7900 Growth Hormone Secretion Disruption Leads to Sex Dimorphic Effects on Mices Reproduction

Abstract Disclosure: G.A. Alves: None. R. Frazao: None. Growth hormone (GH) is required for sexual maturation and sex steroid mediation of the ovulatory cycle. In humans and animal models, late puberty onset and infertility can be seen in cases of GH secretion disruption. Hypothalamic nuclei containing either kisspeptin or leptin receptor-expressing neurons, required for puberty onset and fertility, are GH-responsive. The selectively induced ablation of GH receptors from Kiss1-expressing cells in female mice is not required for puberty onset despite the downregulation of Kiss1 and Gnrh1 hypothalamic expression in pubertal animals. In contrast, the lack of GH signaling in leptin receptor-expressing cells leads to late sexual maturation but no modulation of Kiss1 or Gnrh1 hypothalamic levels in female mice. The impact of disrupted GH secretion throughout the development on hypothalamic areas associated with reproductive function remains unclear. To determine whether GH secretion disruption differentially affects female and male mice reproduction, we selected mice that hypersecrete GH (here denominate as bGH) or with spontaneous GH deficiency (Ghrhrlit/lit), as well as their littermates (control) for the experiments. We recorded mice’s body weight gain and sexual maturation during development, as well as body length and hypothalamic mRNA expression at the adult stage. We further assess the estrous cycle length of female mice and the fertility rate of male and female animals. As predicted, male and female bGH mice showed increased body weight gain during development and increased nasoanal length compared to control mice. The Ghrhrlit/lit male and female mice showed decreased body weight gain and lower nasoanal length than control mice. bGH and Ghrhrlit/lit female mice showed similar puberty timing to control mice, whereas bGH and Ghrhrlit/lit male mice exhibited a late puberty onset. Interestingly, bGH female mice exhibited disrupted estrous cycles and were infertile, whereas Ghrhrlit/lit female mice showed no differences in estrous cycle length compared to control animals and were fertile. While it is known that Ghrhrlit/lit male mice are subfertile, bGH male mice exhibited no fertility deficit. In contrast to control mice, bGH mice showed upregulated AgRP mRNA expression levels, whereas Pomc expression levels were downregulated, despite no differences in Kiss1, Gnrh1, Esr1, and Tac3 mRNA expression. AgRP and Pomc levels were downregulated in Ghrhrlit/lit females, whereas Tac3 and Ghrh mRNA expression were upregulated compared to control animals. Our findings suggest a GH-induced sexually dimorphic modulation of the HPG axis. Adequate GH signaling seems required for puberty transition in male mice, while GH hypersecretion impairs female mice's fertility despite not affecting puberty onset. Whether changes in metabolism or a specific class of neurons contribute to the observed effects needs further investigation. Presentation: 6/3/2024