IMS Menopause Live

16 September, 2019: 

Summary

The REPLENISH trial was a phase 3, randomized, double-blind, placebo-controlled, multicenter study, in postmenopausal women with a uterus, evaluating a new form of menopausal hormone therapy (MHT). Capsules containing estradiol plus progesterone (E2/P4) with four different dosages (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, and 0.25 mg/50 mg) were tested. The primary endpoints were the efficacy to treat vasomotor symptoms within a three months substudy and the proof of endometrial safety after 12 months treatment. The positive results of these two primary trial endpoints have already been reported [1]. The REPLENISH trial also tested the changes in cardiometabolic parameters during treatment with these oral E2/P4 formulations in comparison to placebo, as recently published in "Climacteric", the official journal of the International Menopause Society [2]. One thousand six hundred eighty-four postmenopausal women received one of the four E2/P4 doses (1 mg/100mg [n=415], 0.5 mg/100mg [n=424], 0.5 mg/50mg [n=421], 0.25 mg/ 50mg [n=424]), and 151 women received placebo. Participants’ mean age was 54.6 years (range: 40–66 years) and mean body mass index was 26.7 kg/m2 (range:14.0–34.5 kg/m2); most were white (65.4%) or African American (32.1%). Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months were assessed. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1–4%, 6–11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). Overall no clinically significant changes in lipid parameters, coagulation factors or glucose were seen between the treatment groups.

Commentary

From the evaluation of the cardiometabolic parameters in the REPLENISH study, it can be concluded that oral E2/P4 combinations are neutral on lipid and glucose metabolism and on the coagulation system. This is the result of a study using the prospective, placebo-controlled "golden standard design". Total cholesterol, HDL, LDL, triglycerides were assessed, as well as glucose; these parameters are  widely used in clinical practice to screen for cardiovascular risks. Measured coagulation factors included prothrombin time, activated partial thromboplastin time (aPTT), fibrinogen, protein C (factor XIV), protein S, antithrombin III, and factor V Leiden. These parameters are also widely assessed in other studies investigating changes in hemostatis under MHT. Changes in fasting lipids and glucose levels were not significant and these parameters remained within normal ranges. In contrast, negative changes in lipid and glucose metabolism have been seen in a variety of studies using oral estrogens combined with synthetic progestogens; oral formulations have often induced hypercoagulability and other negative vascular (e.g. vasoconstrictory) effects [3-6]. Only five women discontinued the study because of changes in lipids or coagulation factors, reported as adverse events [2].

9 September 2019: 

Systematic reviews and meta-analyses are increasingly popular since they provide the best and most reliable unbiased analysis of the existing evidence, which is essential for evidence-based clinical practice. Different approaches and techniques are commonly used to generate this evidence. Understanding the benefits and limitations of these techniques is essential when interpreting the results of a meta-analysis. Riley et al. published an important methodological article in the British Medical Journal [1] that precisely explained two important approaches used in meta-analyses: the fixed effects and random effects models, and when each should be used. They also introduced the concept of the prediction interval (PI) which will be increasingly used in meta-analyses studies. They explained the difference between the confidence interval (CI) and the PI and their applications and interpretations in evidence-based clinical practice. They explained why a PI could provide a more complete summary of the clinical implications of the findings of a meta-analysis that is generally provided by a CI. In meta-analyses, fixed effects models assume that the true effect of treatment for each study included in the meta-analysis is the same or fixed. In other words, there is no between-study difference or heterogeneity in the true treatment effect (assessed by a statistical analysis called the I²) [2]. The differences seen between studies in a fixed effect model are due to random or chance variations in sampling, such that if all studies had a large (infinite) sample size, the differences in study estimates would vanish. On the other hand, the random effects models allow for real differences (heterogeneity) in the treatment effect from study to study. So, the observed estimates of treatment effect can vary between studies because of real differences due to both random and non-random variation. Sources of heterogeneity could include differences in study populations (e.g. age of patients), interventions received (e.g. dose of drug), follow-up length etc. as well as sample size [1, 3]. In meta-analyses, when data are pooled and analysed using random effects models, it is standard to report a CI around the effect estimate. However, when heterogeneity is large, some authors have proposed reporting a PI along with a CI to have a better appreciation of the uncertainty around the effect estimate [1, 4]. The PI, used in this way, is a relatively new concept. The CI and PI are not the same thing. A CI is a range of values, which indicates the degree of uncertainty about a population parameter, for example, the mean blood pressure of a population. A PI, on the other hand, is the interval within which you would expect a future mean value of blood pressure to fall in a new research study.

Putting theory into practice

Our recent systematic review with meta-analyses of 46 reports from 36 randomized controlled trials (RCTs) showed that the effect of testosterone therapy improved a range of sexual function parameters in postmenopausal women [5]. For the sexual desire outcome, in 15 studies that included 3,762 postmenopausal women, we used a random effects meta-analysis as discussed above. This approach assumed that there may be both random and non-random variations (heterogeneity) across the studies that may influence the outcome of interest (sexual desire). In addition, we computed the 95% CI and the 95% PI for the effect estimate of testosterone therapy on sexual desire. The random effects meta-analysis showed that testosterone therapy was effective for improving sexual desire in postmenopausal women when using 95% CI (SMD 0·36, 95% CI 0·22 to 0·50). However, the I2 value for the pooled estimate of sexual desire was 69%, which indicated moderately high heterogeneity between the included studies. So, in order to estimate the potential effects of testosterone on sexual desire in future individual studies, the 95% PI was also estimated. We observed that the PI was much wider than the CI and included zero (SMD 0·36, 95% PI -0.12 to 0.84). This means that although on average the effect of testosterone for the completed studies is positive for sexual desire, a future study may not have a treatment effect, which is different from zero (no difference between treatment and placebo). It is critical to realize that CI and PI convey different but complementary information.

Rakib Islam

Research Fellow, Women’s Health Research Program, Monash University, Australia

4 September 2019: 

The first Global Position Statement on the use of testosterone in the treatment of women, led by the International Menopause Society (IMS), was published on September 2nd in four leading international medical journals:

• Climacteric
• Maturitas
• The Journal of Sexual Medicine
• The Journal of Clinical Endocrinology and Metabolism.

The statement was authored by a diverse team of leading experts belonging to nine leading medical internationally-esteemed organisations:

• The International Menopause Society
• The International Society for Sexual Medicine
• The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia
• The American College of Obstetricians and Gynecologists
• The North American Menopause Society
• The European Menopause and Andropause Society
• The International Society for the Study of Women’s Sexual Health
• The Royal College of Obstetricians and Gynaecologists
• The Endocrine Society

and endorsed by several additional Societies.

Key messages to Health Care Professionals are:

• The consensus follows years of debate regarding testosterone therapy for women and, for the first time, provides agreement from experts about the known benefits and potential risks of testosterone therapy for premenopausal and postmenopausal women.
• Testosterone can be effective at improving sexual wellbeing for postmenopausal women with hypoactive sexual desire dysfunction (HSDD). Benefits include improved sexual desire, function and pleasure, together with reduced concerns and distress about sex.
• There is insufficient data to support the use of testosterone for the treatment of any other symptom or clinical condition, or for disease prevention.
• As female formulations are not available, male formulations can be judiciously used in doses that achieve blood concentrations of testosterone that approximate premenopausal physiological concentrations.
• The panel recommends against the use of compounded testosterone.
• The international panel calls on industry, researchers and funding organisations to recognise the need for further research into testosterone therapy for menopausal women and the development and licensing of products indicated specifically for women.

26 August, 2019: 

Summary

A new study from the UK addressed whether a person’s genetic risk of dementia modifies the extent to which healthy lifestyle factors are associated with a reduced risk of dementia. The study included a very large, population-based sample of more than 500,000 White adults age 60 and over from the UK. Participants were categorized into low, intermediate, or high genetic risk of dementia based on a polygenic risk score (i.e., a weighted estimate of genetic risk for dementia from a number of single nucleotide repeats or SNPS). They were also categorized into favorable (3-4 healthy lifestyle factors), intermediate (2 healthy lifestyle factors), and unfavorable (0-1 healthy lifestyle factors) lifestyle categories based on four factors - healthy diet, physical activity, alcohol consumption and smoking. Lifestyle factors were assessed at baseline and incident all-cause dementia was assessed from hospital records and death records an average of 8 years later. Results showed that for those with an intermediate genetic risk of dementia, an intermediate or favorable lifestyle was associated with a decreased risk of dementia compared to an unfavorable lifestyle. Among those at the highest genetic risk of dementia, a favorable lifestyle was associated with a lower risk of dementia compared with an intermediate or unfavorable lifestyle. In other words, findings suggested it may be possible to lower the risk of dementia through lifestyle modification but that the greater the genetic risk of dementia, the healthier the lifestyle must be.

Commentary

The Commentary refers to the paper 'Association of Lifestyle and Genetic Risk With Incidence of Dementia' by Lourida I, et al., published in JAMA 2019 July 19, https://www.ncbi.nlm.nih.gov/m/pubmed/31302669

Menopause practitioners have an important role to play in counseling patients on how lifestyle factors at midlife can affect their later health, including their risk for dementia. Women are right to fear dementia, as two-thirds of patients with Alzheimer’s disease are female [1] and every clinical trial of a pharmacological agent to prevent or treat Alzheimer’s disease has failed. The benefits of multicomponent lifestyle interventions on cognition and perhaps dementia risk are supported by numerous observational studies as well as a growing number of randomized clinical trials [2]. These lifestyle interventions are multi-faceted and focus on increasing adherence to the Mediterranean Diet, physical activity, cognitive engagement, and social engagement, as well as smoking cessation and moderate use of alcohol. Some but not all of those interventions were evaluated in the JAMA study. The number of healthy behaviors is key, as prior studies [2] and the current JAMA article show an additive role of lifestyle factors. How much physical activity is necessary to minimize cognitive difficulties? Favorable physical activity was defined on either the basis of duration (i.e., > 150 minutes of moderate activity or 75 minutes of vigorous activity per week) or frequency (i.e., moderate physical activity at least 5 days a week or vigorous activity once a week). Moderate consumption of alcohol was defined as 0 to 14 g/d for women, or about one glass of wine per day. Although this study included a white-only population of European ancestry, prior work demonstrates that lifestyle modification works also for diverse populations [2] though the moderating effect of genetic risk of dementia in that population is yet to be determined.

19 August 2019: 

UK media recently reported that a Birmingham-based company called ProFaM (Protecting Fertility and Menopause) were offering a “new” procedure for women: cryopreservation of autologous ovarian tissue to delay menopause through later reimplantation. The company, co-founded by Arri Coomarasamy, Christiani Amorim, Yousri Afifi and Simon Fishel, four world-renowned experts in reproductive medicine, are proposing to perform laparoscopy in premenopausal women, within 40 years of age, to collect sections of ovarian tissue. The ovarian tissue is frozen at -150C and preserved in an authorised bank until women reach the menopause, when it is then thawed and transplanted back into the body, where it will replace the function of the original ovaries.

This is not a new procedure. It was developed for cancer patients undergoing potentially gonadotoxic treatments and was first described by Kutluk Oktay and collegues in 2000 in a patient who had undergone bilateral salpingo-oophorectomy by age 29 and for whom wedges of ovarian tissue had been cryopreserved. Ovarian tissue was later reimplanted in an attempt to cure persistent menopausal symptoms [1]. In 2004, another pioneering group lead by Jacques Donnez achieved a livebirth after successful orthotopic transplantation of cryopreserved ovarian tissue in a woman with stage IV Hodgkin's lymphoma [2]. Other groups worldwide, like that lead by Xiangyan Ruan, have gone on to successfully perform the procedure on patients with the specific short-term goal of achieving a pregnancy [3, 4]. The procedure is specifically indicated for fertility preservation in child and adolescent patients and patients who cannot delay cancer treatment to pursue other methods of fertility preservation such as oocyte or embryo cryopreservation[5,6].

ProFaM’s objective, in the case of naturally menopausal women, is hormonal preservation. The idea behind this procedure is to prevent, by reimplanting functioning ovarian tissue, debilitating conditions which occur more frequently in women after the menopause, such as cardiovascular disease and osteoporosis. Moreover, the procedure would potentially delay bothersome symptoms of the menopause to an age when a woman is not struggling with family and career issues. Nine cases of UK women, age range 22-36, were reported to have undergone the protocol thus far.

29 July 2019: 

However, authors note that non-oral formulations are preferred because of the adverse lipoprotein effects of oral testosterone. So far, adverse side effects of non-oral formulations appear to be restricted to small weight gain, mild acne and increased hair growth, but more research on long-term effects is needed.

The most comprehensive systematic review and meta-analysis of testosterone treatment for women undertaken, including 46 reports on 36 trials, involving 8,480 women, published in The Lancet Diabetes & Endocrinology journal, suggests it can significantly improve sexual wellbeing for postmenopausal women. Benefits include improved sexual desire, function and pleasure, together with reduced concerns and distress about sex. Although best known as a male hormone, testosterone is important for female sexual health, contributing to libido and orgasm as well as helping to maintain normal metabolic function, muscle strength, cognitive function and mood. Levels decline naturally over a woman’s lifespan, and can also drop sharply following surgical menopause.

Prior research has suggested that testosterone therapy can improve sexual function in women, but the available formulations have been designed for men and evidence for their safety or for adverse side-effects in women is scant.

“Our results suggest it is time to develop testosterone treatment tailored to postmenopausal women rather than treating them with higher concentrations formulated for men,” says senior author Professor Susan Davis from Monash University, Australia. “Nearly a third of women experience low sexual desire at midlife, with associated distress, but no approved testosterone formulation or product exists for them in any country and there are no internationally-agreed guidelines for testosterone use by women. Considering the benefits we found for women’s sex lives and personal wellbeing, new guidelines and new formulations are urgently needed.” [1]

In this study, scientists reviewed 46 reports about 36 randomised controlled trials, conducted between January 1990 and December 2018 and involving 8,480 participants aged 18 to 75 years, approximately 95% of whom were post-menopausal. The trials compared testosterone treatment to a placebo or to an alternative hormone treatment such as oestrogen, with or without progestogen. The authors reviewed the effects of treatments on sexual function and on measures of heart, cognitive and musculoskeletal health.

22 July, 2019: 

Summary

In a randomized cross-over study by Park et al., the expression of structural proteins and protein regulatory markers was measured in muscle samples collected from women who had received transdermal estradiol (E2) or placebo the preceding week and were either in the early postmenopause (EPM, ≤6 years since menopause, n=13) or late postmenopause (LPM, >10 years since menopause, n=14) stages [1]. In response to acute E2 treatment, dephosphorylation (activation) of forkhead box O3 (FOXO3) protein, that triggers apoptosis, and expression of muscle-specific ring finger protein (MuRF1), that triggers muscle protein degradation, were found to decrease in EPM but not in LPM women. This suggests that the beneficial effects of E2 on muscle protein breakdown may be dependent on the time after menopause.

Commentary

Sarcopenia is defined as age-related loss in muscle mass and strength [2]. Its prevalence has been reported to increase from 37% in women in their forties to 57% in women in their fifties, suggesting a link between menopause and the pathogenesis of this disease [3]. Although the mechanism underlying the possible negative effect(s) of estrogen deficiency on the loss of muscle mass and strength are yet to be elucidated, both direct (through estrogen receptors [ER] expressed on skeletal muscle cells) and indirect (via increase in pro-inflammatory cytokines induced by a rapid decrease in estrogen) pathways could be involved [2]. In line with this concept, menopausal hormone therapy has been supposed to protect postmenopausal women from muscle loss. For example, the Women’s Health Initiative trial assessed body composition and found that women on estrogen-progestin treatment did not lose lean body mass, compared to those on placebo who did [4].

8 July, 2019

Summary

Even though vasomotor symptoms (VMS) and migraine are highly prevalent and often coexist during the menopause transition, interactions between the two are understudied, and it is possible there are shared physiologic mechanisms. The authors of this study investigated potential associations between VMS and migraine using the longitudinal Study of Women’s Health Across the Nation (SWAN).[1] They included 467 women with a self-reported history of migraine diagnosis made by a medical provider, and 2,466 women without a migraine diagnosis served as controls. VMS (assessed as number of days hot flashes and night sweats were experienced in the prior two weeks and converted to a mean symptom frequency) were self-reported at baseline and annually during follow up which varied between 2 and 10 years with greater than half of the women completing all 10 assessment. Vaginal dryness symptoms, also related to menopause, but without vasomotor origin, were also assessed using a frequency score. For an additional control comparison, the authors further examined the association of VMS and vaginal dryness with back pain, another pain disorder, to investigate the specificity of the association of VMS and migraine. Study results showed that a prior diagnosis of migraine predicted a higher frequency of hot flashes (p = 0.0036) and night sweats (p = 0.0138) after adjusting for all covariates. Significant interactions between migraine diagnosis and reproductive stage were noted, with higher frequencies of VMS in women with migraine, particularly in perimenopause. There was no association between migraine diagnosis and vaginal dryness. In a small subgroup of women with back pain, no association between back pain and hot flashes or night sweats was identified when compared to women with no back pain. The authors theorize that declining estrogen levels during the menopause transition are associated with hypothalamic changes which may explain the increased frequency of both VMS and migraine during this time frame.

11 July, 2019

Commentary on "Impact of natural menopause on multiple sclerosis: a multicentre study" by Baroncini D, et al.

Summary

In their recent paper, Baroncini et al [1] evaluated changes in relapse rate and clinical disability, as measured by the Expanded Disability Status Scale (EDSS) score, associated with menopause in women with multiple sclerosis (MS). They asked 148 women from the Lombardia region of Italy about their menopausal history, and then collected their relevant clinical information from medical records. Most of the women were on self-injectable MS treatments and, at the time of menopause, the group overall had mild-moderate disability (mean EDSS was 2.3, and the range was 0-7.5). Only 3% of women used hormone replacement therapies after menopause. The primary finding was that annualized relapse rate (average number of relapses in one year) decreased from 0.21 relapses a year on average before menopause, to 0.13 relapses a year after menopause. This represented a 38% decrease in relapses. However, this finding was no longer considered statistically significant when the investigators controlled for possible confounding factors, like age and MS duration. The second finding was that after menopause, increases in EDSS score were steeper, i.e there was more rapid worsening of disability. This more rapid progression of disability remained statistically significant after adjusting for confounding factors.

28 June, 2019

Who are the women that live longer?

Summary

A new study from the Netherlands attempted to find markers that may predict higher longevity in women [1]. A subgroup of the Netherlands Cohort Study (NLCS) consisted of those who were born in 1916-1917 and were followed until death or until reaching age 90 (in the years 2006-2007). Out of 2697 eligible women with complete data, 928 lived to be 90 and 1769 died at earlier ages. Lifestyle, dietary habits, reproductive and medical history, and cancer risk factors were collected when women were around age 70, using a self-administered 11-page questionnaire. Mortality was recorded based on a linkage with central national registries. The results were rather disappointing, as very few parameters were found to significantly correlate with longevity: age at first childbirth, and ever-use of HRT in women with an early menopause (< 50 years) were associated with the likelihood of reaching the age of 90 years. Many other variables, generally thought to be relevant to longevity, failed to show a linkage (i.e., age at menarche or at menopause, menstruation lifespan, history of childbirth).

Commentary

Despite the universal wish to better understand the reasons why women live longer than men, and what might in general be the reasons for extreme longevity, this Dutch study did not provide definite answers. Interestingly for menopause specialists, ever-use of HRT in women entering menopause before age 50 did influence longevity.

Personally, I was not surprised to see the above results, since the issue of longevity is certainly very complex, involving genetic and medical, dietary, socio-economical, environmental and other factors. Just one example that might affect the outcomes of this particular cohort: the participating women were born during World War 1 and lived several years within their occupied country during World War 2. I would imagine that this might have had an impact on future health and disease, on physical and emotional parameters and on reproductive factors. Also, and not taking a view as an expert epidemiologist or a statistician, the fact that the cohort was rather small, and the variables tested were so many, makes it a-priori very difficult to reach significance for any potential association.