Summary

Lam et al. [1] recently reported a systematic review and meta-analysis aimed at assessing the efficacy of behavioral interventions on sleep outcomes among peri- and postmenopausal women, as measured by standardized scales and objective methods (polysomnography, actigraphy). Secondarily they evaluated the safety of these methods through the occurrence of adverse events. The authors performed searches within MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science using an appropriate search strategy in order to retrieve relevant papers of randomized controlled trials (RCTs) evaluating the effects of behavioral interventions on sleep quality. Risk of bias was also assessed with classical tools used for this purpose. All data were pooled in a meta-analysis using a random-effects model. A total of nineteen articles reporting results from 16 RCTs were included, representing a total of 2,108 peri- and postmenopausal women. Overall, behavioral interventions showed a statistically significant effect on sleep outcomes. Subgroup analyses revealed that cognitive behavioral therapy (CBT), physical exercise and mindfulness/relaxation improved sleep, as measured using both subjective (i.e the Pittsburg Sleep Quality Index) and objective measures. Low- and moderate-intensity exercise also improved sleep outcomes. No serious adverse events were reported. Overall risk of bias ranged from some concern to serious, and the certainty of the body of evidence was assessed to be of very low quality. The investigators conclude that their meta-analysis provides evidence that behavioral interventions, specifically, CBT, physical exercise, and mindfulness/relaxation, are effective treatments to improving sleep outcomes among peri- and postmenopausal women.

Commentary

During the menopausal transition, as the ovarian function declines, there is an increase in the prevalence of various symptoms or complaints that affect female quality of life [2]. In this population, sleep problems (i.e. sleep disruption and insomnia) are frequently reported, with a prevalence ranging from 40 to 48% [3] and mostly related to vasomotor symptom [4]. Despite this, the cause is most likely to be multifactorial including factors such as premenopausal sleep status, hormone levels, comorbidities, aging, and chronic pain [5]. Although pharmacological interventions such as menopause hormone therapy, antidepressants, and hypnotics have been reported to be effective in treating menopause-related sleep disruption and chronic insomnia, some women are unwilling to begin pharmacological treatments because of adverse effects, contraindications, or personal preference. In this sense, behavioral interventions may be safe alternatives. Frequent behavioral therapies for insomnia include exercise, CBT, sleep restriction therapy (SRT), stimulus control therapy, and mindfulness or relaxation therapy. CBT for insomnia mainly combines several different behavioral techniques including SRT, stimulus control therapy, sleep hygiene, and relaxation therapy [6]. These techniques are supposed to be first line treatments and work through mechanisms such as the alteration of dysfunctional beliefs regarding sleep, education and adjustment of maladaptive behaviors that contribute to sleep problems, and attenuation of cognitive and autonomic arousal levels [6]. Despite this, practitioners still tend to rely on pharmacological interventions and data regarding the effectiveness of behavioral interventions for sleep outcomes has not been well characterized in peri- and postmenopausal women. Bearing this mind, the authors of the present commented research [1] aimed at evaluating the efficacy of behavioral interventions on sleep outcomes in peri- and postmenopausal women, measured by standardized scales and objective methods, secondarily evaluating the safety of these methods through the occurrence of adverse events. They meta-analyzed data of 16 RCTs that included a total of 2,108 peri- and postmenopausal women. Analysis found that behavioral interventions specifically, CBT, physical exercise, and mindfulness/relaxation, had a positive effect on sleep outcomes. Subgroup analyses revealed that these behavioral interventions improved sleep. Low- and moderate-intensity exercise also improved sleep outcomes and there were no serious reported adverse events. Physical exercise seems to promote sleep through several mechanisms including reduction of anxiety and depression, thermos- and cytokine regulation, changes in neurochemistry, and a phase shift of the circadian system [7]. Nevertheless, the exact mechanism is still unclear but might be related to exercise, type and intensity. In this sense, the authors recommend that future research should perform comparison of the types and intensities of exercise, as well as increase more studies related to CBT and relaxation/mindfulness techniques, in order to provide less vague guidelines for the management of sleep problems during female midlife. We agree with Lam et al [1].

The authors appropriately expose that their meta-analysis is limited by the high level of heterogeneity within studies, mainly because of the non-standardized nature of the behavioral interventions. A major limitation of all of sleep studies has been the use of tools that perform a subjective assessment of sleep outcomes. However, the authors did aim to only analyze those that used validated objective tools, which indeed is a strength of the meta-analysis. Despite this, investigators conclude that their study provides evidence that behavioral interventions, specifically, CBT, physical exercise, and mindfulness/relaxation, are effective treatments for the improvement of sleep outcomes in mid-life women (peri- and postmenopausal). There is a need for more research in this field.

 
Peter Chedraui, MD, PhD
Instituto de Investigación e Innovación en Salud Integral
Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador

References

1. Lam CM, Hernandez-Galan L, Mbuagbaw L, Ewusie JE, Thabane L, Shea AK. Behavioral interventions for improving sleep outcomes in menopausal women: a systematic review and meta-analysis. Menopause. 2022 Sep 6. doi: 10.1097/GME.0000000000002051.
https://pubmed.ncbi.nlm.nih.gov/36067398/

2. Chedraui P, Aguirre W, Calle A, et al. Risk factors related to the presence and severity of hot flushes in mid-aged Ecuadorian women. Maturitas. 2010;65(4):378-82.
https://pubmed.ncbi.nlm.nih.gov/20031350/

3. Blümel JE, Cano A, Mezones-Holguín E, et al. A multinational study of sleep disorders during female mid-life. Maturitas. 2012;72(4):359-66.
https://pubmed.ncbi.nlm.nih.gov/22717489/

4. Kravitz HM, Zhao X, Bromberger JT, et al. Sleep disturbance during the menopausal transition in a multi-ethnic community sample of women. Sleep. 2008l;31(7):979-90.
https://pubmed.ncbi.nlm.nih.gov/18652093/

5. Baker FC, de Zambotti M, Colrain IM, Bei B. Sleep problems during the menopausal transition: prevalence, impact, and management challenges. Nat Sci Sleep. 2018;10:73-95.
https://pubmed.ncbi.nlm.nih.gov/29445307/

6. Babson KA, Feldner MT, Badour CL. Cognitive behavioral therapy for sleep disorders. Pschiatr Clin North Am. 2010;33(3):629-40.
https://pubmed.ncbi.nlm.nih.gov/20599137/

7. Youngstedt SD. Effects of exercise on sleep. Clin Sports Med. 2005;24(2):355-65.
https://pubmed.ncbi.nlm.nih.gov/15892929/ 

Summary

Recently, Lotz et al. [1] reported the results of a retrospective study carried out on 17 women with premature menopause (spontaneous or induced) who had undergone ovarian tissue transplantation to restore their fertility, and were diagnosed with endometriosis during laparoscopic transplantation. The authors were interested in determining how endometriotic lesions after cytotoxic treatment and premature menopause might be explained, and whether endometriosis affects pregnancy rates. During surgery, it was found that twelve women had stage I endometriosis and five stage II endometriosis according to the rASRM classification; endometriosis foci were completely removed and ovarian tissue was transplanted into the pelvic peritoneum. Of the 17 women with endometriosis, 4 women were reported to have dysmenorrhea complaints, but none of the women reported general pelvic pain or dyspareunia. Prior to transplantation, four women who had taken hormone replacement therapy, four oral contraceptives and two tamoxifen. Following ovarian transplantation, pregnancy rate was 41.2% and the live birth rate was 35.3%. Pregnancy occurred in three cases after spontaneous conception, in four women after a natural cycle IVF/ICSI. The investigators concluded that there is an under-researched association between endometriosis in women entering premature or early menopause either after gonadotoxic treatment or due to primary ovarian insufficiency, recommending that specialists need to be aware of this condition as more and more women will use cryopreserved ovarian tissue transplant as an option to fulfill their desire to have children.

a systematic review and meta-analysis

22 August 2022

Summary

Liu et al. [1] recently reported a systematic review and meta-analysis that evaluated the potential of structured exercise to alleviate the subjective frequency and severity of vasomotor symptoms (VMS). For this, the authors searched four databases in order to identify randomized controlled trials (RCTs) that evaluated the effect of structured exercise (i.e. aerobic training) on the severity and/or frequency of VMS in menopausal women. Two reviewers independently screened records for eligibility, extracted data and assessed risks of bias and evidence certainty using the Cochrane and the GRADE tools (Grading of Recommendations Assessment, Development and Evaluation). Data were pooled, when appropriate, using random-effect meta-analyses. The researchers appraised a total of twenty-one RCTs involving 2,884 participants. Compared to no-treatment (controls), exercise significantly improved severity of VMS (10 studies, standardized mean difference [SMD] = 0.25; 95% CI: 0.04 to 0.47, p = 0.02, very low certainty of evidence). The effect size was attenuated when studies with a high risk of bias were excluded (SMD = 0.11, 95% CI: -0.03 to 0.26, p = 0.13). No significant changes in vasomotor frequency were found between exercise and controls (SMD = 0.14, 95% CI: -0.03 to 0.31, p = 0.12, high certainty of evidence). The authors conclude that exercise might improve VMS severity, indicating that future rigorous randomized clinical trials (RCTs) addressing the limitations of their review are warranted to explore the optimal exercise prescription to target the severity of VMS. 

15 August 2022

Summary

Recently, Mezones-Holguin et al. [1] reported the results of a study aimed at evaluating the association between menopausal status and female sexual function among mid-aged women with human immunodeficiency virus (HIV) infection. This was a cross-sectional study performed on 221 sexually active HIV-infected women aged 40 to 59, based on a secondary analysis of a three-hospital survey performed in Lima, Perú. Menopausal status was classified according to Stages of Reproductive Aging Workshop criteria (STRAW+10), the exposure variable was categorized as binary (non-postmenopausal and postmenopausal) and as multinomial (pre-, peri-, and postmenopausal). The 6-item Female Sexual Function Index (FSFI, total score 19 or less) was used to define low sexual function (LSF). In addition, socio-demographic and clinical variables were assessed that included age, used highly active antiretroviral therapy scheme, disease duration (time since diagnosis), depressive symptoms, and co-morbidities. Poisson generalized linear models were used. Studied women women had a median age of 47.0 years (interquartile range: 7.5), 25.3% were premenopausal, 25.8% were perimenopausal, and 48.9% were postmenopausal. The authors found that 64.3% had LSF. The frequency of LSF was 53.6% among non-postmenopausal women and 75.0% in postmenopausal ones. Postmenopausal status was associated with LSF in both the crude (cPR= 1.39; 95% CI: 1.13-1.71) and the adjusted regression models (aPR= 1.38; 95% CI: 1.12-1.71). The authors conclude that HIV-infected postmenopausal women have a higher prevalence of LSF than those non-postmenopausal ones, even when adjusting for multiple potential confounders.

a prospective cohort sub study of the Aspree trial.

8 August 2022

Summary

Blood testosterone concentrations in women decline during the reproductive years and reach a nadir in the 7^th decade after which concentrations increase and are restored to those of reproductive age women in the 8^th decade. The present commented study [1], which was a prospective cohort sub-study of the longitudinal randomized ASPREE trial aimed to establish the association between the concentration of testosterone in the blood and the risk of major adverse cardiovascular events (MACE) and all-cause mortality in healthy older women. Eligible participants were women aged at least 70 years from Australia with unimpaired cognition, no previous MACE, and a life expectancy of at least 5 years. Women using hormonal or steroid therapy were ineligible for inclusion. Concentrations of sex steroids were measured with liquid chromatography-tandem mass spectrometry whilst SHBG was measured with immunoassay. Results were divided into four quartiles and lower and higher concentrations were compared. Primary endpoints were risk of MACE and all cause mortality. Associations with sex steroid concentrations were assessed using Cox proportional hazards regression that included age, body mass index, smoking status, alcohol consumption, diabetes, hypertension, dyslipidemia, impaired renal function, and treatment allocations in the Aspree trial (aspirin vs placebo). A total of 5,535 women were included in the final analysis. Median age at entry was 74.0 years (interquartile range [IQR] 71.7-77.7). During a median follow up of 4.4 years (24,553 person years) 144 (2.6%) women had a first MACE (incidence 5.9 per 1,000 person years). During a median 4.6 years (IQR 3.8-5.6) of follow up (25,295 person years) 200 (3.6%) of the 5,535 women died, an incidence rate of 7.9 per 1,000 person years. In the fully adjusted models, higher concentrations of testosterone were associated with lower incidences of MACE (quartile 4 vs quartile 1 HR 0.57 [95% CI: 0.36-0.91] as were higher concentrations of DHEA (Q4 vs Q1 0.61 [95% CI 0.38-0.97]. For Oestrone, a lower risk of MACE was observed for Q2 only when compared to Q1. No association was seen between SHBG and MACE or between any hormone or SHBG and all-cause mortality. Blood concentrations of testosterone and DHEA above the lowest quartile in older women were associated with first ever MACE. Given that physiological effects of DHEA are mediated through its steroid metabolites, if these findings were to be replicated, trials investigating testosterone therapy for the primary prevention of ischemic cardiovascular disease events in older women would be warranted.

25 July 2022

Summary

Recent studies have shown that women aged 70 years and older have blood testosterone (T) concentrations similar to those of premenopausal women [1,2,], and that circulating T concentrations tend to increase with age from the 8th decade, while concentrations of T’s adrenal precursor dehydroepiandrosterone (DHEA) decline [3,4]. This lead Islam and collaborators to investigate the associations between these sex steroids and cardiovascular disease (CVD) in a large cohort of women aged at least 70 years [5]. They reported on first major adverse (ischaemic) cardiovascular events (MACE) in 5,535 women, mean age 74 years, followed-up for a median of 4.4 years. After adjusting for established risk factors for MACE and study treatment allocation, Islam et al. [5] reported that women with blood T and /or DHEA concentrations in the lowest quartile had almost a 2-fold greater risk of a first MACE compared with women with higher T/DHEA levels (i.e hazard ratios for the highest quartile versus the lowest quartile were 0.57 [95% CI, 0.36 to 0.91, p=0.02] for T and 0.61 [95% CI, 0.38 to 0.97, p=0.04] for DHEA. No meaningful findings for oestrone or sex hormone binding globulin (SHBG) were seen. Divergence of the cumulative hazard curves for MACE for the lowest quartiles of T and DHEA were statistically significantly different from the other higher quartiles by the third year of follow-up. The authors concluded that higher androgen blood levels are not deleterious to cardiovascular health in older women and that further studies of T and MACE in older women are needed.

18 July 2022

Summary

Gambacciani et al. [1] performed a prospective pilot study to evaluate the effects of associating a neodymium:yt-trium–aluminum–garnet (Nd:YAG) laser with a vaginal erbium laser (VEL), as a non-ablative photothermal therapy for superficial dyspareunia in postmenopausal women (PMW) suffering of the genitourinary syndrome of menopause (GSM). Two groups of sexually active PMW reporting superficial dyspareunia were selected: one (n= 15, VEL) was treated using an erbium:yttrium–aluminum–garnet laser crystal with a wavelength of 2,940 nm; and the other group (n =15, VEL + Nd:YAG) was treated with VEL and after by Nd:YAG laser treatment. Treatment consisted of three laser applications at 30-day intervals. Symptoms were assessed before, after each laser application and after 1 and 3 months from the end of the treatment, using the subjective visual analog scale (VAS) for superficial dyspareunia. All the participants (n = 30) of the both groups showed a rapid and significant improvement of superficial dyspareunia over time independently of age and years since menopause. The VEL + Nd:YAG group showed a greater improvement of superficial dyspareunia; this difference was evident since the first treatment and remained stable over time. Authors conclude that this pilot study demonstrates that the addition of Nd:YAG to VEL may induce greater improvement in superficial dyspareunia in PMW with GSM.

11 July 2022

Summary

A recent cross-sectional study was conducted by an Indian university on whether women's cognitive abilities are sensitive to the severity of menopausal symptoms [1]. The study involved 404 rural women aged 40 to 65 years who completed the Green Climacteric Scale to assess the severity of menopausal symptoms and the Hindi Mini-Mental State Examination scale to assess certain cognitive performances. Possible associations of the menopausal symptoms were assessed to the overall cognitive performance and five cognitive domains (orientation, registration, attention, recall, and language/visuo-spatial skills). The results found that women experiencing severe menopausal symptoms (higher Total Greene climacteric score) presented significantly lower average values for orientation, registration, attention, recall, and language/visuo-spatial skills as compared to women with mild menopausal symptoms. Multivariate linear regression analysis found that severe depression and sexual dysfunction were significantly and negatively associated with overall cognitive scores. The authors conclude that the cognitive performance of women was sensitive to severe depression and sexual dysfunction.

27 June 2022

Summary

Vulvar lichen sclerous (VLS) is an important concern after the menopause and is caused by chronic vulvar inflammation associated to low levels of estrogen. Pruritus and burning sensation in the affected areas of depigmentation are usually the most frequently reported symptoms, causing dyspareunia and sexual dysfunction. Topic corticoid treatment, although effective, is often discontinued after a long time due to the low adherence [1,2]. In this sense, alternative treatments have been proposed such as microablative fractional radiofrequency (MFR). In a recent pilot study, Kamilos et al. [3] assessed the effects of MFR (including clinical response and histomorphometrics) in 26 postmenopausal women with symptomatic and histologically confirmed VLS divided into three groups according to previous management with corticosteroids: G1, no previous corticosteroid treatment; G2, treated with corticosteroid for up to 5 years; and G3, treated for more than 5 years. After each session they were examined for their symptoms on a visual analog scale and completed a satisfaction questionnaire. Morphometric findings of vulvar biopsies were performed at enrollment and after the last treatment session in 11 cases. After two to three MFR sessions, most participants in all groups became either ‘‘asymptomatic’’ or ‘‘much better’’ than prior to treatment and were ‘‘very satisfied’’ or ‘‘satisfied’’ with the intervention. Upon enrollment, pruritus and burning sensation were the most frequently reported symptoms. Nearly 40% of women in all groups reported complete remission of symptoms. The improvement was rated as moderate or higher by 80%, 76%, and 66% of participants in groups 1, 2, and 3, respectively. The symptomatic improvement persisted for a mean of 11 months (range, 7–16) after the treatment. Type III collagen concentration significantly increased and was associated with important symptom improvement. The authors conclude in their pilot study that may be an effective and safe treatment for symptomatic VLS.

20 June 2022

Summary

Weber et al. [1] reported on a longitudinal study that was conducted over three waves from 2005 through 2016. For the duration of the study, all 85 subjects were in their perimenopause stage (STRAW+10 stage -2 to stage +1a) and evaluated over 400 bi-annual visits. A comprehensive neuropsychological battery was administered, menopausal symptoms evaluated and 17β-estradiol and follicle stimulating hormone (FSH) measured. Multilevel latent profile analysis was used to identify cognitive profiles. All of the recorded visits were sorted into 4 subgroups according to cognitive profiles. After adjusting for STRAW+10 stages and demographic factors, the regression analyses were conducted to determine differences in hormones and symptoms. Most women showed no global impairment, while a significant minority developed weaknesses in verbal learning and memory that were related to both hormonal flux and menopausal symptoms. Compared to women who were cognitively normal, those who had weaknesses in verbal learning and memory were differentiated by less hormonal variability and more sleep disturbance, while women with strength in verbal learning and memory had fewer depressive and vasomotor symptoms (VMS). The investigation showed a significant heterogeneity in cognition during the perimenopause. The authors suggested that cognitive profile analysis should be taken into account to identify at risk populations in order to provide appropriate interventions.