Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep.
ABSTRACT The goal of this study was to explore mechanisms that mediate hypersecretion of LH and progressive loss of cyclicity in female sheep exposed during fetal life to excess testosterone. Our working hypothesis was that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH (but not FSH) secretion and, thus, hypersecretion of LH in adulthood, and that this results from altered developmental gene expression of GnRH and estradiol (E2) receptors, gonadotropin subunits, and paracrine factors that differentially regulate LH and FSH synthesis. We observed that, relative to controls, females exposed during fetal life to excess testosterone, as well as the nor-aromatizable androgen dihydrotestosterone, exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. Luteinizing hormone hypersecretion was more evident in adults than in prepubertal females, and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal testosterone excess induced developmental changes in gene expression of pituitary GnRH and E2 receptors and paracrine modulators of LH and FSH synthesis in a manner consistent with subsequent amplification of LH release. Together, this series of studies suggests that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH response, leading to LH hypersecretion and acyclicity in adulthood, and that this programming involves developmental changes in expression of pituitary genes involved in LH and FSH release.
Article: GnRH--a missing link between testosterone concentrations in yolk and plasma and its intergenerational effects.[show abstract] [hide abstract]
ABSTRACT: Despite the strong interest in hormone-mediated maternal effects two key questions concerning their mechanisms are as yet unanswered: First, whether the deposition of hormones in the egg yolk is coupled with the levels of these hormones in the maternal circulation, and second, whether epigenetic changes as induced by embryonic exposure to maternal yolk hormones impinge on yolk hormone deposition at adulthood. We investigated the responsiveness to gonadotropin-releasing hormone (GnRH) in female canaries whose embryonic exposure to yolk testosterone had been manipulated. This enabled us to study to what extent GnRH interlinks testosterone concentrations in female circulation and egg yolk as well as the intergenerational potential of hormone-mediated maternal effects. As expected, canary females responded to GnRH with a rise in plasma testosterone. The GnRH-responsiveness was positively correlated with the yolk testosterone content. Factors stimulating the release of GnRH will, therefore, lead to an increase of testosterone in both plasma and egg, posing a potential constraint on the yolk hormone deposition due to testosterone related trade-offs within the laying female. Exposure to elevated yolk testosterone levels as embryo reduced the GnRH-responsiveness in adulthood, potentially limiting environmental influences on yolk testosterone deposition, but the concentrations of yolk testosterone itself were not affected.PLoS ONE 01/2011; 6(7):e22675. · 4.09 Impact Factor
Article: Neonatal exposure to single doses of estradiol or testosterone programs ovarian follicular development-modified hypothalamic neurotransmitters and causes polycystic ovary during adulthood in the rat.[show abstract] [hide abstract]
ABSTRACT: To investigate the hormones participating in early follicular development and hypothalamic neurotransmitters in rats during adulthood. Experimental basic study. University animal laboratory. Twenty-three neonatal rats injected with single subcutaneous injection of estradiol valerate (EV), testosterone propionate (TP), or dihydrotestosterone (DHT) and killed by decapitation at 60 days of age. Measurements of neurotransmitter in ventromedial hypothalamus-arcuate nucleus (VMH-AN) and ovarian morphometry in the adult rat. Noradrenaline (NA), dopamine (DA), serotonin (5-HT), glutamic acid (Glu), and gamma-aminobutyric acid (GABA) content by high performance liquid chromatography medial basal hypothalamus and ovarian morphology. EV exposure increased 5-HT, DA, NA, and Glu and decreased GABA levels in the VMH-AN. Exposure to TP increased Glu and decreased 5-HT in the VMH-AN. Neonatal EV and TP decreased the number of primordial follicles but EV increased the atresia of antral follicles and TP decreased it. Neonatal exposure to DHT did not cause morphologic changes in the adult ovary. Neonatal exposure to EV activated the reproductive hypothalamus and permanently modified ovarian follicular development. TP exposure had some similar effects as EV at the hypothalamus, and it modified ovarian development mimicking the effects of EV. This last effect could be through TP conversion to estradiol because DHT, a nonaromatizable androgen, did not modify follicular development.Fertility and sterility 12/2011; 96(6):1490-6. · 3.97 Impact Factor
Article: Enhanced thecal androgen production is prenatally programmed in an ovine model of polycystic ovary syndrome.[show abstract] [hide abstract]
ABSTRACT: One of the hallmarks of polycystic ovary syndrome (PCOS) is increased ovarian androgen secretion that contributes to the ovarian, hormonal, and metabolic features of this condition. Thecal cells from women with PCOS have an enhanced capacity for androgen synthesis. To investigate whether this propensity is a potential cause, rather than a consequence, of PCOS, we used an ovine prenatal androgenization model of PCOS and assessed ewes at 11 months of age. Pregnant Scottish Greyface ewes were administered 100 mg testosterone propionate (TP) or vehicle control twice weekly from d 62 to 102 of gestation, and female offspring (TP = 9, control = 5) were studied. Prenatal TP exposure did not alter ovarian morphology or cyclicity, or plasma androgen, estrogen, and gonadotropin concentrations, at this stage. However, follicle function was reprogrammed in vivo with increased proportions of estrogenic follicles (P < 0.05) in the TP-exposed cohort. Furthermore, in vitro the thecal cells of follicles (>4 mm) secreted more LH-stimulated androstenedione after prenatal androgenization (P < 0.05), associated with increased basal expression of thecal StAR (P < 0.01), CYP11A (P < 0.05), HSD3B1 (P < 0.01), CYP17 (P < 0.05), and LHR (P < 0.05). This provides the first evidence of increased thecal androgenic capacity in the absence of a PCOS phenotype, suggesting a thecal defect induced during fetal life.Endocrinology 11/2011; 153(1):450-61. · 4.46 Impact Factor