Honingberg et al (JAMA)... № 882

...(published online November 18, 2019 doi: https://doi.org/10.1001/jama.2019.19191) reported that both premature (before 40 years) natural and surgical menopause are associated with higher incident Cardiovascular Disease (for a composite outcome that included coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism.  In a cohort study that included 144 260 postmenopausal women, For natural premature menopause, the hazard ratio was 1.36; for surgical premature menopause, the hazard ratio was 1.87.

At the latest San Antonio Breast cancer symposium... № 883

...(December 2019, https://www.abstractsonline.com/pp8/#!/7946/presentation/2229), Chlebowski et al presented the long-term Breast cancer outcomes from the WHI Estrogen plus Progestin and Estrogen-alone trials.

During the intervention period, with 238 incident breast cancers, CEE-alone significantly reduced breast cancer incidence (HR 0.76 95%CI 0.58, 0.98, P = 0.04). As previously reported, subgroup analyses indicated CEE-alone was particularly beneficial for women with no prior HT use (interaction P = 0.04) and women with gap time >= 5 years (interaction P = 0.01). Post-intervention, through 16.1 years of cumulative follow-up, with 520 incident breast cancers, CEE-alone use continued to significantly reduce breast cancer incidence (HR 0.77 95% CI 0.65-0.92, P = 0.005) while subgroup differences were attenuated and were no longer statistically significant.

During the intervention period, with 360 incident breast cancers, CEE plus MPA use significantly increased breast cancer incidence (HR 1.26 95% CI 1.02, 1.56, P = 0.04) with increase in breast cancer incidence greater in women with prior HT use (interaction P = 0.02) and women with gap time < 5 years (interaction P = 0.002). Post-intervention, through 18.3 years cumulative follow-up, with 1,003 incident breast cancers, CEE plus MPA continued to significantly increase breast cancer incidence (HR 1.29 95% CI 1.14, 1.47, P < 0.001) while subgroup differences were attenuated and were no longer statistically significant.
The authors Conclusions: CEE-alone and CEE plus MPA use have opposite effects on breast cancer incidence. CEE alone significantly decreases breast cancer incidence which is long term and persists over a decade after discontinuing use. CEE plus MPA use significantly increases breast cancer incidence which is long term and persists over a decade after discontinuing use. As a result of the attenuation of subgroup interactions: all postmenopausal women with prior hysterectomy using CEE-alone have the potential benefit of experiencing a reduction in breast cancer incidence while all postmenopausal women using CEE plus MPA have the potential risk of experiencing an increase in breast cancer incidence.

Arterial Stiffness Accelerates Within 1 Year of the Final Menstrual Period: The SWAN Heart Study. № 884

Samargandy et al (Arterioscler Thromb Vasc Biol. 2020 Jan 23:ATVBAHA119313622. doi: 10.1161/ATVBAHA.119.313622. [Epub ahead of print]) determined whether and when women experience changes in arterial stiffness relative to the final menstrual period (FMP) and whether these changes differ between black and white midlife women studying 339 participants from the SWAN Heart Ancillary study (Study of Women’s Health Across the Nation). The interval within 1 year of FMP is a critical period for women when vascular functional alterations occur. These findings underscore the importance of more intensive lifestyle modifications in women transitioning through menopause.
Women had ≤2 carotid-femoral pulse-wave velocity (cfPWV) exams over a mean±SD of 2.3±0.5 years of follow-up. Annual percentage changes in cfPWV were estimated in 3 time segments relative to FMP and compared using piecewise linear mixed-effects models. At baseline, women were 51.1±2.8 years of age and 36% black.
Annual percentage change (95% CI) in cfPWV varied by time segments: 0.9% (-0.6% to 2.3%) for >1 year before FMP, 7.5% (4.1%-11.1%) within 1 year of FMP, and -1.0% (-2.8% to 0.8%) for >1 year after FMP. Annual percentage change in cfPWV within 1 year of FMP was significantly greater than the other 2 time segments; P<0.05 for both comparisons. Adjusting for concurrent cardiovascular disease risk factors explained part of the change estimates but did not eliminate the difference.

Black women had greater increase in cfPWV compared with white women in the first segment; P for interaction, 0.04.

The authors concluded that the interval within 1 year of FMP is a critical period for women when vascular functional alterations occur. These findings underscore the importance of more intensive lifestyle modifications in women transitioning through menopause.

Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers. № 885

Mavaddat N et al (Breast Cancer Res. 2020 Jan 16;22(1):8. doi: 10.1186/s13058-020-1247-4.) evaluated the effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers in a multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers, followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women.
There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar.
We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.

Breast Cancer Risk in Postmenopausal Women With Medical History of Thyroid Disorder in the Women’s Health Initiative № 886

Chien-Hsiang Weng et al . (Thyroid
2020 Apr;30(4):519-530.  doi: 10.1089/thy.2019.0426. Epub 2020 Feb 3) conducted a prospective cohort study of multiethnic U.S. postmenopausal women aged 50 to 79 years enrolled in both clinical trial and observational study arms between 1993 and 1998 and followed up through February 28, 2017. Development of invasive breast cancer after enrollment was recorded and a history of hyper- or hypothyroidism before the diagnosis of breast cancer was identified. The effect modification by MHT in both study arms was analyzed. All statistical tests were two sided.

Results: Among a total of 134,122 women included in the study, 8137 participants developed invasive breast cancer during the follow-up period. There was a significant inverse association of invasive breast cancer among women with a history of hypothyroidism (hazard ratio [HR] 0.91,[95% CI] 0.86-0.97) and among women who had taken levothyroxine [HR 0.89, 95% CI 0.82-0.96]. Evaluating effect modification by MHT use, the inverse association between hypothyroidism treated with thyroid replacement medications and breast cancer risk was strongest in non-MHT users [HR 0.80, 95% CI 0.69-0.93]. The results did not significantly differ by race/ethnicity. Although a history of hyperthyroidism was associated with an increased risk of invasive breast cancer [HR 1.11, 95% CI 0.91-1.35], this finding did not reach statistical significance. They did not see significant differences in the breast cancer Surveillance, Epidemiology, and End Results stages, histologic types, morphologic grades, or receptor status (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) according to thyroid disorder status.

Conclusions: Compared with women with no history of thyroid disorder, hypothyroidism was associated with a lower risk of breast cancer. This was mainly seen among those who received thyroid replacement therapy and had never used MHT. Among the treatment options for hypothyroidism, levothyroxine had the strongest inverse association with breast cancer risk.

Associations Between Maternal Antenatal Corticosteroid Treatment and Mental and Behavioral Disorders in Children № 887

Question  Is maternal antenatal corticosteroid treatment associated with mental and behavioral disorders in children?

Katri Räikkönen et al (JAMA. 2020;323(19):1924-1933. doi:10.1001/jama.2020.3937) used a population-based retrospective cohort study in Finland that included 670 097 children, exposure to maternal antenatal corticosteroid treatment, compared with nonexposure, was significantly associated with mental and behavioral disorders in children (hazard ratio, 1.33).

Meaning   These findings may help inform decisions about maternal antenatal corticosteroid treatment.

Here are some more details of the study.

Design, Setting, and Participants  Population-based retrospective cohort study using nationwide registries of all singleton live births in Finland surviving until 1 year and a within-sibpair comparison among term siblings. Children were born between January 1, 2006, and December 31, 2017, and followed up until December 31, 2017.

Exposures  Maternal antenatal corticosteroid treatment.

Main Outcomes and Measures  Primary outcome was any childhood mental and behavioral disorder diagnosed in public specialized medical care settings.

Results  Of the 674 877 singleton children born in Finland during the study period, 670 097 were eligible for analysis. The median length of follow-up was 5.8 (interquartile-range, 3.1-8.7) years. Of the 14 868 (2.22%; 46.1% female) corticosteroid treatment–exposed children, 6730 (45.27%) were born at term and 8138 (54.74%) were born preterm; of the 655 229 (97.78%; 48.9% female) nonexposed children, 634 757 (96.88%) were born at term and 20 472 (3.12%) were born preterm. Among the 241 621 eligible term-born maternal sibpairs nested within this population, 4128 (1.71%) pairs were discordant for treatment exposure. Treatment exposure, compared with nonexposure, was significantly associated with higher risk of any mental and behavioral disorder in the entire cohort of children (12.01% vs 6.45%; absolute difference, 5.56% [95% CI, 5.04%-6.19%]; adjusted hazard ratio [HR], 1.33 [95% CI, 1.26-1.41]), in term-born children (8.89% vs 6.31%; absolute difference, 2.58% [95% CI, 1.92%-3.29%]; HR, 1.47 [95% CI, 1.36-1.69]), and when sibpairs discordant for treatment exposure were compared with sibpairs concordant for nonexposure (6.56% vs 4.17% for within-sibpair differences; absolute difference, 2.40% [95% CI, 1.67%-3.21%]; HR, 1.38 [95% CI, 1.21-1.58]). In preterm-born children, the cumulative incidence rate of any mental and behavioral disorder was also significantly higher for the treatment-exposed compared with the nonexposed children, but the HR was not significant (14.59% vs 10.71%; absolute difference, 3.38% [95% CI, 2.95%-4.87%]; HR, 1.00 [95% CI, 0.92-1.09]).

Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial № 902

Keren Shahar-Nissan et al (Lancet. 2020 Oct 10;396(10257):1070. doi: 10.1016/S0140-6736(20)32075-4.PMID: 33038969 ) aimed to investigate whether valaciclovir can prevent vertical transmission of cytomegalovirus to the fetus in pregnant women with a primary infection acquired early in pregnancy using an RCT and assigned to oral valaciclovir (8 g per day, twice daily) or placebo from enrolment until amniocentesis at 21 or 22 gestational weeks.

The final analysis included 45 patients (all singletons) in the valaciclovir group and 45 patients (43 singletons and two sets of twins) in the placebo group. In the valaciclovir group, including both first trimester and periconceptional infections, five (11%) of 45 amniocenteses were positive for cytomegalovirus, compared with 14 (30%) of 47 amniocenteses in the placebo group (p=0·027; odds ratio 0·29, 95% CI 0·09-0·90 for vertical cytomegalovirus transmission). Among participants with a primary cytomegalovirus infection during the first trimester, a positive amniocentesis for cytomegalovirus was significantly less likely in the valaciclovir group (two [11%] of 19 amniocenteses) compared with the placebo group (11 [48%] of 23 amniocenteses; p=0·020. No clinically significant adverse events were reported.

Interpretation: Valaciclovir is effective in reducing the rate of fetal cytomegalovirus infection after maternal primary infection acquired early in pregnancy. Early treatment of pregnant women with primary infection might prevent termination of pregnancies or delivery of infants with congenital cytomegalovirus.

Funding: None.

Long-term Use of Hormone Replacement Therapy is Associated With a Lower Risk of Developing High-risk Serrated Polyps in Women № 904

Dylan E O’Sullivan  et al (J Clin Gastroenterol. 2021 Aug 18. doi: 10.1097/MCG.0000000000001606. ) reported  Data from a cross-sectional study of 1384 women undergoing screening-related colonoscopy between 2008 and 2016 were analyzed. Modified Poisson regression models with robust error variance were used to determine the relative risk (RR) of developing adenomatous polyps, serrated polyps, high-risk adenomatous polypss (HRAPs), and high-risk serrated polyps (HRSPs) associated with pregnancy, menopausal status, and the use of HRT (duration and type).

Results: Women that used HRT for ≥6 years were at a significantly lower risk of developing a [HRSP :RR: 0.53; 95% CI: 0.29-0.97]. Irrespective of the duration of use, the use of HRT that included progesterone alone or with estrogen was associated with a significantly lower risk of developing a HRSP (RR: 0.54; 95% CI: 0.30-0.95). The use HRT with progesterone for ≥6 years was associated with a nonsignificant lower risk of developing a HRSP (RR: 0.42; 95% CI: 0.17-1.04). None of the reproductive factors assessed or HRT were associated with the development of adenomatous polyps or HRAPs.

Conclusions: The results of this study suggests that the long-term use of HRT, and therapies that include progesterone are associated with a lower risk of developing HRSPs. These results could have implications for targeted screening for serrated polyps among women.

Effect of Fractional Carbon Dioxide Laser vs Sham Treatment on Symptom Severity in Women With Postmenopausal Vaginal Symptoms: A Randomized Clinical Trial № 905

Fiona G Li et al JAMA 2021 Oct 12;326(14):1381-1389 evaluated the efficacy of fractional carbon dioxide laser for treatment of vaginal symptoms associated with menopause in a double-blind, randomized, sham-controlled trial with 12-month follow-up at a single tertiary referral hospital in Sydney, Australia. Enrollment commenced on September 19, 2016, with final follow-up on June 30, 2020. Participants were postmenopausal women with vaginal symptoms substantive enough to seek medical treatment. Of 232 participants approached, 85 were randomized. Three treatments using a fractional microablative carbon dioxide laser system performed 4 to 8 weeks apart, with 43 women randomized to the laser group and 42 to the sham group.

The co-primary outcomes were symptom severity assessed using a visual analog scale (VAS; range, 0-100; 0 indicates no symptoms and 100 indicates the most severe symptoms) and the Vulvovaginal Symptom Questionnaire (VSQ; range, 0-20; 0 indicates no symptoms and 20 indicates the most severe symptoms) at 12 months.

The minimal clinically important difference was specified as a 50% decrease in both VAS and VSQ severity scores. Of 85 randomized participants (mean [SD] age, 57 [8] years), 78 (91.7%) completed the 12-month follow-up. From baseline to 12 months, there was no significant difference between the carbon dioxide laser group and the sham group in change in symptom severity

Conclusions and relevance: Among women with postmenopausal vaginal symptoms, treatment with fractional carbon dioxide laser vs sham treatment did not significantly improve vaginal symptoms after 12 months.

Menopause Per se Is Associated with Coronary Artery Calcium Score: Results from the ELSA-Brasil № 906

Marília I H Fonseca 1 et al  J Womens Health (Larchmt). 2021 Sep 14.  doi:  0.1089/jwh.2021.0182. Online ahead of print.

Background: Menopause and aging deteriorate the metabolic profile, but little is known about how they independently contribute to structural changes in coronary arteries. We compared a broad cardiometabolic risk profile of women according to their menopausal status and investigated if menopause per se is associated with presence of coronary artery calcium (CAC) in the ELSA-Brasil. Materials and Methods: All participants, except perimenopausal women, who had menopause <40 years or from non-natural causes or reported use of hormone therapy were included. Sample was stratified according to menopause and age categories (premenopause ≤45 years, premenopause >45 years, and postmenopause); their clinical profile and computed tomography-determined CAC were compared using Kruskal-Wallis and chi squared test for frequencies. Associations of CAC (binary variable) with menopause categories adjusted for traditional and nontraditional covariables were tested using logistic regression. Results: From 2,047 participants 51 ± 9 years of age, 1,175 were premenopausal (702 ≤ 45 years) and 872 were postmenopausal women. Mean values of anthropometric variables, blood pressure, lipid and glucose parameters, branched-chain amino acids (BCAA), and homeosthasis model assessment (HOMA-IR), as well as frequencies of morbidities, were more favorable in premenopausal, particularly in younger ones. In crude analyses, CAC >0 was associated with triglyceride-rich lipoprotein remnants, dense low-density lipoprotein, BCAA, and other variables, but not with HOMA-IR. Menopause was independently associated with CAC >0 (odds ratios 2.37 [95% confidence interval 1.17-4.81]) when compared to the younger premenopausal group.

Conclusion: Associations of menopause with CAC, independent of traditional and nontraditional cardiovascular risk factors, suggest that hormonal decline per se may contribute to calcium deposition in coronary arteries.

Age at menopause and risk of lung cancer: A systematic review and meta-analysis № 907

Hsin-Fang Chung et al Maturitas 2021 Nov;153:1-10.

doi: 10.1016/j.maturitas.2021.07.010

Previous reviews have found that menstrual and reproductive factors are associated with lung cancer risk, but evidence on a possible association with age at menopause is inconsistent. This review aimed to determine the association of early and late menopause with lung cancer risk. Publications were reviewed and obtained through PubMed, EMBASE and Scopus database search up to March 2021. The pooled relative risks (RRs) or odds ratios (ORs) and corresponding 95% CIs were estimated using a random-effects meta-analysis. Twenty-eight studies were included in at least one meta-analysis, of age at menopause (lowest vs highest; n=26), early menopause (≤45 vs ≥50/51 years or middle; n=11), late menopause (≥55 vs <50 years or middle; n=6), or continuous (per additional year; n=6). We found that early menopause was associated with lung cancer in both cohort studies (RR 1.26, 1.10-1.41; n=6) and case-control studies (OR 1.38, 1.11-1.66; n=5). Three large cohort studies showed that the increased risk was primarily evident among smokers (RR 1.38, 1.10-1.66) but not among non-smokers (RR 1.02, 0.63-1.40). Four case-control studies found that late menopause was also associated with lung cancer (OR 1.29, 1.08-1.51); conversely, the association was mainly observed among non-smokers (OR 1.35, 1.11-1.59) but not among smokers (OR 1.05, 0.75-1.36). In conclusion, evidence from this review indicates an increased risk of lung cancer in women who experience early menopause (≤45 years), although this risk is primarily among smokers. Large prospective cohort studies are needed to confirm the association between late menopause (≥55 years) and lung cancer risk among non-smokers. PROSPERO registration: CRD42020205429.

Menopausal symptoms in epithelial ovarian cancer survivors: a GINECO VIVROVAIRE2 study № 908

F Gernier et al Gynecol Oncol. 2021 Oct 11;S0090-8258(21)01419-0.

Epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study ( n = 166, with relapse-free ≥3 years after the end of treatment) investigated the main menopausal symptoms and gynecological management of EOC survivors (EOCS).

166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM).

Results: Mean age at the survey was 62 [21-83] years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had surgical menopause (SM). Half of patients reported vasomotor symptoms (VMS). Seventy-two percent of EOCS with SM had VMS compared to 41% with natural menopause (NM) (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT).

The authors’ Conclusions: VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms.

Age at menopause in women living with HIV № 910

Clara E Van Ommen et al reported a systematic review on “Age at menopause in women living with HIV”

(Menopause  . 2021 Dec 1;28(12):1428-1436. DOI: 10.1097/GME.0000000000001871)

Their Findings were the following based on 9 studies. Across studies, the age at menopause for WLWH fell between 46 and 50 years. Five of seven studies reported that WLWH had an earlier menopausal transition than HIV negative controls/the general population. Six studies reported on the prevalence of POI or early menopause among WLWH, with all studies demonstrating an increased prevalence of both among WLWH.

Overall, they also highlighted the need for further investigation with studies that include an HIV negative control group and biochemical confirmation of menopause to better understand whether menopause truly is occurring earlier among WLWH.

Age at menopause and risk of lung cancer № 911

Hsin-Fang Chung et al conducted a systematic review about “Age at menopause and risk of lung cancer” Maturitas. 2021 Nov; 153:1-10.doi: 10.1016/j.maturitas.2021.07.010. Epub 2021 Jul 21.

28 studies were included. They found that early menopause was associated with lung cancer in both cohort studies (RR 1.26, 1.10-1.41; n=6) and case-control studies (OR 1.38, 1.11-1.66; n=5). Three large cohort studies showed that the increased risk was primarily evident among smokers (RR 1.38, 1.10-1.66) but not among non-smokers (RR 1.02, 0.63-1.40). Four case-control studies found that late menopause was also associated with lung cancer (OR 1.29, 1.08-1.51); conversely, the association was mainly observed among non-smokers (OR 1.35, 1.11-1.59) but not among smokers (OR 1.05, 0.75-1.36).
In conclusion, evidence from this review indicates an increased risk of lung cancer in women who experience early menopause (≤45 years), although this risk is primarily among smokers. Large prospective cohort studies are needed to confirm the association between late menopause (≥55 years) and lung cancer risk among non-smokers.

Association Between Laparoscopically Confirmed Endometriosis and Risk of Early Natural Menopause (ENM) № 912

Madhavi Thombre Kulkarni et al (JAMA Netw Open. 2022 Jan 4;5(1):e2144391.

doi: 10.1001/jamanetworkopen.2021.44391) reported an “Association Between Laparoscopically Confirmed Endometriosis and Risk of Early Natural Menopause (ENM)” using a large, population-based cohort study (the Nurses’ Health Study II cohort questionnaires from the 1989 to 2015).

The sample included premenopausal women aged 25- 42 years at baseline or enrollment in 1989. Cumulative follow-up rate was greater than 90%, and participants continued follow-up until the onset of ENM, age 45 years, hysterectomy, oophorectomy, cancer diagnosis, death, loss to follow-up, or end of follow-up in May 2017, whichever occurred first. Data analyses were conducted from October 26, 2020, to April 27, 2021.

During 1 508 462 person-years of follow-up, 6640 participants reported being diagnosed with endometriosis, 99 993 never reported endometriosis, and 2542 reported experiencing ENM. In the age- and calendar time-adjusted model, laparoscopically confirmed endometriosis was associated with a 50% greater risk for ENM [HR], 1.51; 95% CI, 1.30-1.74). A similar risk was observed after adjusting for race and ethnicity and time-varying anthropometric and behavioral factors (HR, 1.46; 95% CI, 1.26-1.69). With additional adjustment for reproductive factors, the HR of ENM was attenuated but significant (HR, 1.28; 95% CI, 1.10-1.48).

Conclusions and relevance: This cohort study found a risk for ENM in women with laparoscopically confirmed endometriosis. These women compared with those without endometriosis may be at a higher risk for shortened reproductive duration, particularly those who were nulliparous or never used oral contraceptives.

Randomized controlled trial of metformin in women with components of metabolic syndrome: intervention feasibility and effects on adiposity and breast density. № 913

Edgar Tapia et al (Breast Cancer Res Treat. 2021 Nov;190(1):69-78.

doi: 10.1007/s10549-021-06355-9. Epub 2021 Aug 12.) conducted a Phase II double-blind,  “randomized controlled trial of metformin in women with components of metabolic syndrome: intervention feasibility and effects on adiposity and breast density”. Eligible participants were randomized to receive metformin (850 mg BID, n = 76) or placebo (n = 75) for 12 months. Outcomes included breast density, assessed by fat/water MRI with change in percent breast density as the primary endpoint, anthropometric measures, and intervention feasibility.

Results: Seventy-six percent in the metformin arm and 83% in the placebo arm (p = 0.182) completed the 12-month intervention. Adherence to study agent was high with more than 80% of participants taking ≥ 80% assigned pills. The most common adverse events reported in the metformin arm were gastrointestinal in nature and subsided over time. Compared to placebo, metformin intervention led to a significant reduction in waist circumference (p < 0.001) and waist-to-hip ratio (p = 0.019). Compared to placebo, metformin did not change percent breast density and dense breast volume but led to a numerical but not significant decrease in non-dense breast volume (p = 0.070).

Genetic insights into biological mechanisms governing human ovarian ageing № 914

Katherine S Ruth et al (Nature. 2021 Aug;596(7872):393-397. doi: 10.1038/s41586-021-03779-7. Epub 2021 Aug 4.) reported
“Genetic insights into biological mechanisms governing human ovarian ageing”.

They identified 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Dyspareunia in Women № 915

Dyspareunia (pain with intercourse) greatly affects the quality of life, libido, relationships, and self-image of the estimated 15% of women who have this condition, and evenmore so among postmenopausal women. Its prevalence is underestimated, and it is rarely treated, beacause of shyness to discuss it with health providers and low priority for clinocians.
Gross and Brbacker wrote wrote a review paper (JAMA. Published online April 18, 2022. doi:10.1001/jama.2022.4853) insisting on the importance of initiating asking questions to patients about Dyspareunia.
We reproduce also a table from this article.

Dyspareunia Categories, Common Etiologies, Evaluation Findings, and Treatment ConsiderationsAbbreviations: DHEA, dehydroepiandrosterone; GI, gastrointestinal

Hormone and receptor activator of NF-κB (RANK) pathway gene expression in plasma and mammographic breast density in postmenopausal women № 916

Hormones impact breast tissue proliferation. Studies investigating the associations of circulating hormone levels with mammographic breast density have reported conflicting results. Due to the limited number of studies, Rachel Mintz et al (Breast Cancer Res . 2022 Apr 14;24(1):28.DOI: 10.1186/s13058-022-01522-2) investigated the associations of hormone gene expression as well as their downstream mediators within the plasma with mammographic breast density in postmenopausal women.

They recruited postmenopausal women at their annual screening mammogram and used the NanoString nCounter platm to quantify gene expression of hormones in plasma. They measured volumetric percent density, dense volume, and non-dense volume.
They report that one unit increase in ESR1, RANK, and TNFRSF18 gene expression was associated with 8% (95% CI 0-15%, p value = 0.05), 10% (95% CI 0-20%, p value = 0.04) and % (95% CI 0-9%, p value = 0.04) higher volumetric percent density, respectively. There were no associations between gene expression of other markers and volumetric percent density. One unit increase in osteoprotegerin and PGR gene expression was associated with 12% (95% CI 4-19%, p value = 0.003) and 7% (95% CI 0-13%, p value = 0.04) lower non-dense volume, respectively.
Conclusion: These findings provide new insight on the associations of plasma hormonal and RANK pathway gene expression with mammographic breast density in postmenopausal women and require confirmation in other studies.

Serum follicle stimulating hormone and five-year change in adiposity in healthy postmenopausal women № 917

Lindsey J Mattick et al (J Clin Endocrinol Metab 2022 Apr 18;dgac238. doi: 10.1210/clinem/dgac238. Online ahead of print.) evaluated the potential independent role of the interrelationships of FSH and estradiol in postmenopausal adiposity changes, using a sample of 667 postmenopausal women from the Women’s Health Initiative Buffalo OsteoPerio Ancillary Study. They studied the associations of serum FSH and estradiol levels with dual x-ray absorptiometry (DXA)-derived adiposity measures via cross-sectional and longitudinal analyses (5-year follow-up).

Results: In cross-sectional analyses, FSH levels were inversely associated with all measures of adiposity in models adjusted for age, years since menopause, smoking status, pack years, and hormone therapy (HT) use; these associations were not influenced by adjustment for serum estradiol. In longitudinal analyses, the subset of women who discontinued HT over follow-up (n=242) experienced the largest increase in FSH (+33.9 mIU/mL) and decrease in estradiol (-44.3 pg/mL) and gains in all adiposity measures in unadjusted analyses. In adjusted analyses, an increase in FSH was associated with a gain in percent total body fat, total body fat mass, and subcutaneous adipose tissue.

Conclusions: While cross-sectional findings suggest that FSH is inversely associated with adiposity, the longitudinal findings suggest that greater increases in FSH were associated with greater increases in percent total body fat, total body fat mass and subcutaneous adipose tissue. Future studies are needed to provide additional insight into FSH-adiposity mechanisms in larger samples.

Menopausal Hormone Therapy Formulation and Breast Cancer Risk № 918

Abenhaim, Haim A et al  (Obstetrics & Gynecology: June 2022 – Volume 139 – Issue 6 – p 1103-1110 doi: 10.1097/AOG.0000000000004723) evaluated whether the increased risk of breast cancer is dependent on the formulation of menopausal hormone therapy (HT) used. They performed a population-based case–control study of women aged 50 years or older using data from the U.K. Clinical Practice Research Datalink. Women with incident cases of breast cancer were age-matched (1:10) with a control group of women with comparable follow-up time with no history of breast cancer. Exposures were classified as ever or never for the following menopausal HT formulations: bioidentical estrogens, animal-derived estrogens, micronized progesterone, and synthetic progestin. Logistic regression analyses were performed to estimate the adjusted effect of menopausal HT formulation on breast cancer risk.

Between 1995 and 2014, 43,183 cases of breast cancer were identified and matched to 431,830 women in a control group. In adjusted analyses, compared with women who never used menopausal HT, its use was associated with an increased risk of breast cancer (odds ratio [OR] 1.12, 95% CI 1.09–1.15). Compared with never users, estrogens were not associated with breast cancer (bioidentical estrogens: OR 1.04, 95% CI 1.00–1.09; animal-derived estrogens: OR 1.01, 95% CI 0.96–1.06; both: OR 0.96, 95% CI 0.89–1.03). Progestogens appeared to be differentially associated with breast cancer (micronized progesterone: OR 0.99, 95% CI 0.55–1.79; synthetic progestin: OR 1.28, 95% CI 1.22–1.35; both OR 1.31, 0.30–5.73).

Although menopausal HT use appears to be associated with an overall increased risk of breast cancer, this risk appears predominantly mediated through formulations containing synthetic progestins. When prescribing menopausal HT, micronized progesterone may be the safer progestogen to be used.

Patterns of Sexual Activity and the Development of Sexual Pain Across the Menopausal Transition № 919

Waetjen, L. Elaine et al for the Study of Women’s Health Across the Nation (SWAN) (Obstetrics & Gynecology: June 2022 – Volume 139 – Issue 6 – p 1130-1140 doi: 10.1097/AOG.0000000000004810) examined whether patterns of sexual intercourse frequency and demographic, menopausal status, genitourinary, health, and psychosocial factors are associated with developing sexual pain across the menopausal transition.

These were longitudinal analyses of questionnaire data from the SWAN Study

Of the 2,247 women with no sexual pain at baseline, 1,087 (48.4%) developed sexual pain at least “sometimes” up to 10 follow-up visits over 13 years.

There was no consistent association between prior patterns of sexual intercourse frequency and development of sexual pain. Reasons for interruptions in intercourse activity at the prior visit, including lack of interest (aHR 1.64, 95% CI 0.74–3.65) and relationship issues (aHR 0.36, 95% CI 0.04–2.88), were not associated with developing pain. Being postmenopausal using hormone therapy (aHR 3.16, 95% CI 1.46–6.85), and reported vaginal dryness (aHR 3.73, 95% CI 2.88–4.83) were most strongly associated with incident sexual pain.

Long-term and short-term declines in sexual intercourse frequency across the menopausal transition were not associated with increased hazard of developing pain with intercourse. This empirical evidence does not support the common belief that a reduction in women’s sexual frequency is responsible for their symptoms of sexual pain.

Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults № 920

Meryl S. LeBoff et al reported in the July 28, 2022 N Engl J Med 2022(; 387:299-309 DOI:10.1056/NEJMoa2202106) that Supplemental Vitamin D did not reduce Incident Fractures in Midlife and Older Adults. They tested this In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D 3 (2000 IU per day), n−3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, non vertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses.

Among 25,871 participants (50.6% women, they confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D 3 , as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% CI, 0.89 to 1.08; P=0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P=0.96). There was no modification of the treatment effect according to baseline characteristics,
including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial.
The Authors concluded that Vitamin D 3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis.

Association of Progestogens and Venous Thromboembolism Among Women of Reproductive Age № 921

Cockrum, et al (Obstetrics and gynaecology 140(3):477-487, September 2022) evaluated associations between use of seven progestogens and incident acute venous thromboembolism (VTE) among women of reproductive age, using a nested matched case–control study. They identified women aged 15–49 years from January 1, 2010, through October 8, 2018, in the IBM MarketScan databases, a nationwide sample of private insurance claims in the United States.

After exclusions, 21,405 women with incident acute VTE (case group), identified by diagnosis codes, were matched 1:5 by year of birth and index date through risk set sampling to 107,025 women without prior VTE (control group). From lowest to highest systemic dose based on a modified hierarchy, progestogens studied were levonorgestrel-releasing intrauterine device (LNG-IUD), oral norethindrone, etonogestrel implant, oral progesterone, oral medroxyprogesterone acetate, oral norethindrone acetate, and depot medroxyprogesterone acetate (DMPA). Conditional logistic regression models adjusted for 16 VTE risk factors were used to estimate odds ratios and 99% CIs for incident acute VTE associated with current progestogen use compared with nonuse. The primary analysis treated each progestogen as a binary exposure. Dose, which varied for oral formulations, and chronicity were explored separately. Significance was set at P <.01 to allow for multiple comparisons.
Current use of higher-dose progestogens was significantly associated with increased odds of VTE compared with non-use (oral norethindrone acetate: adjusted odds ratio [aOR] 3.00, 99% CI 1.96–4.59; DMPA: aOR 2.37, 99% CI 1.95–2.88; and oral medroxyprogesterone acetate: aOR 1.98, 99% CI 1.41–2.80). Current use of other progestogens was not significantly different from nonuse (LNG-IUD, etonogestrel implant, and oral progesterone) or had reduced odds of VTE (oral norethindrone). Sensitivity analyses that assessed misclassification bias supported the primary findings.
Conclusion: Among reproductive-aged women using one of seven progestogens, only use of norethindrone acetate and medroxyprogesterone acetate—considered higher-dose progestogens—was significantly associated with increased odds of incident acute VTE. The roles of progestogen type, dose, and indication for use warrant further study.

Coronary artery calcium and bone mineral density by serial CTA: Does menopausal hormone therapy modify the association? № 922

Lavanya Cherukuri et al (Randomized Controlled Trial Clin Imaging. 2022 Oct;90:26-31.)

Introduction: Both osteoporosis and cardiovascular disease (CVD) increase in women after menopause. Estrogen deficiency is thought to be an underlying mechanism for both these conditions.
Methods: Healthy menopausal women (n = 374, age 42-58 years) underwent cardiac CT scans over four years as participants in the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, controlled trial to Women randomized to either oral conjugated equine estrogens (o-CEE, n = 104), transdermal 17β-estradiol (t-E2, n = 119) or placebo (n-115). CAC (Agatston units, AU), and BMD (mg/cm3) were measured from thoracic vertebrae at baseline and at the 4 years of the study using validated software. ANOVA and multiple linear regression analyzed the association between incident CAC or progression of CAC and BMD among the treatment groups.
Results: At baseline 374 women, 40 participants with CAC >0 had greater decrements in BMD than the 334 participants with CAC = 0 at baseline, The average change in BMD in o-CEE group with CAC was -9.6 ± 13.3 versus -3.1 ± 19.5 in those with zero CAC, p = 0.0018. With t-E2, BMD changed by -11.7 ± 26.2 in those with CAC versus +5.7 ± 26.2 in the zero CAC group, p ≤ 0. 0001. Similarly in the 66 participants that showed progression of CAC >1, had more BMD loss, than those with stable CAC regardless of the treatment.
Conclusion: Progression of bone loss is reduced among women treated with o-CEE or t-E2. Progression of CAC is associated with greater BMD loss, a relationship that is differentially modified by t-E2 and o-CEE.

Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study № 923

Søren Cold et al (J Natl Cancer Inst. 2022 Jul 20;djac112. doi: 10.1093/jnci/djac112. ) studied longitudinally a national cohort of postmenopausal women, diagnosed 1997-2004 with early-stage invasive estrogen receptor-positive nonmetastatic breast cancer (BC), who received no treatment or 5 years of adjuvant endocrine therapy. Some women suffering from genitourinary syndrome were treated with vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT). The authors ascertained prescription data on VET or MHT, from a national prescription registry and evaluated mortality and risk of recurrence.

Results: Among 8461 women who had not received VET or MHT before BC diagnosis, 1957 and 133 used VET and MHT, respectively, after diagnosis. Median follow-up was 9.8 years for recurrence and 15.2 years for mortality.
The adjusted relative risk of recurrence was 1.08 (95% confidence interval [CI] = 0.89 to 1.32) for VET (1.39 [95% CI = 1.04 to 1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62 to 1.78) for MHT. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71 to 0.87) and 0.94 (95% CI = 0.70 to 1.26) for VET and MHT, respectively.

Conclusions: In postmenopausal women treated for early-stage estrogen receptor-positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors.

Association of Premenopausal Bilateral Oophorectomy With Parkinsonism and Parkinson Disease № 924

Rocca et al (JAMA Netw Open 2022 Oct 3;5(10):e2238663. doi: 10.1001/jamanetworkopen.2022.38663) assesed the whether women who underwent premenopausal bilateral oophorectomy were at increased risk of parkinsonism and Parkinson Disease (PD) and whether the associations varied by age at oophorectomy and by receipt of estrogen replacement therapy using combined cohort studies (the Mayo Clinic Cohort Study of Oophorectomy and Aging 1 and 2, which were based on the Rochester Epidemiology Project medical records-linkage system), comprising  5499 women  of those, 2750 women underwent bilateral oophorectomy for a benign indication before spontaneous menopause between January 1, 1950, and December 31, 2007 (oophorectomy cohort), and 2749 age-matched women who did not undergo bilateral oophorectomy were randomly sampled from the general population (reference cohort). Data were analyzed from March 1 to April 30, 2022. The date of oophorectomy was considered the index date for both groups.

Exposures: Medical record documentation of bilateral oophorectomy abstracted from a medical records-linkage system (Rochester Epidemiology Project).

Main outcomes and measures: Incidence and risk of parkinsonism or PD, with diagnoses confirmed by in-person examination or medical record review.

Results: Among 5499 participants (median [IQR] age, 45.0 [40.0-48.0] years; 5312 [96.6%] White), 2750 women (2679 White [97.4%]) underwent bilateral oophorectomy at a median age of 45.0 years (IQR, 40.0-48.0 years), and 2749 women (2633 White [95.8%]) with a median age of 45.0 years (IQR, 40.0-48.0 years) at the index date were included in the reference cohort. Bilateral oophorectomy was associated with an increased risk of parkinsonism overall (hazard ratio [HR], 1.59; 95% CI, 1.02-2.46) and in women younger than 43 years at oophorectomy (HR, 7.67; 95% CI, 1.77-33.27). There was a pattern of increasing risk with younger age at the time of oophorectomy using 4 age strata (≥50 years: HR, 1.43 [95% CI, 0.50-4.15]; 46-49 years: HR, 1.55 [95% CI, 0.79-3.07]; 40-45 years: HR, 1.36 [95% CI, 0.64-2.89]; <40 years: HR, 8.82 [95% CI, 1.08-72.00]; P = .02 for trend). The number needed to harm was 53 women overall and 27 women younger than 43 years at the time of oophorectomy. Bilateral oophorectomy was also associated with an increased risk of PD in women younger than 43 years at oophorectomy (HR, 5.00; 95% CI, 1.10-22.70), with a number needed to harm of 48 women. Among women who underwent oophorectomy at 45 years and younger, the risk was lower in women who received estrogen after the procedure and through age 50 years compared with women who did not. For parkinsonism, the HRs were 1.72 (95% CI, 0.54-5.53) vs 2.05 (95% CI, 0.80-5.23); for PD, the HRs were 1.53 (95% CI, 0.29-8.23) vs 2.75 (95% CI, 0.84-9.04). However, the differences were not significant.

Conclusions and relevance: In this study, premenopausal women who underwent bilateral oophorectomy before age 43 years had an increased risk of parkinsonism and PD compared with women who did not undergo bilateral oophorectomy. These findings suggest that a reduction in the practice of prophylactic bilateral oophorectomy in premenopausal women at average risk of ovarian cancer may have substantial benefit for reducing the risk of parkinsonism and PD.

Laser versus sham for genitourinary syndrome of menopause: A randomised controlled trial № 925

Ann-Sophie Page et al (BJOG 2022 Nov 8 DOI: 10.1111/1471-0528.17335) assessed whether CO 2- laser treatment is more effective than sham application in relieving the
Most Bothersome Symptom (MBS) in women with Genitourinary Syndrome of Menopause (GSM) using a Single center, sham controlled, double-blind, randomised trial. All participants eventually received three consecutive laser and three consecutive sham applications, either first laser followed by sham, or conversely. The authors Conclusions were that In women with GSM, the treatment response 12 weeks after laser application was comparable to that of sham applications. There were neither obvious differences for secondary outcomes. No serious adverse events were reported.

Association of Vaginal Estradiol Tablet With Serum Estrogen Levels in Women Who Are Postmenopausal: Secondary Analysis of a Randomized Clinical Trial № 926

Caroline M. Mitchell et al compare serum estrogen concentrations with the use of vaginal estrogen, 10 μg, tablet vs placebo in women who are postmenopausal. (JAMA Netw Open.
2022 Nov 1;5(11):e2241743. doi: 10.1001/jamanetworkopen.2022.41743.) in a secondary, post hoc analysis of data from a randomized clinical trial of treatment for moderate to
severe genitourinary syndrome in women who are postmenopausal. In this post hoc analysis, baseline and week 12 serum estradiol, estrone, and sex hormone-binding globulin
(SHBG) concentrations were measured by a chemiluminescent assay. A total of 174 women, mean (SD) age 61 (4) years, were included. Those in the estrogen group (n = 88) were more likely to have higher geometric mean (SD) week 12 serum estradiol concentrations (4.3 [2.2 pg/mL]) than those in the placebo group (n = 86) (3.5 [2.1] pg/mL) (P = .01). Adjusted for pretreatment hormone concentrations, age, clinical site, and body mass index, assignment to the estrogen vs placebo treatment group was significantly associated with higher week 12 estradiol concentrations (23.8% difference; 95% CI, 6.9%-43.3%). Most (121 of 174 [69.5%]) participants had enrollment serum estradiol concentrations higher than 2.7 pg/mL. Of women starting treatment at estradiol levels lower than or equal to 2.7 pg/mL, 38.1% (8 of 21) in the estrogen group and 34.4% (11 of 32) in the placebo group had estradiol concentrations higher than 2.7 pg/mL after 12 weeks of study participation (P = .78). Treatment assignment was not associated with week 12 estrone or SHBG concentrations.

Conclusions and relevance: In this secondary analysis of a randomized clinical trial, a significant, although small, increase in serum estradiol levels was noted after 12 weeks of vaginal estrogen administration. The clinical relevance of this small increase is uncertain.