N° 908

Menopausal symptoms in epithelial ovarian cancer survivors: a GINECO VIVROVAIRE2 study

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.


N° 907

Age at menopause and risk of lung cancer: A systematic review and meta-analysis

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.


N° 906

Menopause Per se Is Associated with Coronary Artery Calcium Score: Results from the ELSA-Brasil

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.


N° 905

Effect of Fractional Carbon Dioxide Laser vs Sham Treatment on Symptom Severity in Women With Postmenopausal Vaginal Symptoms: A Randomized Clinical Trial

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.


N° 904

Long-term Use of Hormone Replacement Therapy is Associated With a Lower Risk of Developing High-risk Serrated Polyps in Women

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.


N° 902

Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial

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.

N° 887

Associations Between Maternal Antenatal Corticosteroid Treatment and Mental and Behavioral Disorders in Children

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]).


N° 886

Breast Cancer Risk in Postmenopausal Women With Medical History of Thyroid Disorder in the Women’s Health Initiative

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.

N° 885
Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.
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.

N° 884
Arterial Stiffness Accelerates Within 1 Year of the Final Menstrual Period: The SWAN Heart Study.

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.

N° 883
At the latest San Antonio Breast cancer symposium (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.


N° 882 Honingberg et al (JAMA. 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.