Natural Menopause Research Articles

Early menopause and premature ovarian insufficiency: problems and perspectives

In this review we summarize current data on prevalence, etiology and pathogenesis resulting in premature ovarian insufficiency (POI). In particular, genetic, autoimmune, metabolic, iatrogenic disorders as well as unfavorable impact of environmental factors represent key pathogenetic mechanisms underlying POI development. Clinical picture of this disease is mainly manifested by oligo- and amenorrhea as well as genitourinary menopausal syndrome (GUMS). Special attention is paid to a link between such clinical signs and psychosocial discomfort not being a life-threatening condition but still able to markedly lower quality of woman’s life and considered as a comorbidity with type 2 diabetes mellitus, osteoporosis and cardiovascular diseases. Hormone replacement therapy (HRT) serves as the first-line therapeutic approach for treating POI, which is performed according to the principles similar to those used to perform menopausal hormone therapy (MHT) in case of natural menopause that should be continued until reaching at least the average age for the onset of menopause. Topical estriol therapy eliminates GUMS symptoms, which in turn positively affects sexual function and woman’s psychosocial status and contributes to improved quality of life. The data from recent studies examining topical estriol therapy in POI demonstrated high efficacy and safety. Finally, we also discuss diverse strategies to support reproductive function in women with POI.

Nonpharmacological therapies for the management of menopausal vasomotor symptoms in breast cancer survivors.

Breast cancer affects millions of women worldwide, and for many, therapy results in treatment-induced menopause. Menopausal symptoms in breast cancer survivors are often more severe, frequent, and of greater duration compared with natural menopause. Hot flushes and night sweats pose a significant burden for many women, with limited therapeutic options as menopausal hormone therapy is contraindicated. Guidelines recommend non-hormonal pharmacological agents including clonidine, gabapentin, and some antidepressants. However, some women may be reluctant to use medications due to concerns about side effects. The aim of this narrative review was to appraise recent evidence for nonpharmacological treatments for vasomotor symptoms in breast cancer survivors including cognitive behavioural therapy, hypnosis, yoga, mindfulness, acupuncture, and lifestyle changes. A literature search was conducted. Studies were included if they were randomised and involved breast cancer survivors and nonpharmacological treatments for menopausal vasomotor symptoms. Twelve studies met the criteria, and three studies of exercise in healthy menopausal women were included. Cognitive behavioural therapy reduces menopausal symptoms and perceived impact of hot flushes and night sweats in breast cancer survivors and is cost effective. The efficacy of hypnosis as a treatment for menopausal vasomotor symptoms in women with breast cancer is supported by two randomised controlled trials. Yoga and acupuncture may reduce vasomotor symptom frequency and/or burden. Studies of exercise as an intervention for vasomotor symptoms in healthy menopausal women have not shown benefit. Evidence for nonpharmacological interventions supports cognitive behavioural therapy and hypnosis in the management of vasomotor symptoms in breast cancer survivors.

Supplementation of fenugreek with choline-docosahexaenoic acid attenuates menopause induced memory loss, BDNF and dendritic arborization in ovariectomized rats.

Cognitive impairment due to natural or surgical menopause is always associated with estrogen deficiency leading to reduced brain-derived neurotrophic factor (BDNF). Reduced BDNF levels in menopause affect neuronal maturation, survival, axonal and dendritic arborization and the maintenance of dendritic spine density. Conventional long-term estrogen replacement therapy reported causing the risk of venous thromboembolism and breast cancer. To overcome these undesirable effects, phytoestrogens have been used in menopause-induced condition without the risk of side effects. Therefore, the aim of the present study was to investigate the effect of dietary supplementation of fenugreek seed extract (FG) either alone or in combination with choline-DHA on BDNF and dendritic arborization of pyramidal neurons in CA1 and CA3 regions of the hippocampus in ovariectomized rats. Female Wistar rats of 9-10months old were divided into six groups as normal control (NC); ovariectomy (OVX); OVX + FG; OVX + choline-DHA; OVX + FG + choline-DHA; and OVX + estradiol. All the groups, except NC, were ovariectomized. After 2weeks of ovariectomy, dietary supplementation was initiated for a period of 30days. After supplementation, behavioral studies, BDNF levels and dendritic arborization were estimated. Ovariectomized (OVX) rats showed reduced BDNF levels, dendritic branching points and dendritic intersections of pyramidal neurons in CA1 and CA3 regions of the hippocampus. OVX rats supplemented with FG with choline-DHA showed significantly improved BDNF levels, dendritic branching points and dendritic intersections. These results are demonstrating that FG with choline-DHA supplementation can be an alternative for estrogen replacement therapy to modulate menopause-induced learning and memory deficits.

Anti-Müllerian Hormone in the Diagnosis and Prediction of Premature Ovarian Insufficiency.

The menopause and its pathological version, premature ovarian insufficiency (POI), are characterized by the cessation of follicle growth in the ovary, with consequent lack of estrogen production and amenorrhea. The measurement of a specific product of ovarian follicles would therefore be expected to be a valuable biomarker in women with POI, and to be of likely clinical value in the diagnosis and perhaps prediction of POI. Anti-Müllerian hormone (AMH) is produced by the granulosa cells of growing follicles and is therefore likely to be of value in this context. Current data indicate that measurement of AMH is an accurate indicator of POI in many situations and has diagnostic validity and may facilitate more timely diagnosis. AMH seems to be of limited value in predicting age at natural menopause, even with multiple measurements, and there are scarce data regarding prediction of POI, other than when it is imminent, and in some contexts where there is an immediate iatrogenic threat to ovarian function. AMH therefore appears to have considerable value as a diagnostic test for POI, but apart from highlighting broadly those at increased risk, it has inadequate precision to be able to predict accurately the timing of onset of impending POI.

Premature and Early Menopause in Relation to Cardiovascular Disease.

Postmenopausal women have an increased risk for cardiovascular diseases. It has been postulated that the loss of ovarian function and subsequent deficiency of endogenous estrogens after menopause contributes to this elevated risk of cardiovascular disease in postmenopausal women. Compared with woman entering menopause at the mean age of 51 years, in women with early menopause or premature ovarian insufficiency the risk for cardiovascular disease is even greater. These women lack the cardioprotective effect of endogenous estrogens for many more years than do women entering natural menopause. The majority of data assessing the risk of cardiovascular disease in relation to age at menopause and specifically premature menopause are derived from large epidemiological cohort studies. In addition, observations in women undergoing bilateral oophorectomy at an early age provide convincing evidence regarding association between early menopause or POI and the development of cardiovascular events and mortality. Moreover, genetic variants associated with earlier age at menopause have also been found to increase the risk of cardiovascular events in women. It has been substantiated that hormone replacement therapy (HRT) decreases the risk for ischemic heart disease and eliminates the increased cardiovascular disease mortality. It is therefore crucial to start HRT as soon as possible, particularly in women with premature ovarian insufficiency.

A later menopausal age is associated with a lower prevalence of physical frailty in community-dwelling older adults: The Korean Frailty and Aging Cohort Study (KFACS)

ObjectivesThe aim of this study was to determine whether age at menopause is associated with physical frailty. MethodsThis was a cross-sectional study that included 1264 women (70–84 years) from the Korean and Aging Cohort Study (KFACS) who had records of their ages at menarche and their ages at menopause and had experienced a natural menopause. We used Fried criteria to assess physical frailty status. The ages at menopause and menarche were collected using self-reported questionnaires. ResultsThe prevalence of physical frailty decreased by 5.3 % with each year of increase in age at menopause after adjusting for age, marital status, years of education, diabetes mellitus, hypertension, polypharmacy, hospitalizations, falls, and hormone replacement therapy (p = 0.005). The prevalence of frailty significantly decreased by 4.1 % when the reproductive span increased by a year (p = 0.019). ConclusionsThis study found that a later menopausal age was associated with a lower risk of frailty using Fried criteria. In addition, it showed that a longer reproductive span was associated with a lower prevalence of frailty.

Relationships Between Vasomotor Symptoms and Mood in Midlife Urban Chinese Women: Observations in a Prospective Study.

During the menopausal transition, there is a greater likelihood of the prevalence of various bothersome symptoms, including vasomotor symptoms (VMS) and mood symptoms. To investigate the association among bothersome VMS and symptoms of anxiety and depression in Chinese women during perimenopause and early in menopause. This study included 430 midlife Chinese women who had experienced natural menopause and were followed up for 10 years. A structured questionnaire was provided annually, comprising the VMS Bother Score (range 1-8) from the Menopause-Specific Quality of Life questionnaire, the Hospital Anxiety and Depression Scale, and other physical and behavioral factors. Among the 430 women evaluated, 78.8% had experienced VMS during long-term follow-up. The overall level of VMS bother score was relatively low (1.92 ± 1.32). Both anxiety and depressive symptoms were significantly associated with VMS bother. After adjusting for potential covariates, the association between anxiety or depression symptoms and VMS bother remained highly significant. Menopausal stage, body mass index, general health, follicle-stimulating hormone, and estradiol were independent contributors to VMS. In time-lagged (1-year) models, VMS bother scores significantly predicted the risk of symptoms of both anxiety and depression the following year. In contrast, anxiety symptoms, rather than depressive symptoms, could predict VMS bother the following year. The prevalence of VMS in our cohort was higher than has been previously reported; however, the overall level of bother was relatively low. This study demonstrated a strong relationship between VMS bother and mood symptoms in Chinese women progressing from perimenopause through natural menopause.

Clinical profile of 550 cases of surgical and natural menopause

Background: Menopause represents the permanent cessation of menstrual periods and the loss of fertility due to the loss of ovarian function. It can occur spontaneously (natural menopause) or it can be surgically induced. They are different entirely. One is a natural stage of life that all women experience, the other is the result of surgery, that is, bilateral oophorectomy. Surgical menopause is when surgery, rather than the natural aging process, causes a woman to go through menopause. The ovaries are the main source of estrogen production in the female body. Their removal triggers immediate menopause, despite the age of the person having surgery. While surgery to remove the ovaries can operate as a stand-alone procedure, it is sometimes performed in addition to hysterectomy to reduce the risk of developing chronic diseases. This study was designed to compare the effects of the natural and the surgical menopause.
 Methods: This prospective observational study was conducted in the Department of Obstetrics and Gynaecology of Z. H. Sikder Women’s Medical College & Hospital, Dhaka from January 2016 to December 2018. During the study period a total of 275 patients with surgical menopause (total abdominal hysterectomy with bilateral salpingo-oophorectomy was done in all cases) and 275 patients with natural menopause were enrolled. After taking written consent detailed information about the patients was collected in a predesigned data collection sheet for each patient.
 Results: Age of most of the patients in surgical menopause group was within 41 to 50 years and most patients were >50 years old in natural menopause group. Most of the patients were illiterate in both groups and maximum patients were in poor socio-economic condition in both groups. Hot flush (48.0% vs 28.0%), palpitation (28.0% vs 4.0%) and dryness of vagina (12.0% vs 0.0%) were higher and body ache (32.0% vs 48.0%), tiredness (8.0% vs 36.0%), insomnia (8.0% vs 28.0%), depression (4.0% vs 16.0%), lack of concentration (0.0% vs 4.0%), loss of memory (0.0% vs 16.0%) and irritability (4.0% vs 8.0%) were found significantly lower in surgical menopause than natural menopause group. Dyspareunia (72.0% vs 28.0%), dysuria (92.0% vs 40.0%) and increased frequency of urination (68.0% vs 36.0%) were significantly higher in surgical menopause than natural menopause group. Urgency, hesitancy and incontinence of urination were significantly lower in surgical menopause than natural menopause group.
 Conclusion: Ovaries were removed in all of the surgical menopause cases, which may be the reason of more deleterious effects in surgical menopause than natural menopause. So, it is highly recommended to preserve ovaries in hysterectomies due to benign indications.
 Birdem Med J 2020; 10(3): 168-171

Abstract 1169: Racial/ethnic differences in postmenopausal breast cancer incidence and risk factors: Results from the Multiethnic Cohort (MEC) Study

Abstract The impact of hormone-related factors on breast cancer risk has been well-studied; however, data on racial/ethnic minorities, especially Native Hawaiian women, remain relatively scarce. MEC participants completed a baseline questionnaire providing information on hormone-related factors. During a median follow-up of 20 years, 4,634 incident invasive breast cancer cases were identified among 81,511 postmenopausal women (20,003 White, 16,060 African American, 5,468 Native Hawaiian, 22,333 Japanese American, and 17,647 Latina). We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of: (1) race/ethnicity with estrogen receptor positive (ER+) and negative (ER-) breast cancer risk and (2) hormone-related factors with ER+ and ER- breast cancer risk across race/ethnicity. Models were adjusted for baseline age and body mass index (BMI), parity, as well as ages at menarche, menopause, and first birth. Compared to Whites, age-adjusted ER+ breast cancer risk was higher in Native Hawaiians (HR 1.42 [CI 1.26-1.60]), lower in African Americans (0.72 [0.66-0.80]) and Latinas (0.54 [0.49-0.60]), and similar in Japanese Americans (0.97 [0.89-1.05]). Risk for ER- disease was higher in African Americans (1.41 [1.15-1.72]) than in Whites, but no difference was observed in Native Hawaiians, Latinas or Japanese Americans. These results were unchanged after adjustment for hormone-related factors. In the full population, parity and a later age at natural menopause were associated with a decreased ER+ breast cancer risk, and postmenopausal hormone (PMH) use and a higher BMI with an increased risk. There was no significant interaction of these factors with race/ethnicity (p-value for interaction [p-int] ≥0.10). In race/ethnicity specific analyses, parity (vs nulliparity) was associated with lower ER+ breast cancer risk in Whites (0.72 [0.59-0.87]), Japanese Americans (0.57 [0.44-0.74]), and Latinas (0.63 [0.46-0.86]). Age at menopause (≥55 vs <45 years) was inversely associated with ER+ disease risk in African Americans (0.69 [0.52-0.91]) and Japanese Americans (0.69 [0.57-0.84]). PMH use (ever vs never) increased ER+ breast cancer risk by 17-36% in all racial/ethnic groups except Native Hawaiians. BMI (≥30 vs <25 kg/m2) was associated with a 22-66% increased risk of ER+ disease in all racial/ethnic groups. For ER- breast cancer, ever use of oral contraceptives was the only factor associated with risk in the full population (p-int 0.45) and we observed an increased risk of ER- disease in Whites (1.52 [1.09-2.12]) and African Americans (1.80 [1.30-2.51]). Although we observed different associations across racial/ethnic groups for several hormone-related factors with risk of ER+ disease, these did not appear to explain the observed racial/ethnic differences in breast cancer incidence. Citation Format: Danja Sarink, Loic Le Marchand, Lenora W. Loo, Song-Yi Park, Kami K. White, V Wendy Setiawan, Anna H. Wu, Lynne R. Wilkens, Melissa A. Merritt. Racial/ethnic differences in postmenopausal breast cancer incidence and risk factors: Results from the Multiethnic Cohort (MEC) Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1169.

Associations Between Reproductive and Hormone-Related Factors and Risk of Nonalcoholic Fatty Liver Disease in a Multiethnic Population

Despite apparent differences between men and women in the prevalence and incidence of nonalcoholic fatty liver disease (NAFLD), there are limited epidemiologic data regarding the associations of reproductive and hormone-related factors with NAFLD. We examined the associations of these factors and exogenous hormone use with NAFLD risk in African American, Japanese American, Latino, Native Hawaiian, and white women. We conducted a nested case-control study (1861 cases and 17,664 controls) in the Multiethnic Cohort Study. NAFLD cases were identified using Medicare claims data; controls were selected among participants without liver disease and individually matched to cases by birth year, ethnicity, and length of Medicare enrollment. Reproductive and hormone-related factors and covariates were obtained from the baseline questionnaire. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% CIs. Later age at menarche was associated inversely with NAFLD (Ptrend= .01). Parity, regardless of number of children or age at first birth, was associated with increased risk of NAFLD (OR, 1.25; 95% CI, 1.05-1.48). Oral contraceptive use also was linked to increased risk of NAFLD (OR, 1.14; 95% CI, 1.01-1.29; duration of use Ptrend= .04). Compared with women with natural menopause, those with oophorectomy (OR, 1.41; 95% CI, 1.18-1.68) or hysterectomy (OR, 1.33; 95% CI, 1.11-1.60) had an increased risk of NAFLD. A longer duration of menopause hormone therapy (only estrogen therapy) was linked with an increasing risk of NAFLD (OR per 5 years of use, 1.08, 95% CI, 1.01-1.15). Findings from a large multiethnic study support the concept that menstrual and reproductive factors, as well as the use of exogenous hormones, are associated with the risk of NAFLD.

Hot Flashes: Clinical Summary of the ONS Guidelines™ for Cancer Treatment-Related Hot Flashes in Women With Breast Cancer and Men With Prostate Cancer.

Cancer-related hot flashes are often a lasting and distressing side effect of hormone-blocking therapies that are most often experienced by women with breast cancer and men with prostate cancer treated with these therapies. Hot flashes have been defined as a sensation of heat that may be accompanied by facial flushing, perspiration, chills, heart palpitations, night sweats, and feelings of anxiety. The frequency and intensity of hot flashes can cause fatigue and sleep disturbances that diminish quality of life and reduce adherence with prescribed therapies that block estrogens or androgens. Hot flashes are reported to be significantly more frequent and severe in women treated for breast cancer than in women undergoing natural menopause. They also commonly occur in men treated for prostate cancer with surgical or chemical castration to block the synthesis of androgens that can fuel cancer growth.

Indicators of the immune system after correction of climacteric syndrome in women with uterine leiomyoma and endometrial hyperplasia

Indicators of the immune system after correction of climacteric syndrome in women with uterine leiomyoma and endometrial hyperplasia

Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause.

Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40years of age. Known genetic causes account for 25-30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/- female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders.

The Role of Sex-Specific Risk Factors in the Risk Assessment of Atherosclerotic Cardiovascular Disease for Primary Prevention in Women.

Robust evidence is emerging regarding the contribution of sex-specific risk factors to a woman's unique risk of atherosclerotic cardiovascular disease (ASCVD). This review summarizes the available literature regarding the association of sex-specific risk factors and ASCVD in women. The American College of Cardiology and American Heart Association Guidelines recommend estimation of 10-year risk of a first ASCVD event using the 2013 Pooled Cohort Equations. This can be further personalized by identifying sex-specific risk factors present in a woman's history. There are multiple vulnerable periods across a woman's life course that are associated with increased risk of ASCVD. Risk factors across the reproductive life course that have been shown to correlate with higher risk for future ASCVD include early menarche, adverse pregnancy outcomes (such as pre-eclampsia or preterm birth), and early natural or surgical menopause. In addition, certain conditions that are more common among women, including autoimmune diseases, history of chest irradiation, and certain chemotherapies, also need to be considered. Finally, risk assessment can be refined with subclinical disease imaging (coronary calcium score) if there remains uncertainty about clinical management with lipid-lowering therapies for primary prevention after inclusion of these risk enhancers. Risk assessment for ASCVD in women requires a personalized approach that incorporates sex-specific risk factors to guide primary prevention measures, such as lipid-lowering therapies. Coronary calcium score imaging may also help further refine risk assessment, but no clinical trials conducted to date have addressed this question.

Serum phosphorus levels in natural menopausal women and surgical menopausal women: A comparative study

Aim: comparison of serum phosphorus levels in natural menopausal women with surgical menopausal women. Methods: The present analytical cross sectional study was conducted on patients (out patients and in patients) in Department of Obstetrics and Gynecology, Kamla Nehru Hospital, attached to IGMC Shimla. Group 1 (N=60): Women who had undergone hysterectomy with bilateral salpingo oophorectomy at least 6 month ago. Group 2 (N=60): Women who have attained natural menopause at least 1 year ago. Serum phosphorus was estimated by Molybdate U.V. method in mg/dl after the relevant quality control checks. Results: In the present study maximum number of the patients 26 (43.3%) were in the age group of 46-50 years for the post-surgical menopausal group and in the natural menopausal group maximum number of the patients were in the age group of 51-55 years 23 (38.3%). Maximum numbers of patients are multiparous in both groups. Total number of women having hypophosphatemia were 12 in which 3 (5.0%) were natural menopausal and 9 (15%) were postsurgical menopausal. Total number of women having hyperphosphatemia were 4 in which all were postsurgical menopausal. Conclusions: The prevalence of osteoporosis is very high in this part of India. Both natural and post- surgical menopausal women have lower levels of serum phosphorus.

Abstract B41: Racial/ethnic disparities in epithelial ovarian cancer and its risk factors: The Multiethnic Cohort Study

Abstract Background: Age-adjusted incidence rates of epithelial ovarian cancer (EOC) are highest rates in White and Hispanic women, and lower in African American and Asian/Pacific Islander women. We investigated the extent to which reproductive and lifestyle factors explain racial/ethnic differences in EOC risk among White, African American, Native Hawaiian, Japanese American, and Hispanic women in the Multiethnic Cohort (MEC) Study. Methods: The study included 91,682 participants who completed a baseline questionnaire on hormone-related and other lifestyle factors. Incident invasive EOC cases were identified from tumor registries. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between (1) race/ethnicity and EOC risk and (2) hormone-related factors and EOC risk across racial/ethnic groups. Exposures included parity, ages at first birth, menarche, and natural menopause, menopausal status, exogenous hormone use, and body mass index. Models were adjusted for age, menopausal status, parity, and oral contraceptive (OC) use. Results: During a median of 20 years of follow-up, 155 EOC cases occurred among Whites, 93 among African Americans, 57 among Native Hawaiians, 161 among Japanese Americans, and 141 among Latinas. Compared to Whites, African Americans and Japanese Americans had a lower EOC risk (HR 0.74 [CI 0.57-0.97] and HR 0.79 [CI 0.63-0.99], respectively) while Native Hawaiians had a suggestive higher risk (HR 1.36 [CI 0.99-1.85]). EOC risk in Latinas did not differ from that in Whites (HR 0.97 [CI 0.76-1.22]). Parity and OC use were significantly inversely associated with EOC risk in the full population. These risk patterns were observed across race/ethnicity (pint ≥0.43), with the strongest inverse associations among Japanese Americans (≥4 vs. 0 children, HR 0.45 [CI 0.26-0.79], ptrend <0.01; ≥5 years vs. never OC use, HR 0.35 [CI 0.16-0.78]). Though there was no association in the full population, age at natural menopause (≥55 vs. ≤45 years, HR 2.60 [CI 1.24-5.42]) and postmenopausal hormone use (≥5 years vs. never, HR 2.13 [CI 1.30-3.49]) were positively associated with EOC risk among Latinas. There were no significant associations among White, African American, or Native Hawaiian women for any of the risk factors tested. Conclusion: Our results suggest that differences in risk among ethnic groups were not fully explained by established risk factors and differences in risk remained, with increased risk observed in Native Hawaiians and lower risk in Latinas and Japanese Americans, compared to Whites. EOC is a rare disease, and case numbers limited our ability to further explore associations across the racial/ethnic groups in the MEC study. Citation Format: Danja Sarink, Song Yi Park, Loic Le Marchand, Kami White, Brenda Hernandez, Lynne Wilkens, V. Wendy Setiawan, Anna Wu, Melissa A. Merritt. Racial/ethnic disparities in epithelial ovarian cancer and its risk factors: The Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B41.

Reproductive history and progressive multiple sclerosis risk in women

Being a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case–control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P < 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) (P = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48–52) and controls (median, interquartile range: 51 years, 49–53) (P = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) (P = 0.069) with a pregnancy-dose effect [para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1–3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) (P = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age (R2 = 0.359, P < 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause (n = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age (n = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean ±standard deviation: 10.0 ± 9.4 years) (P = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1–3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) (P = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (R2 = 0.229, P < 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.

Severe Postmenopausal Genital Pain Treated Successfully With Prolonged Estrogen Therapy: A Case Series and Narrative Review.

The aim of the study was to describe a debilitating postmenopausal condition of continuous burning genital pain that remitted with prolonged estrogen focused on the vulvar vestibule. Postmenopausal patients with constant genital pain seen by the author in a specialty vulvar health clinic comprised an institutional review board-approved descriptive case series. Examinations to localize pain used 4% lidocaine topical solution. Each patient received estradiol nightly as vestibule crème or constantly by transdermal route and was followed by serial examinations and follow-up telephone contact. Statistical tests included Student t test, Fisher exact test, and Pearson correlation coefficient. Between 2008 and 2016, 16 women presented with constant genital pain that was partly or fully extinguishable with topical vestibular lidocaine, and their pain slowly responded to prolonged vestibule-directed estradiol therapy. The mean age was 66.8 years (± 11.2). The mean pain score was 5 (range = 2-10 on a 0-10 scale). Seven (44%) characterized their pain as debilitating, and 13 (81%) had accompanying urinary symptoms. In 9 patients (56%), ovaries had been removed before natural menopause at ages 27-50 years (mean = 39), followed by minimal or no estrogen therapy. Prolonged estrogen therapy eliminated constant pain in 69% and mitigated it in 31%. Information about this severe but remediable condition that is associated with lack of estrogen may guide specialists who are treating complex vulvar pain. The patients' clinical histories and therapeutic courses invite a review of estrogen receptor physiology related to urogenital pain conditions.

The effect of surgical menopause after bilateral oophorectomy on hormonal changes, mucociliary clearance, and quality of life.

The removal of the ovaries for any reason causes surgical menopause. Hormonal changes that occur progressively over 5-10years in natural menopause occur acutely in surgical menopause. Signs of estrogen deficiency appear suddenly and are permanent after this surgery. This study investigated the short- and long-term effects of estrogen deficiency occurring after surgical menopause on both nasal mucociliary activity and sinonasal symptoms. This prospective study included women aged 20-45years who were not in the menopause, who had a planned bilateral oophorectomy and who attended the Gynecology Clinic at the Faculty of Medicine at a university hospital between January 2018 and December 2019. The nasal mucociliary clearance time, and blood Estradiol (E2) and FSH levels were measured once in the preoperative period, and at the postoperative 3rd, 6th, 9th, and 12th months. At the same times, the Sinonasal Outcome Test 22 (SNOT-22) was also applied. The average age of the 47 patients was 41.2 ± 2.7. The mean serum estradiol levels of the women were 164.7 ± 63.4pg/ml in the preoperative period, 14.8 ± 3.7pg/ml at the postoperative 3rd month, 12.5 ± 3.5pg/ml at the postoperative 6th month, 11.6 ± 3.0pg/ml at the postoperative 9th month, and 11.1 ± 2.7pg/ml at the postoperative 12th month. The mean FSH levels of the women were 9.4 ± 2.4 mIU/ml in the preoperative period, 60.5 ± 9.6 mIU/ml at the postoperative 3rd month, 61.9 ± 9.4 mIU/ml at the postoperative 6th month, 63.0 ± 9.3 mIU/ml at the postoperative 9th month, and 64.6 ± 8.7 mIU/ml at the postoperative 12th month. The changes in postoperative mean estradiol and FSH levels over a year were significant and consistent with menopausal symptoms (p < 0.001). The mean mucociliary clearance times were 12.6 ± 1.2 before menopause, 13.2 ± 1.7 at the postoperative 3rd month, 14.5 ± 1.7 at the postoperative 6th month, 17.5 ± 1.6 at the postoperative 9th month, and 19.4 ± 1.9 at the postoperative 12th month. The extension of the mean mucociliary clearance time over 1 year was significant (p < 0.001). The mean scores for the SNOT-22 were 17.3 ± 6.9 before the operation, 17.8 ± 6.0 at the postoperative 3rd month, 19.6 ± 6.9 at the postoperative 6th month, 23.4 ± 10.4 at the postoperative 9th month, and 36.1 ± 10.0 at the postoperative 12th month. The mean scores for rhinologic symptoms were 5.2 ± 1.9 (3-11) in the preoperative period, 5.7 ± 2.0 (3-12) at the postoperative 3rd month, 7.1 ± 2.3 (4-14) at the postoperative 6th month, 9.3 ± 3.3 (4-16) at the postoperative 9th month, and 11.9 ± 3.3 (6-18) at the postoperative 12th month. The 1-year change in the SNOT-22 scores was found to be significant (p < 0.001). After bilateral oophorectomy, menopausal hormonal values were acutely high in women. At the 1-year postmenopausal follow-up, the mean scores for the SNOT-22 had increased significantly. In other words, quality of life decreased in parallel with prolonged nasal mucociliary clearance time.

Impact of cyclophosphamide on gonadotropins in menopausal systemic lupus erythematosus patients: Relation to disease activity and damage

BackgroundSystemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that affects females at reproductive age, where lupus patients experience menopause at younger age. It is debated whether early menopause in lupus patients results from gonadotoxic effect of cyclophosphamide treatment or an autoimmune mediated ovarian injury. Aim of the workTo identify menopausal symptoms and characteristics in an Egyptian cohort of SLE females and its relation to disease activity, disease damage, lupus nephritis and treatment. Patients and methods120 consecutive SLE female patients above the age of 35 were studied. Disease activity was assessed by SLE Disease Activity Index (SLEDAI), and accumulated damage by Systemic Lupus International Collaborative Clinics-Damage Index (SLICC-DI). Laboratory assessment was done including follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels. ResultsThe mean age of the patients was 45.1 ± 8.2 years (35–63 years) and the age at menopause was 45.2 ± 7.3 years (26–54 years). Their mean disease duration was 5.1 ± 5.7 years (1 month to 21 years). The mean SLEDAI was 4.7 ± 3.5 and SLICC-DI was 0.63 ± 0.82. 24 (20%) of patients had premature menopause, 29.2% had natural menopause and 50.8% were menstruating. There was a significant negative correlation between LH and SLEDAI. There was a significant correlation of FSH and LH with the cumulative cyclophosphamide dose. ConclusionSLE patients have early mean age of menopause at 45 years. High LH is associated with lower disease activity. High cumulative cyclophosphamide dose is associated with high FSH and LH. cyclophosphamide is potentially associated with premature menopause.