Fetal Programming: Prenatal Androgen Disrupts Positive Feedback Actions of Estradiol but Does Not Affect Timing of Puberty in Female Sheep1

Abstract

We studied the impact of prenatal androgen exposure on the timing of onset of puberty, maintenance of cyclicity in the first breeding season, and the LH surge mechanism in female sheep. Pregnant sheep were injected with testosterone propionate (100 mg i.m.) twice each week from Day 30 to Day 90 (D30-90) or from Day 60 to Day 90 (D60-90) of gestation (term = 147 days). Concentrations of plasma progesterone and gonadotropins were measured in blood samples collected twice each week from control (n = 10), D60-90 (n = 13), and D30-90 (n = 3) animals. Rate of weight gain and initiation of estrous behavior were also monitored. After the first breeding season, when the animals entered anestrus, competency of the gonadotropin surge system to respond to estradiol positive feedback was tested in the absence or presence of progesterone priming for 12 days. Prenatally androgenized females had similar body weight gain and achieved puberty (start of first progestogenic cycle) at the same time as controls. Duration of the breeding season and the number of cycles that occurred during the first breeding season were similar between control and prenatally androgenized sheep. In contrast, prenatal exposure to androgens compromised the positive feedback effects of estradiol. Onset of LH/FSH surges following the estradiol stimulus was delayed in both groups of androgenized ewes compared with the controls in both the absence and presence of progesterone priming. In addition, the magnitude of LH and FSH surges in the two animals that surged in the D30-90 group were only one third and one half, respectively, of the magnitudes observed in the control and D60-90 groups. The present findings indicate that disruption of the surge system can account for the fertility problems that occur during adulthood in prenatally androgenized sheep.

Disordered follicle development in ovaries of prenatally androgenized ewes

“…Ovaries from androgenized animals were larger and contained either an increased number of large antral follicles, follicular cysts (with a thin or absent membrana granulosa) or an increased stroma (or both; Sharma et al 2002). In one case, the ovary of an androgenized animal was almost completely occupied by a large follicular cyst.…”

Response to the gonadotropin releasing hormone agonist leuprolide in immature female sheep androgenized in utero

“…In normal control females, the tonic increase in LH secretion begins at 30 weeks of age in contrast to the earlier initiation of tonic LH secretion, which is usually displayed at 10 weeks of age in T-females (Wood et al, 1991;Wood et al, 1995). However, in other studies of prenatally androgenized females with intact ovaries, females unexpectedly did not show the early increase in tonic LH secretion leading to puberty but rather puberty was achieved at the same time as controls (Sharma et al, 2002;Birch et al, 2003). Our results provide additional support to the findings of Sharma and colleagues (2002), since we observed that the onset of puberty in two androgenized females was almost coincident with two control females.…”

“…Recently, it has been established that the prenatal androgen exposure (PAE) in females born to testosterone (T)-treated sheep or monkey mothers is associated with growth retardation, infertility, obesity and insulin resistance during adulthood, although some of these characteristics could be expressed early in the extra-uterine life Recabarren et al, 2003;2005;Birch et al, 2003). Ovarian acyclicity, ovarian follicular disruption in prenatally T-treated sheep manifested as a reduction in number of 2-mm follicles, an increase in the size of large follicles and prolonged persistence, associated with hypergonadotropism comparable to those seen in PCOS, have been observed as well, all of which may be initiated early during post-natal life or during fetal development (Sharma et al, 2002;Birch et al, 2003;West et al, 2001;Padmanabhan et al, 1998).…”

La exposición prenatal a andrógenos como factor de reprogramación fetal

“…Adicionalmente, la administración de dihidrotestosterona a la madre permite diferenciar el efecto de los andrógenos aromatizables de los no aromatizables, estableciéndose que la aromatización es necesaria para prevenir el alza preovulatoria de la hormona liberadora de gonadotropinas (GnRH), una característica de la hembra 33,34 .…”