A rise in prepubertal DHEA in the spiny mouse reveals the effect of adrenarche on the reproductive axis

Adrenarche, characterized by rising adrenal dehydroepiandrosterone (DHEA) levels, precedes puberty and has been implicated in reproductive maturation, and disorders like polycystic ovary syndrome (PCOS). However, the mechanisms by which DHEA influences the hypothalamic-pituitary–gonadal (HPG) axis remain poorly understood, largely due to the absence of an appropriate animal model. The spiny mouse (genus Acomys), which has a prolonged juvenile phase and endogenous prepubertal DHEA production, provides a valuable system to investigate the effects of early-life exposure to DHEA. We confirmed the spiny mouse prepubertal rise in circulating DHEA levels, which occurs independently of HPG axis activation, and concomitantly with increased expression of pituitary Prl and various ovarian steroidogenic and estrogen-responsive genes, including Prlr. In cultured cells, DHEA induced Prlr and Prl expression seemingly via the estrogen receptor. Adrenalectomy (Adx) revealed that DHEA is synthesized outside the adrenal glands, possibly the ovaries. Treatment of these mice with DHEA led to extensive changes in their ovarian transcriptomes, including upregulation of immune response-related genes, and downregulation of cholesterol metabolism and estrogen synthesis genes, most notably Cyp19a1. The reduced Cyp19a1 expression is likely due to the elevated Amhr2, and was accompanied by a high androgen-to-estrogen ratio, comprising DHEA-induced, PCOS-like characteristics. The rise in DHEA during an extended juvenile phase establishes the spiny mouse as a suitable model for studying the consequences of adrenarche. Our findings also reveal that increasing further these prepubertal DHEA levels alters ovarian gene expression and steroidogenesis, offering insights into how early androgen excess may predispose to reproductive dysfunction.