Fetal Programming: Excess Prenatal Testosterone Reduces Postnatal Luteinizing Hormone, But Not Follicle-Stimulating Hormone Responsiveness, to Estradiol Negative Feedback in the Female

Abstract

Exposure of female sheep fetuses to excess testosterone (T) during early to midgestation produces postnatal hypergonadotropism manifest as a selective increase in LH. This hypergonadotropism may result from reduced sensitivity to estradiol (E 2 ) negative feedback and/or increased pituitary sensitivity to GnRH. We tested the hypothesis that excess T before birth reduces responsiveness of LH and FSH to E 2 negative feedback after birth. Pregnant ewes were treated with T propionate (100 mg/kg in cotton seed oil) or vehicle twice weekly from d 30 -90 gestation. Responsiveness to E 2 negative feedback was assessed at 12 and 24 wk of age in the ovaryintact female offspring. Our experimental strategy was first to arrest follicular growth and reduce endogenous E 2 by administering the GnRH antagonist (GnRH-A), Nal-Glu (50 g/kg sc every 12 h for 72 h), and then provide a fixed amount of exogenous E 2 via an implant. Blood samples were obtained every 20 min at 12 wk and every 10 min at 24 wk before treatment, during and after GnRH-A treatment both before and after E 2 implant. GnRH-A ablated LH pulsatility, reduced FSH by approximately 25%, and E 2 production diminished to near detection limit of assay at both ages in both groups. Prenatal T treatment produced a precocious and selective reduction in responsiveness of LH but not FSH to E 2 negative feedback, which was manifest mainly at the level of LH/GnRH pulse frequency. Collectively, these findings support the hypothesis that prenatal exposure to excess T decreases postnatal responsiveness to E 2 inhibitory feedback of LH/GnRH secretion to contribute to the development of hypergonadotropism. (Endocrinology 146: 4281-4291, 2005)

Role of androgens in normal and pathological ovarian function

“…However, other studies failed to observe an increase in ovarian weight (Smith et al 2009, Hogg et al 2012) and numbers of growing follicles (preantral and/or antral) (Hogg et al 2012). The endocrine PCOS feature of LH excess has also been observed in some (Sarma et al 2005, Savabieasfahani et al 2005 but not all (West et al 2001, Hogg et al 2012 female ewes prenatally exposed to testosterone or TP. Moreover, while prenatal testosterone treatment was found to selectively increase granulosa cell AR expression in antral follicles (Ortega et al 2009), suggesting increased AR activity; the predominant PCOS feature of hyperandrogenism has not been observed, with serum testosterone levels similar to that of control females (Hogg et al 2012).…”

Prenatal programming of the female reproductive neuroendocrine system by androgens

“…The control of episodic GnRH release is also influenced by the prenatal steroid environment such that the suppressive actions of both oestrogen (Steiner et al 1976, Dumesic et al 1997, Sharma et al 2005 and progesterone (Robinson et al 1999, Moenter et al 2005 on gonadotrophin secretion are substantially reduced (Fig. 2).…”

Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth restricted offspring

“…Testosterone is an important regulator of growth and differentiation during fetal development (8,47). Human and animal studies report that the hypothalamuspituitary-adrenal (HPA) axis is an endocrine system sensitive to in utero insults (6,30,35), and subsequent HPA axis alterations may lead to changes in the pituitary-gonadal axis (29,44,45). Thus an insult during fetal life may alter testosterone leading to adverse adaptations later in life.…”