Excess female adrenal androgen secretion is a consequence of in utero androgenic excess in sheep

Abstract Excess androgenic steroid exposure during development in female sheep alters metabolic and reproductive function in postnatal life, with phenotypes reminiscent of health-relevant aspects of Polyendocrine Metabolic Ovarian Syndrome (PMOS) in women. We hypothesised that altered steroid exposure during in utero life would alter female postnatal adrenal function. Prenatal steroid excess was created by fetal steroid injections, on d62 and d82 of gestation, designed to separately create excess androgenic exposure (testosterone propionate, n = 14), oestrogenic exposure (diethylstilbestrol, n = 7) and glucocorticoid excess exposure (dexamethasone, n = 11) with controls (n = 11) treated with vehicle alone. Adrenal function tests and qPCR measurement of adrenal steroidogenic genes were the outcomes measured. In post-pubertal female offspring, specifically prenatal androgenic excess was associated with exaggerated testosterone secretory response to ACTH (P < 0.05), in the absence of alterations in cortisol secretion. Altered androgen secretory response was associated with increased STAR, HSD3B1 and HSD17B mRNA (P < 0.05). Neither adrenal androgen secretion nor steroidogenic gene expression was altered prior to puberty. During fetal life (day 90 of gestation), only STAR was altered in prenatal androgenic excess females (P < 0.05), to a similar level as observed in a control cohort of male fetuses. We conclude that the postnatal, post-pubertal ovine adrenal gland is hyperandrogenic because of prenatal androgen excess. Lay summary Steroid hormones are responsible for our development in fetal life. If there is too much or too little of a steroid hormone before we are born, it can affect our health in the future. If a female fetus is exposed to too much male-type hormone in the middle of pregnancy, after puberty, they develop features seen in women with Polyendocrine Metabolic Ovarian Syndrome (PMOS). The classic feature of PMOS is increased male-type hormones from the ovaries where cells in the ovaries are set up to make more male-type hormone. In women, half of all the male-type hormones come from the adrenal gland. We looked at the effects of giving more male-type hormones in the middle of pregnancy to female sheep fetuses as we know that they get the features of PMOS after puberty. In this study, we showed that the cells in the adrenal gland are also set up to make more male-type hormone after puberty. We checked if this was specifically due to the effects of male hormone exposure before birth and found that increased female hormone or stress hormone does not have the same effect. This means that it is likely not just the ovary whose function is altered in PMOS but also the adrenal gland.