19 July 2021

Summary

García-Alfaro et al [1] published the results of a cross-sectional study that aimed at determining the impact of age, age at menopause, body mass index (BMI), and lumbar and hip bone mineral density (BMD) on muscle strength of 392 young postmenopausal women (65 or less years), with no physical disabilities and normal serum 25-hydroxyvitamin D levels (≥30 ng/ml). They analyzed variables such as age, age at menopause onset, BMI, BMD (measured with DXA scanning and expressed as lumbar and hip T-scores), and dominant hand grip strength (measured with a digital dynamometer). Mean age of the whole sample was 57.30 ± 3.69 years with a mean age at menopause onset of 50.46 ± 2.16 years and a mean BMI of 24.93 ± 3.78 k/m². Mean DXA results were lumbar T-score of -1.16 ± 1.18 and a mean hip T-score of -0.98 ± 0.93. Mean grip force of the dominant hand was 24.10 kg, with 12.2% (48/392) of women diagnosed as having dynapenia (cut-off value of <20 kg). There was a weak but significant inverse correlation between grip strength in the dominant hand and age (r = -0.131, p = 0.009). Multivariate logistic regression analysis determined that earlier age at menopause onset (50 or less years) was significantly associated with a higher risk of dynapenia (OR 2.741, 95% CI 1.23-6.11, p = 0.014). No other significant association was found with the other variables. The authors conclude that 12.2% of the studied young postmenopausal population with normal vitamin D status had dynapenia. Female age and age at menopause were significantly correlated with an increased dynapenia risk.

Commentary

During the menopausal transition and the early postmenopausal years, progressive estrogen depletion causes loss of bone mass due to an imbalance between bone resorption and bone formation. In addition, there is a reduction of muscle mass and strength and a redistribution of body fat from the periphery to the abdominal region [2,3]. There is a growing interest in recent years regarding the association of dynapenia, defined as the loss of muscle strength related to age, and BMI and nutrition. Indeed, a direct correlation has been observed between muscle strength and bone mass, that is, lower hand grip strength correlating with lower BMD, and hence higher rates of vertebral fractures [4]. Hand grip strength can be measured with a hand dynamometer, being an easy/simple and quick test to be performed in the clinical scenario, and most importantly is the fact that hand grip force correlates with leg strength. Although BMI has been used to assess nutritional status, this index is not as appropriate as DXA for the evaluation of body composition. As the authors state, although body weight is related to BMD, when body composition is analyzed with DXA, total body fat is the best predictor of bone status. Vitamin D status is another important factor correlating with muscle function, strength, balance, not to mention its role over bone status of elder women.

25 January 2021

Summary

Improvements in oncology have led to an increased survival of cancer patients. Indeed, breast cancer patients live long enough to reach the natural age of menopause. In addition, in many of them, one of the main adverse effects of their received oncotherapy is premature ovarian failure caused by the cessation of gonadal function. Indicating menopausal hormone therapy (MHT) in these type of patients has become increasingly difficult as multiple clinical studies suggest an increased risk of recurrence and mortality with the use of MHT. The use of therapy must be supported according to oncological and endocrine factors, the oncotherapy received and the type of compound to be used: estrogen alone, estrogen plus progestogen and progestogen only, always balancing risk – benefit [1]. The pattern of expression of the estrogen receptor is not sufficient to predict the effect of estrogen or progesterone; since the biological effect depends on the tissue and type of tumor, the interaction with isoforms, growth factors, coactivators and corepressors.
Taking into account the aforementioned, MHT is chosen according to the type of cancer and its characteristics, risk factors of each patient and their preferences. In breast cancer survivors it is difficult to choose which is the best therapy, since according to the interpretation of the International Menopause Society "IMS", all hormonal therapy would be contraindicated. Hence, questions arise regarding molecules such as tibolone, the use of estrogens alone and local hormonal therapy, which could be considered according to the scenario of each patient and their history.

Commentary

The IMS guideline is clear in emphasizing that non-hormonal methods are preferred in receptor-negative or positive breast cancer survivors who have menopausal symptoms, and MHT is contraindicated. However, there is controversy in the literature in this regard: observational and case-control studies suggest that MHT does not increase disease recurrence [2,3]. Contrary to this, clinical studies such as the HABITS were suspended after 2.1 years because their results showed a higher risk of breast cancer recurrence (n = 434, 26 cases of recurrence in the MHT group compared to 7 cases in the group that did not receive MHT, hazard ratio [HR] 3.3) [4]. The 10-year follow-up results from the Stockholm trial also indicated an increased risk of breast cancer recurrence. In the study of Fahlen et al [5], a HR of 3.6 was detected for disease recurrence (n = 378, mean duration of MHT 26 months, recurrent rate among MHT users was 7.4% vs. non-users 2.1%) [5].

18 January 2021

Summary

Sriprasert et al. [1] performed a post hoc analysis of a United States multicenter randomized clinical trial (REPLENISH trial) in order to identify the association between the dose of estradiol (E2) and serum E2 levels and metabolic parameters among early (<6 years; n=1,216) as compared to late (≥10 years, n=297) postmenopausal women. To this end, four doses of TX-001HR (a new oral formulation of combined E2 and progesterone [P4]) were tested against placebo. Linear mixed-effects models adjusted for P4 levels were used to verify the associations between E2 (dose and serum levels) and changes in the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and glucose measured at six visits over 12 months.
They found that higher E2 doses and serum E2 levels were significantly related to lower TC and LDL-C and higher HDL-C levels in early but not in late postmenopausal women. These associations weakened with longer time since menopause onset. Higher E2 serum levels were also associated with lower fasting glucose and higher TG levels in early postmenopausal women. The authors concluded that the dose of E2 differentially affects metabolic measures among early compared with late postmenopausal women, supporting the timing hypothesis of the benefits of E2 therapy on cardiovascular disease risk.

Commentary

During the menopausal transition, due to a decline in ovarian function and estrogen secretion, women are subject to bio-psycho and social changes that can impair their quality of life.  More importantly, after menopause, cardiovascular risk increases significantly, partly due to estrogen deprivation. Moreover, an increase in weight and other factors (i.e sedentary lifestyle, dietary habits, etc) negatively impact metabolic parameters, making women more susceptible to cardiovascular events. Various studies suggest that estrogens have positive effects on female lipid profile and vasculature due to their antioxidant effect [2], gene modulation expression [3] and regulation of the inflammatory pathway [4]. Despite this evidence,  women and professionals are still reluctant to use menopausal hormone treatment (MHT), especially when cardiovascular risk factors such as obesity, hypertension, diabetes, and smoking, are present. Although cardiovascular disease is the leading cause of death in women after menopause, many require MHT, especially those who are symptomatic and in the early postmenopausal stage.

11 January 2021

On October 19th Menopause Live issued the following commentary:
 

Serum estradiol in women taking oral estrogen therapy

Summary
 
Sriprasert et al have reported the findings of an unplanned post hoc analysis of serum estradiol levels in 275 women who were randomised 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.

Commentary
 
As the authors have discussed, and fully referenced in their paper, previous studies have demonstrated higher BMI and alcohol consumption are associated with higher serum estradiol concentrations, and smoking with lower estradiol concentrations in women taking oral estrogen therapy. The study has multiple study limitations, with significant ones including no mention of timing of each blood draw to the prior dose of estradiol, the adjustment of serum estradiol for a single baseline value, and the conclusion about alcohol use and serum estradiol being based on 11 women who reported consuming more than 2 standard drinks per day. With regard to the latter, although there are plausible explanations as to why high alcohol consumption might influence serum estradiol through effects on hepatic metabolism, regular consumption of 3 or more standard drinks per day may be associated with nutritional deficits that complicate the picture. Nonetheless, this is not a new finding.
The controversial issue raised in this paper is the authors’ recommendation that clinicians take into account women’s BMI, alcohol use and smoking when considering the dose of estrogen therapy to prescribe. It is over simplistic to base dosing and treatment effects on serum estradiol when we know that estrogen biosynthesis and action is complex and subject to vast individual variation. The variation resides not only in the conversion between estradiol, estrone and estrone sulphate in peripheral tissues, but also in tissue sensitivity which is modulated by receptor sensitivity and receptor modulators (coactivators and corepressors). Thus, serum estradiol may not reflect overall tissue exposure to estrogen.
Women who are overweight or obese are more likely to experience moderate to severe vasomotor symptoms, despite fat tissue being a major source of estrone and estradiol biosynthesis in postmenopausal women [2].   It is also not uncommon, in my experience, for overweight/obese women to require a generous dose of estrogen replacement to alleviate their symptoms.  Consequently, the dose should not be informed by BMI. Rather, BMI informs the best route of administration, and the dose should be that needed to alleviate symptoms. As higher BMI increases the risk of venous thromboembolic events (VTE), nonoral menopausal hormone therapy (MHT) should be considered first line for obese women [3]. Similarly, nonoral MHT is first line for smokers to minimise the risk of VTE [3].
So, do the findings from this study inform how to prescribe estrogen to minimise side effects and maximise compliance?  I suggest not, as 1) the findings cannot be extrapolated to nonoral estrogen therapy which should be used for smokers and overweight/obese women and 2) it is prudent to commence most women on low dose estrogen and titrate the dose according to symptoms as one can never predict who will experience complete symptoms relief with a low dose, or equally who will have side effects even with low dose therapy.

Susan R Davis MBBS, FRACP, PhD, FAHMS
Professor of Women's Health and NHMRC Senior Principal Research Fellow
Director, Women's Health Research Program
School of Public Health and Preventive Medicine,
Monash University, Melbourne, Australia

14 December 2020

Summary

This study from the urogynaecology department in Athens is a randomized, assessor-blinded controlled trial of the Erbium YAG smooth laser in postmenopausal women with symptomatic stage 2 or 3 vaginal prolapse who had opted to undergo surgery (1).

All 30 women in the study had extensive assessment of their symptoms by various appropriately validated questionnaires and by physical assessment using the POP-Q scoring system (Pelvic Organ Prolapse Quantification System).  The primary endpoint, defined as the ‘objective cure rate,’ was the proportion of patients with POP-Q stage 0 or 1. Secondary endpoints included measurements of all POP-Q points and subjective cure rates assessed by the Pelvic Floor Distress Inventory Questionnaire short-form [PFDI-20], Pelvic Floor Impact Questionnaire short- form [PFIQ-7] and the Patients Global Impression of Improvement [PGI-I]). The women were randomised to receive either Laser therapy (n=15) or a watchful-waiting group (n=15) who were not offered any additional therapy such as pelvic floor muscle training or a pessary. Laser therapy was performed using the Er:YAG laser (Intimalase Fotona SMOOTHTM), and all women in the laser group received one treatment at monthly intervals for three consecutive months. The treatments were all performed by an experienced independent physician blinded to the study objective. Outcomes in both groups were assessed at baseline and 4 months post-baseline. The POP-Q assessment was carried out by another independent physician who was blinded to participant allocation. Patient-reported outcome questionnaires, as above, were completed at baseline and 4 months.

The study found that after three Er:YAG laser treatments, there was no improvement in the pelvic anatomy as judged by the POP-Q assessment, and none of the participants in this study were objectively or subjectively cured following laser therapies. There were no changes in the patient-reported outcomes, and the laser therapy results were no different from those of the watchful-waiting group. No adverse events were reported by any of the participants.  The authors conclude that their study results do not support the use of intravaginal Er:YAG laser as a therapeutic option in postmenopausal patients with symptomatic pelvic organ prolapse.

19 November 2020

Summary

The article by Mauvais-Jarvis et al. [1] is a mini-review that highlights experimental evidence on the potent immunomodulatory role of steroid hormones 17β-estradiol (E2) and progesterone (P4). The review discusses how different concentrations of estrogens, P4, and androgens between women and men and genetic factors may explain the lower mortality in women compared to men. Moreover, the role of the proinflammatory cytokine storm in coronavirus disease, how females exhibit more significant immune responses to viruses, the evolution f coronavirus disease in èregnant women and the immune-modulatory function of estrogen-progestin therapies are illustrated. The authors also claim that acute combined E2 and P4 treatment may represent a safe and viable strategy that deserves to be tested in clinical trials to mitigate severe COVID-19 outcomes. The possibility of off-label use of these approved drugs for human use as potentially life-saving therapeutics needs to be explored.

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).