# Reduced Akr1b7 signaling drives ovarian aging and reproductive dysfunction

## TL;DR

Reduced Akr1b7 signaling in mice leads to ovarian aging and fertility issues by disrupting hormone balance and oocyte development.

## Contribution

This study identifies Akr1b7 as a key regulator of ovarian function and aging in mice.

## Key findings

- Akr1b7−/− mice show impaired oocyte Akt activation and follicular development.
- Akr1b7 deficiency increases immature oocyte ovulation and reduces litter size.
- Reduced Akr1b7 signaling elevates progesterone and mimics ovarian aging.

## Abstract

Natural ovarian aging is associated with a progressive decline in female fertility. Here, we comprehensively analyzed RNA expression during ovarian aging in mice during the estrous cycle following ovulation stimulation. The transient activation of the Aldo-keto reductase Akr1b7 pathway observed in the ovaries of young mice was absent in older mice. Akr1b7−/− mice exhibit attenuated oocyte Akt activation, impaired follicular development, an increased proportion of ovulated immature oocytes, and decreased litter size. The estrous cycle is extended in Akr1b7−/− mice due to a prolonged diestrous stage, driven by sustained progesterone levels. This elevation in progesterone was associated with the reduced expression of Cyp17a1, a progesterone-metabolizing enzyme in the Akr1b7-positive theca cell layers. Together, these findings identify Akr1b7 as a regulator of ovarian signaling, hormone homeostasis, and reproductive function, with the disruption of this pathway producing phenotypes associated with declining fertility.

•Akr1b7 loss impairs Akt activation in primordial follicles and disrupts oocyte maturation•Akr1b7 deficiency accelerates immature oocyte ovulation and reduces litter size•Akr1b7 deletion decreases Cyp17a1 expression and prolongs diestrus by elevating progesterone•Reduced Akr1b7 signaling recapitulates ovarian aging phenotypes in mice

Akr1b7 loss impairs Akt activation in primordial follicles and disrupts oocyte maturation

Akr1b7 deficiency accelerates immature oocyte ovulation and reduces litter size

Akr1b7 deletion decreases Cyp17a1 expression and prolongs diestrus by elevating progesterone

Reduced Akr1b7 signaling recapitulates ovarian aging phenotypes in mice

Health sciences; Endocrinology; Endocrine system physiology; Female reproductive endocrinology; Endocrine regulation