IMS Menopause Live

9 November 2020

Use of hormone replacement therapy (HRT) and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases [1]. A Critique.

Prepared by Nick Panay & Susan Davis on behalf of the International Menopause Society

Summary

Design and Methods
 
This paper describes two nested case-control studies using data from the two largest UK primary care databases. QResearch and Clinical Practice Research Datalink (CPRD) GOLD, utilising linked data from Hospital Episode Statistics (HES), Office for National Statistics (ONS) mortality data and cancer registry data (QResearch only). From the QResearch database, all cases of incident breast cancer were identified using general practice, hospital admission, mortality, and cancer registry records. From CPRD, when linked general practice, hospital admission (up to 31 December 2017), and mortality data records (up to 13 February 2018) were used to identify cases, and, when not linked, general practice records only. HRT prescription information was extracted for all estrogens, progestogens, and tibolone from practice records.
 
Results
 
59 999 and 38 612 (98 611) cases of breast cancer were identified in QResearch and CPRD, respectively, matched by age to 457 498 female controls. Compared with never use, long term use of systemic HRT (>/= 5 years) was found to be associated with an increased risk of breast cancer. The adjusted OR was 1.15 (95% CI 1.09 to 1.21) in women using estrogen and 1.79 (1.73 to 1.85) for combined estrogen and progestogen therapy. In those using combined estrogen and progestogen therapy, the increased risk was highest for norethisterone (1.88; 1.79 to 1.99) and lowest for dydrogesterone (1.24; 1.03 to 1.48). Past long term estrogen therapy and past short term combined therapy were not associated with an increased risk as opposed to past long term combined MHT usage, which remained slightly increased (1.16; 1.11 to 1.21). In terms of absolute numbers, this equated to 3-8 extra cases per 10 000 women-years with estrogen-only and 9-36 extra cases per 10 000 women-years in estrogen and progestogen users, depending on the age group. No increase in risk was associated with vaginal estrogen preparations.

19 October 2020

Summary

Sriprasert et al. have reported the findings of an unplanned post hoc analysis of serum estradiol levels in 275 women who were randomized to oral micronized estradiol 1mg/day, with/without vaginal micronized progesterone, in the ELITE trial [1]. Although the initial treatment was with 1mg estradiol/day, dose reduction was permitted. Hence some women switched to either 0.5mg/0.25mg micronized estradiol daily during the study. The findings suggest that women with a higher BMI or women who consumed more than 2 standard alcoholic drinks/day had higher serum estradiol concentrations, whereas smoking was associated with lower serum estradiol. Although the authors point out that expert societies recommend against titrating estrogen therapy against serum estradiol concentrations, they also comment that serum estradiol is associated with treatment effects [1]. Hence, the authors recommend that these lifestyle variables need to be taken into account by clinicians when prescribing the dose of menopausal estrogen therapy.

25 May 2020

Summary 

This publication from the WHI project was based on data from the observational study cohort and the control arm of the hormone therapy clinical trial [1]. The primary analysis included participants who completed baseline physical examination, demographic, medical history, and self-reported dietary questionnaires, out of which a calculation of the daily magnesium intake was made. The primary outcome was incident hospitalization for heart failure (HF), which was ascertained yearly by medical record abstraction of all self-report hospitalizations. The cohort consisted of 97725 postmenopausal women 50-79 years old, of whom 2153 HF cases were observed over a median follow-up of 8.1 years. The median dietary magnesium intake across quartiles were 149 mg/day for women in the lowest quartile (Q4), 363 mg/day for the highest quartile (Q1) of intake. The non-adjusted Hazard Ratio (HR) of incident hospitalized HF for Q4 was 1.20 (1.06–1.36), compared to the value for Q1, which served as the reference. The corresponding adjusted HR was 1.32 (1.02–1.71). While many parameters and variables were considered and analyzed, the final conclusion was simple “low magnesium intake in a multiracial cohort of postmenopausal women was associated with a higher risk of incident HF, especially HF with reduced ejection fraction”.

11 May 2020

Summary

Burkard and colleagues investigate the influence of onset of menopause and of HRT use on the incidence of hand osteoarthritis (hOA), one of the most common forms of arthritis[1]. This is an epidemiological study in primary care electronic healthcare records from the well-established UK Clinical Practice Research Datalink (CPRD). All women turning 45 were identified and followed for up to 20 years, searching for codes and dates for hOA, menopause and any HRT use. The authors used careful design: 4 controls for every case, adjusting statistically for confounding factors, and also stratifying the results based on timing of current or past HRT use, including the effects of HRT cessation. Key findings were that menopause was a risk for hOA (OR 1.42, CI 1.29-1.57) and the highest proportion of cases of hOA were in the year after menopause, with incidence dropping with increasing time. 55% of cases developed their hOA within four years after menopause. Current users of HRT who started their HRT within 3 months of menopause were relatively protected from incident hOA compared with HRT never users (OR 0.72; CI 0.55-0.96). Cessation of HRT tended to increase incident hOA for the first 18 months; however an overall association of HRT with hOA in women became non-significant if being post-menopausal was considered (OR 0.98, 0.85-1.14).

27 April, 2020

Summary

Using data from women who were 45 – 50 years old in 1996 followed through the Australian Longitudinal Study of Women’s Health (ALSWH) [1]. Xu et al. studied the association between age at natural menopause and the burden of chronic disease assessed by prevalence in 2010 and incidence from 2010 through 2016 [2]. Participants provided data at 3-year intervals in the ALSWH. After exclusions for missing eligibility data, and loss to follow-up prior to 2010, 11258 women were available for the study. Of those, 4196 were excluded for surgical menopause, and 1420 were excluded for missing outcome data, leaving 5107 women for analysis. Age at natural menopause (ANM) was categorized as < or = 40, 41-45, 46-49, 50-51, 52-53 and > or = 54 years. Premature menopause was defined as natural menopause at the age of < or = 40, and the prevalence was 2.3% (N=119). Multi-morbidity was defined as the occurrence of 2 or more of the following chronic conditions: diabetes, hypertension, heart disease, stroke, arthritis, osteoporosis, asthma, chronic obstructive pulmonary disease, depression, anxiety and breast cancer. Using ANM of 50-51 as the reference group, women with premature menopause had a crude Odds Ratio (OR) for the prevalence of multimorbidity of 3.57; 95% CI 1.39 – 9.19 that was reduced to 1.98; 95% CI 1.31 – 2.98, after adjusting for a variety of confounders including parity, education, BMI, physical activity, smoking status and ever use of menopausal hormone therapy (MHT). In the adjusted model, the OR for the incidence of multimorbidity during the 6-year follow-up was 3.03; 95% CI 1.62 – 5.64 in women with premature menopause. Of the 11 conditions, women with premature menopause had significant increased risks for diabetes, stroke, osteoporosis and COPD, but not for hypertension, heart disease, arthritis, asthma, depression, anxiety or breast cancer. The association between ANM and multimorbidity was not linear, and significant findings were limited to the women with ANM < or = 40 compared with women having ANM at 50-51 years.

20 April 2020: 

Summary

Calcium supplement use has been common in North America since calcium balance studies in the 1970s suggested that balance was directly related to the intake of this element [1]. Subsequent more rigorous analyses of balance studies [2] and randomized controlled trials of calcium supplements on bone density [3] and fractures [4,5] have not supported calcium supplement use. Recently, Bailey et al. have used data from an observational study of women entering the menopause and compared fracture rates and changes in bone mineral density (BMD) over a 10-year period between users and non-users of calcium supplements [6]. Supplement use had no impact on fracture incidence (relative risk 1.16, P=0.5) nor on bone loss in those who were perimenopausal at study entry. In women who were premenopausal at study entry, there was no difference in the unadjusted bone loss but, after adjustment, spine BMD loss was 0.36%/year and 0.47%/year in supplement users and non-users, respectively, and hip BMD loss was 0.35%/year and 0.44%/year in the two groups (P≤0.002).

30 March 2020: 

Summary

This randomized double-blind placebo-controlled study by Geiger et al. assessed the effects of transdermal estrogens on sleep independent of its well known beneficial effects on vasomotor symptoms (VMS) and mood improvement. A group of 172 healthy perimenopausal and early postmenopausal women age 45-60 were randomized to 100 micrograms of transdermal estradiol with progesterone 200 mg for 12 days every 3 months for 12 months versus placebo. Standard questionnaires, including the 14 item St. Mary’s Sleep Questionnaire, the 20 item CES-D (the Center for Epidemiologic Studies-Depression Scale), and the Greene Climacteric subScale for VMS were administered at baseline and in the estrogen-only months. After controlling for baseline levels, transdermal estrogen reduced both minutes to fall asleep (-0.12 p=0.02), and number of awakenings (-0.11 p=0.02). Multivariate analyses found that reductions in VMS and mood improvement could not fully explain the improvement in sleep difficulties. The authors concluded that the efficacy of hormone therapy (HT) could not only be explained by improvements in vasomotor or depressive symptoms but through other biological mechanisms [1].

23 March 2020: 

a comment on Climacteric Editor’s Choice 

"Medical and gynecological comorbidities in adult women with Turner syndrome: our multidisciplinary clinic experience" by Farquahar M et al.

Summary

Turner syndrome (TS), associated with complete or partial loss of the second X chromosome, is the most frequent genetic disorder affecting females and occurs in 1/2500 live female births [1]. TS is characterised by short stature and gonadal dysgenesis but affects multiple organ systems [1] and is associated with increased morbidity and mortality [2,3]. Using retrospective chart review, the study by Farquhar and colleagues [4] examined the prevalence of a range of chronic health conditions in a cohort of women with TS aged ≥18 years who attended a Canadian academic hospital multidisciplinary clinic for routine screening [5] at least once between February 2015 and July 2018. Demographic data, karyotype, medical history, and results of screening investigations were collected. Defined comorbidities included hypothyroidism, dysglycemia, decreased bone density, gynaecological/ cardiac and renal abnormalities, hypertension, cerebrovascular event, hearing loss, cancer history, and coeliac disease. The cohort was divided into women < 40 and ≥ 40 years, and statistical analysis of the prevalence of comorbidities was performed for the whole group and subgroups. The cohort comprised 122 women with TS, having a mean age of 37.7 (range 19-68) years (40% aged ≥ 40 years), and having XO as the commonest karyotype (39%). The average age of diagnosis was 11.4±9.1 years, with women aged < 40 years diagnosed at an earlier age and more likely to receive growth hormone. Current hormone therapy was reported by 84.4% of women with the combined oral contraceptive pill (COC) preferred (47.6% overall), although COC use was lower in women ≥ 40 years (27.2%). Overall, co-morbidity prevalence varied from hearing loss (41%), cardiac abnormality (36.1%) gynaecological disorder (35%), low bone density (29.5%), hypothyroidism (~25%), renal abnormalities (18.8%), dysglycemia (16%), hypertension (14%) to coeliac disease (9%). Women aged ≥ 40 years had a greater number of comorbidities compared with women < 40 years (2.9±2.0 versus 1.6±1.5; p=0.004). A significantly higher comorbidity prevalence in the older sub-group was observed for hypothyroidism, dysglycemia, gynaecological conditions, hypertension, and hearing loss.

16 March 2020: 

Summary

Matthews and colleagues performed a longitudinal study in women (n=300) transitioning through menopause [1]. The women were recruited from the Study of Women’s Health Across the Nation (SWAN). Actigraphy, sleep diaries, and self-reported sleep complaints were measured at baseline and on three other occasions over 12 years ( at mean ages, 52, 55, and 64 years). The study aimed at investigating sleep through time in relation to age and other possible factors, such as health problems, anxiety, and depression, stress levels, season of assessment, self-reported race/ethnicity (Black, Chinese, and White), educational attainment, vasomotor symptoms, postmenopausal status, as well as single marital status. The authors verified whether the decline in sleep duration and continuity would remain significant after adjustment for covariates that impacted sleep. They observed that race/ethnicity, menopausal status, vasomotor symptoms, and work status were key factors that covaried with sleep duration, continuity, and timing in midlife women over 12 years of follow-up. The study suggested that midlife women’s actigraphy measures of sleep characteristics may not worsen with age. Indeed, the authors observed that women experienced longer sleep duration and decreased WASO (wake after sleep onset), even though there were no changes in the number of sleep complaints.

27 January, 2020

A comment on Climacteric Editor’s Choice "Sexual quality of life in men and women after cancer" by L. R. Schover

Summary

There is a global agreement about the fact that cancers and cancer therapies have a negative impact on the sexual health of men and women with prevalence rates on average of 50-60%. There is also global agreement that patients are very often left alone with their sexual problems and that there is not adequate care. In this review [1], the physical and psychosocial consequences of cancers and cancer treatment on the sexual life of male and female patients are summarized. The barriers and gaps are described. Lack of information and counseling during oncological care, reluctance of patients to bring up sexual issues in a medical environment, lack of training of oncological professionals, lack of time, lack of education material, non-familiarity with the variety of sexual orientations and preferences, focusing on heterosexual penetrative intercourse, etc.. The review [1] describes the short history of initiatives in the US to respond to these barriers and gaps. The National Comprehensive Cancer Network (NCCN) issued guidelines (2019 (https://www.nccn.org/professionals/physician_gls/default.aspx#supportive)), ASCO also issued a guideline in 2017 (https://www.asco.org/research-guidelines/quality-guidelines/guidelines/patient-and-survivor-care#/28976) with some agreement on the basic requirements. The cancer team should initiate discussion about sexuality and provide follow-up visits with the possibility to refer to multidisciplinary treatment.