Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women
The effect of aging on the number of non-growing follicles (NGF) and early-growing follicles (EGF) was studied in humans through use of a database obtained by pooling two subsets of ovarian pairs (2 x 43 pairs) collected in two distinct populations. A previously suggested model of exponential regression of NGF counts in relation to the subject's age was tested but did not adequately fit the observed data points. This lack of fit is attributable mainly to the existence of a significant relation between a woman's age and the corresponding NGF count decay rate. Consequently, various regression models were tested. Two different periods of decay rate were observed for each population of small follicles. The first corresponds to younger ages with a decay rate that is slow for both types of follicles, although faster for NGF than for EGF. The second period corresponds to older ages with an accelerated decay rate that appears similar for NGF and EGF. The changing points were found at 38.0 +/- 2.4 and 39.0 +/- 1.9 yr (mean +/- SD) for NGF and EGF, respectively. Extrapolation of the fitted model suggested the presence of approximately 402,000 healthy NGF per ovary at birth and a total exhaustion of the follicular stock at around 74 yr of age. These results support the view that depletion of the NGF pool is caused mainly by atresia in younger women but mainly by entrance of NGF into the growing pool in older women. The mechanisms triggering accelerated entrance into the growth phase of NGF are discussed in relation to the previously reported increase in FSH plasma levels that starts in the late thirties, approximately, and precedes the menopausal period by several years.
Early-life nutritional deprivation may influence lifelong health, but its role in the broader process of reproductive aging remains underexplored. Guided by the Developmental Origins of Health and Disease framework, this study investigates the impacts of fetal/infant and adolescent exposure to famine on age at natural menopause, a key indicator of reproductive aging. The study sample comprised 4256 women from the China Health and Retirement Longitudinal Study. Participants were categorized into fetal/infant (1959-1962 births) or adolescent (1942-1946 births) famine-exposed cohorts and non-exposed controls. Multivariable linear and logistic regression models were used to assess associations between famine exposure and age at natural menopause or early menopause, adjusting for sociodemographic, economic, and behavioral covariates. Famine exposure was associated with an earlier age at natural menopause: 1.16 years earlier for fetal/infant exposure (β = -0.12, p = 0.002), and 0.72 years earlier for adolescent exposure (β = -0.07, p = 0.014); it was also associated with increased odds of early menopause (odds ratio [OR] = 1.05, 95 % confidence interval [CI] 1.01-1.10). No significant association with premature menopause was observed. Nutritional deprivation during critical developmental windows-particularly adolescence-has distinct, long-term effects on the trajectory of reproductive aging. These observational findings, which cannot establish causality, underscore the importance of early-life nutrition in shaping female reproductive health and are consistent with the Developmental Origins of Health and Disease framework in reproductive health.
What is the association between endometriosis and the type and age of menopause? Women with endometriosis had a 7-fold increased risk of undergoing surgical menopause rather than natural menopause and were more likely to experience premature or early menopause, both surgically and naturally. Endometriosis is associated with reduced ovarian reserve, but evidence on its relationship with the type of menopause (surgical vs natural) and timing (especially premature and early menopause) is limited. Women with endometriosis are more likely to undergo hysterectomy and/or oophorectomy (either unilateral or bilateral), but the average age of these surgeries remains unclear. STUDY DESIGN, SIZE, The study analysed individual-level data from 279 948 women in five cohort studies conducted in the UK, Australia, Sweden, and Japan between 1996 and 2022. PARTICIPANTS/MATERIALS, SETTING, Women whose menopause type and age could not be determined due to premenopausal hysterectomy with ovarian preservation or use of menopausal hormone therapy were excluded. Endometriosis was identified through self-reports and administrative data. Surgical menopause was defined as premenopausal bilateral oophorectomy. Fine-Gray subdistribution hazard models estimated hazard ratios (HRs) for surgical and natural menopause. Age at menopause was determined by the ages at the final menstrual period or bilateral oophorectomy. Linear regression assessed mean differences in menopause age, while multinomial logistic regression estimated odds ratios (ORs) for categorical menopause age: <40 (premature), 40-44 (early), 45-49, 50-51 (reference), 52-54, and ≥55 years. Spontaneous premature ovarian insufficiency (POI) was defined as natural menopause before age 40 years. MAIN Endometriosis was identified in 3.7% of women. By the end of follow-up, 7.9% had surgical menopause and 58.2% experienced natural menopause. Using a competing risk model, women with endometriosis had a 7-fold increased risk of surgical menopause (HR: 7.54, 95% CI 6.84, 8.32) and were less likely to experience natural menopause (HR: 0.40, 95% CI 0.33, 0.49). On average, surgical menopause occurred 1.6 years (19 months) earlier (β: -1.59, 95% CI -1.77, -1.42) in women with endometriosis. Among women who experienced natural menopause, it was 0.4 years (5 months) earlier (β: -0.37, 95% CI -0.46, -0.28) for those with endometriosis. Women with endometriosis were twice as likely to experience premature surgical menopause (<40 years) (OR: 2.11, 95% CI 2.02, 2.20) or 1.4 times more likely to develop spontaneous POI (OR: 1.36, 95% CI 1.17, 1.59). They were also at increased odds of early surgical and natural menopause (40-44 years). LIMITATIONS, This study could not differentiate between subtypes and stages of endometriosis or assess treatments for ovarian endometrioma, which may impact ovarian reserve. Self-reported menopause type and age could introduce recall bias. Given the consistent findings across individual studies, our results are likely to be generalizable to different populations, highlighting the need for tailored management of endometriosis to prevent medically induced or premature menopause. Long-term monitoring of women with endometriosis is recommended, given their elevated risk of surgical menopause and premature or early menopause, which are associated with adverse health outcomes in later life. STUDY FUNDING/COMPETING INTEREST(S): The InterLACE Consortium is funded by the Australian National Health and Medical Research Council project grant (APP1027196) and Centres of Research Excellence (APP1153420). G.D.M. is funded by the Australian National Health and Medical Research Council Leadership Fellowship (APP2009577). This research is funded in part by the Japan Society for the Promotion of Science (JSPS 19KK0235, 23KK0167). The authors have no conflict of interest. Where authors are identified as personnel of the International Agency for Research on Cancer or WHO, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO. N/A.
The mouse is a tractable model for human ovarian biology; however, its utility is limited by incomplete understanding of how transcription and signaling differ interspecifically and with age. We compared ovaries between species using three-dimensional imaging, single-cell transcriptomics, and functional studies. In mice, we mapped declining follicle numbers and oocyte competence during aging; in human ovaries, we identified cortical follicle pockets and decreases in density. Oocytes had species-specific gene expression patterns during growth that converged toward maturity. Age-related transcriptional changes were greater in oocytes than in granulosa cells across species, although mature oocytes change more in humans. We identified ovarian sympathetic nerves and glia; axon density increased in aged ovaries and, when ablated in mice, perturbed folliculogenesis. This comparative atlas defines shared and species-specific hallmarks of ovarian biology.
1. Define premature ovarian insufficiency, diagnostic criteria, risk factors and comorbidities.
2. Discuss health concerns, as well as health and hormone management of patients suffering with POI.
3. Discuss restorative fertility approaches to those with POI.