Metabolic effects of early-onset menopausal transition

Abstract The mean age at natural menopause is 51 years, preceded by a gradual decline of ovarian function (climacteric phase). One percent of women, however, experience menopause by the age of 40 (premature ovarian insufficiency, POI), and up to 12% experience menopause by the age of 45 (early menopause, EM). Women with POI are known to be at risk for some adverse health outcomes, especially osteoporosis and cardiovascular diseases, while less is known about the health consequences of EM. For some diseases, like diabetes, the evidence on the association of menopausal status and age at menopause is controversial. The objective of this study was to investigate health outcomes in women experiencing menopausal transition by their mid-40s, compared to premenopausal women at the same age. The main outcomes were a cardiovascular risk profile, glucose metabolism, vitamin D status and prevalence of thyroid autoantibody positivity and dysfunction. The study population consisted of female participants from the prospective Northern Finland Birth Cohort 1966 (NFBC1966) who participated in the NFBC1966 46-year follow-up study. The 46-year-old participants were divided into two groups—climacteric and preclimacteric—based on their level of follicle-stimulating hormone (FSH) and menstrual anamnesis. The study outcomes were compared between the groups at the age of 46 and some outcomes also at the age of 31. The study results suggest that early-onset climacteric transition is an independent risk factor for adverse changes in body composition, lipid profile, liver enzymes and insulin sensitivity. The risk for thyroid dysfunctions in climacteric women was also slightly increased, even though the prevalence of thyroid autoantibody positivity did not increase. Interestingly, the use of hormone replacement therapy (HRT) was associated with higher vitamin D status in climacteric women, as the results were adjusted with factors known to be related to vitamin D status. In conclusion, early-onset menopausal transition should be considered a risk factor for adverse health outcomes. Healthy lifestyle habits and the use of HRT may be beneficial in reducing this risk.Tiivistelmä Keskimäärin 51 vuoden iässä nainen saavuttaa vaihdevuodet eli menopaussin. Tätä edeltää munasarjojen toiminnan vähitellen tapahtuva hiipuminen eli klimakteerinen vaihe. Noin yksi prosentti naisista saavuttaa menopaussin alle 40 vuoden iässä (ennenaikainen menopaussi), ja jopa 12 prosenttia 40–45-vuotiaana (varhainen menopaussi). Ennenaikainen menopaussi lisää monien epäedullisten terveysvaikutusten, erityisesti osteoporoosin sekä sydän- ja verisuonisairauksien riskiä, kun taas varhaisten vaihdevuosien terveysvaikutuksista on vain vähän tutkimustietoa. Useiden sairauksien, kuten diabeteksen, kohdalla tutkimusnäyttö sairauden puhkeamisriskin yhteydestä menopaussi-ikään ei ole toistaiseksi selkeää. Tutkimuksen tarkoituksena oli selvittää 46 vuoden ikään mennessä alkavan klimakteerisen vaiheen terveysvaikutuksia: sydän- ja verisuonisairauksien riskitekijöitä, sokeriaineenvaihduntaa, D-vitamiinipitoisuuksia ja kilpirauhasen autoimmuunivasta-aineiden ja toimintahäiriöiden yleisyyttä. Tutkimuspopulaatio koostui Pohjois-Suomen syntymäkohortti 1966 naisista, jotka osallistuivat kohortin 46-vuotisseurantatutkimukseen. Nämä naiset jaettiin kahteen ryhmään vaihdevuositilanteensa perusteella. Ryhmäjako perustui follikkelia stimuloivan hormonin (FSH) arvoon ja tietoihin sen hetkisestä kuukautiskierron toiminnasta. Terveysmuuttujia verrattiin tutkimusryhmien välillä 46 vuoden ja osaa muuttujista myös 31 vuoden iässä. Tutkimustulosten perusteella varhainen vaihdevuosien alkamisikä on itsenäinen riskitekijä epäedullisiin muutoksiin kehonkoostumuksessa, rasva-arvoissa, maksa-arvoissa sekä insuliiniherkkyydessä. Myös kilpirauhasen toimintahäiriöiden riski oli lievästi suurentunut, mutta autoimmuunivasta-aineiden esiintyvyys ei eronnut ryhmien välillä. Lisäksi todettiin, että hormonikorvaushoidon käyttö oli yhteydessä korkeampaan D-vitamiinipitoisuuteen klimakteerisilla naisilla, ottaen huomioon tunnetut D-vitamiinipitoisuuteen vaikuttavat tekijät. Tutkimuksen perusteella varhainen vaihdevuosien alkamisikä tulisi huomioida riskitekijänä epäedullisille terveysvaikutuksille. Terveelliset elämäntavat ja hormonikorvaushoito todennäköisesti kompensoivat riskiä

Climacteric status at the age of 46:impact on metabolic outcomes in population-based study

Abstract Context: Menopausal transition is associated with increased cardiovascular risks. Available data on the effect of earlier climacterium on these risks are limited. Objective: To compare cardiovascular risk-associated parameters at the ages of 14, 31, and 46 in relation to climacteric status at the age of 46. Design, Setting, and Participants: A prospective cohort study including 2685 women from the Northern Finland Birth Cohort 1966. Main Outcome Measures: Follicle-stimulating hormone, body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), blood pressure (BP), body composition, cholesterol levels, testosterone (T) levels, free androgen index (FAI), high-sensitivity C-reactive protein (hs-CRP), and liver enzymes. Results: Women who were climacteric at the age of 46 had lower BMIs (P = 0.029), T levels (P = 0.018), and FAIs (P = 0.009) at the age of 31. At the age of 46, they had less skeletal muscle (P < 0.001), a higher fat percentage (P = 0.016), higher cholesterol levels [total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), high-density lipoprotein cholesterol (HDL-C; P = 0.022), and triglycerides (P = 0.008)], and higher alanine aminotransferase (P = 0.023) and γ-glutamyltransferase (P < 0.001) levels compared with preclimacteric women. Waist circumference, WHR, BP, and hs-CRP levels did not differ between the groups. Of the climacteric women, 111/381 were using hormone-replacement therapy (HRT). In subanalysis that excluded the HRT users, triglycerides, HDL-C, and body fat percentage did not differ among the groups. Conclusions: Earlier climacterium is associated with mainly unfavorable metabolic changes

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

Abstract Objectives: 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

Climacteric status is associated with sexual dysfunction at the age of 46:a population-based study

Abstract Objectives: Increasing age and menopausal transition increase the risk of sexual dysfunction. Sexual dysfunction is common in women experiencing menopause before the age of 40 years, whereas evidence on sexual function in women experiencing menopause in their mid-40s is scarce. We aimed to investigate sexual function in 46-year-old women in relation to their menopausal status. Methods: This study cross-sectionally evaluated sexual function of women in a prospective population-based Northern Finland Birth Cohort 1966 (NFBC1966). A 46-year follow-up study of NFBC1966 included a broad questionnaire evaluating health, lifestyle, and life situation, as well as menstrual history and sexual function, and blood sampling analysis including follicle stimulating hormone and free androgen index (FAI). The participants were divided into two groups by their menopause status, defined by follicle-stimulating hormone and menstrual history. We performed logistic regression models in which parameters of sexual function were dependent factors and climacteric status, self-reported health, FAI, relationship status, smoking, and education level were independent variables. Results: The study population included 2,661 women. In regression models, more advanced climacteric status was associated with higher frequency and difficulty level of low sexual desire and vaginal dryness (odds ratios with 95% confidence intervals: 2.80 [2.12‐3.71], 3.22 [2.43‐4.27], 3.83 [2.82‐5.20], 3.75 [2.75‐5.12], respectively), lower frequency of sexual thoughts (1.34 [1.02‐1.75]), and higher frequency of problems with intercourse (2.35 [1.51‐3.66]). Lower FAI and poorer health were associated with impaired sexual function. Conclusions: The current study suggests that women experiencing menopausal transition in their mid-40s are at risk of impaired sexual function

Is climacterium by the mid-40s associated with thyroid dysfunction or autoimmunity? A population-based study

Abstract Objective: We investigated whether more advanced climacteric stage in the mid-40s is associated with thyroid autoimmunity and dysfunction. Methods: This cross-sectional cohort study included 2,569 46-year-old women. Thyroid hormone, thyroid peroxidase antibodies, and follicle-stimulating hormone levels were determined. Using menstrual history and follicle-stimulating hormone levels, the participants were divided into climacteric (n = 340) and preclimacteric (n = 2,229) groups. Women diagnosed with premature ovarian insufficiency (menopause by 40 y of age) were excluded. The use of thyroid medication was evaluated from the medication reimbursement register. The prevalence of thyroid medication use, laboratory-based thyroid dysfunction, and thyroid peroxidase antibody positivity was compared between the two groups. The association between climacteric status and thyroid disorders was investigated using a logistic regression model including smoking and thyroid antibody status. Results: At 46 years old, climacteric women used thyroid medication more often than preclimacteric women (9.1% vs 6.1%; P = 0.04). There was no difference in the prevalence of subclinical or clinical hypothyroidism and hyperthyroidism in nonmedicated participants (5.5% vs 5.0%; P = 0.7) or thyroid peroxidase antibody positivity (14.0% vs 15.0%, P = 0.7). In the regression model, being climacteric (OR = 1.6; 95% CI 1.1–2.3; P = 0.02) and antibody positivity (OR 4.9; 95% CI 3.6–6.6; P < 0.001) were associated with a higher prevalence of thyroid dysfunction. Conclusions: More advanced climacteric stage in the mid-40s was slightly associated with thyroid dysfunction but not thyroid autoimmunity

Is climacterium by the mid-40s associated with thyroid dysfunction or autoimmunity?:a population-based study

Abstract Objective: We investigated whether more advanced climacteric stage in the mid-40s is associated with thyroid autoimmunity and dysfunction. Methods: This cross-sectional cohort study included 2,569 46-year-old women. Thyroid hormone, thyroid peroxidase antibodies, and follicle-stimulating hormone levels were determined. Using menstrual history and follicle-stimulating hormone levels, the participants were divided into climacteric (n = 340) and preclimacteric (n = 2,229) groups. Women diagnosed with premature ovarian insufficiency (menopause by 40 y of age) were excluded. The use of thyroid medication was evaluated from the medication reimbursement register. The prevalence of thyroid medication use, laboratory-based thyroid dysfunction, and thyroid peroxidase antibody positivity was compared between the two groups. The association between climacteric status and thyroid disorders was investigated using a logistic regression model including smoking and thyroid antibody status. Results: At 46 years old, climacteric women used thyroid medication more often than preclimacteric women (9.1% vs 6.1%; P = 0.04). There was no difference in the prevalence of subclinical or clinical hypothyroidism and hyperthyroidism in nonmedicated participants (5.5% vs 5.0%; P = 0.7) or thyroid peroxidase antibody positivity (14.0% vs 15.0%, P = 0.7). In the regression model, being climacteric (OR = 1.6; 95% CI 1.1–2.3; P = 0.02) and antibody positivity (OR 4.9; 95% CI 3.6–6.6; P < 0.001) were associated with a higher prevalence of thyroid dysfunction. Conclusions: More advanced climacteric stage in the mid-40s was slightly associated with thyroid dysfunction but not thyroid autoimmunity

Onset of the climacteric phase by the mid-forties associated with impaired insulin sensitivity:a birth cohort study

Abstract Objective: To investigate whether the early-onset menopausal transition is associated with deteriorated glucose tolerance in women in their mid-forties. Methods: A cross-sectional analysis of a cohort study including 2,632 women of the Northern Finland Birth Cohort 1966. The participants were divided into two groups by their menstrual history and follicle-stimulating hormone values at age 46: climacteric and preclimacteric women. Glucose and insulin parameters, as well as mathematical indices derived from them to evaluate insulin sensitivity, were compared between the groups. The results were adjusted for measured body mass index and smoking. The possible effect of hormone therapy was investigated in subanalyses excluding hormone therapy users. Results: Climacteric women (n = 379) were more often current smokers at age 46 (P = 0.008), and their body mass indices increased more from 31 to 46 years (P = 0.013), compared to preclimacteric women (n = 2,253). In a multivariable generalized linear model, being climacteric at age 46 was associated with several findings suggesting decreased insulin sensitivity: increased glycated hemoglobin (P < 0.001), 2-hour oral glucose tolerance test 30- and 60-minute insulin (P = 0.040 and 0.006, respectively), and area under the insulin curve (P = 0.005). Being climacteric also was associated with a decreased the McAuley (P = 0.024) and Belfiore indices (P = 0.027) and glucose tolerance test 60-minute glucose (P = 0.015). In subanalyses excluding hormone therapy users (n = 94), the results did not change significantly. Conclusions: Earlier onset of climacteric transition is associated with impaired insulin sensitivity in middle-aged women

Early-onset climacterium is not associated with impaired vitamin D status:a population-based study

Abstract Objective: To investigate vitamin D status in women with the onset of the climacteric phase by age 46 as both early menopause and inadequate vitamin D status may increase the risk of adverse health outcomes. Methods: A cross-sectional study included 2,544, 46-year-old women from a birth cohort. Women were divided into the following two groups according to their menstrual history and follicle-stimulating hormone (FSH) concentration: 1) climacteric (FSH ≥25 IU/L and amenorrhea ≥4 mo,n = 351) and 2) preclimacteric women (FSH <25 IU/L and having regular/irregular menstrual cycles, n = 2,193). Serum 25-hydroxyvitamin D (25(OH)D) concentrations were compared between the groups. A linear regression model was performed to investigate which factors are associated with 25(OH)D status. Results: Mean serum 25(OH)D concentrations were higher in climacteric compared with preclimacteric women (68.1 ± 19.8 nmol/L vs 65.2 ± 19.3 nmol/L, P = 0.01). However, in the linear regression model, climacteric status was not associated with 25(OH)D status (multivariable adjusted mean difference 4.5 nmol/L, 95% confidence interval −1.4 to 10.4, P = 0.137). A total of 76 of the climacteric women were using systemic estrogen hormone therapy (HT). In a subanalysis, including only climacteric women, the use of HT was associated with higher 25(OH)D status (multivariable adjusted mean difference 5.9 nmol/L, 95% confidence interval 1.3–10.5, P = 0.013). Conclusions: The onset of the climacteric phase by age 46 was not associated with inadequate 25(OH)D concentrations, whereas HT use was associated with higher 25(OH)D status in women with early-onset climacterium

Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata

Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.Peer reviewe