Language

English

Publication Date

3-24-2025

Journal

Endocrinology

DOI

10.1210/endocr/bqaf071

PMID

40208112

PMCID

PMC12006740

PubMedCentral® Posted Date

4-10-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Excessive androgen levels can severely affect female health. However, most existing models of androgen excess rely on exogenous androgen administration, which does not fully capture the effect of elevated local ovarian testosterone on reproductive and metabolic functions. Here, we report the development of a novel hyperandrogenic mouse model, Cyp17TM-625, generated by combining CRISPR-Cas9 and a Tet-On doxycycline system to induce Cyp17A1 overexpression in ovarian theca-interstitial cells. As a result, Cyp17TM-625 mice exhibited significantly elevated Cyp17A1 messenger RNA and protein levels, accompanied by increased testosterone concentrations without alterations in basal levels of estradiol, progesterone, luteinizing hormone, or follicle-stimulating hormone. These mice demonstrated subfertility, evident by smaller and fewer litters, prolonged estrous cycles, and an increased number of unhealthy follicles with abnormally shaped oocytes. Despite these marked reproductive changes, body weight and glucose homeostasis remained comparable to Con-625 mice. Notably, withdrawal of doxycycline reversed testosterone overexpression and restored fertility over time. This model recapitulates reproductive dysfunction but not the metabolic disturbances, commonly observed in exogenous androgen models. The Cyp17TM-625 mouse line is a unique model for investigating the effects of local excess androgens on ovarian function. It also serves as a valuable tool for studying fertility restoration following the withdrawal of testosterone.

Keywords

Animals, Female, Steroid 17-alpha-Hydroxylase, Testosterone, Mice, Ovary, Mice, Transgenic, Disease Models, Animal, Hyperandrogenism, Estrous Cycle, testosterone, hyperandrogenism, reproduction, ovary

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.