12 April 2022

Summary

Due to the results of the 2002 WHI, many women decided to follow the advice of their doctors and switch from using synthetic hormones to using compounded bioidentical hormone therapy (cBHT). This led to an increase in the prescription of these compounds in the last decade to up to around 33 million annual prescriptions and with a progressive increasing trend. This prompted the FDA to ask NASEM (National Academy of Science, Engineering, and Medicine) to evaluate the available evidence on cBHT, concluding that there was a lack of high-quality research establishing the safety and efficacy of cBHT, and that studies with a higher level of evidence were needed, as well as a systematic review and a meta-analysis. Bearing this in mind, Liu and collaborators [1], carried out a systematic review and meta-analysis based on protocols registered in PROSPERO and carried out in accordance with the Cochrane Manual for Systematic Reviews of Interventions and the checklist of 27 items Preferred Reporting Items for Systematic Review and Meta-Analysis Statement (PRISMA) [2,3], in order to evaluate the existing evidence related to the safety and efficacy of cBHT that are prescribed to peri- and postmenopausal women. The authors searched across systems, choosing for analysis randomized controlled trials (RCTs) that compared outcomes in peri- and postmenopausal women using cBHT against placebo or FDA-approved hormonal products. They analyzed bias, according to the Cochrane risk of bias tool and took primary outcomes of safety (changes in lipid profile and glucose metabolism) and efficacy (changes in symptoms of vaginal atrophy). Secondary outcomes included changes in the endometrium, risk of adverse events, vasomotor symptoms, change in hormone levels, and change in bone mineral density.

28 March 2022

Summary

The role of obesity and weight change in breast-cancer development is complex and incompletely understood. Recently, Ellingjord-Dale et al. [1] recently reported the results of a study that investigated the effects of long-term weight change and the risk of breast-cancer risk taking into account body mass index (BMI) at 20 years of age, menopausal status, hormone replacement therapy (HRT) and hormone-receptor status. The authors used data related to weight collected at three different time points from women who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study in order to analyze the association between weight change since age 20 up to mid-adulthood and risk of breast cancer. A total of 150,257 women (median age 51 years at cohort entry) were followed for a mean 14 years (standard deviation = 3.9) during which 6,532 breast-cancer cases occurred. In comparison to those with stable weight (± 2.5 kg), long-term weight gain of more than 10 kg was positively associated with postmenopausal breast-cancer risk in women who were lean at age 20 [hazard ratio (HR) = 1.42; 95% CI 1.22–1.65], were ever HRT users (HR = 1.23; 95% CI 1.04–1.44), never HRT users (HR = 1.40; 95% CI 1.16–1.68) and in estrogen and progesterone receptor positive (ER+PR+) breast cancer cases (HR = 1.46; 95% CI 1.15–1.85). The authors conclude that long-term weight gain was positively associated with postmenopausal breast cancer in women who were lean at age 20, both in HRT ever users and non-users, and hormone-receptor-positive breast cancer.

21 March 2022

Summary

Hysterectomy is the most common treatment option for women with uterine fibroids, providing definitive relief of the associated burdensome symptoms. Nevertheless, as with all surgical interventions, it is associated with the risk of complications, short-term morbidities, and mortality. Although all these aspects have previously been described, information regarding the potential long-term risks of hysterectomy is only recently becoming available. Bearing this in mind, recently, Madueke-Laveaux et al. [1] conducted a systematic review of the literature to identify long-term risks related to hysterectomies performed for uterine fibroids with or without oophorectomies since the short-term risks of both morbidity and mortality have already been widely studied. They included in their review studies published between 2005 and December 2020 that assessed the long-term impact of hysterectomy for benign pathology in women, identifying 29 relevant studies. The review of the identified articles showed that hysterectomy even with ovarian preservation can increase the risk of cardiovascular events (very strongly associated with hypoestrogenism), certain cancers (i.e urinary tract), the need for further surgery, and premature ovarian failure and menopause that lead to long-term sequelae such as fragility fractures, cognitive impairment and impairment of quality of life in different domains. In addition, when hysterectomy was performed in younger women (< 44 years) a significant higher rate of depression was found after 10 years of follow-up when compared to menopausal women over 50 years with established menopause. The authors remark that it is important to recognize that the available studies examine possible associations and hypotheses rather than causality, hence the results should be taken with caution.

14 March 2022

Summary

The preventive management of breast cancer often involves endocrine targeted treatments including tamoxifen and aromatase inhibitors. These have shown to lead to fewer diagnosis of estrogen receptor-positive breast cancers but have not consistently demonstrated reduced mortality related to breast cancer. The following paper to be commented is a review of the evidence of different treatments to reduce risk of future breast cancer [1]. A meta-analysis of four randomised prevention trials has shown that tamoxifen reduced the 10 year cumulative incidence of invasive breast cancers by 33% [2]. However, there was no beneficial effect on mortality demonstrated. Interventions such as magnetic resonance imaging screening and risk reduction bilateral mastectomy have shown to be effective interventions. Despite this, in the Women’s Health Initiative (WHI) randomized, controlled trial, ER-positive, PR-negative cancers were statistically significantly reduced in the group given conjugated equine estrogen and also deaths from breast cancer were reduced by 40% [3]. This finding has not been demonstrated for any other pharmacological intervention. This information needs to be widely disseminated to clinicians.

28 February 2022

Summary

Cipriani et al. [1] published the results of an observational - retrospective analysis that aimed at exploring the effects of testosterone treatment over clitoral color Doppler ultrasound (CDU) parameters in pre- and postmenopausal women with sexual dysfunction (n=81) after 6 months. For this, authors analyzed four groups of women: those that had received transdermal 2% testosterone alone (n=23, T), combined with vaginal estrogens (n=9, T+E), local vaginal estrogen (n=12, E), or vaginal moisturizers (n=37, M). Women underwent physical, laboratory, and genital CDU examinations at both visits (baseline and after 6 months) and completed different validated questionnaires, including the Female Sexual Function Index (FSFI). The main finding was that there was a significant increase in the clitoral artery’s blood flow. After six months, T therapy significantly increased clitoral artery peak systolic velocity (PSV) when compared to both M and E groups. In addition, as compared to baseline, T treatment was related with significantly higher FSFI scores (total and desire, pain, arousal, lubrication, orgasm domain scores) at 6 months. Similar findings were observed in the T + E group. No significant differences in the variations of total and high-density lipoprotein-cholesterol, triglycerides, fasting glycemia, insulin and glycated hemoglobin levels were found among the four groups and no adverse events were observed. The authors concluded that in women with sexual dysfunction, systemic T administration, either alone or combined with local estrogens, was associated with a positive effect on clitoral blood flow and a clinical improvement in sexual function, showing a good safety profile.

21 February 2022

Summary

Recently, Sinatora et al. [1] reported the results of a study aimed at investigating the relationship between inflammatory biomarkers and the metabolic syndrome (MS) in postmenopausal women (n=52, aged 50 to 79 years), in addition to performing cutoff points for IL-10, IL-6, and TNF-α in the diagnosis of MS. This was a cross-sectional observational study based on STROBE in which data were collected from obese (body fat percentage [% BF] ≥ 35%) postmenopausal women (at least 5 years), not on hormone therapy, and taking into consideration different diagnostic criteria for the MS (International Diabetes Federation (IDF); National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III), and Harmonized criteria), comorbidities, and values of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor- α (TNF-α), fasting glycemia (FG), triglycerides (TG), total cholesterol (TC), very low-density lipoproteins (VLDL-C), low-density lipoprotein (LDL-C), and high-density lipoprotein (HDL-C). Other analyzed parameters included body mass index (BMI), waist circumference (WC), and body composition as determined with bioelectrical impedance analysis. The authors found no significant difference between the methods and no interaction between the method and the presence of MS. However, for the values of WC, BF%, TNF-α, and IL-10/TNF-α ratio, a significant effect of the MS was observed. Those with the MS displayed lower values of BF% and TNF-α and higher values of the IL-10/TNF-α ratio. The higher IL-10/TNF-α ratio in the MS group was related to the greater anti-inflationary action of IL-10 and the IL-10/TNF-α ratio showed significant accuracy to discriminate women with MS according to the NCEP-ATP III criteria. The authors conclude that BF% and the lower TNF-α values in the groups with MS highlight the relationship between these variables. Higher IL-10/TNF-α ratio values in the MS group suggest that higher IL-10 concentrations may be contributing to the reduction of TNF-α in the MS group. Furthermore, the IL-10/TNF-α ratio showed significant accuracy to discriminate patients with MS according to the NCEP criteria. 

14 February 2022

Summary

The dry eye disease (DED) is a tear production disorder caused by a variety of factors, with dry eyes as the main symptom, and accompanied by binocular itching, foreign body sensation, burning sensation, or photophobia, blurred vision, and other manifestations. Severe symptoms of the DED can mainly affect the patient's visual function, resulting in decreased daily activities and poorer quality of life. Recently, Garcia-Alfaro et al [1] published the results of an observational study which was performed in a group of 1,947 peri- and postmenopausal women. It was found that the prevalence of dry eye symptoms was high in both peri- and postmenopausal women, and the prevalence of dry eye symptoms and Ocular Surface Disease Index (OSDI) scores were higher in postmenopausal women than in perimenopausal ones. The severity of DED symptoms increased with age and decreased with postponement of age at menopause. These findings suggest that menopausal status may be associated with the prevalence and severity of DED symptoms in women. During the menopausal transition and postmenopausal period, hormone levels change, and estrogen and androgen synthesis are reduced, which can cause lacrimal gland and meibomian gland dysfunction, which leads to tear deficiency, tear lipid deficiency, and changes in the kerato-conjunctiva, resulting in the higher prevalence of DED symptoms. Considering that female sex is an important risk factor for eye dryness, the objective data provided by the OSDI questionnaire and ocular examination supports early diagnosis of DED in peri- and postmenopausal women. Menopausal hormone therapy or other related treatments should be given opportunely, thus the DED can be successfully managed, and female quality of life be improved.

24 January 2022

Summary

Recently, Monterrosa-Castro and collaborators [1] published the results of a sub-analysis of a larger cross-sectional study (The CAVIMEC project [Quality of life in the menopause and Colombian Ethnics]), that aimed at identifying the frequency of sleep complaints (SC) and associated menopausal symptoms in apparently healthy women aged 40 to 59 (n=585), that resided in three different capital cities of the Colombian Caribbean. Researchers performed a door to door survey that included collecting sociodemographic characteristics and applying validated form and scales: Menopause Rating Scale (MRS), Jenkins Sleep Scale (JSS), Perceived Psychological Stress (perceived stress), Goldberg Anxiety and Depression Scale, SCOFF scale (eating disorders), and Loneliness Scale of Hughes. For the analysis women were divided into two groups, those with SC and those without SC, as determined by the JSS. Crude and adjusted logistic regressions were performed using SC as a dependent variable and sociodemographic characteristics and the results of the used scales as independent variables. The authors found that according to the JSS a 16.5% of women had SC, with no observed differences in terms of age, body mass index (BMI), or high blood pressure. More women with SC had depression, anxiety, the perception of loneliness, severe menopausal symptoms (MRS: somatic, psychological, urogenital subdomains), and quality of life severe impairment; with no observed differences found in terms of eating disorders and perceived stress. According to the adjusted logistic regression model, only depression was significantly related to SC (OR: 9.81 95% CI: 1.29-74.3, p<0.05). The investigators conclude that in the studied mid-aged Colombian cohort, SC was present in nearly 17% and associated with depressive symptoms.

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].