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Forebrain AR Deletion Restores PR Expression but not Reproduction in Prenatally Androgenized Female Mice
Emily E A Lott1, Melanie Prescott1, Kyoko Potapov1
1Centre for Neuroendocrinology and Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand.
Endocrinology
|November 8, 2025
Summary
Prenatal androgen excess (PNA) programs reproductive issues in females, similar to PCOS. Deleting androgen receptors in neurons did not fully reverse these PNA-induced reproductive deficits in mice.
Area of Science:
- Neuroendocrinology
- Reproductive Biology
- Genetics
Background:
- Prenatal androgen excess (PNA) is linked to polycystic ovary syndrome (PCOS) and causes long-term reproductive problems in females.
- Impaired steroid hormone feedback, particularly to progesterone, is a suspected neuroendocrine cause of reproductive dysfunction in PCOS and PNA models.
- PNA is thought to affect the brain, disrupting the GnRH neuronal network and the hypothalamic-pituitary-ovarian axis.
Purpose of the Study:
- To investigate if androgen-sensitive neurons mediate the programming of reproductive deficits by PNA.
- To determine if deleting androgen receptors (AR) specifically in neurons can prevent or reverse PNA-induced reproductive dysfunction.
Main Methods:
- Generated PNA female mice with neuron-specific AR deletion (NeurARKO) using Cre-lox technology.
- Confirmed embryonic AR deletion in the generated mice.
- Assessed reproductive phenotypes and brain progesterone receptor expression in PNA NeurARKO and control mice.
Main Results:
- PNA-induced reproductive traits (delayed puberty, acyclicity, subfertility) were not improved in NeurARKO mice compared to controls.
- Downregulation of brain progesterone receptor expression, seen in PNA mice, was prevented in PNA NeurARKO mice.
- Neuronal AR deletion did not rescue the overall reproductive deficits caused by PNA.
Conclusions:
- Neuronal androgen receptors play a role in the PNA-induced downregulation of progesterone receptor expression in the brain.
- While neuronal AR signaling contributes to impaired progesterone feedback sensitivity in PNA, its deletion alone is insufficient to fully restore reproductive function.
