Developmental changes on the hypothalamic-pituitary-gonadal axis of transgenic hCGβ+ mice offspring derived from cabergoline-treated females

RULLI, S.; POUTANEN, M.; MARCIAL LÓPEZ, C.A.; HUHTANIEMI, I.; RATNER, L.; CALANDRA, R.

Módena

Conferencia; IV International Conference on Gonadotropins and Receptors; 2017

An increased response of the gonads to luteinizing hormone (LH) or human chorionic gonadotropin (hCG) by binding to the LH/hCG receptor is the pivotal signal that leads to an enhanced steroidogenesis. Altered secretion of LH/hCG has been related to many pathologies of the reproductive axis. Transgenic female mice expressing hCGβ under the ubiquitin promoter (hCGβ+) produce elevated levels of hCG, prolactin, progesterone and testosterone, are infertile, obese, and develop pituitary and mammary tumors in old age. We have previously demonstrated that a short-term treatment of juvenile hCGβ+ females with the dopamine agonist cabergoline is able to normalize the phenotypic changes of hCGβ+ females and to recover fertility in adulthood, even in the presence of high levels of hCG (Endocrinology 153:5980-5992, 2012). The aim of this study was to analyze the possible influence of the maternal environment (hCG and/or the cabergoline treatment) on the hypothalamic-pituitary-gonadal axis of both transgenic and nontransgenic offspring. Three-week-old wild-type (WT) or hCGβ+ females were treated with cabergoline (500 µg/dose) every other day for one week. At reproductive age, these females were crossbred with hCGβ+ or WT males, respectively, and the offspring phenotype was analyzed at 3 weeks of age and in adulthood. The phenotype of hCGβ+ offspring derived from cabergoline-treated hCGβ+ females x WT males was normalized, in terms of serum hormone profile and ovarian gene expression of Lhcgr, Cyp11a1, Cyp17a1 and Cyp19a1. Furthermore, theestrous cycles were regular and the mice were fully fertile. At six months of age, females exhibited normalized pituitary and body weights, without signs of tumor development. No changes were found in nontransgenic littermates. In order to define if these findings were due to hCG or to long-lasting effects of cabergoline during gestation, we crossbred cabergoline-treated WT females x hCGβ+ males. Surprisingly, the phenotype of transgenic hCGβ+ offspring was normalized as well. These results showed that a short-term treatment with cabergoline applied to females prior to their active reproductive age prevented phenotypic alterations on the offspring. It remains to be investigated if other conditions with altered gonadotropin secretion may also be prevented by a cabergoline treatment to the mother prior to pregnancy, as well as possibleepigenetic mechanisms involved. The fact that a long-lasting specific effect of cabergoline may impact on the developing hypothalamic-pituitary-gonadal axis and be manifested later in life deserves a more detailed consideration.