Physiology

Reproductive experience promotes permanent body growth independently of growth hormone

Gabriel O de Souza
Willian O dos Santos
Frederick Wasinski
Ligia MM de Sousa
Andressa G Amaral
Daniela O Gusmao
Edward O List
John J Kopchick
Gimena Fernandez
Mario Perelló
Carla RP Oliveira
Manuel H Aguiar-Oliveira
Jose Donato Jr. author has email address

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
The Institute of Molecular Medicine and Aging, Heritage College of Osteopathic Medicine, Ohio University, Athens, United States
Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology, La Plata, Argentina
Department of Surgical Sciences, Functional Pharmacology and Neuroscience, University of Uppsala, Uppsala, Sweden
Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Brazil

https://doi.org/10.7554/eLife.111456.2

Open access
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Figures and data

Pregnancy promotes permanent body growth in wild-type and GH-deficient mice.
(A-C) Differences relative to baseline in body, lean, and fat mass in virgin WT (n = 15), primiparous wild-type (WT; n = 13), virgin Ghrhr^lit/lit(n = 6), and primiparous Ghrhr^lit/lit (n = 13). (D) Representative image showing differences in longitudinal growth between virgin and multiparous WT and Ghrhr^lit/lit mice. (E-I) Body length, body weight, lean mass, fat mass, and liver mass in multiparous WT (n = 13) and Ghrhr^lit/lit (n = 13) mice, relative to age-matched virgin WT (n = 15) and Ghrhr^lit/lit (n = 12) mice. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Statistical analysis was performed using two-way ANOVA and Holm-Sidak’s multiple comparisons test.

Growth is primarily induced during the first pregnancy.
(A-B) Changes in body weight and lean mass in wild-type (WT) virgins (n = 15), after the first pregnancy (n = 13), in virgins matched for age at the second pregnancy (n = 15), after the second pregnancy (n = 13), and after a late first pregnancy (n = 8). (C-D) Changes in body weight and lean mass in Ghrhr^lit/litvirgins (n = 6), after the first pregnancy (n = 13), in virgins matched for age at the second pregnancy (n = 12), and after the second pregnancy (n = 13). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Statistical analysis was performed using unpaired two-tailed Student’s t-test or one-way ANOVA and Newman-Keuls multiple comparisons test.

Increased GH secretion in pregnant WT mice but not in pregnant Ghrhr^lit/lit mice.
(A-B) Representative examples of the pattern of GH secretion in two pregnant and virgin WT mice and in two pregnant and virgin Ghrhr^lit/lit mice. (C-H). Total GH secretion, GH pulse frequency, pulsatile GH secretion, GH pulse amplitude, basal (non-pulsatile) GH secretion, and contribution of basal secretion to total GH secretion in virgin WT (n = 6), pregnant WT (n = 5), virgin Ghrhr^lit/lit (n = 6), and pregnant Ghrhr^lit/lit(n = 3) mice. The pregnant mice were at gestational ages 14-17 days. *, P < 0.05; **, P < 0.01; ****, P < 0.0001. Statistical analysis was performed using two-way ANOVA and Holm-Sidak’s multiple comparisons test.

Pregnancy differentially modulates hepatic GHR signaling in WT and Ghrhr^lit/lit mice.
(A-C) Western blot analysis to determine the hepatic expression of STAT5b and pSTAT5 proteins in virgin WT (n = 6), pregnant WT (n = 6), virgin Ghrhr^lit/lit (n = 6), and pregnant Ghrhr^lit/lit (n = 6) mice. (D-K) Serum IGF-1 levels and hepatic mRNA expression in virgin WT (n = 11), pregnant WT (n = 10), virgin Ghrhr^lit/lit (n = 8), and pregnant Ghrhr^lit/lit(n = 7) mice. The pregnant mice were at gestational ages 14-17 days. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Statistical analysis was performed using two-way ANOVA and Holm-Sidak’s multiple comparisons test.

Pregnancy-induced body growth is preserved despite disruption of GH-, ghrelin-, and estrogen-related signaling pathways.
(A-C) The effects of first and second pregnancies on body weight, lean mass, and fat mass in control virgin (n = 10), control 1^st pregnancy (n = 7), control second pregnancy (n = 5), Alb^ΔGHR virgin (n = 17), Alb^ΔGHR 1^st pregnancy (n = 9), and Alb^ΔGHR second pregnancy (n = 6). (D-E) Body weight and lean mass in control virgin (n = 5), control 1^st pregnancy (n = 14), GHSR KO virgin (n = 4), and GHSR KO 1^st pregnancy (n = 13). (F-H) Body weight, lean mass, and fat mass in control virgin (n = 7), control 1^st pregnancy (n = 4), Alb^ΔERα virgin (n = 7), and Alb^ΔERα 1^st pregnancy (n = 4). (I-K) The effects of first and second pregnancies on body weight, lean mass, and fat mass in control virgin (n = 11), control 1^st pregnancy (n = 11), control second pregnancy (n = 6), Nestin^ΔGHR virgin (n = 6), Nestin^ΔGHR 1^st pregnancy (n = 6), and Nestin^ΔGHR second pregnancy (n = 3). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Statistical analysis was performed using two-way ANOVA and Holm-Sidak’s multiple comparisons test.

Evidence of post-pregnancy growth in women with isolated GH deficiency.
(A) In a cohort of women with isolated GH deficiency caused by a loss-of-function mutation in the GHRHR gene, nulliparous women (n = 8) were shorter than those with one or more pregnancies (n = 9). **, P = 0.009 (unpaired two-tailed Student’s t-test). (B) Comparison of foot size between two sisters with IGHD, one nulliparous and another primiparous. Image of the feet of two sisters with severe isolated GH deficiency caused by a homozygous loss-of-function mutation in the GHRHR gene. In addition to a larger shoe size, subject 2, who had a heterozygous son 9 years ago, is also taller than her nulliparous sister.

Characteristics of the six subjects with IGHD who had one or more pregnancies.

Experimental timeline illustrating the study design.
The schematic was created with the assistance of OpenAI image-generation tools and subsequently reviewed and edited by the authors for scientific accuracy.

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