all-cause mortality in healthy older women. METHODS: SHOW was a prospective cohort substudy of the longitudinal randomised ASPREE trial. Eligible participants were women aged at least 70 years from Australia with unimpaired cognition, no previous MACE, and a life expectancy of at least 5 years. Participants who were receiving hormonal or steroid therapy were ineligible for inclusion. We measured serum concentrations of sex steroids with liquid chromatography-tandem mass spectrometry and of SHBG with immunoassay. We compared lower concentrations of sex hormones with higher concentrations using four quartiles. Primary endpoints were risk of MACE and all-cause mortality, the associations of which with sex steroid concentrations were assessed using Cox proportional hazards regression that included age, body-mass index, smoking status, alcohol consumption, diabetes, hypertension, dyslipidaemia, impaired renal function, and treatment allocation in the ASPREE trial (aspirin vs placebo). ASPREE is registered with ClinicalTrials.gov, NCT01038583. FINDINGS: Of the 9180 women recruited to the ASPREE trial between March 10, 2010, and Dec 31 2014, 6358 participants provided sufficient biobank samples at baseline and 5535 were included in the final analysis. Median age at entry was 74·0 years (IQR 71·7-77·7). During a median 4·4 years of follow-up (24 553 person-years), 144 (2·6%) women had a first MACE (incidence 5·9 per 1000 person-years). During a median 4·6 years of follow-up (3·8-5·6), 200 women died (7·9 per 1000 person-years). In the fully adjusted models, higher concentrations of testosterone were associated with a lower incidence of MACE (quartile 4 vs quartile 1: hazard ratio 0·57 [95% CI 0·36-0·91]; p=0·02), as were higher concentrations of DHEA (quartile 4 vs quartile 1: 0·61 [0·38-0·97]; p=0·04). For oestrone, a lower risk of MACE was seen for concentrations in quartile 2 only, compared with quartile 1 (0·55 [0·33-0·92]; p=0·02). In fully adjusted models, no association was seen between SHBG and MACE, or between any hormone or SHBG and all-cause mortality. INTERPRETATION: Blood concentrations of testosterone and DHEA above the lowest quartile in older women were associated with a reduced risk of a first-ever MACE. Given that the physiological effects of DHEA are mediated through its steroid metabolites, if the current findings were to be replicated, trials investigating testosterone therapy for the primary prevention of ischaemic cardiovascular disease events in older women would be warranted. FUNDING: The National Health and Medical Research Council of Australia, US National Institute on Aging, the Victorian Cancer Agency, the Commonwealth Scientific and Industrial Research Organisation, and Monash University.

Development of Ice-Shelf Estuaries Promotes Fractures and Calving.

As the global climate warms, increased surface meltwater production on ice shelves may trigger ice-shelf collapse and enhance global sea-level rise. The formation of surface rivers could help prevent ice-shelf collapse if they can efficiently evacuate meltwater. Here, we present observations of the evolution of a surface river into an ice-shelf estuary atop the Petermann Ice Shelf in northwest Greenland, and identify a second estuary at the nearby Ryder Ice Shelf. This surface hydrology process can foster fracturing and enhance calving. At the Petermann estuary, sea ice was observed converging at the river mouth upstream, indicating a flow reversal. Seawater persists in the estuary, after the surrounding icescape is frozen. Along the base of Petermann estuary, linear fractures were initiated at the calving front and propagated upstream along the channel. Similar fractures along estuary channels shaped past large rectilinear calving events at the Petermann and Ryder Ice Shelves. Increased surface melting in a warming world will enhance fluvial incision, promoting estuary development, longitudinal fracturing orthogonal to ice-shelf fronts, and increase rectilinear calving. Estuaries could develop in Antarctica within the next half-century, resulting in increased calving and accelerating both ice loss and global sea-level rise.