Prenatal Dihydrotestosterone Differentially Masculinizes Tonic and Surge Modes of Luteinizing Hormone Secretion in Sheep*

148

103

Preovulatory GnRH and LH surges depend on activation of estrogen (E 2 )-inducible progesterone receptors (PGRs) in the preoptic area (POA). Surges do not occur in males, or in perinatally androgenized females. We sought to determine whether prenatal androgen exposure suppresses basal or E 2 -induced Pgr mRNA expression or E 2 -induced LH surges (or both) in adulthood, and whether any such effects may be mediated by androgen receptor activation. We also assessed whether prenatal androgens alter subsequent GnRH pulsatility. Pregnant rats received testosterone or vehicle daily on Embryonic Days 16-19. POA-hypothalamic tissues were obtained in adulthood for PgrA and PgrB (PgrA؉B) mRNA analysis. Females that had prenatal exposure to testosterone (pT) displayed reduced PgrA؉B mRNA levels (P Ͻ 0.01) compared with those that had prenatal exposure to vehicle (pV). Additional pregnant animals were treated with vehicle or testosterone, or with 5␣-dihydrotestosterone (DHT). In adult ovariectomized offspring, estradiol benzoate produced a 2-fold increase (P Ͻ 0.05) in PgrA؉B expression in the POA of pV females, but not in pT females or those that had prenatal exposure to DHT (pDHT). Prenatal testosterone and DHT exposure also prevented estradiol benzoate-induced LH surges observed in pV rats. Blood sampling of ovariectomized rats revealed increased LH pulse frequency in pDHT versus pV females (P Ͻ 0.05). Our findings support the hypothesis that prenatal androgen receptor activation can contribute to the permanent defeminization of the GnRH neurosecretory system, rendering it incapable of initiating GnRH surges, while accelerating basal GnRH pulse generator activity in adulthood. We propose that the effects of prenatal androgen receptor activation on GnRH neurosecretion are mediated in part via permanent impairment of E 2 -induced PgrA؉B gene expression in the POA.

Section: Discussionsupporting

confidence: 54%

Neuroendocrine Consequences of Prenatal Androgen Exposure in the Female Rat: Absence of Luteinizing Hormone Surges, Suppression of Progesterone Receptor Gene Expression, and Acceleration of the Gonadotropin-Releasing Hormone Pulse Generator1

Foecking

Szabó

Schwartz

et al. 2005

148

103

“…A recent study by Masek et al [12] suggests that aromatization of prenatal T mediates differentiation of the surge control of LH from operating in male sheep, because exposure of fetal ewes to T, but not to the nonaromatizable androgen DHT, blocks the LH surge response to estrogen priming. In contrast, both T and DHT treatment advances the pubertal rise in LH, suggesting that the tonic mode of gonadotropin secretion is masculinized by androgen.…”

Section: Discussionmentioning

confidence: 99%

“…The aromatization hypothesis was originally developed through research with rats and other short-gestation species, in which sexual differentiation occurs largely during the early postnatal period. Recent indirect evidence suggests that this mechanism may also apply to the sheep, an animal with a long gestation, in which masculinization occurs prenatally [12]. However, to our knowledge, it has never been demonstrated that the brain of the fetal sheep can aromatize androgens to estrogens.…”

Section: Introductionmentioning

confidence: 99%

Estrogen Synthesis in Fetal Sheep Brain: Effect of Maternal Treatment with an Aromatase Inhibitor1

Roselli

Resko

Stormshak

2003

The aim of the present study was to determine whether the fetal lamb brain has the capacity to aromatize androgens to estrogens during the critical period for sexual differentiation. We also determined whether administration of the aromatase-inhibitor 1,4,6-androstatriene-3,17-dione (ATD) could cross the placenta and inhibit aromatase activity (AA) in fetal brain. Eight pregnant ewes were utilized. On Day 50 of pregnancy, four ewes were given ATD-filled Silastic implants, and the other four ewes received sham surgeries. The fetuses were surgically delivered 2 wk later (Day 64 of gestation). High levels of AA (0.8-1.4 pmol/h/mg protein) were present in the hypothalamus and amygdala. Lower levels (0.02-0.1 pmol/h/mg protein) were measured in brain stem regions, cortex, and olfactory bulbs. The Michaelis-Menten dissociation constant (K(m)) for aromatase in the fetal sheep brain was 3-4 nM. No significant sex differences in AA were observed in brain. Treatment with ATD produced significant inhibition of AA in most brain areas but did not significantly alter serum profiles of the major sex steroids in maternal and fetal serum. Concentrations of testosterone in serum from the umbilical artery and vein were significantly greater in male than in female fetuses. No other sex differences in serum steroids were observed. These data demonstrate that high levels of AA are found in the fetal sheep hypothalamus and amygdala during the critical period for sexual differentiation. They also demonstrate that AA can be inhibited in the fetal lamb brain by treating the mother with ATD, without harming fetal development.

“…The mean assay sensitivity was 0.78 ng/ml. An LH surge was determined to have occurred if hormone values exceeded twice the average baseline concentration for a minimum of 6 h [19]. The time of onset of the LH surges, the peak LH concentrations, and time of the LH peak were compared among the groups using a one-way ANOVA.…”

Section: Determination Of Circulating Lh and P Concentrationsmentioning

confidence: 99%

Prenatal Programming of Reproductive Neuroendocrine Function: The Effect of Prenatal Androgens on the Development of Estrogen Positive Feedback and Ovarian Cycles in the Ewe1

Unsworth

Taylor

Robinson

2005

Exposure of the female ovine fetus to male hormones during a sensitive window of in utero life causes disruption to reproductive function. In some animals, androgen exposure completely abolishes reproductive cycles, but in others, cycles are progressively lost with age. The present study tested two predictions: that noncycling, androgenized animals are unable to respond to estrogen with a preovulatory-like surge of LH (estrogen positive feedback), and that the androgenized animals that exhibit a progressive loss of cycles also show a progressive loss of estrogen positive feedback. Androgenized ewes were generated by injection of their mothers with testosterone propionate twice per week from Day 30 to Day 90 of pregnancy (term, 147 days). Control ewes received no injections. Whether ewes could exhibit estrogen positive feedback was tested on five occasions before puberty (30 wk) and once during the anestrous period. All control animals had repeated reproductive cycles in both the first and second breeding season, and all showed robust LH surges during test periods. Despite the fact that 64% of androgenized animals showed reproductive cycles, estrogen positive feedback could be demonstrated in only 6.1% of trials. Subsequent experiments revealed that the lack of response to estrogen in androgenized animals was not because of pituitary insensitivity to GnRH, a requirement for higher concentrations of estrogen, or a surge that was delayed relative to the time of estrogen administration. The mechanisms by which some androgenized ewes can produce normal reproductive cycles in the apparent absence of estrogen positive feedback are currently unknown.