Research

Influence of ERbeta selective agonism during the neonatal period on the sexual differentiation of the rat hypothalamic-pituitary-gonadal (HPG) axis

Heather B Patisaul, Sandra M Losa-Ward, Karina L Todd, Katherine A McCaffrey and Jillian A Mickens

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Biology of Sex Differences 2012, 3:2 doi:10.1186/2042-6410-3-2

Published: 19 January 2012

Abstract (provisional)

Background

It is well established that sexual differentiation of the rodent hypothalamic-pituitary-gonadal (HPG) axis is principally orchestrated by estrogen during the perinatal period. Here we sought to better characterize the mechanistic role the beta form of the estrogen receptor (ERbeta) plays in this process.

Methods

To achieve this, we exposed neonatal female rats to three doses (0.5, 1 and 2 mg/kg) of the ERbeta selective agonist diarylpropionitrile (DPN) using estradiol benzoate (EB) as a positive control. Measures included day of vaginal opening, estrous cycle quality, GnRH and Fos co-localization following ovariectomy and hormone priming, circulating luteinizing hormone (LH) levels and quantification of hypothalamic kisspeptin immunoreactivity. A second set of females was then neonatally exposed to DPN, the ERalpha agonist propyl-pyrazole-triol (PPT), DPN+PPT, or EB to compare the impact of ERalpha and ERbeta selective agonism on kisspeptin gene expression in pre- and post-pubescent females.

Results

All three DPN doses significantly advanced day of vaginal opening and induced premature anestrus. GnRH and Fos co-labeling, a marker of GnRH activation, following ovariectomy and hormone priming was reduced by approximately half at all doses, the magnitude of which was not as large as with EB or what we have previously observed with the ERalpha agonist PPT. LH levels were also correspondingly lower, compared to control females. No impact of DPN was observed on the density of kisspeptin immunoreactive (-ir) fibers or cell bodies in the arcuate (ARC) nucleus, and kisspeptin-ir was only significantly reduced by the middle (1 mg/kg) DPN dose in the preoptic region. The second experiment revealed that EB, PPT and the combination of DPN+PPT significantly abrogated preoptic Kiss1 expression at both ages but ARC expression was only reduced by EB.

Conclusion

Our results indicate that selective agonism of ERbeta is not sufficient to completely achieve male-typical HPG organization observed with EB or an ERalpha agonist.