Bone health in women with premature ovarian insufficiency/early menopause: a 23-year longitudinal analysis.

STUDY QUESTION: What is the frequency of, and predictors for, osteoporosis, fractures, and osteoporosis management (investigation, treatment) in women with premature ovarian insufficiency (POI; menopause <40 years) and early menopause (EM; menopause 40-44years)? SUMMARY ANSWER: Over the 23-year follow-up duration, at a mean age of 68 years, women with POI/EM had higher osteoporosis/fracture risk and prevalence, higher osteoporosis screening and anti-osteoporosis medication use compared to women with usual age menopause; increasing age was predictive of increased risk of osteoporosis/fracture and menopause hormone therapy (MHT) prior to or at study entry (aged 45-50 years) was protective. WHAT IS KNOWN ALREADY: Women with POI/EM have increased risk of osteoporosis and fractures with limited data regarding risk factors for reduced bone density and fractures. Clinical guidelines recommend screening with dual X-ray absorptiometry (DXA) and treatment with MHT for most women with POI/EM to reduce osteoporosis and fracture risk; however, studies indicate gaps in osteoporosis knowledge, guideline uptake, and management adherence by clinicians and women. STUDY DESIGN, SIZE, DURATION: The Australian Longitudinal Study on Women's Health is a prospective longitudinal study of Australian women. This study uses the cohort of women born between 1946 and 1951, surveyed nine times between 1996 and 2019. Data from the Australian administrative health records, including hospital admissions data (fractures, osteoporosis), Medicare Benefits Schedule (DXA), and the Pharmaceutical Benefits Scheme (PBS; MHT, anti-osteoporosis medication, available only from 2002) were linked to survey data. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survey respondents with self-reported age of menopause were included. POI/EM was defined as menopause <45 years. T-test or chi-square were used for comparisons at baseline (P < 0.05 indicates significance). Generalized estimating equations for panel data explored predictors for the longitudinal outcomes of osteoporosis, fractures, DXA rates, MHT use, and anti-osteoporosis medication (in women with osteoporosis/fracture, from Survey 4 onwards only). Univariable regression was performed, and variables retained where P < 0.2, to form the multivariable model, and bootstrapping with 100 repetitions at 95% sampling of the original dataset to ensure robustness of results. MAIN RESULTS AND THE ROLE OF CHANCE: Eight thousand six hundred and three women were included: 610 (7.1%) with POI/EM. Mean (SD) baseline age was 47.6 (1.45) years in the entire cohort and mean (SD) age of menopause was 38.2 (7.95) and 51.3 (3.04) years in women with POI/EM and usual age menopause, respectively (P < 0.001). Over the 23 years, of women with POI/EM, 303 (49.7%) had osteoporosis/fractures, 421 (69.0%) had DXA screening, 474 ever used MHT (77.7%), and 116 (39.1%) of those with osteoporosis/fractures used anti-osteoporosis medication. Of women with usual age menopause, 2929 (36.6%) had osteoporosis/fractures, 4920 (61.6%) had DXA screening, 4014 (50.2%) used MHT, and 964 (33.0%) of those with osteoporosis/fractures used anti-osteoporosis medication. Compared to women with menopause at age ≥45 years and after adjusting for other risk factors, women with POI/EM had increased risk of osteoporosis (odds ratio [OR] 1.37; 95% CI 1.07-1.77), fractures (OR 1.45; 1.15-1.81), DXA testing (OR 1.64; 1.42-1.90), MHT use (OR 6.87; 5.68-8.30), and anti-osteoporosis medication use (OR 1.50; 1.14-1.98). In women with POI/EM women, increasing age was associated with greater risk of osteoporosis/fracture (OR 1.09; 1.08-1.11), and MHT prior to or at study entry (aged 45-50 years), was protective (OR 0.65, 0.45-0.96). In women with POI/EM, age (OR 1.11; 1.10-1.12), fractures (OR 1.80, 1.38-2.34), current smoking (OR 0.60; 0.43-0.86), and inner (OR 0.68; 0.53-0.88) or outer regional (OR 0.63; 0.46-0.87) residential location were associated with DXA screening. In women with POI/EM, increasing age (OR 1.02; 1.01-1.02), and currently consuming alcohol (OR 1.17; 1.06-1.28), was associated with having ever used MHT. In the 299 women with POI/EM and osteoporosis/fractures, only 39.1% ever received treatment with an anti-osteoporosis medication. Increasing age (OR 1.07; 1.04-1.09) and lower BMI (OR 0.95; 0.92-0.98) were associated with greater likelihood of treatment with anti-osteoporosis medication. LIMITATIONS, REASONS FOR CAUTION: Survey data including age of menopause were self-reported by participants; fracture questions were not included in the 2001 survey, and location or level of trauma of self-reported fractures was not asked. Additional risk/protective factors such as vitamin D status, calcium intake, and exercise were not able to be included. Due to sample size, POI and EM were combined for all analyses, and we were unable to differentiate between causes of POI/EM. PBS data were only available from 2004, and hospital admissions data were state-based, with all of Australia were only available from 2007. WIDER IMPLICATIONS OF THE FINDINGS: This study supports previous literature indicating increased risk of osteoporosis and fractures in women with POI, and adds evidence for women with POI/EM, where there was a relative paucity of data. This is the first study to analyse a variety of clinical and demographic risk factors for osteoporosis and fractures in women with POI/EM, as well as analysing investigation and treatment rates. In these women, using MHT prior to or at study entry, aged 45-50 years, was protective for osteoporosis/fractures; however, having ever used MHT was not, highlighting the importance of early treatment with MHT in these women to preserve bone strength. Although women with POI/EM and osteoporosis or fractures were more likely to use anti-osteoporosis medications than those with usual age menopause, overall treatment rates are low at <40%, demonstrating a significant treatment gap that should be addressed to reduce future fracture risk. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Australian NHMRC Centre of Research Excellence Women's Health in Reproductive Life (CRE-WHIRL, project number APP1171592). A.R.J. is the recipient of a National Health and Medical Research Council post-graduate research scholarship (grant number 1169192). P.R.E. is supported by a National Health and Medical Research Council grant 1197958. P.R.E. reports grants paid to their institution from Amgen, Sanofi, and Alexion, honoraria from Amgen paid to their institution, and honoraria from Alexion and Kyowa-Kirin. TRIAL REGISTRATION NUMBER: N/A.

Insufficient use of menopausal hormone therapy in Swedish women with early or premature menopause caused by bilateral oophorectomy: a register-based study.

OBJECTIVE: To investigate the use of menopausal hormone therapy (MHT) in premenopausal women after bilateral oophorectomy. DESIGN: Retrospective register-based cohort study. SETTING: Sweden. POPULATION: Swedish women aged 35-44 years without malignancy who underwent bilateral oophorectomy in 2005-2020 were identified using The Swedish National Quality Register of Gynaecological Surgery (GynOp). METHODS: Data from GynOp were cross-linked with data on dispensed drugs extracted from the Swedish Prescribed Drug Register. MAIN OUTCOME MEASURES: Proportion of women dispensed MHT at least once within 1 year after surgery. Repeated treatment episodes were defined, and the proportion of 'person time' covered by dispensations was analysed. RESULTS: In total, 1231 of all women (n = 1706) were dispensed MHT at some point after surgery, with 1177 women dispensed MHT within 1 year. This proportion increased from 64% in 2005 to 84% in 2019 (p < 0.001). In the total population, 4537 'treatment years' transpired, corresponding to 43% of the mean time covered. In women dispensed MHT within 1 year, the proportion of time covered was 63%. CONCLUSIONS: Only 69% of all women without malignancy of any kind who underwent bilateral oophorectomy were dispensed MHT within 1 year after surgery, and the duration of treatment was limited. It is important to study further the reasons behind the low dispensation rate in this group to increase adherence to current treatment guidelines, improve quality of life, and avoid increased morbidity and mortality.

Previous cancers in women diagnosed with premature ovarian insufficiency: A nationwide population-based case-control study.

INTRODUCTION: To investigate the occurrence of previous cancer diagnoses in women suffering from premature ovarian insufficiency (POI) and compare it with the general population, shedding light on the association between cancer, cancer treatments, and POI. MATERIAL AND METHODS: We conducted a nationwide case-control study based on registry data from various sources, including the Social Insurance Institution, Finnish Population Information System, and Finnish Cancer Registry spanning from 1953 to 2018. Our participants comprised all women in Finland who, between 1988 and 2017, received hormone replacement therapy reimbursement for ovarian insufficiency before the age of 40 years (n = 5221). Controls, matched in terms of age and municipality of residence, were selected from the Finnish Population Information System (n = 20 822). Our main exposure variable was a history of cancer diagnosis preceding the diagnosis of POI. We analyzed odds ratios (OR) to compare the prevalence of previous cancers in women with POI with that in controls, stratifying results based on cancer type, age at cancer diagnosis, and the time interval between cancer diagnosis and POI. We also assessed changes in OR for previous cancer diagnoses over the follow-up period. RESULTS: Out of the women diagnosed with POI, 21.9% had previously been diagnosed with cancer, resulting in an elevated OR of 36.5 (95% confidence interval [CI] 30.9 to 43.3) compared with 0.8% of the controls. The risk of developing POI was most pronounced during the first 2 years following a cancer diagnosis, with an OR of 103 (95% CI 74.1 to 144). Importantly, this risk remained elevated even when the time interval between cancer and POI exceeded 10 years, with an OR of 5.40 (95% CI 3.54 to 8.23). CONCLUSIONS: This study reveals that 21.9% of women with POI have a history of cancer, making the prevalence of cancer among these women 27.5 times higher than age-matched controls in the Finnish population. The risk of developing POI is most substantial in the first 2 years following a cancer diagnosis. These findings underscore the role of cancer treatments as an etiological factor for POI and emphasize the importance of recognizing the risk of POI in cancer survivors for early diagnosis and intervention.

Possible association between subclinical hypothyroidism and age at menopause in Colombian women.

OBJECTIVE: To evaluate the association between subclinical hypothyroidism with early menopause, premature menopause, and last menstrual bleeding before the natural age of menopause. METHODS: This was a cross-sectional study conducted in 643 postmenopausal women aged 40-69 years. Groups were formed according to last menstrual episode: ≥45 [Natural age at menopause], 40-44 and [Early menopause], <40 [Premature menopause], and <45 [last menstrual episode before the natural age of menopause]. The Zulewski scale was applied to identify manifestations related to hypothyroidism and subclinical hypothyroidism, diagnosed with a serum TSH > 4.5 µIU/mL plus T4-free between 0.7 and 1.9 ng/dL. RESULTS: It was found that 24.4% had the last menstrual episode before the natural age of menopause, 18.6% had early menopause, and 5.7% had premature menopause. Subclinical hypothyroidism was diagnosed in 4.5% of patients. Among women with subclinical hypothyroidism, there was a higher frequency of early menopause, premature menopause, and last menstrual episode before the natural age of menopause, than in women without subclinical hypothyroidism (p < 0.05). Paresthesia (50%) and dry skin (40.7%) were the most reported hypothyroidism-related manifestations. Early menopause, premature menopause, and last menstrual episode before the natural age of menopause were associated with subclinical hypothyroidism, OR: 3.37 [95% CI: 1.40-8.10], OR: 4.31 [95% CI: 1.24-14.97], and OR: 3.57 [95% CI: 1.57-8.10], respectively. CONCLUSIONS: The last menstrual episode before the natural age of menopause, early menopause, and premature menopause were significantly associated with a higher chance of subclinical hypothyroidism.

Association of genetic disorders and congenital malformations with premature ovarian insufficiency: a nationwide register-based study.

STUDY QUESTION: Are genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)? SUMMARY ANSWER: A wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI. WHAT IS KNOWN ALREADY: POI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7-15% of POI cases. STUDY DESIGN, SIZE, DURATION: This population-based study included 5011 women diagnosed with POI in 1988-2017. The data were collected from various national registries and covers women with POI nationwide. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date. MAIN RESULTS AND THE ROLE OF CHANCE: Of the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1-1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1-39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2-43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10-14 years old, OR 24.1, 95% CI 15.1-38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had. LIMITATIONS, REASONS FOR CAUTION: Some women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers. WIDER IMPLICATIONS OF THE FINDINGS: GD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations. STUDY FUNDING/COMPETING INTEREST(S): Oulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Is there a link between infertility, miscarriage, stillbirth, and premature or early menopause? Results from pooled analyses of 9 cohort studies.

BACKGROUND: Some reproductive factors (such as age at menarche and parity) have been shown to be associated with age at natural menopause, but there has been little quantitative analysis of the association between infertility, miscarriage, stillbirth, and premature (<40 years) or early menopause (40-44 years). In addition, it has been unknown whether the association differs between Asian and non-Asian women, although the age at natural menopause is younger among Asian women. OBJECTIVE: This study aimed to investigate the association of infertility, miscarriage, and stillbirth with age at natural menopause, and whether the association differed by race (Asian and non-Asian). STUDY DESIGN: This was a pooled individual participant data analysis from 9 observational studies contributing to the InterLACE consortium. Naturally postmenopausal women with data on at least 1 of the reproductive factors (ie, infertility, miscarriage, and stillbirth), age at menopause, and confounders (ie, race, education level, age at menarche, body mass index, and smoking status) were included. A multinomial logistic regression model was used to estimate relative risk ratios and 95% confidence intervals for the association of infertility, miscarriage, and stillbirth with premature or early menopause, adjusting for confounders. Between-study difference and within-study correlation were taken into account by including study as a fixed effect and indicating study as a cluster variable. We also examined the association with number of miscarriages (0, 1, 2, ≥3) and stillbirths (0, 1, ≥2), and tested whether the strength of association differed between Asian and non-Asian women. RESULTS: A total of 303,594 postmenopausal women were included. Their median age at natural menopause was 50.0 years (interquartile range, 47.0-52.0). The percentages of women with premature and early menopause were 2.1% and 8.4%, respectively. The relative risk ratios (95% confidence intervals) of premature and early menopause were 2.72 (1.77-4.17) and 1.42 (1.15-1.74) for women with infertility; 1.31 (1.08-1.59) and 1.37 (1.14-1.65) for women with recurrent miscarriages; and 1.54 (1.52-1.56) and 1.39 (1.35-1.43) for women with recurrent stillbirths. Asian women with infertility, recurrent miscarriages (≥3), or recurrent stillbirths (≥2) had higher risk of premature and early menopause compared with non-Asian women with the same reproductive history. CONCLUSION: Histories of infertility and recurrent miscarriages and stillbirths were associated with higher risk of premature and early menopause, and the associations differed by race, with stronger associations for Asian women with such reproductive history.

Risk factors of menopause after allogeneic hematopoietic cell transplantation in premenopausal adult women.

OBJECTIVES: Allogeneic hematopoietic stem-cell transplantation (HCT) is the only curative option for most hematologic malignancies. However, HSCT can cause early menopause and various complications in premenopausal women. Therefore, we aimed to investigate risk factors predicting early menopause and its clinical implications among survivors post HCT. METHODS: We retrospectively analyzed 30 adult women who had received HCT at premenopausal status between 2015 and 2018. We excluded patients who had received autologous stem cell transplantation, had relapsed, or died of any cause within 2 years of HCT. RESULTS: The median age at HCT was 41.6 years (range, 22-53). Post-HCT menopause was identified in 90% of myeloablative conditioning (MAC) HCT and 55% of reduced-intensity conditioning (RIC) HCT (p = .101). In the multivariate analysis, the post-HCT menopausal risk was 21 times higher in a MAC regimen containing 4 days of busulfan (p = .016) and 9.3 times higher in RIC regimens containing 2-3 days of busulfan (p = .033) than that of non-busulfan-based conditioning regimens. CONCLUSIONS: Higher busulfan dose in conditioning regimens is the most significant risk factor affecting post-HCT early menopause. Considering our data, we need to decide on conditioning regimens and individualized fertility counseling before HCT for premenopausal women.

Care after premenopausal risk-reducing salpingo-oophorectomy in high-risk women: Scoping review and international consensus recommendations.

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Prevalence of premature ovarian insufficiency (POI) and its relationship with female reproductive factors in Iranian women: a cross-sectional study from the Persian (Shahedieh) cohort data.

BACKGROUND: In premature ovarian insufficiency, the cessation of menstruation, and cessation of ovarian function occurs before the age of 40, and this phenomenon is associated with many complications and problems for women. Since several factors can affect this situation, this study was conducted to determine the relationship between fertility history, and premature ovarian failure. METHODS: This cross-sectional study was conducted on the data of the first phase of cohort study, which was a sample of 10,000 people from an Iranian adult population (age: 35-70 years). 1276 women were included who naturally experienced menopause from this population. They were separated into three groups based on the age of menopause: premature ovarian failure for those who reached menopause before the age of 40, early menopause for those who reached menopause between the ages of 40 and 45, and natural menopause for those who reached menopause at or after the age of 45. The demographic and fertility characteristics of two groups of women, one with premature ovarian failure and the other with early menopause, were compared with a group of women experiencing normal menopause. The comparison was based on frequency and percentage. Moreover, the odds ratio (OR) of these two groups compared to normal group was crudely calculated, and adjusted based on age at the time of the interview using a logistic regression model. SPSS 23 software was used to fit models and calculations. RESULTS: The prevalence of premature ovarian failure was 3%. The likelihood of premature ovarian failure decreases as the number of live births rises. The risk is considerably higher for births ranging from zero to three children compared to those with more than four. Increased duration of breastfeeding is associated to a reduced risk of premature ovarian failure compared to the spontaneous occurrence (OR = 0.98, 95% CI (0.97, 0.99)). This relationship is maintained even after adjusting for age (OR = 0.98, 95% CI (0.97, 0.99). CONCLUSION: Based on the results of present study, it can be concluded that the factor of the number of births, and the duration of breastfeeding affect reducing the occurrence of POI, therefore, in health and treatment programs and policies, encouragement to have children, which is now part of the policies population of Iran, and the importance, and benefits of breastfeeding for mother and baby should be emphasized more.

Association of In Utero Exposures With Risk of Early Natural Menopause.

Suboptimal pregnancy conditions may affect ovarian development in the fetus and be associated with early natural menopause (ENM) for offspring. A total of 106,633 premenopausal participants in Nurses' Health Study II who provided data on their own prenatal characteristics, including diethylstilbestrol (DES) exposure, maternal cigarette smoking exposure, multiplicity, prematurity, and birth weight, were followed from 1989 to 2017. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of in utero exposures with ENM. During 1.6 million person-years of follow-up, 2,579 participants experienced ENM. In multivariable models, women with prenatal DES exposure had higher risk of ENM compared with those without it (HR = 1.33, 95% CI: 1.06, 1.67). Increased risk of ENM was observed for those with low (<5.5 pounds (<2.5 kg)) versus normal (7.0-8.4 pounds (3.2-3.8 kg)) birth weight (HR = 1.21, 95% CI: 1.01, 1.45). Decreasing risk was observed per 1-pound (0.45-kg) increase in birth weight (HR = 0.93, 95% CI: 0.90, 0.97). Prenatal smoking exposure, being part of a multiple birth, and prematurity were not associated with ENM. In this large cohort study, lower birth weight and prenatal DES exposure were associated with higher risk of ENM. Our results support a need for future research to examine in utero exposures that may affect offspring reproductive health.

Reproductive complications after stroke: Long-lasting impairment of gonadotropin-releasing hormone neuronal network?

Some studies have demonstrated that stroke may increase the risk of pregnancy complications and early menopause. In addition, preclinical investigations revealed the middle cerebral artery occlusion could affect hypothalamus. Since hypothalamus is the core of central circuits regulating reproductive processes, impairment of hypothalamic gonadotropin-releasing hormone neuronal network following stroke might be manifested in long-lasting reproductive disorders.

Women with HIV transitioning through menopause: Insights from the Swiss HIV Cohort Study (SHCS).

OBJECTIVES: We aimed to assess prevalence and age at menopause, identify factors associated with early menopause and explore the provision and utilization of healthcare in women living with HIV in Switzerland. METHODS: This was a retrospective Swiss HIV Cohort Study analysis from January 2010 to December 2018. Descriptive statistics to characterise the population and menopause onset. Logistic regression analysis to identify risk factors for early menopause. RESULTS: Of all women in the SHCS, the proportion of postmenopausal women tripled from 11.5% (n = 274) in 2010 to 36.1% (n = 961) in 2018. The median age at menopause was 50 years. Early menopause (< 45 years) occurred in 115 (10.2%) women and premature ovarian insufficiency (POI) (< 40 years) in 23 (2%) women. Early menopause was associated with black ethnicity (52.2% vs. 21.6%, p < 0.001), but not with HIV acquisition mode, CDC stage, viral suppression, CD4 cell count, hepatitis C, smoking or active drug use. While 92% of the postmenopausal women underwent a gynaecological examination during the 36 months before menopause documentation, only 27% received a bone mineral density measurement within 36 months after the last bleed and 11% were on hormone replacement therapy at the time of menopause documentation. CONCLUSIONS: The median age of women living with HIV at menopause is around 2 years lower than that reported for HIV-negative women in Switzerland. HIV care providers need to adapt their services to the requirements of the increasing number of women living with HIV transitioning through menopause. They should be able to recognize menopause-associated symptoms and improve access to bone mineral density measurement as well as hormone replacement therapy.

Incidence and familial risk of premature ovarian insufficiency in the Finnish female population.

STUDY QUESTION: What is the incidence of premature ovarian insufficiency (POI), has the incidence of POI changed over time, and what is the risk of POI among relatives of POI women? SUMMARY ANSWER: The incidence of POI increased among females aged 15-19 years from 2007 onwards and decreased in older age groups, and among relatives of women with POI the risk of POI is significantly increased. WHAT IS KNOWN ALREADY: So far, there has been no good quality, nationwide studies of the incidence of POI. Early menopause has been associated with the elevated risk of early menopause among relatives, but the knowledge of the familial risk of POI is scarce. Lower socioeconomic status has been associated with lower age at natural menopause. STUDY DESIGN, SIZE, DURATION: Population-based study with 5011 women diagnosed with POI in 1988-2017. The data were collected from national registries and covers POI subjects in entire Finland. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with hormone replacement therapy reimbursement for POI were identified from Social Insurance Institution (SII). We calculated POI incidence in different age groups and studied the changes in the incidence rate over time in 5-year segments. Four population-based controls were selected from the Digital and Population Data Services Agency (DVV) for each POI woman. Family members of the POI cases and controls were identified from the DVV and linked to SII reimbursement data to identify POI diagnoses among them. The familial risk of POI was estimated with a logistical regression model. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence was highest in the 35-39 age group, ranging from 73.8/100 000 women-years in 1993-1997 to 39.9/100 000 women-years in 2013-2017. From 2007, the incidence among 15- to 19-year-olds rose from 7.0 to 10.0/100 000 women-years in 2015-2017. Cumulative incidence of POI for women under 40 years in 1988-2017 was 478/100 000 women. The relative risk of POI among relatives of women with POI was 4.6 (95% CI 3.3-6.5) compared to relatives of women without POI. POI women tended to have slightly lower socioeconomic status and level of education compared to controls. LIMITATIONS, REASONS FOR CAUTION: For some women with POI, diagnosis or reimbursement may be lacking. However, we presume that these women represent a minority due to the nature of the disease and the economic benefits of reimbursement. Some changes in the incidence of POI can reflect changes in clinical practice and changing treatments and reimbursement criteria. WIDER IMPLICATIONS OF THE FINDINGS: The risk of developing POI is significantly higher in women who have first-degree relatives diagnosed with POI. Raising awareness of the increased risk might lead to earlier diagnosis and initiation of hormonal replacement therapy, possibly preventing adverse effects of low oestrogen levels, such as osteoporosis. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by the Oulu University Hospital. H.S. received a grant from Finnish Menopause Society. S.M.S. received a grant from the Finnish Menopause Society, the Finnish Medical Foundation and the Juho Vainio Foundation. The authors do not have any competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Early natural menopause is associated with poor lung health and increased mortality among female smokers.

BACKGROUND: Early natural menopause has been regarded as a biomarker of reproductive and somatic aging. Cigarette smoking is the most harmful factor for lung health and also an established risk factor for early menopause. Understanding the effect of early menopause on health outcomes in middle-aged and older female smokers is important to develop preventive strategies. OBJECTIVE: This study aimed to examine the associations of early menopause with multiple lung health and aging biomarkers, lung cancer risk, and all-cause and cause-specific mortality in postmenopausal women who were moderate or heavy smokers. STUDY DESIGN: This study was conducted on postmenopausal women with natural (n=1038) or surgical (n=628) menopause from the Pittsburgh Lung Screening Study. The Pittsburgh Lung Screening Study is a community-based research cohort of current and former smokers, screened with low-dose computed tomography and followed up for lung cancer. Early menopause was defined as occurring before 45 years of age. The analyses were stratified by menopause types because of the different biological and medical causes of natural and surgical menopause. Statistical methods included linear model, generalized linear model, linear mixed-effects model, and time-to-event analysis. RESULTS: The average age of the 1666 female smokers was 59.4±6.7 years, with 1519 (91.2%) of the population as non-Hispanic Whites and 1064 (63.9%) of the population as current smokers at baseline. Overall, 646 (39%) women reported early menopause, including 198 (19.1%) women with natural menopause and 448 (71.3%) women with surgical menopause (P<.001). Demographic variables did not differ between early and nonearly menopause groups, regardless of menopause type. Significant associations were identified between early natural menopause and higher risk of wheezing (odds ratio, 1.65; P<.01), chronic bronchitis (odds ratio, 1.73; P<.01), and radiographic emphysema (odds ratio, 1.70; P<.001) and lower baseline lung spirometry in an obstructive pattern (-104.8 mL/s for forced expiratory volume in the first second with P<.01, -78.6 mL for forced vital capacity with P=.04, and -2.1% for forced expiratory volume in the first second-to-forced vital capacity ratio with P=.01). In addition, early natural menopause was associated with a more rapid decline of forced expiratory volume in the first second-to-forced vital capacity ratio (-0.16% per year; P=.01) and incident airway obstruction (odds ratio, 2.02; P=.04). Furthermore, women early natural menopause had a 40% increased risk of death (P=.023), which was mainly driven by respiratory diseases (hazard ratio, 2.32; P<.001). Mediation analyses further identified that more than 33.3% of the magnitude of the associations between early natural menopause and all-cause and respiratory mortality were explained by baseline forced expiratory volume in the first second. Additional analyses in women with natural menopause identified that the associations between continuous smoking and subsequent lung cancer risk and cancer mortality were moderated by early menopause status, and females with early natural menopause who continued smoking had the worst outcomes (hazard ratio, >4.6; P<.001). This study did not find associations reported above in female smokers with surgical menopause. CONCLUSION: Early natural menopause was found to be a risk factor for malignant and nonmalignant lung diseases and mortality in middle-aged and older female smokers. These findings have strong public health relevance as preventive strategies, including smoking cessation and chest computed tomography screening, should target this population (ie, female smokers with early natural menopause) to improve their postmenopausal health and well-being.

Does climacteric status impact regulation of the autonomic nervous system at the age of 46 years?

OBJECTIVE: To investigate whether an earlier-onset climacteric phase is associated with autonomic imbalance at the age of 46 years. METHODS: This cross-sectional birth cohort study included 2661 women aged 46 years. Participants were divided into climacteric (n = 359) and preclimacteric (n = 2302) groups based on menstrual history and follicle stimulating hormone values. The mean heart rate (HR), low-frequency (LF) power, high-frequency (HF) power and LF/HF ratio were analyzed from heart rate variability recordings. The variables were compared between the groups using multivariable linear regression models, including body mass index, smoking and physical activity. The effects of hormone therapy and hot flashes on autonomic function were evaluated in sub-analyses. RESULTS: Climacteric women had a lower mean HR in seated (71.9 ± 10.5 vs. 72.6 ± 10.4 bpm, p = 0.015) and standing (81.2 ± 12.8 vs. 83.6 ± 12.1 bpm, p = 0.002) positions compared to preclimacteric women, and the differences remained significant after the adjustments. In the sub-analyses, more frequent hot flashes were associated with a lower LF power and LF/HF ratio in the sitting position. CONCLUSIONS: The present study suggested an association between greater parasympathetic activation in women with more advanced climacteric status at the age of 46 years.

Exploration of fertility and early menopause related information needs and development of online information for young breast cancer survivors.

BACKGROUND: Approximately half of premenopausal women diagnosed with breast cancer desire to conceive after they finish treatment. Counseling about the risk of infertility prior to cancer treatment has been proven to improve quality of life after cancer treatment. As a result of this, guidelines focus on informing women on this topic prior to treatment. However, it is equally important to provide fertility related information after primary treatment has been completed, when the wish to conceive might become actual. Therefore, the aim of this study was to identify the fertility and early menopause related information needs of young breast cancer survivors and to design, develop and implement online information material with input of stakeholders. METHODS: A phenomenological qualitative study consisting of four phases was performed: identification of information needs through semi-structured interviews from a professional perspective (1) and a patient perspective (2). Exploration of stakeholders perspective regarding development and implementation of online information material (3) and development and implementation of the information material (4). RESULTS: Professionals indicated that there are no guidelines regarding the provision of fertility related information during cancer survivorship. Survivors reported unmet information needs. Women identified the following as most important information needs (a) fertility preservation options, (b) the risk of menopause or infertility, and (c) long term consequences of early menopause. A wide range of stakeholders involved in breast cancer care were interviewed. Based on their proposed design the information material was implemented on a nationwide website aiming at informing and supporting breast cancer patients. CONCLUSIONS: Fertility and early menopause related information needs of young breast cancer survivors and their professionals were identified. Information material has been designed, developed and nationally implemented. This way, professionals in breast cancer care are provided with an information tool that helps them meet the information needs and preferences of their patients.

Risk factors for natural menopause before the age of 45: evidence from two British population-based birth cohort studies.

BACKGROUND: Menopause that occurs before the age of 45 and is not medically induced (referred to here as 'early natural menopause') affects around one in 10 women and has serious health consequences. These consequences include increased risk of all-cause mortality, cardiovascular disease, osteoporosis, and type 2 diabetes. METHODS: We investigate risk factors for the onset of natural menopause before the age of 45 in two population-based prospective cohort studies in Britain: the 1958 cohort following 8959 women and the 1970 cohort following 8655 women. These studies follow women from birth to adulthood, and we use harmonized data on birth and early life characteristics, reproductive health, health behaviour, and socioeconomic characteristics for 6805 women who were pre-menopausal, peri-menopausal or had undergone natural menopause. Of these 6805 women, 3614 participated in the 1958 cohort (of which 368 had early menopause) and 3191 participated in the 1970 cohort (of which 206 had early menopause). Taking a life course approach, we focus on three distinct life stages - birth/early life, childhood, and early adulthood - to understand when risk factors are most harmful. Respecting the temporal sequence of exposures, we use a series of multivariable logistic regression models to estimate associations between early menopause and each potential risk factor adjusted for confounders. RESULTS: We find that early menopause is influenced by circumstances at birth. Women born in lower social class families, whose mother smoked during the pregnancy or who were breastfed 1 month or less were more likely to undergo early menopause. Early menopause is also associated with poorer cognitive ability and smoking in childhood. Adult health behaviour also matters. Smoking is positively correlated with early menopause, while regular exercise and moderate frequency of alcohol drinking in women's early thirties are associated with reduced risk of early menopause. The occurrence of gynaecological problems by women's early thirties is also linked to early menopause. CONCLUSIONS: We demonstrate that characteristics at different periods of life are associated with early menopause. Some of these associations relate to modifiable behaviours and thus the risks of early menopause and the adverse health outcomes associated with it may be preventable.

The association between thrombophilic genes alterations and poor ovarian response in infertile women: a retrospective case-control study.

This research aimed to retrospectively investigate the possible association between poor ovarian stimulation and selected thrombophilia markers in Iranian women with infertility. For this study 100 Iranian infertile women, with a history of at least three Assisted Reproduction Technology (ART) failures (50 with a poor ovarian response and 50 with a normal response), referred to Royan Institute were selected. Targeted genetic variation evaluation for Factor V G1691A, F II Prothrombin G20210A, MTHFR C677T, MTHFR A1298C was performed by PCR-RFLP followed by Sanger Sequencing. The association between these variants and the ovarian response was examined. The results showed an association between Factor V G1691A mutation and poor ovarian response. The heterozygosity rate of the FVL was significantly different between poor responders compared with the normal response group (p-value ≤ 0.05). In conclusion screening of this polymorphism can be used as a genetic determinant of ovarian response functioning through a vascular mechanism. A larger study with bigger sample size is recommended.Impact statementWhat is already known on this subject? Thrombophilia is a multi-genetic disease that is associated with changes in homeostatic mechanisms. Some studies have suggested that thrombophilia has no relationship with poor ovarian response and reduced ovarian reserve in general infertile population undergoing ART.What do the results of this study add? Our results showed a significant association between the FVL heterozygote mutation and poor ovarian response.What are the implications of these findings for clinical practice and/or further research? Screening of FVL polymorphism may be suggested as a predictive test for ovarian stimulation response in infertile women undergoing ART. Further prospective studies with bigger sample size evaluating other thrombophilia markers and ovarian response, as well as further in-vitro studies may help clarify the biological mechanisms behind the effect of the FVL polymorphism on ovarian response, oocyte quality and embryo quality.

Is Alcohol Consumption Associated With Risk of Early Menopause?

Earlier age at menopause is associated with increased long-term health risks. Moderate alcohol intake has been suggested to delay menopause onset, but it is unknown whether alcohol subtypes are associated with early menopause onset at age 45 years. Therefore, we aimed to evaluate risk of early natural menopause among 107,817 members of the Nurses' Health Study II who were followed from 1989 to 2011. Alcohol consumption overall and by subtypes, including beer, red wine, white wine, and liquor, was assessed throughout follow-up. We estimated hazard ratios in multivariable models that were adjusted for age, body mass index, parity, smoking, and other potential confounders. Women who reported moderate current alcohol consumption had lower risks of early menopause than did nondrinkers. Those who reported consuming 10.0-14.9 g/day had a lower risk of early menopause than did nondrinkers (hazard ratio = 0.81, 95% confidence interval: 0.68, 0.97). Among specific beverages, evidence of lower early menopause risk was confined to consumption of white wine and potentially red wine and liquor, but not to beer. Data from this large prospective study suggest a weak association of moderate alcohol intake with lower risk of early menopause, which was most pronounced for consumption of white and red wine and liquor. High consumption was not related to lower risk of early menopause.

Association of oral contraceptives and tubal ligation with risk of early natural menopause.

STUDY QUESTION: What is the association of oral contraceptives (OCs) and tubal ligation (TL) with early natural menopause? SUMMARY ANSWER: We did not observe an association of OC use with risk of early natural menopause; however, TL was associated with a modestly higher risk. WHAT IS KNOWN ALREADY: OCs manipulate hormone levels, prevent ovulation, and may modify the rate of follicular atresia, while TL may disrupt the blood supply to the ovaries. These mechanisms may be associated with risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. STUDY DESIGN, SIZE, DURATION: We examined the association of OC use and TL with natural menopause before the age of 45 years in a population-based study within the prospective Nurses' Health Study II (NHSII) cohort. Participants were followed from 1989 to 2017 and response rates were 85-90% for each cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included 106 633 NHSII members who were premenopausal and aged 25-42 years at baseline. Use, duration and type of OC, and TL were measured at baseline and every 2 years. Menopause status and age were assessed every 2 years. Follow-up continued until early menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, or loss to follow-up. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs adjusted for lifestyle, dietary, and reproductive factors. MAIN RESULTS AND THE ROLE OF CHANCE: Over 1.6 million person-years, 2579 members of the analytic cohort experienced early natural menopause. In multivariable models, the duration, timing, and type of OC use were not associated with risk of early menopause. For example, compared with women who never used OCs, those reporting 120+ months of OC use had an HR for early menopause of 1.01 (95% CI, 0.87-1.17; P for trend=0.71). TL was associated with increased risk of early menopause (HR = 1.17, 95% CI, 1.06-1.28). LIMITATIONS, REASONS FOR CAUTION: Our study population is homogenous with respect to race and ethnicity. Additional evaluation of these relations in more diverse populations is important. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the largest study examining the association of OC use and TL with early natural menopause to date. While TL was associated with a modest higher risk of early menopause, our findings do not support any material hazard or benefit for the use of OCs. STUDY FUNDING/COMPETING INTEREST(S): The study was sponsored by UO1CA176726 and R01HD078517 from the National Institutes of Health and Department of Health and Human Services. The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have no competing interests to report. TRIAL REGISTRATION NUMBER: N/A.