18 October 2021

Summary

Bretas et al. [1] have recently published data of fourteen sexually active postmenopausal women with vulvovaginal atrophy, aged 45 to 65 with aim of evaluating the clinical response and collagen remodeling in the vaginal wall after three monthly sessions of carbon dioxide (CO2) laser application. Women filled out clinical questionnaires (Vaginal Health Index [VHI], the Female Sexual Function Index [FSFI] and the International Consultation on Incontinence Questionnaires Short Form [ICIQ-SF]), gynecological examinations and histological techniques before and after 20 weeks of treatment. Biopsies were taken from the lateral vaginal wall at baseline week 0 (left wall) and week 20 (right wall). Tissue samples were stained with hematoxylin and eosin, Periodic Acid-Schiff (PAS), Picrosirius Red Stain and Orcein dyes. Immunohistochemical study was used to quantify collagens I and III in the samples. Mean age of participants was 54.4 ± 4.5 years, with an average time of amenorrhea of 7.6 ± 5.1 years. After 20 weeks of treatment with laser, total FSFI and VHI scores increased whereas ICIQ-SF scores decreased. Vaginal pH did not significantly change. Histological studies showed significant increases in the total and superficial epithelial cell layers, and type III collagen fibers. Immunohistochemical studies confirmed the significant increase in collagen III. The authors conclude that histological findings evidenced a reversal of epithelial atrophy and collagen remodeling of the vaginal wall confirmed by immunohistochemical analysis.

Commentary

The management of vulvovaginal atrophy is a major issue for both patients and those taking care of postmenopausal women. Despite different available treatments, the eradication of the problem is not feasible with the current available options. In addition, if clinical problems are untreated, the evolution is progressive due to the presence of other co-morbid conditions.  Bretas et al. [1] reported the results of a pilot study based on the monthly vaginal application of CO₂ laser (three sessions) to postmenopausal women aged 54 (menopause onset 7 years average); in addition of including both clinical and histological assessments. This approach is relevant because it included the subjective perception of the patient and there was also a histological assessment of effect of the laser application. The used questionnaires were well-know and validated tools for those working in the field of assessing vaginal and urinary symptoms. In addition, vaginal biopsies were performed to women before and after the complete treatment. The used histological techniques such as hematoxylin-eosin, PAS and others are considered standards.

11 October 2021

Summary

Recently, a group of Korean internists published a paper in the journal Scientific Reports describing the results of their analysis of the national health insurance database focusing on the effects of menopausal hormone therapy (MHT) on the incidence of end-stage renal disease (ESRD)[1]. As a total, 4,905 Korean postmenopausal women developed ESRD, among the 1.46 million followed-up for 9 years since 2009. Adjusted hazard ratios (HRs) [95% confidence interval] for ESRD development according to their MHT duration were: no MHT, reference; MHT < 2 years; 0.634 [0.556-0.723]; 2-5 years, 0.721 [0.597-0.871]; > 5 years, 0.654 [0.531-0.806], implying that MHT protects kidneys irrespective of its duration, with ~30% reduced risk of ESRD. Subgroup analyses showed that the beneficial effect of MHT was more pronounced in women aged <65 years and those with diabetes or hypertension, whereas MHT was associated with reduced risk of ESRD similarly in women with body mass index (BMI) < 25 or > 25, or in those with or without pre-existing chronic kidney diseases. The study showed a protective effect of MHT on kidneys on the largest scale ever reported.
 

Commentary

For many decades, the discussion about the benefits of MHT to prevent chronic diseases in postmenopausal women has centered around cardiovascular diseases and osteoporosis. The effects of MHT on metabolic disorders related to the former, such as dyslipidemia and diabetes, has also been intensively studied, whereas kidneys have hardly been paid enough attention. For example, words “kidney” or “kidneys” cannot be found in the encyclopedic “2016 IMS Recommendations on women’s midlife health and menopause hormone therapy”, which seems to cover almost all the aspects of life that MHT could have any effects on [2]. The negligence may partly be due to the discrepancy found in the past few papers with smaller scales than the present one on the effects of MHT on kidney functions: one study reported a higher prevalence of microalbuminuria in MHT users than non-users [3], while another found that MHT was associated with better estimated glomerular filtration rate (eGFR) and blood pressure (BP) levels than non-users [4].

27 September 2021

Summary

Langton et al. [1] have examined the association of oral contraceptive (OC) use and tubal ligation (TL) with natural menopause before the age of 45 years in a population-based study within the prospective Nurses’ Health Study II (NHSII) cohort. Participants were followed from 1989 to 2017 and response rates were 85-90% for each cycle. A total of 106,633 NHSII participants were included who were premenopausal (aged 25-42) at the initiation of the study. The use, duration and type of OC and TL were recorded at the beginning of the study and every 2 years. Menopausal status and age were evaluated every 2 years. Follow-up continued until early menopause, age 45, hysterectomy, oophorectomy, death, cancer diagnosis, or loss to follow-up occurred. Authors used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals adjusted for lifestyle, dietary, and reproductive factors. Over 1.6 million person-years, 2,579 participants of the analytic cohort experienced early natural menopause. In multivariable models, the duration, timing, and type of OC use were not associated with the risk of early menopause. Compared to women who never used OCs, those reporting 120+ months of OC use did not have a significant risk for early menopause (HR 1.01 95% CI: 0.87-1.17; p for trend=0.71). Contrary to this, TL was associated with a modest increased risk of early menopause (HR = 1.17, 95% CI, 1.06-1.28).

13 September 2021

Summary

Hyvärinen et al. [1] carried out a study with the aim of predicting the age of natural menopause (ANM) in middle aged women. They used Cox models with dependent covariates, selecting predictors with lasso regression. For this research, authors analyzed the NAMS longitudinal study "Study of estrogen regulation of muscle apoptosis" consisting of 6,878 women initially screened of which 1,393 were finally surveyed and divided into pre- and perimenopausal. Of these, data of 279 participants (45 to 55 years of age) and that of 105 women that completed bleeding diaries were analyzed. Results were quantified with c-indices, mean and standard deviations of absolute errors. Regression models included alcohol consumption, vasomotor symptoms, self-reported physical activity, and relationship status as predictors, as well as, estradiol and follicle-stimulating hormone levels, menstrual cycle length, smoking, education, and the use of hormonal contraception. After analysis of the models, the authors conclude that in addition to the levels of sex hormones, rhythm of the menstrual cycle and menopausal symptoms, lifestyle habits and socioeconomic factors can provide useful information for the prediction of ANM.

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.