Age-related female infertility

Age-related female infertility is the age-associated reduction in probability of conception and live birth arising from declining follicle number, oocyte competence and ovarian-somatic support. The page covers the continuous decline in fecundability as well as clinically diagnosed infertility. It is distinct from premature-ovarian-insufficiency: many affected women continue to menstruate and produce oocytes.

The official FY2026 ICD-10-CM alphabetic index assigns age-related female infertility to N97.8; the tabular label is “female infertility of other origin.” N97.9 is the unspecified code ¹. ICD-11 GA31 is the broader female-infertility category, subdivided by primary versus secondary infertility and origin but not by an age-specific mechanistic subtype ¹.

Age and fecundability

In the prospective North American PRESTO cohort (2,962 pregnancy planners), fecundability declined approximately linearly with female age rather than at a single threshold. Relative to ages 21–24, adjusted fecundability ratios were 0.82 (95% CI 0.64–1.05) at 34–36, 0.60 (0.44–0.81) at 37–39 and 0.40 (0.22–0.73) at 40–45 ². These population averages do not define an individual molecular cutoff.

Mechanistic contributors

Mechanistic detail lives on the more specific entity pages:

• Follicle-reserve depletion reduces the number of recruitable follicles.
• Oocyte aging raises aneuploidy risk and impairs developmental competence.
• Cumulus and granulosa-cells can lose metabolic, proteostatic and paracrine support.
• Stromal fibroblast activation and matrix stiffening may impair follicle and granulosa-cell function.
• Dysregulated ribosome-biogenesis and protein-synthesis may add proteotoxic stress in selected reproductive cells, but their causal share is not established.

Rapamycin trial evidence

Li et al. randomized 100 women with prior IVF failure, 50 per arm, to standard treatment with or without oral sirolimus 1 mg/day for 21–28 days before oocyte retrieval. The mature-oocyte outcome was null: median 3 (Q1–Q3 1–4) versus 2 (1–3), P=0.108. Three control and five sirolimus participants produced no MII oocyte, leaving 47 versus 45 for embryo analyses; zygote, day-3 embryo and morphology-based good-quality-embryo counts favored sirolimus. Blastocyst comparisons were selected subsets (21 versus 12), not the full randomized groups ³.

Clinical pregnancy among participants who reached transfer was 20/40 versus 11/39 (reported RR 1.77, 95% CI 0.98–3.19; P=0.047). This was a secondary per-transfer analysis after post-randomization attrition, not intention-to-treat efficacy among all 50 randomized participants per arm. Transfer stage was selected after treatment. Among pregnant participants who had reached their due date, live birth was 10/14 versus 6/8 and statistically null; six versus three pregnancies were still ongoing at cutoff ³.

The confidence interval for clinical pregnancy includes 1, treatment was not placebo-controlled, adverse-event reporting was insufficient and randomized live-birth follow-up was incomplete. The trial does not establish improved cumulative live birth or long-term reproductive safety.

Matrix-targeting evidence

Wu et al. associated human ovarian age and several ovarian pathologies with greater cortical stiffness and IL-11. Genetic or RNA inhibition of il-11-signaling reduced ovarian stiffness and improved selected follicle, ovulation or litter outcomes in rodents ⁴. In the adult siIl11 arms, pregnancy counts favored treatment but were nonsignificant when recalculated (mouse 3/8 versus 6/8, P≈0.315; rat 3/10 versus 6/10, P≈0.370), despite highly significant printed values. There was no human intervention, and matrix softening cannot replace follicles that have already been depleted.

The human tissue findings were cross-sectional. Germline Il11ra1 loss tested protection rather than reversal, the adult systemic siRNA experiments were not ovary-specific, and the locally delivered AAV experiment was underreported. No anti-IL-11 antibody was tested in an intact ovary; antibody evidence was confined to cultured fibroblasts ⁴.

Current care and investigational status

Embryo and mature-oocyte cryopreservation are established methods for preserving fertility potential before further aging; they bank younger embryos or gametes and do not reverse ovarian aging. Outcomes remain strongly dependent on age at cryopreservation and the number of oocytes stored ^{5 6}. IVF can assist conception but likewise does not restore a depleted follicle pool or reverse oocyte aging.

Neither sirolimus nor IL-11 inhibition is standard fertility-preservation care. A separate placebo-controlled low-dose rapamycin ovarian-aging pilot, NCT05836025, remained active but not recruiting as of the literature check and had no posted efficacy results ⁷.

Evidence boundaries

• The data-derived transcriptomic transition near age 34 in Li et al. is not a diagnostic cutoff.
• Improved embryo counts do not imply improved euploidy or live birth.
• Neither IL-11 suppression nor brief rapamycin exposure is a standard fertility-preservation treatment.
• Cryopreservation preserves material collected at a younger age; it does not rejuvenate an older ovary. gap/needs-replication gap/needs-human-replication gap/long-term-unknown

Footnotes

Footnotes

1. CDC/NCHS, ICD-10-CM FY2026 Index to Diseases and Injuries and Tabular List (Infertility, female, age-related → N97.8; N97.8 “female infertility of other origin”; N97.9 “unspecified”) · WHO, ICD-11 MMS 2026-01, GA31 female infertility ↩ ↩²

2. doi:10.1016/j.ajog.2017.09.002 · Wesselink AK et al. · Am J Obstet Gynecol 2017;217:702.e1–702.e8 · prospective preconception cohort, n=2,962 ↩

3. li-2025-ribosome-age-related-infertility · doi:10.1016/j.xcrm.2025.102424 · Li J et al. · Cell Reports Medicine 2025;6:102424 ↩ ↩²

4. wu-2026-il11-ovarian-stiffness · doi:10.1038/s43587-026-01159-2 · Wu M et al. · Nature Aging 2026;6:1395–1416 ↩ ↩²

5. doi:10.1016/j.fertnstert.2021.02.024 · Practice Committees of ASRM and SART · evidence-based oocyte-cryopreservation guideline · age-dependent outcomes and limits of available evidence ↩

6. ASRM Practice Committee · Fertility preservation in patients with medical indications: a committee opinion · 2026 · embryo/mature-oocyte cryopreservation and age/oocyte-number counseling ↩

7. ClinicalTrials.gov NCT05836025, Effect of Rapamycin in Ovarian Aging · randomized double-blind placebo-controlled pilot · active, not recruiting; record checked 2026-08-09 ↩