Using a Novel Animal Model to Uncover the Effects of Prepubertal Adrenal Androgens on the Reproductive Axis

Introduction:
Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) are produced by the adrenal glands at adrenarche, at least 2-3 years before the gonadal steroidogenesis at puberty. Adrenarche is considered unique to humans and some apes, but was discovered recently in Egyptian spiny mice, providing a new model to investigate the effects of adrenarche on maturation of the reproductive axis.

Main Aim:
To investigate the role of the prepubertal increase in DHEA and DHEAS during adrenarche on maturation of the reproductive axis.

Methods:
RNA sequencing was performed on hypothalami and ovaries of prepubertal female spiny mice aged 7-8 (pre-adrenarche) and 23-24-days (adrenarcheal), and pituitary mRNA analyzed by qPCR. GH3 lactotroph cells and KK-1 granulosa cells were used to validate DHEA effects on gene expression.

Results:
Hypothalamic mRNA levels of Mkrn3 decreased and Dlk1 increased in the adrenarcheal mice. Myelin-associated gene expression was lower compared to pre-adrenarche mice, however within the adrenarcheal group, expression levels were positively correlated to DHEA levels. Ovarian expression of steroidogenic enzymes and gonadotropin receptors (Fshr and Lhcgr) significantly increased in adrenarche. Pituitary prolactin and ovarian prolactin receptor mRNA levels were also elevated in adrenarche. Furthermore, DHEA treatment in GH3 cells increased prolactin mRNA levels, and in KK-1 cells increased prolactin receptor mRNA levels, suggesting a role for DHEA-induced prolactin in the ovary before puberty.

Conclusions:
Pre-pubertal adrenal synthesis of DHEA during adrenarche might regulate brain development and myelination in the hypothalamus, as well as ovarian steroidogenesis and responsiveness to pituitary hormones to promote ovarian maturation.