Welcome to the June 2020 issue of Climacteric. I hope this issue will provide you with much stimulating reading during this time of shut down and social distancing.
This narrative review aims to synthesize evidence on factors that may influence the severity, occurrence, and incidence of vasomotor symptoms (VMS) that encompass hot flushes and/or night sweats. Findings showed that different factors such as biological, demographic, behavioral, social, and non-traditional were associated with VMS. The most consistent risk factors of VMS were: being in later menopausal stages, smoking, lower socioeconomic status, higher follicle stimulating hormone levels, ethnicity, and higher body mass index. Most studies were either cross-sectional or observational in design, and were conducted in western countries. A more nuanced understanding of the factors contributing to VMS can assist clinicians in screening women for optimal VMS counseling and treatment. This review found that further large-scale studies set in developing countries that examine VMS factors are warranted.
This commentary, part of a series of articles on Research methodology, highlights how important it is to assess research methodology and critically examine each paper you read rather than a brief perusal of an abstract.
A concise and timely assessment of a recent Lancet paper commenting on breast cancer risk. Appropriately placed in this journal after a paper on research methodology.
This study aimed to evaluate the association between the intensity of menopausal symptoms and highly active antiretroviral therapy adherence in middle-aged women with human immunodeficiency virus infection.
This study suggested that lower bone mineral density and increased loss rate of bone mineral density were associated with a higher risk of carotid calcification plaques in Chinese postmenopausal women.
This study aimed to assess the effects of daily use of Cimicifuga racemose on endothelial function through flow-mediated dilation of the brachial artery, when used for 28 days by healthy postmenopausal women.
This study aimed to compare the efficacy and safety of ossein-hydroxyapatite complex versus calcium carbonate for preventing bone loss during perimenopause in current clinical practice.
This study aimed to determine the associations among menopausal status, menopausal symptoms, and depressive symptoms in midlife women in Hunan, China.
T cell-mediated injury plays an important role in the pathogenesis of autoimmune premature ovarian insufficiency (POI). The purpose of this study was to assess the percentage of CD4+CD25+FOXP3+ regulatory T (Treg) cells and the level of forkhead box protein 3 (FOXP3) mRNA expression in POI patients.
Increasing 17β-estradiol (E2) dose and serum E2 levels were associated with changes in coagulation/anti-coagulation measures. The associations were stronger among women ≥ 10 years since menopause when initiating E2. The timing of E2 therapy, E2 dose, and serum E2 levels relative to time since menopause may modify the venous thromboembolism risk.
This study aimed to test the hypothesis that the development of functional luteal phase dominant follicles is associated with increased endometrial growth as women transition to menopause.
A strong, well-established non-linear relationship exists between fragile X mental retardation premutation and menopausal age. The aim of this study is to evaluate whether this relationship continues into the normal CGG repeat range.
A strong, well-established non-linear relationship exists between fragile X mental retardation premutation and menopausal age. The aim of this study is to evaluate whether this relationship continues into the normal CGG repeat range.
July 20th, 2020
Rasa Kazlauskaite et al.  conducted a 17-years prospective, longitudinal study with the participation of 2,149 women traversing menopause, in order to determine the association between metabolic syndrome (MS) exposure and cognitive function evolution. Women from seven US sites were enrolled in the Study of Women’s Health Across the Nation (SWAN), a study of health and aging during the menopausal transition. MS was diagnosed in 635 women (29.5%), the mean age at their cognitive baseline was 50.7±2.9 years, and 51.6% of women had bleeding patterns consistent with early perimenopause or premenopause. The prevalence of MS was lower among women in premenopause and early perimenopause or treated with hormone therapy. Three domains of cognitive function were evaluated: perceptual speed, episodic memory and working memory. The results were adjusted for sociodemographic, lifestyle, sleep, mood, and menopausal stages/hormone therapy factors and potential confounders in the association between MS and cognitive function scores. The authors found an accelerated decline in perceptual speed, but not in episodic or working memory, in women with MS at midlife, compared with those without exposure to MS. Potential limitations of this study are the evaluation of a limited number of cognitive tests and the lack of information about the overall duration of MS exposure and its consequences on other cognitive domains.
MS is a cluster of interrelated conditions, with a high prevalence in the adult population, which increases with age and in the postmenopausal period . The association between MS and diabetes mellitus, insulin resistance, cardiovascular and cerebrovascular diseases is widely recognized .MS has also been associated with cognitive dysfunction. Several etiopathogenic factors have been proposed to explain the cognitive impairment associated with the MS and its disorders: chronic inflammation, neuroinflammation, immune dysregulation, oxidative stress, mitochondrial dysfunction, impaired vascular reactivity, and abnormal brain lipid metabolism [4,5]. Reduced visuospatial ability in women with PCOS compared with control subjects was described and was linked to higher levels of HbA1c, suggesting a role for altered glycemic control in cognitive disturbances. (6) Worse cognitive performance in an attentional interference task, which involves executive functions, was previously demonstrated in subjects with MS during exercise compared to controls . Obesity has been clearly identified as an independent factor for cognitive decline and Alzheimer’s Disease . Gut microbiota, metabolic dysfunction and cognitive function have been correlated factors. An unhealthy diet, a sedentary lifestyle, genetics and environmental mechanisms, among others, impact on gut microbiota composition and microbial-derived compounds. Abnormal microbiota leads to increased intestinal permeability and the passage of bacteria and their products through the gastrointestinal mucosa, promoting chronic inflammation, which underlies obesity, metabolic disorders and cognitive dysfunction . Previous reports have shown longitudinal declines in cognitive performance in midlife women . The present study  confirms, in a large 17-years prospective, longitudinal study, the association of an accelerated decline in perceptual speed with the MS in women during the menopause transition and postmenopause. This evidence constitutes a new incentive for clinicians to adopt preventive and therapeutic strategies during a woman’s life in order to avoid the consequences of metabolic syndrome and its associated comorbidities.The prime emphasis in management of the metabolic syndrome is to control the modifiable risk factors (obesity, physical inactivity, and atherogenic diet) through lifestyle changes. Specific pharmacological interventions are often needed to control hyperglycemia, hypertension and dyslipidemia. New exciting research shows preclinical evidence for the therapeutic efficacy of central cholinergic stimulation in alleviating obesity-associated inflammation, neuroinflammation, and metabolic derangements , intermittent fasting can improve cardiovascular and metabolic risk, through reductions in oxidative damage and inflammation (11). Microbiota modulation may also be a new interesting approach (9).
Sonia Cerdas Pérez
Endocrinologist, Hospital Cima, San José
University of Costa Rica
August 17th, 2020
This paper  is a collaboration between the Early vs Late Interventions Trial (ELITE)  investigators, and the manufacturers of a commercially available, FDA approved, oral estradiol and progesterone combination preparation (Bijuva®; TherapeuticsMD; Boca Raton, FL). In this post-hoc analysis, the investigators reanalyzed coagulation factors assessed in the REPLENISH clinical trial. The REPLENISH trial  was a phase 3, randomized, double-blinded, placebo-controlled, multicenter trial designed to determine the efficacy of four different doses of estradiol with progesterone for reduction of VMS and on endometrial safety (ClinicalTrials.gov as NCT01942668). The REPLENISH study had several characteristics optimal for the investigation reported here. These include:
1) adequate sample size (n=1845),
2) random assignment to one of five estradiol (E2) and progesterone (P4) intervention groups,
3) a range of varying daily E2/P4 doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg),
4) a matching placebo group,
5) adequate duration (as long as 12 months) to investigate coagulation effects (biomarkers not events), and
6) a prospective study design.
Of those enrolled, 1215 women were classified as early menopausal (<6 years since menopause), and 297 were in the late menopausal group (>10 years since menopause) for the purpose of this post-hoc analysis. This “age/time” since menopause classification was comparable to the analysis in ELITE .
As complications of the prothrombotic impact of oral estrogens are the subject of multiple reviews, they will not be recounted here [4, 5]. Suffice it to say, in large, randomized clinical trials, like the Women’s Health Initiative (WHI), thrombotic complications represented the principle source of serious adverse effects . The REPLENISH dataset analyzed here, like the results reported by Curb et al  in WHI, offers insights into potential differences in coagulation effects between oral estradiol and progesterone vs conjugated equine estrogens + medroxyprogesterone acetate [8, 9], and the impact of time since menopause (early: less than 6 years postmenopausal vs late: more than 10 years following the last menstrual period) on thrombosis risk. The authors hypothesize that oral estradiol (E2) has a differential effect on coagulation factors, as a marker of thrombosis risk, according to time since menopause, in other words, a gap or timing hypothesis , but specifically for thrombosis.
In this post-hoc analysis, higher E2 doses and serum E2 concentrations were associated with statistically significant reductions in several coagulation and anti-coagulation measures compared to baseline. These included the prothrombin time, the activated partial thromboplastin time, antithrombin, fibrinogen, protein C, and protein S over the 12-month intervention and follow-up period. The associations of the E2 dose and serum E2 levels with coagulation and anti-coagulation measures were statistically of greater magnitude in late versus early postmenopausal women.
The serum P4 concentration did not have a statistically significant effect on coagulation or anti-coagulation measures and did not confound the association between the E2 dose and serum E2 level with any coagulation or anti-coagulation measures, a finding consistent with previous reports, and unlike contraceptive progestogens including medroxyprogesterone acetate commonly used in menopausal hormone therapy .
Oral hormone therapy has long been assumed to increase pro-coagulation risk whether by increasing procoagulant factors or decreasing anticoagulant factors or some combination of both. By implication, these biochemical changes are assumed to be the underlying cause for the thrombotic and thromboembolic events in those hormone therapy investigations. However, those data have commonly been confounded by combining early and late postmenopausal women, or by including conjugated equine estrogens with its higher thrombotic risk compared with estradiol [8, 9]. If the results presented here by Sriprasert and colleagues can be replicated in healthy early postmenopausal women less than 6 years since their final menses, the benefit/risk ratio of oral estradiol and natural progesterone can be shifted toward benefit. These results also suggest a gap or timing hypothesis for venous thrombotic or thromboembolic risk, as has been the controversial explanation for many of the cardiovascular outcomes in clinical trials over the last 20 years [2, 10].
James A. Simon, MD
Clinical Professor, George Washington University
Medical Director, IntimMedicine Specialists
Washington, DC, USA
June 29th, 2020
Is there a relationship between endogenous progesterone and postmenopausal breast cancer risk?
Trabert and colleagues investigated the influence of circulating endogenous progesterone on the incidence of postmenopausal breast cancer through a prospective case-cohort study based on a bone follow-up to the Fracture Intervention Trial (B-FIT, n=15595). Participants were not receiving exogenous hormone therapy at the time of blood sampling (1992-1993) . Cancer incidence was based on questionnaire responses with subsequent requests from medical record verification and/or cancer registry linkage at clinical sites. One thousand eight hundred eleven cases were excluded from possible selection in the case-cohort study. Of the remaining 13784 eligible participants, 515 were randomly selected for the subcohort within a 10-year age and clinical center strata. After additional exclusions, 405 incident breast cancer cases diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within a 10-year age and clinical center strata. Progesterone assays, using a liquid chromatography–tandem mass spectrometry assay were completed in July 2017. Participants’ mean (SD) age at blood draw was 67.2 (6.2) years, and most were non-Hispanic white (384 [94.8%]). Mean (SD) age for women with breast cancer was 73 (6.4) years at diagnosis (range, 56-89). The key findings were that progesterone concentrations displayed a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels had a 16% increased risk of postmenopausal breast cancer per SD increase in progesterone (HR, 1.16; 95% CI,1.00-1.35; P=.048). In conclusion, in postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer.
The debate between MHT and breast cancer risk has always been a hot topic. More than 50 observed studies have shown that hormone therapy can increase breast cancer risk. From the Women’s Health Initiative (WHI) study, we found the breast cancer risk mainly depends on the progestogen components . Some large clinical studies, including the E3N study and Finnish study, found that estradiol combined with progesterone or dydrogesterone showed a lower breast cancer incidence than that of other synthetic progestogens within 5-8 years [3,4]. Mohammed and colleagues found progesterone inhibited estrogen-mediated growth and ERα+ breast tumour explants and had increased anti-proliferative effects. At the same time, they found that tamoxifen combination with progesterone had the highest degree of tumour inhibition . Our team has also focused on MHT and breast cancer risk for many years; from in vitro experiments and in vivo animal experiments, we found some synthetic progestogens can promote the proliferation of breast cancer cells or growth of tumour if there is an overexpression of progesterone receptor membrane component 1 (PGRMC1), whereas natural progesterone does not have these effects [6-8]. Many other studies have also found that different progestogens have different effects. In contrast to synthetic progestogens, progesterone in combination with estrogen has not been associated with increased breast cancer risk. This publication  could not support previous findings.
Some confounding factors need to be considered in the present study, such as:
(1) In the B-FIT project, the questionnaire was completed by 64% of eligible women; was there a sampling bias？
(2) During a follow-up of 12 years; many other breast cancer factors could have affected the incidence of breast cancer, such as environment and diet, MHT regimens and types
(3) The serum samples of the study were stored at -20 °C for three years, then -70 °C for more than 20 years (27-28 years), therefore the stability of progesterone and its metabolites could have been affected .
Also, even without considering the above potential confounders, the HR is only 1.16, indicating this study was underpowered to detect a very weak association.
To summarize, the current paper from the JAMA 2020 is interesting but the authors should be very careful to conclude that in postmenopausal women, higher circulating progesterone levels are associated with increased risk of breast cancer.
Xiangyan Ruan MD, PhD
Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Are circulating endogenous progesterone levels associated with breast cancer risk in postmenopausal women?
A recent paper by Trabert and coworkers  aimed at shedding some light on this issue by looking at minimal concentrations of progesterone and metabolites with “high-performance liquid chromatography-tandem mass spectrometry” assay, which is much more sensitive than methods used in previous studies.
The Authors, in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (FIT) , were able to quantify prediagnostic serum levels of progesterone and progesterone metabolites, in particular the cancer-inhibiting 4-pregnenes (e.g., 3α-dihydroprogesterone[3αHP]) and cancer-promoting 5α-pregnanes (e.g., 5α-dihydroprogesterone[5αP]). They found that women with higher circulating progesterone levels were at increased risk for breast cancer with a linear association between levels and risk, except for women in the lowest quintile of estrogen levels. Contrary to expectations, the ratio of 5αP relative to 3αHP was not associated with the risk of breast cancer. The associations between the ratio of 5αP relative to 3αHP, and progesterone relative to estradiol were also null. Age, body mass index or prior oral contraceptive use did not modify progesterone associations with breast cancer and 5αP/3αHP- associations with breast cancer.
A previous study in 2014  evaluated the effect of circulating endogenous estrogens and their metabolites on breast cancer risk in the same cohort. As expected, elevated circulating estradiol levels were associated with increased breast cancer risk. The effect of endogenous progesterone, possibly because of the almost undetectable circulating levels in postmenopausal women, is much less clear. In the only previous study of endogenous progesterone and postmenopausal breast cancer risk, published in 2004, there was no association between progesterone levels and breast cancer risk . However, the low sensitivity of the assay available at the time (30% of the samples had undetectable levels of progesterone) may have limited the study’s ability to find an association. Studies reporting increased breast cancer risk with menopausal estrogen plus progestin therapy, do not provide direct evidence as to the potential association between endogenous progesterone and this risk. Indeed, they evaluated the use of exogenous synthetic progestogens [5,6,7], which can have anti-androgenic, pro-androgenic, glucocorticoid, and anti-mineralocorticoid effects . The studies reporting on the use of estrogens plus natural progesterone found a much weaker association. [9-10]. The study by Trabert is the first suggesting a possible association of progesterone levels and breast cancer risk in postmenopausal women, provided that they have at least moderate to high circulating total estradiol levels. Interestingly, in the lowest quintile of circulating estradiol, the breast cancer risk decreased with increasing levels of circulating progesterone, whereas, in the higher quintiles of circulating estradiol, the breast cancer risk increased with increasing levels of circulating progesterone.
Given that the women in the study were not using exogenous hormones since at least four months from the blood draw, this study suggests a differential role of progesterone at physiologic levels, possibly modulated by the level of circulating estradiol.
This observation needs to be confirmed but adds to our knowledge on the synergistic activity of estrogens and progesterone, even at very low levels, on breast cells.
The authors conclude: “Further research is also needed to evaluate the role of progesterone metabolites and the interaction between progesterone and estradiol with breast cancer risk.”
Nicoletta Biglia MD, PhD
Associate Professor of Obstetrics and Gynaecology, The University of Torino School of Medicine
Director, Academic Division of Obstetrics and Gynaecology, Mauriziano Umberto I Hospital, Torino, Italy
Is there a relationship between endogenous progesterone and postmenopausal breast cancer risk?
Are circulating endogenous progesterone levels associated with breast cancer risk in postmenopausal women?
Date of release: June 16th, 2020
In this study, Branigan and colleagues  assessed whether the use of endocrine therapy (tamoxifen, raloxifene, aromatase inhibitors (AI)) among breast cancer patients was associated with risk of neurodegenerative diseases including all-cause dementia, Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). They conducted a retrospective cohort study of 57,843 women aged 45 and older with a diagnosis of breast cancer between January 1, 2007, and March 31, 2017, using a Humana insurance claims dataset primarily comprised of women in the Southeastern region of the United States. The use of endocrine therapy was defined by at least one medication charge occurring after the diagnosis of breast cancer; neurodegenerative diseases were diagnosed based on ICD-9 or ICD-10 codes. To minimize confounding, propensity score matching was conducted based on age at receiving endocrine therapy, race/ethnicity, comorbidities, and the Charlson comorbidity index. In the propensity score-matched cohort, endocrine therapy users were at a reduced risk of AD, but not non-AD dementia, MS, PD, or ALS. When stratifying by type of endocrine therapy, both tamoxifen and aromatase inhibitors, but not raloxifene, were associated with a reduced risk of AD. Removal of women who received intravenous chemotherapy in the unadjusted analyses did not change the results. The authors conclude that the results show the beneficial effects of endocrine therapy as a prophylactic treatment for the potential prevention of AD.
Almost 13% of women will receive a breast cancer diagnosis in their lifetime. About 75% of all breast cancers are hormone receptor-positive, and patients are typically advised to undergo endocrine therapy, about two-thirds of which take at least one type. Of women with estrogen-receptor-positive tumours, those who are premenopausal typically receive tamoxifen with or without ovarian suppression, whereas those who are postmenopausal often receive AI alone, tamoxifen followed by AI or AI followed by tamoxifen . Raloxifene is currently recommended for breast cancer prevention in postmenopausal women.
Given the large number of women who take endocrine therapies and the increased survival after breast cancer, it is important to assess the long-term benefits and risks of use. Clinical trials and large epidemiological studies have examined the associations between endocrine therapy use and cognitive decline or risk of dementia, with mixed results typically showing either a detrimental effect of the use on cognition and risk of dementia or no effect [4-7]. In contrast, one study using the Taiwanese National Health Insurance Research Database reported that the use of tamoxifen for five years or more was associated with a reduced risk of dementia . The current study by Branigan and colleagues  also found a reduced risk of AD dementia, but not other dementias, with the use of tamoxifen or AI.
Given that the Branigan et al. study  is the largest to date, with over 50,000 women, the question arises as to whether the study results should lead to consideration of tamoxifen or AI as a prophylactic treatment for the prevention of AD? The short answer is no.
The study has a number of important limitations, some of which are acknowledged by the authors. First, findings are based on an observational study of a claims database that cannot infer causality. As with other claims databases, neurodegenerative disease outcomes are only identified by diagnosis code, and this method is known to have low sensitivity.
Second, information on menopause status, stage of breast cancer, the status of first breast cancer diagnosis versus recurrence, hormone receptor status, and previous use of menopausal hormone therapy was not available. These factors, as previously discussed, can significantly impact the association between endocrine therapy use and risk of dementia and are important to consider in the study design . Indeed, since endocrine therapy is generally only used for the treatment of hormone-positive tumours, without knowledge of tumour status it is difficult to determine whether an association with dementia risk is due to the endocrine therapy or the characteristics of the tumour.
Third, and a common limitation of many studies is the short duration between the start of endocrine therapy and the diagnosis of dementia. The median (standard deviation) time to diagnosis of AD was 3.1 (2.4) years for those not taking endocrine therapy, and 3.3 (2.2) among endocrine therapy users. AD is a slowly progressive neurodegenerative disease with a long duration of cognitive symptoms prior to a diagnosis. Thus, some of the women had cognitive symptoms at the time of the breast cancer diagnosis. It is likely these symptoms could impact the type of breast cancer therapy prescribed; propensity matching could not account for this bias.
In summary, the findings from the current study should not provide the impetus to prescribe tamoxifen or AI for the prevention of AD. Limitations of this study do highlight the difficulty in examining associations between endocrine therapy and AD and the need to consider multiple factors when interpreting the associations.
Michelle M. Mielke, Ph.D.
Professor of Epidemiology and Professor of Neurology, Mayo Clinic, Rochester, MN; Director of the Mayo Clinic Specialized Center of Research Excellence on Sex Differences
1. Branigan GL, Soto M, Neumayer L, Rodgers K, Brinton RD. Association between hormone-modulating breast cancer therapies and incidence of neurodegenerative outcomes for women with breast cancer. JAMA Netw Open 2020; 3:e201541.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69:7-34.
3. Zwart W, Terra H, Linn SC, Schagen SB. Cognitive effects of endocrine therapy for breast cancer: keep calm and carry on? Nat Rev Clin Oncol 2015; 12:597-606.
4. Schilder CM, Seynaeve C, Beex LV, Boogerd W, Linn SC, Gundy CM, Huizenga HM, Nortier JW, van de Velde CJ, van Dam FS, Schagen SB. Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. J Clin Oncol 2010; 28:1294-1300.
5. Legault C, Maki PM, Resnick SM, Coker L, Hogan P, Bevers TB, Shumaker SA. Effects of tamoxifen and raloxifene on memory and other cognitive abilities: cognition in the study of tamoxifen and raloxifene. J Clin Oncol 2009; 27:5144-5152.
6. Ording AG, Jensen AB, Cronin-Fenton D, Pedersen L, Sorensen HT, Lash TL. Null association between tamoxifen use and dementia in Danish breast cancer patients. Cancer Epidemiol Biomarkers Prev 2013; 22:993-996.
7. Bromley SE, Matthews A, Smeeth L, Stanway S, Bhaskaran K. Risk of dementia among postmenopausal breast cancer survivors treated with aromatase inhibitors versus tamoxifen: a cohort study using primary care data from the UK. J Cancer Surviv 2019; 13:632-640.
8. Sun LM, Chen HJ, Liang JA, Kao CH. Long-term use of tamoxifen reduces the risk of dementia: a nationwide population-based cohort study. QJM 2016; 109:103-109.
Date of release: June 9th, 2020
The belief that having high testosterone is bad for cardiometabolic health is entrenched in medical training. This has been explored again by Rasmussen and colleagues in their recent paper published in the Journal of the Endocrine Society . They have reported on associations between baseline total testosterone, SHBG and calculated free testosterone and development of type 2 diabetes (T2D) in a sample of 8876 women, mean age 38.5 years and a median follow up of 8.1 years. The sample was recruited from the national database of Danish women who underwent first-time measurement of endogenous androgens at the Nationally approved laboratory, Danish State Serum Institute, Copenhagen, Denmark, from January 1, 2007, until December 31, 2015. It was not stated why women were having their androgens measured. Eligible women were aged 18 to 50 years, with no established chronic morbidity, including no history of PCOS, hirsutism and were not known to be taking oral contraception, androgens, diuretics, cardiovascular or anti-glycemic medications at the time blood was drawn. The investigators did not appear to have information regarding menopause status, smoking behaviour, or body mass index (BMI) to include in the analysis. During the follow-up period, 69 women developed T2D. The investigators reported that women in the lowest quartile of SHBG, and highest quartiles of estimated free testosterone and total testosterone were more likely to develop T2D. Their conclusion was that “Higher levels of plasma total and free testosterone were associated with increased risk of type 2 diabetes among women”.
Does this study reassure us that higher testosterone is indeed bad? I would suggest no. Rather, this paper reaffirms a strong association between low SHBG and T2D, as previously reported , and indicates a need for a greater understanding of the association between SHBG and T2D. The analysis unfortunately is missing important variables, such as smoking and menopause status, as well as BMI. It has been clearly established that women who smoke have higher testosterone levels [3, 4]. Furthermore, smoking is associated with an increased risk of T2D . In Denmark in 2010, approximately 20% of women were smokers, and this percentage may have been higher in 2007. BMI and menopausal status each influence diabetes risk and higher BMI is associated with lower SHBG. Additionally, the clinical indication for the measurement of testosterone in these women was not known. Testosterone is not something measured routinely in otherwise well women. With respect to the results, women were evaluated according to which quartile of total testosterone, SHBG and calculated free testosterone they fitted into. The adjusted risk of T2D was not increased for women in the second or third quartile of total testosterone versus the lowest quartile, and only just reached significance for the highest, versus the lowest, quartile (IRR 1.97 (95%Ci 1.01-3.85). In contrast, the association between SHBG and T2D risk is striking; women in the highest quartile of SHBG versus the lowest were substantially less likely to develop T2D (IRR 0.06, 95% CI 0.02-0.21). There is evidence that SHBG may be metabolically active. SHBG levels vary in women, with levels inversely linked to central adiposity and insulin levels [6-8]. SHBG is a strong independent marker of insulin resistance and T2D risk  and has been implicated in the pathogenesis of type 2 diabetes and CVD . Strong, inverse relationships between both insulin resistance and SHBG , independent of sex steroids have been demonstrated. Taken together this study is a reminder that testosterone physiology in women is complex, that the understanding of the role of testosterone in women needs a multidimensional perspective, that includes an understanding of the role of SHBG.
Director, the Women's Health Research Program, School of Public Health and Preventive Medicine,
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
1. Rasmussen JJ, Selmer C, Frøssing S, Schou M, Faber J, Torp-Pedersen C, Gislason GH, Køber L, Hougaard DM, Cohen AS, Kistorp C. Endogenous testosterone levels are associated with risk of type 2 diabetes in women without established comorbidity, Journal of the Endocrine Society, May 15, 2020.
2. Ding EL, Song Y, Manson JE, et al.: Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009;361:1152-1163.
3. Davison SL, Bell R, Donath S, Montalto JG, Davis SR: Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. 2005;90:3847-3853.
4. Skiba MA, Bell RJ, Islam RM, Handelsman DJ, Desai R, Davis SR: Androgens during the reproductive years, what's normal for women? J Clin Endocrinol Metab. 2019.
5. Jee SH, Foong AW, Hur NW, Samet JM: Smoking and risk for diabetes incidence and mortality in Korean men and women. Diabetes Care. 2010;33:2567-2572.
6. Nestler JE, Strauss JF, 3rd. Insulin as an effector of human ovarian and adrenal steroid metabolism. Endocrinology and metabolism clinics of North America. 1991;20:807-823.
7. Goodman-Gruen D, Barrett-Connor E: Sex hormone-binding globulin and glucose tolerance in postmenopausal women. The Rancho Bernardo Study. Diabetes Care. 1997;20:645-649.
8. Randolph JF, Jr., Sowers M, Gold EB, et al.: Reproductive hormones in the early menopausal transition: relationship to ethnicity, body size, and menopausal status. J Clin Endocrinol Metab. 2003;88:1516-1522.
9. Davis SR, Robinson PJ, Moufarege A, Bell RJ: The contribution of SHBG to the variation in HOMA-IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women. Clin Endocrinol (Oxf). 2012;77:541-547.
Date of release: 25 May, 2020
Dietary magnesium and incident heart failure in the WHI study
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 . 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”.
Magnesium plays an essential role in human physiology, primarily needed in the process of energy production . For some reason, magnesium has not received much public attention in contrast to other nutrients such as calcium, iron, vitamin D and the B complex. Although a large proportion of the population worldwide consume a lower than recommended daily allowance of magnesium , blood levels are usually kept within the normal range, and clinical hypomagnesemia is uncommon . The association of magnesium deficiency with cardiovascular risk factors such as hypertension or type 2 diabetes mellitus, or with cardiovascular disease has been well documented . However, a link with HF was scarcely mentioned. A recent systematic review on nutraceuticals in patients with HF did point at magnesium as a relevant potential factor. Nonetheless, it stated that studies were too small or underpowered to accurately appraise clinical outcomes . An earlier publication of data from NHANES III study on a sample comprised of 445 individuals aged 50+ years with congestive HF (54.4% males), concluded that the Prognostic Nutritional Index in participants in the top quintile (higher scores indicating optimal nutritional status) showed significantly greater intakes of magnesium . Despite the large sample size of the WHI study and the sizable number of HF patients, the HRs related to magnesium consumption at Q4 vs. Q1 were not so impressive, reflecting a relatively small difference in absolute numbers between the groups. Needless to point out that a study like WHI, which collected data on a diversified population and analyzing/adjusting for so many variables, casts some doubt on the strength of the results. Unlike the recommendation for older people to keep an optimal dietary intake plus perhaps some supplemental calcium, the situation regarding magnesium is different. National health agencies have dissimilar guides for the desired daily magnesium allowances. For example, the current UK (NHS) recommendation for adult, non-pregnant women aged 19 and over is 270 mg/day , whereas the US (NIH) dietary advice for women above age 51 is higher – 320 mg/day . A US survey published back in 2003 provided relevant nutritional data from 4257 participants aged 20 or older . Race differences in mean intake of magnesium were recorded - 256 mg/d among Caucasian women, 202 mg/d among African American women, and 242 mg/d among Mexican American women. Since the natural sources of magnesium lie in leafy and other vegetables and fruits, nuts, brown rice, whole grain bread and dairy products, it is quite evident that racial and ethnical, social and economic parameters influence food consumption habits and thus play a significant role in the amount of daily ingested magnesium. The above WHI findings remind us of the somewhat forgotten pivotal part of magnesium in maintaining the normal function of many bodily organs, and the potential adverse effects of low dietary consumption. However, in my view, the strength of the current findings should be addressed cautiously. Furthermore, the WHI investigators already published their HF results in a 2013 paper, concluding that “among WHI participants with incident HF hospitalization, intakes of Ca, Mg and K were not significantly associated with subsequent mortality” . This statement is in line with the results of the assessment of causality in associations of serum calcium and magnesium levels with HF . In contrast with earlier studies that demonstrated an inverse association between serum magnesium and heart failure risk, “this assessment could not support previous findings suggesting a link between serum calcium and magnesium and heart failure, but this study was underpowered to detect weak associations”. To summarize, the current paper from the WHI “publication factory” is interesting but not that important from the clinical perspective.
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
The Hebrew University Hadassah Medical School, Jerusalem, Israel
Wu WC, Huang M, Taveira TH, Roberts MB, Martin LW, Wellenius GA, Johnson KC, Manson JE, Liu S, Eaton CB. Relationship between dietary magnesium intake and incident heart failure among older women: the WHI. J Am Heart Assoc. 2020 Apr 7;9(7):e013570.
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Date of release: 11 May, 2020
Is there a relationship between menopause, use of HRT and onset hand osteoarthritis?
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. 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).
It has long been observed that osteoarthritis starts at the time of menopause in some women [2-4]. However clear evidence for true association or causation has been lacking to date. The close association for about half of women demonstrated here between a new diagnosis of hOA and onset of menopause increases the likelihood of this being a true association, at least for some women. A spike in incidence of hOA around the age of 50, the typical age of menopause, had already shown at population level by the co-authors . This study adds by relating menopause to disease onset at an individual level. An identifiable subgroup with ‘perimenopausal onset’ of hOA would have implications for both our understanding and management of the disease. Effects of female sex hormone deficiency on disease pathogenesis, pain experience or local inflammation could all modulate disease presentation and its severity. A limitation, even in this large, longitudinal dataset, is the sensitivity and specificity of coding of conditions under investigation. 3440 hOA cases were identified of 438, 674 (i.e. 0.78% of women over 45). This is despite using broad inclusions, including hand pain (which could represent a variety of conditions) and subsequent any site OA, attempting to increase sensitivity. According to Versus Arthritis, ~12% of women age 45-64 in UK would be expected to have symptomatic hOA . This apparent under-ascertainment could lead to significant bias affecting findings. Similarly, date of menopause is more likely documented when around the time of other presenting conditions (listed in only 25% of cases and 19% controls), potentially introducing further bias. hOA diagnosis not being coded sufficiently in the UK is arguably another key finding here; this reduces our ability to document its true impact, plan care and carry out high-quality research. There are prior conflicting reports on the effects of HRT on hOA, with some studies suggesting HRT increases its prevalence . Women often seek HRT for a number of reasons, including musculoskeletal symptoms, which could lead to such apparent positive associations; menopause itself and age are also confounders, properly accounted for here. The study highlights why one must not oversimplify; stratification demonstrates that those starting early HRT are in fact protected from hOA, but that this protection is lost further post-menopause, particularly in past users. There are no data on whether the trend to increased risk on stopping HRT was after abrupt cessation or weaning in these 29 cases – this phenomenon has also been observed clinically . What is not clear is whether those developing hOA after HRT cessation were always destined to develop the disease, with HRT perhaps just postponing its onset, or whether new disease is triggered by this manoeuvre. This would seem of critical importance. Half of women will have musculoskeletal symptoms of menopause, but these are often largely neglected . This study shines a light on our need to better understand the interaction between musculoskeletal symptoms, arthritis, menopause and HRT. While the findings in no way support a change in practice to use of HRT, they do suggest that in an area of high unmet clinical need, further mechanistic and clinical studies seeking to understand this association better are called for.
Fiona E Watt
Associate Professor, Kennedy Institute of Rheumatology, NDORMS, University of Oxford Honorary Consultant Rheumatologist, Oxford University Hospitals NHS Trust
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Watt FE, Carlisle K, Kennedy D, Vincent TN. Menopause and hormone replacement therapy are important aetiological factors in hand osteoarthritis: results from a cross-sectional study in secondary care. Maturitas, Volume 81, Issue 1, 128