Fetal Programming: Testosterone Exposure of the Female Sheep During Midgestation Disrupts the Dynamics of Its Adult Gonadotropin Secretion During the Periovulatory Period1

Abstract

Prenatal exposure of the female sheep to excess testosterone (T) leads to hypergonadotropism, multifollicular ovaries, and progressive loss of reproductive cycles. We have determined that prenatal T treatment delays the latency of the estradiol (E2)-induced LH surge. To extend this finding into a natural physiological context, the present study was conducted to determine if the malprogrammed surge mechanism alters the reproductive cycle. Specifically, we wished to determine if prenatal T treatment 1) delays the onset of the preovulatory gonadotropin surge during the natural follicular phase rise in E2, 2) alters pulsatile LH secretion and the dynamics of the secondary FSH surge, and 3) compromises the ensuing luteal function. Females prenatally T-treated from Day 60 to Day 90 of gestation (147 days is term) and control females were studied when they were approximately 2.5 yr of age. Reproductive cycles of control and prenatally T-treated females were synchronized with PGF2alpha, and peripheral blood samples were collected every 2 h for 120 h to characterize cyclic changes in E2, LH, and FSH and then daily for 14 days to monitor changes in luteal progesterone. To assess LH pulse patterns, blood samples were also collected frequently (each 5 min for 6 h) during the follicular and luteal phases of the cycle. The results revealed that, in prenatally T-treated females, 1) the preovulatory increase in E2 was normal; 2) the latencies between the preovulatory increase in E2 and the peaks of the primary LH and FSH surges were longer, but the magnitudes similar; 3) follicular-phase LH pulse frequency was increased; 4) the interval between the primary and secondary FSH surges was reduced but there was a tendency for an increase in duration of the secondary FSH surge; but 5) luteal progesterone patterns were in general unaltered. Thus, exposure of the female to excess T before birth produces perturbances and maltiming in periovulatory gonadotropin secretory dynamics, but these do not produce apparent defects in cycle regularity or luteal function. To reveal the pathologies that lead to the eventual subfertility arising from excess T exposure during midgestation, studies at older ages must be conducted to assess if there is progressive disruption of neuroendocrine and ovarian function.

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

“…Thus, one would predict from the precocious initiation of neuroendocrine puberty in this model that precocious initiation of ovulatory cycles would occur had the ovaries not been removed in such prenatal T females. This is not the case as determined by our earlier studies in which progestogenic cycles occurred at the normal time (10,14,16,18) or this study, where progestogenic cycles began later in the prenatal T animals. Although onset of progestogenic cycles did not occur early, circulating levels of LH, based on infrequent sampling (twice weekly), were found to be higher postnatally in prenatal T females compared with control females (14).…”

“…Although onset of progestogenic cycles did not occur early, circulating levels of LH, based on infrequent sampling (twice weekly), were found to be higher postnatally in prenatal T females compared with control females (14). LH pulse frequency was also found to be higher during the follicular phase of sheep treated prenatally with T from d 60 -90 gestation (18). In the present study, the increased LH pulse frequency and mean LH concentrations during the pretreatment period both at 12 and 24 wk of age in the prenatal T females provides additional evidence for hypergonadotropism.…”

“…The reduced responsiveness to E 2 negative feedback is likely to contribute, at least in part, to the developing hypergonadotropism in the prenatal T females (14,18), although other mechanisms such as increased pituitary gonadotropic responsiveness to GnRH may be involved. That the prenatal T female becomes hypergonadotropic is evidenced by 1) the higher circulating levels of LH during the prepubertal period (14), 2) the increased follicular phase LH pulse frequency (18), and 3) the absence of progesterone negative feedback (17).…”

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).…”

“…Excess prenatal exposure to testosterone or TP leads to irregular cycling and oligo-or anovulation in adult ewes (Clarke et al 1976), with the severity of disruption higher in females treated earlier in gestation (days 30-80), than in those exposed later (Clarke et al 1977, Savabieasfahani et al 2005. Prenatal treatment with testosterone or TP in ewes between the days of 30-90 of gestation induces the PCOS ovarian characteristics of increased ovarian weight (West et al 2001, Forsdike et al 2007, polycystic ovaries (West et al 2001, Forsdike et al 2007, increased follicular recruitment (Clarke et al 1977, West et al 2001, Smith et al 2009) and increased presence of large antral follicles (Manikkam et al 2006, Steckler et al 2007.…”