Central growth hormone signaling is not required for the timing of puberty

in Journal of Endocrinology
Correspondence should be addressed to R Frazao: rfrazao@usp.br
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Growth hormone (GH) is a key factor in the regulation of body growth, as well as a variety of other cellular and metabolic processes. Neurons expressing kisspeptin and leptin receptors (LepR) have been shown to modulate the hypothalamic-pituitary-gonadal (HPG) axis and are considered GH responsive. The presence of functional GH receptors (GHR) in these neural populations suggests that GH may regulate the HPG axis via a central mechanism. However, there have been no studies evaluating whether or not GH-induced intracellular signaling in the brain plays a role in the timing of puberty or mediates the ovulatory cycle. Toward the goal of understanding the influence of GH on the central nervous system as a mediator of reproductive functions, GHR ablation was induced in kisspeptin and LepR-expressing cells or in the entire brain. The results demonstrated that GH signaling in specific neural populations can potentially modulate the hypothalamic expression of genes related to the reproductive system or indirectly contribute to the progression of puberty. GH action in kisspeptin cells or in the entire brain was not required for sexual maturation. On the other hand, GHR ablation in LepR cells delayed puberty progression, reduced serum leptin levels, decreased body weight gain and compromised the ovulatory cycle in some individuals, while the lack of GH effects in the entire brain prompted shorter estrous cycles. These findings suggest that GH can modulate brain components of the HPG axis, although central GH signaling is not required for the timing of puberty.

 

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    Validation of the Kiss1-KO model. Epifluorescence photomicrographs showing the distribution of the Kiss1-Cre/GFP-positive cells (green cytoplasmic staining) in the anteroventral periventricular nucleus (AVPV, A, B, C) and in the arcuate nucleus (ARH, D, E, F). Mice were treated with saline (A, D) or porcine growth hormone (GH; B, C, E, F). The GH-responsive cells were identified by pSTAT5-positive staining (red nuclear staining). Double-labeled cells appear as yellowish/orange (arrows; B). In the Kiss1-KO model the Kiss1-Cre/GFP-positive cells in the AVPV did not express GH-induced pSTAT5 (C). 3V, third ventricle. Scale bar: 50 µm.

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    Validation of the LepR-KO model. (A, B and C) Epifluorescence photomicrograph showing the distribution of the leptin receptor (LepR) expressing cells (red cytoplasmic staining) in the arcuate (ARH, A, B) and in the ventral premammillary nucleus (PMv, C, D). Control or the LepR-KO mice were treated with porcine growth hormone (GH). The GH-responsive cells were identified by the phosphorylation of STAT5 (pSTAT5)-positive staining (green nuclear). Double-labeled cells appear as yellowish/orange (arrows). 3V, third ventricle. Scale bar: 100 µm.

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    Hypothalamic mRNA expression analysis at 42 days of age. (A) Graphs comparing the mRNA expression between control and Kiss-KO mice (n = 7 per group). (B) Graphs comparing the mRNA expression between control, LepR-KO and Brain-KO mice (n = 8/6 per group). *P < 0.005, **P < 0.005. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0242.

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    Metabolic and hormonal evaluation of control and Kiss1-KO mice at 42 days of age. (A, B, C, D, E and F) Graphs comparing body weight (A), body length (B), serum growth hormone (GH) levels (C), leptin levels (D), estradiol levels (E) and the uterine mass (F) (n = 6/12 per group). P > 0.05. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0242.

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    Metabolic and hormonal evaluation of control, LepR-KO and Brain-KO mice at 42 days of age. (A, B, C, D, E and F) Graphs comparing body weight (A, n = 18/23), body length (B, n = 9/12), serum growth hormone (GH) levels (C), leptin levels (D, n = 8/7 per group) and the uterine mass (E) (n = 6/10 per group). *P < 0.05; **P ≤ 0.007, ****P < 0.0001. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0242.

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    Growth hormone receptor (GHR) ablation from kisspeptin cells does not disrupt the sexual maturation. (A, D) Graphs showing the percentages of control and Kiss1-KO females that exhibited vaginal opening (A) and first estrus (D). (B, E) Average time required for control and KO females to exhibit vaginal opening (B) and first estrus (E). (C, G) Body weight of control and KO mice at specific stages of sexual maturation (C, F) and throughout development (G). (H) Body adiposity was determined by measuring the weight of different adipose fat pads of adult female mice (n = 9/8 per group). P > 0.05. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0242.

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    The growth hormone signaling in kisspeptin cells is not required for sex steroids mediation of the ovulatory cycle. Three consecutives estrous cycles were evaluated. The average length of the cycles (A, B and C) and the average percentage of days in which a predominance of cornified cells (P/E) or leucocytes (D/M) were detected in the vaginal smear were determined (D) in control and Kiss1-KO mice (n = 7 per group). P > 0.05. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0242.

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    Evaluation of sexual maturation in female LepR-KO and Brain-KO mice. (A, D) Graphs showing the percentages of control, LepR-KO and Brain-KO females that exhibited vaginal opening (A) and first estrus (D). (B, E) Average time required for control and KO females to exhibit vaginal opening (B) and first estrus (E). (C, F, G) Body weight of control and KO mice at specific stages of sexual maturation (C, F) and throughout development (G). (H) Body adiposity was determined by measuring the weight of different adipose fat pads of adult female mice. (n = 9–14 per group). **P ≤ 0.004, ***P = 0.0003, ****P ≤ 0.001. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0242.

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    Evaluation of the estrous cycle in female LepR-KO and Brain-KO mice. Three consecutives estrous cycles were evaluated and the average length of a cycle (A, B, C and D) and the average percentage of days in which a predominance of cornified cells (P/E) or leucocytes (D/M) were detected in the vaginal smear were determined in control, LepR-KO and Brain-KO mice (E, n = 7/15 per group). (F) Graph comparing the uterine mass of control, LepR-KO and Brain-KO mice (n = 9/14 per group). *P < 0.05. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0242.

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