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PubMed1998

General ageing and ovarian ageing.

The age related decrease in female fertility is associated with a decrease in follicle numbers and oocyte quality. Meiotic division errors, mitochondrial DNA mutations and ageing itself have been suggested to play a part in the age associated reduction in oocyte quality. During the past decades several hypothesis have been proposed, trying to explain the underlying mechanisms. However, none of them is yet conclusive. This review will consider the main hypotheses regarding the age related reduction in oocyte quality. This will be reviewed together with recent results of studies analysing a possible relationship between ageing and ovarian ageing. On the basis of our own results and those presented in the literature, it is concluded that ovarian ageing may only be related to specific aspects of general ageing.

Aging↗

PubMed2003

Early ovarian ageing: a hypothesis. What is early ovarian ageing?

A concept of early ovarian ageing has been advanced. This theory suggests that some women will experience problems of fecundity at an early age given that the age of menopause is earlier for some women, and there is a fixed time of accelerated atresia leading up to menopause. Various components of this theory are examined based on existing literature. While the theory has merit, and is important to consider in terms of reproductive health, it remains a hypothesis. It is also plausible to consider that a segment of the population will have later ovarian ageing in that menopause can be as late as 58 years for some women. Further, it is not known whether there really is a fixed time of accelerated atresia leading up to menopause in all women. The practical considerations dealing with this hypothetical concern also are not trivial. How will certain women with early ovarian ageing be identified, what hormonal and other factors should be measured, and what advice is reasonable for these young women?

Aging↗

PubMed2026

Mitochondrial Haplotype Shapes the Trajectory of Ovarian Aging in Genetically Heterogeneous Rats.

Ovarian aging leads to permanent reproductive senescence and systemic hormonal changes that predispose women to age-associated comorbidities. Despite these observations, the intrinsic mechanisms driving age-related ovarian decline are poorly defined. Mitochondrial DNA (mtDNA) mutations and instability are strongly associated with aging; however, it remains unknown if naturally occurring mitochondrial genetic variation influences the trajectory of ovarian aging. To address this, we compared two genetically heterogeneous rat cohorts (OKC-HETB and OKC-HETW) that differ in mitochondrial haplotype on a randomized but equivalently distributed nuclear background. The OKC-HETW haplotype was associated with accelerated loss of primordial follicles and pathological remodeling marked by fibrosis, macrophage infiltration, and multinucleated giant cells. These tissue-level pathologies were paralleled by mitochondrial dysfunction, characterized by decreased respiratory complex activity, ATP production, and mtDNA copy number. Mechanistically, we identified a haplotype-specific defect in mitochondrial genome maintenance. Although TFAM expression was normal, and total TFAM protein was elevated, OKC-HETW ovaries showed reduced mitochondrial TFAM abundance, TFAM-mtDNA binding, and TOMM20, suggesting that impaired TOMM20-mediated import is associated with compromised mitochondrial genomic stability. Longitudinal transcriptomic and proteomic analyses further indicate that mitochondrial haplotype influences the rate of ovarian aging, with OKC-HETW ovaries showing accelerated activation of inflammatory and fibrotic pathways alongside suppressed proteostasis and mitochondrial function. These defects corresponded to impairments in ovulation and a trend toward worsening oocyte quality. Collectively, our findings identify mitochondrial haplotype as a heritable modifier of ovarian aging rate that acts in concert with the nuclear genome, and a putative target for preserving ovarian function and female healthspan.

Animals↗

PubMed2004

Ovarian aging and infertility.

Ovarian aging is expressed with altered menstrual cyclicity, endocrine and biochemical profiles and impaired fertility. Shortening of the menstrual cycle may be the first signal of diminished ovarian reserve. Hormonal interplay in the aging ovary is manifested as a monotropic FSH rise, decreased inhibin B concentrations and fluctuating estradiol concentrations. Due to social changes, childbearing has been delayed, thus the group of women in their late thirties seeking infertility treatment has been increasing. Intrauterine insemination (IUI) usually precedes more sophisticated assisted reproductive technology (ART) treatments such as in vitro fertilization-embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI). We present the outcomes of ART treatments achieved in our institution in women over 38 compared to younger women. The pregnancy rate after IUI was 3.7% in women over 38 years, and 28.6% in women less than 38 years; after IVF-ET the cumulative pregnancy rate was 16% (the miscarriage rate 21%) in women over 38, and 28% (13%) in women less than 38 years; the cumulative pregnancy rate after ICSI was 9% (the miscarriage rate 26%) in women over 38, and 27% (the miscarriage rate 14%) in women younger than 38 years. Women in advanced age should therefore be properly counselled and informed about poor success rates, and about the high cost of infertility treatment.

Adult↗

PubMed1998

Ovarian ageing and the general biology of senescence.

Ovarian ageing is not only of major importance in its own right but is also of interest for its relationship with the general biology of senescence. A key feature of ageing is the distinction in higher animals between the immortality of the germ-line and the mortality of somatic cells and tissues. The ovary contains the female germ cells, and it is through these cells that the female contribution to germ-line immortality is effected. It is abundantly clear that individual oocytes can and do age and that the ageing of the ovary plays a major role in initiating or accelerating a series of other senescent changes. To understand how ovarian ageing fits within the general biology of senescence, it is necessary to explain why ageing occurs at all, to examine the likely mechanisms of general ageing, and to ask whether there is anything special about ovarian ageing and its relationship with the human menopause. Research on ovarian ageing interacts with the our emerging understanding of the general biology of senescence at many levels, ranging from the evolution of the human life history to the biochemical and cellular mechanisms of ageing and longevity.

Aging↗

PubMed2006

Efficacy of laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: relationships with chronological and ovarian age.

BACKGROUND: Laparoscopic ovarian diathermy (LOD) has been used successfully as a first-, second- and third-line treatment for ovulation induction in women with polycystic ovary syndrome (PCOS). However, little is known about the predictors for LOD efficacy. The aim of the present study was to evaluate reproductive outcomes in clomiphene citrate (CC)-resistant PCOS patients treated with LOD according to ovarian and chronological age. METHOD: A total of 60 non-obese, primary infertile, CC-resistant women with PCOS were enrolled and treated with LOD. During the following 6 months, all patients underwent ovulation monitoring and timed intercourse. If spontaneous ovulation did not occur within 3 months from surgery, CC (100 mg/day) was administered for 5 days from day 3 of the remaining cycles. The ovulation, abortion and pregnancy rates were assessed and analyzed with patients categorized according to chronological age (group A, <25 years; group B, 25-30 years; group C, 30-35 years; group D, >35 years) and ovarian age (group 1, follicle stimulating hormone (FSH) < 10 mIU/ml; group 2, FSH > 10 mIU/ml). RESULTS: At the end of the study, total ovulation, pregnancy and abortion rates were 57.1, 13.0 and 18.2%, respectively. No difference in all reproductive outcomes was observed between groups A, B and C, whereas the efficacy of LOD was significantly lower in group D. A significant difference in all clinical endpoints was detected between groups 1 and 2. CONCLUSIONS: Our data show that chronological age >35 years and basal FSH value > 10 mIU/ml are related to poor reproductive prognosis in CC-resistant PCOS patients treated with LOD.

Abortion, Spontaneous↗

PubMed2026

Ovarian aging and systemic health: Mechanisms and emerging intervention strategies.

Ovarian aging may contribute to systemic aging via the ovarian-systemic axis. This review outlines intrinsic ovarian cellular defects such as genomic instability, epigenetic shifts, and mitochondrial and proteostasis damage, which may trigger senescence-associated secretory phenotype (SASP)-related inflammaging, fibrosis, and distal pro-aging signals. Ovarian-derived endocrine disruption, especially estrogen decline, broadly affects bodily physiology. We summarize emerging multimodal interventions, including senolytics, metabolic reprogramming, regenerative medicine, and systemic approaches, and we discuss their dual potential to preserve fertility and intercept ovarian contributions to systemic aging. Ovarian aging is possibly associated with female age-related multimorbidity. Ovary-targeted prevention may extend healthspan, as assessed by combined reproductive and systemic clinical evaluations.

Humans↗

PubMed2003

Subfertility reflects accelerated ovarian ageing.

BACKGROUND: The aim of the study was to explore the extent to which accelerated ovarian ageing may lead to subfertility early in reproductive life and eventually cause early menopause. METHODS: The population studied (n = 2393) never used oral contraceptives, hormone replacement therapy or an intrauterine device. Logistic regression analyses were performed using age at menopause as proxy for accelerated ovarian ageing. Measures of ovarian ageing and subfertility were menstrual cycle irregularity, ever consulted a physician for fertility problems, nulliparity, uniparity, miscarriage(s) and time interval >5 years between birth of first and second child. RESULTS: For every 5 years later menopause, the probability of reporting menstrual cycle irregularity was reduced by 26% (OR = 0.74, 95% CI: 0.63-0.86); the probability of ever consulting a physician for fertility problems was reduced by 18% (OR = 0.82, 95% CI: 0.71-0.95); the probability of staying nulliparous was reduced by 22% (OR = 0.78, 95% CI: 0.64-0.96); the probability of being uniparous was reduced by 22% (OR = 0.78, 95% CI: 0.66-0.91); the probability of having a miscarriage was reduced by 11% (OR = 0.89, 95% CI: 0.79-1.01); the probability of a large time interval between birth of first two children was reduced by 27% (OR = 0.73, 95% CI: 0.61-0.89). CONCLUSIONS: Fertility problems are frequently followed by early menopause. The findings support the view that both are an expression of accelerated ovarian ageing.

Abortion, Spontaneous↗

PubMed2006

X-chromosome inactivation and ovarian age during the reproductive years.

OBJECTIVE: To explore whether skewed X-chromosome inactivation (XCI) is related to indicators of ovarian age. DESIGN: The XCI skewing percent and indicators of ovarian age were measured in women with recent pregnancy losses and women with recent livebirths. All analyses adjust for chronologic age and pregnancy outcome. SETTING: Hospital in eastern central New York. PATIENT(S): One hundred thirty-six women with informative XCI assays: 83 with index pregnancy losses and 53 with livebirths. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary indicators of ovarian age were antral follicle count, levels of FSH and inhibin B. A secondary indicator was level of estradiol (E2). RESULT(S): The XCI skewing percent, defined either continuously or categorically (> or =90%), was unrelated to the indicators of ovarian age. The sample was large enough to rule out as unlikely a modest decline in antral follicle count or a modest increase in FSH in relation to skewed XCI. CONCLUSION(S): X-chromosome anomalies are associated with skewed XCI and with premature ovarian failure. Our data raise the possibility that X-chromosome anomalies may not be an important influence on ovarian aging in menstruating women.

Adolescent↗

PubMed2026

Revealing potential biomarkers and metabolic mechanisms of ovarian aging in hens during late laying period based on machine learning and metabolomics.

Ovarian function decline during the late laying period represents a major bottleneck for the economic efficiency of the global poultry industry. However, the underlying metabolic mechanisms and reliable early-warning biomarkers for ovarian aging remain poorly understood. In this study, we performed the first untargeted LC-MS/MS metabolomics analysis of ovarian tissues from Taihe silky fowls at peak laying (30 weeks) and late laying (50 weeks) stages, and employed an ensemble machine learning strategy integrating LASSO, random forest, and support vector machine (SVM) algorithms to identify high-confidence core biomarkers of ovarian aging. Gene expression analysis was further conducted to validate the potential molecular mechanisms. Our results showed that the metabolic profiles of ovarian tissues differed significantly between the two groups. A total of 6 core biomarkers were identified, 4 of which were long-chain acylcarnitines. Mechanistic analysis revealed that downregulation of key genes in the carnitine shuttle system led to impaired mitochondrial fatty acid β-oxidation, which in turn triggered excessive oxidative stress and compromised ovarian endocrine function. In conclusion, this study identifies long-chain acylcarnitines as potential metabolic biomarkers for ovarian aging in Taihe silky fowls. These findings provide novel insights into the metabolic basis of poultry ovarian aging and lay a theoretical foundation for the precise regulation of reproductive performance in indigenous poultry breeds.

Animals↗

PubMed2026

Research progress on multi-mechanism analysis and protection strategies of ovarian aging and fertility decline.

Age-related fertility decline is an increasingly important challenge in reproductive medicine, driven largely by progressive ovarian aging. The aging ovary undergoes functional deterioration characterized by reduced ovarian reserve and declining oocyte quality, ultimately limiting female reproductive lifespan. Although multiple molecular and cellular processes associated with ovarian aging have been identified, these mechanisms are often discussed independently, limiting an integrated understanding of how they interact within the ovary. In this review, we propose an ovary-centered, multi-mechanistic framework to organize current evidence on ovarian aging and fertility decline. We discuss how genomic instability, telomere attrition, mitochondrial dysfunction, oxidative stress, chronic cellular stress responses, and alterations in ovarian signaling and microenvironmental homeostasis collectively contribute to follicle depletion and impaired oocyte competence. Particular emphasis is placed on signaling pathways involved in follicle activation and stress adaptation, including PI3K/AKT/mTOR, FOXO3, Hippo, and AMPK-Sirtuin networks, while acknowledging that many mechanistic relationships remain incompletely defined in physiological ovarian aging. Building on this integrative perspective, we further evaluate mechanism-oriented intervention strategies, including mitigation of cellular stress, metabolic and signaling modulation, optimization of the ovarian microenvironment, established fertility preservation technologies, and emerging exploratory approaches. By integrating current mechanistic and translational evidence, this review provides a conceptual framework for understanding ovarian aging and highlights future directions for evidence-based fertility preservation and reproductive health management in the context of aging.

Humans↗

PubMed2005

In vitro fertilization and embryo transfer in seminatural cycles for patients with ovarian aging.

OBJECTIVE: To investigate whether seminatural cycle is a reasonable management for ovarian aging patients. DESIGN: Prospective study. SETTING: ART Unit, Clamart, France. PATIENT(S): Seventy-five women, 158 cycles. INTERVENTION(S): Infertile women who presented with ovarian aging (defined as low ovarian reserve and characterized by cycle day 3 high FSH, high E2, and/or low inhibin B and/or previous cycle cancellations due to poor ovarian response to COH) were studied. Patients were offered up to three cycles. Treatment was scheduled as follows. From cycle day 8 onward the selection of the dominant follicle was monitored by ultrasound and hormonal measurements. When the dominant follicle appeared, patients received GnRH antagonist and, thereafter, hMG to support further follicular development. MAIN OUTCOME MEASURE(S): Implantation rate and clinical pregnancy. RESULT(S): Twenty-eight of 158 cycles were cancelled (17.7%). Oocyte pickups were performed in 119 (75.3%) cycles, 91 (57.6%) mature oocytes were retrieved, and 67 (42.4%) embryos transferred. Nineteen clinical pregnancies were obtained; the cumulative pregnancy rate per patient, after 3 cycles, was 35.2%. CONCLUSION(S): Use of a seminatural cycle is a reasonable management for patients with ovarian aging who have ovulatory menstrual cycles. It achieves a high implantation rate (28.3%).

Adult↗

PubMed2025

Celastrol modulates IRS1 expression to alleviate ovarian aging and to enhance follicular development.

Ovarian aging significantly contributes to the decline of the female reproductive system, adversely affecting fertility and endocrine homeostasis. To address the challenges posed by reproductive aging, natural products have shown promising preventive and therapeutic effects. Here, we investigated the beneficial effects of natural compound celastrol on ovarian development and aging, together with its underlying mechanisms. We found that celastrol administration at a concentration of 3 mg/kg promoted follicle development in young mice and enhanced porcine oocyte maturation, while regulating granulosa cell proliferation and apoptosis. In 12-month-old mice (equivalent to middle-aged adults), celastrol exhibited similar beneficial effects. Transcriptomic analysis revealed that differentially expressed genes post-celastrol treatment were associated with steroid biosynthesis, estrogen signaling pathways, type 2 diabetes, insulin secretion, meiosis, and apoptosis. Additionally, insulin receptor substrate 1 (IRS1), an adapter protein in insulin signaling, was shown to advance puberty in young mice and to facilitate oocyte maturation. Overexpression of IRS1 in oocytes promoted follicular development and oocyte maturation, resulting in enhanced steroid hormone levels, whereas IRS1 knockdown inhibited these processes. Our findings indicate that celastrol may regulate ovarian development and aging by modulating IRS1 expression and its related pathways, suggesting celastrol as a novel small-molecule compound targeting IRS1, and offering new perspectives for potential therapeutic strategies against reproductive aging and infertility.

Animals↗

PubMed2006

Menstrual cycle markers of ovarian aging and sex steroid hormone genotypes.

We related variation in 4 sex steroid genes to 3 phenotypic indicators of ovarian aging, including no evidence of luteal activity as a marker of anovulatory cycles, shorter or longer menstrual cycle lengths, and the profiles of metabolites of estrogens, progesterone, follicle-stimulating hormone, and luteinizing hormone measured in urine samples collected daily across a menstrual cycle in women aged 43 to 53 years. The study sample included 485 menstruating women without hormone therapy who had collected daily urine hormone samples across 1 menstrual cycle or 50 days, whichever occurred first. There were 14 single nucleotide polymorphisms from 4 genes, including estrogen receptor-alpha (ESR1), estrogen receptor-beta, aromatase, and 17beta hydroxysteroid dehydrogenase type 1, related to ovarian aging phenotypes that include the presence or absence of luteal activity, menstrual cycle lengths < or > 24 to 31 days, and profiles of urinary hormone metabolites. Women with the TT genotype of ESR1 rs3798577 have evidence of advanced ovarian aging compared with women with the CT or CC genotypes, after adjustment for race/ethnicity, chronologic age, and race/ethnicity-specific body mass index. Further, women with the TC and CC genotypes of ESR1 rs2234693 may have a greater likelihood of more advanced ovarian aging than do women with the TT genotype, adjusting for covariates. Using a candidate gene approach, 2 ESR1 polymorphisms are related to 3 phenotypic markers of ovarian aging, suggesting a possible role for the ESR1 gene in the timing of the menopausal transition.

17-Hydroxysteroid Dehydrogenases↗

PubMed2004

Evidence of early ovarian aging in fragile X premutation carriers.

Up to 28% of female fragile X premutation carriers develop premature ovarian failure. To test the hypothesis that fragile X premutation carriers with ovulatory menstrual cycles exhibit hormone changes characteristic of early ovarian aging, 11 regularly cycling fragile X premutation carriers, 24-41 yr old (34.5 +/- 5.7 yr, mean +/- sd), drew daily blood samples across one menstrual cycle. LH, FSH, estradiol, progesterone (P4), inhibin A, and inhibin B levels were compared with levels in 22 age-matched, regularly cycling women, 23-41 yr old (34.6 +/- 5.8 yr), at each cycle stage. Total cycle (26.1 +/- 1.0 vs. 28.2 +/- 0.4 d; P < 0.05) and follicular phase length (12.9 +/- 0.8 vs. 14.5 +/- 0.4 d; P < 0.05) were decreased in fragile X premutation carriers compared with age-matched controls, whereas luteal phase length was similar (13.2 +/- 0.5 vs. 13.7 +/- 0.3 d; P = not significant). FSH was elevated across the follicular (21.9 +/- 3.5 vs. 11.2 +/- 0.5 IU/liter; P < 0.001) and luteal phases (14.6 +/- 3.9 vs. 7.9 +/- 0.5 IU/liter; P < 0.05) in fragile X premutation carriers compared with age-matched controls. Inhibin B in the follicular phase (77 +/- 11 vs. 104 +/- 6 pg/ml; P < 0.05) and inhibin A (3.4 +/- 0.7 vs. 5.8 +/- 0.5 IU/ml; P < 0.01) and P4 [7.3 +/- 1.0 vs. 10.1 +/- 0.7 ng/ml (23.2 +/- 3.0 vs. 32.1 +/- 2.3 nmol/liter); P < 0.05] in the luteal phase were decreased in fragile X premutation carriers compared with age-matched controls, whereas there was no difference in estradiol or LH. In summary, despite regular ovulatory cycles, FSH was increased in fragile X premutation carriers compared with age-matched controls. The increased FSH was accompanied by decreased inhibin B in the follicular phase and inhibin A and P4 in the luteal phase. These hormonal changes suggest that fragile X premutation carriers exhibit early ovarian aging despite regular menstrual cycles. Early ovarian aging in fragile X premutation carriers likely results from decreased follicle number and function, as reflected by lower inhibin B, inhibin A, and P4 levels.

Adult↗

PubMed2004

Antral follicle count and serum follicle-stimulating hormone levels to assess functional ovarian age.

OBJECTIVE: The objective of this study was 2-fold. The first was to estimate side-to-side variation in antral follicle counts. The second was to determine whether basal follicle-stimulating hormone levels on days 2, 3, and 4 of the same menstrual cycle are significantly different. METHODS: Forty-one patients between the ages of 20 and 42 years undergoing monitoring for in vitro fertilization-embryo transfer were evaluated ultrasonographically for antral follicle number. The antral follicle counts were determined for each ovary by experienced ultrasonographers at the time of suppression check ultrasonography. In a separate study, 62 normal subjects (ages 20-25 and 40-45 years) underwent serial sequential serum follicle-stimulating hormone determinations on days 2-4 of the menstrual cycle, and these levels were compared. RESULTS: There was no significant difference between right and left antral follicle counts (P =.30). Serial follicle-stimulating hormone values were not significantly different on days 2, 3, or 4 of the menstrual cycle (P =.22). CONCLUSION: There is no significant difference between right-sided and left-sided antral follicle counts within the same individual. In turn, there is no significant difference in serial follicle-stimulating hormone levels on days 2, 3, or 4 of the menstrual cycle. LEVEL OF EVIDENCE: III

Adult↗

PubMed2002

Women with regular menstrual cycles and a poor response to ovarian hyperstimulation for in vitro fertilization exhibit follicular phase characteristics suggestive of ovarian aging.

OBJECTIVE: To investigate whether follicular phase characteristics associated with ovarian aging can be observed in women of normal reproductive age, who had previously shown a poor response to ovarian hyperstimulation for IVF. DESIGN: Observational, prospective study. SETTING: Tertiary fertility center. PATIENT(S): Eleven regularly cycling, ovulatory women, aged 29-40 years who previously presented with fewer than four dominant follicles after ovarian hyperstimulation for IVF. INTERVENTION(S): Frequent serum hormone assessments and transvaginal ultrasound during the follicular phase of a spontaneous, unstimulated cycle. MAIN OUTCOME MEASURE(S): Duration of the follicular phase; serum LH, FSH, E(2), P, inhibin A, and inhibin B levels; and number of antral follicles observed by ultrasound. Results were compared with the cycle characteristics of a reference population of 38 healthy normo-ovulatory women aged 20-36 years (as published elsewhere). RESULT(S): Poor responders had significantly fewer antral follicles than controls. Median FSH concentrations were significantly higher compared with controls, but the majority had FSH levels within the normal range. Follicular phase P levels were significantly higher in poor responders. Duration of the follicular phase, E(2), and inhibin A and inhibin B serum levels did not differ between poor responders and controls. CONCLUSION(S): Normo-ovulatory regularly cycling women with a previous poor response to ovarian hyperstimulation for IVF show follicular phase characteristics suggestive of ovarian aging.

Adult↗

PubMed2004

Early ovarian ageing: are women with polycystic ovaries protected?

Screening asymptomatic women in the general population for 'early ovarian ageing' will be more effective in high-risk groups. Recent findings support the hypothesis that women with polycystic ovaries (PCO) may have actually been born with a larger pool of resting follicles. The mechanism is almost certainly genetic and occurs in fetal life. If, as is widely accepted, the rate of depletion of the ovarian reserve depends primarily on the size of the remaining pool of small follicles, women with PCO will be unlikely to undergo an accelerated depletion of their follicle pool, normally seen in the late thirties, significantly earlier. In terms of asymptomatic screening for early ovarian ageing in the general population, women with PCO constitute a low-risk group and should therefore be excluded.

Aging↗