Abstract
Disclosure: J. Cassin: None. I. Tripuraneni: None. M. Stamou: None. K.J. Tonsfeldt: None. G.A. Dunn: None. A.X. Duong: None. V. Chen: None. R. Balasubramanian: None. P.L. Mellon: None. We recently reported that male and female Sox2 heterozygous knockout mice (Sox2(het)) are delayed in pubertal onset by 3 days in males and 5 days in females which can, in part, be attributed to a weight gain phenotype (male WT at preputial separation: 15.9±0.6 grams; Sox2(het): 16.1±0.5 and female WT at vaginal opening: 13.5±0.7g; Sox2(het): 13.7±0.3g; Cassin et al. JES, Volume 8, Issue Supplement 1, Oct-Nov 2024). This finding combined with growth phenotypes in idiopathic hypogonadotropic hypogonadism (IHH) patients harboring Sox2 mutations or other Sox gene family mutations (Cassin, Stamou, and Keefe et al. JCI Insight, 2023; Sun and Stamou et al. JCEM, 2024), as well as evidence for the widespread expression of SOX2 in the adult arcuate nucleus (ARC) and paraventricular nucleus (PVN) of the hypothalamus (Cassin, Stamou, and Keefe et al. JCI Insight, 2023), led us to investigate the mechanistic role of Sox2 in the growth hormone (GH) axis. At weaning (21d), there was no difference in weight between Sox2(het) males and their WT littermates (p-value=0.41), while Sox2(het) females weighed slightly less than their WT littermates (p-value=0.04). However, by adulthood (78d), a significant weight deficit existed between Sox2(het) males and their WT littermates (p-value=<0.0001), while there was no longer a difference between Sox2(het) female mice and WT littermates (p-value=0.68). We detected no difference in GH mRNA in the pituitary between WT and Sox2(het) mice in both males (p-value=0.32) and females (p-value=0.72). Further, we performed a gonadotropin-releasing hormone (GnRH) challenge and found that the pituitary was functioning normally with both normal basal serum LH levels as well as an appropriate surge in serum LH following a bolus of GnRH (WT Baseline: 0.44±0.10ng/mL vs. Post-GnRH: 2.28±0.34ng/mL vs Sox2(het) Baseline: 0.44±0.07ng/mL vs Post-GnRH: 1.63±0.31ng/mL). However, growth hormone releasing hormone mRNA levels were elevated in the hypothalamus of female (p-value= 0.02) Sox2(het) mice as compared to WT littermates but not in males (p-value= 0.07). Somatostatin (Sst) mRNA levels were also altered in both male and female Sox2(het) mice with hypothalamic Sst mRNA being higher in female Sox2(het) mice (p-value= 0.002) compared to WT littermates and hypothalamic Sst mRNA being lower in male Sox2(het) compared to WT littermates (p-value= 0.001). These observations point to a clear sex-dependent effect in Sox2(het) mice which mimics the phenotypic data available from Sox family mutations in IHH patients. Together, these data reveal the role of Sox2 in the GH axis and suggest the need for further analysis into both IHH populations harboring Sox family mutations, as well as expanded investigation into IHH patients with GH phenotypes with unknown genetic etiology. Presentation: Saturday, July 12, 2025