Maternal dopamine agonist treatment before pregnancy reverses infertility and hyperprolactinemia in hCG-overexpressing mice through lactation: Evidence of generational effects

: Ratner, Laura D.; Lopez, Agustina Marcial; Giorgio, Noelia P. Di; Poutanen, Matti; Huhtaniemi, Ilpo; Rulli, Susana B.

Publisher: Elsevier BV

: CLARE

: 2025

: Molecular and Cellular Endocrinology

: MOL CELL ENDOCRINOL

: 112538

: 602

: 10

: 0303-7207

: 1872-8057

DOI: https://doi.org/10.1016/j.mce.2025.112538

: https://doi.org/10.1016/j.mce.2025.112538

Dopamine agonists, such as cabergoline (Cab), have demonstrated efficacy in restoring reproductive function in cases of hyperprolactinemia and hormonal dysregulation. This study investigates the long-term consequences of maternal Cab treatment on the reproductive phenotype of the progeny in a female transgenic (TG) mouse model with hyperprolactinemia and infertility due to human chorionic gonadotropin (hCG) beta-subunit overexpression. The TG females that received Cab between weeks 3-4 of life exhibited a reversion of hyperprolactinemia and infertility, whereas WT females retained their fertility. When TG-cab-or WT-Cab-treated females were crossed with WT or TG males, respectively, their female TG offspring showed a reversal of precocious puberty, regularization of estrous cycles, fertility, and prevention of hyperprolactinemia and prolactinomas. Despite the persistent high LH/hCG bioactivity, the normalization of prolactin levels led to a reduction in ovarian luteinization markers and progesterone levels. The TG female pups born to either WT-cab-or TG-cab-treated females exhibited a normalized phenotype, thus suggesting that the effects were indeed due to maternal Cab administration, and not to the transgene. Cross-fostering experiments showed that the long-lasting programming effect of maternal Cab on offspring occurred during lactation because the TG female pups from non-treated WT female/ TG male pregnancies, but nursed by Cab-treated females, were free from the altered TG phenotype. These results suggest that Cab treatment before pregnancy may have a multigenerational effect on the hypothalamic-pituitary-gonadal axis of the offspring, mediated during lactation. This highlights potential implications for generational health and clinical practices regarding the use of dopamine agonists during lactation.

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This study was supported by a grant from CONICET (PIP082), Rene Barón, Williams, and Felipe Fiorellino Foundations from Argentina.