The allostery and modification of hGHRH molecules and specific dimer produced significant fertility effect by proliferating and activating in-situ ovarian mesenchymal stem cells

• Published in: European journal of pharmaceutical sciences 2024-06, Vol.197, p.106768-106768, Article 106768
• Main Authors: Zhang, Xu-Dong, Luo, Qun, Du, Yan, Yang, Li, Yu, Li-Cheng, Feng, Lan, Rao, Dan, Tang, Jing-Xuan, Tan, Hong-Mei, Guo, Xiao-Yuan, Tang, Song-Shan, Liu, Tao, Yue, Feng, Huang, Hui-Xian
• Format: Article
• Language: English
• Subjects: Golden hamster stem cell exhaustion model; Growth hormone-releasing hormone; Molecular allostery and modification; Receptor coordination regulation; Regeneration; Reproduction
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2024.106768

The negative coordination of growth hormone secretagogue receptor (GHS-R) and growth hormone-releasing hormone receptor (GHRH-R) involves in the repair processes of cellular injury. The allosteric U- or H-like modified GHRH dimer Grinodin and 2Y were comparatively evaluated in normal Kunming mice and hamster infertility models induced by CPA treatment. 1–3–9 µg of Grinodin or 2Y per hamster stem-cell-exhaustion model was subcutaneously administered once a week, respectively inducing 75–69–46 or 45–13–50 % of birth rates. In comparison, the similar mole of human menopausal gonadotropin (hMG) or human growth hormone (hGH) was administered once a day but caused just 25 or 20 % of birth rates. Grinodin induced more big ovarian follicles and corpora lutea than 2Y, hMG, hGH. The hMG-treated group was observed many distorted interstitial cells and more connective tissues and the hGH-treated group had few ovarian follicles. 2Y had a plasma lifetime of 21 days and higher GH release in mice, inducing lower birth rate and stronger individual specificity in reproduction as well as only promoting the proliferation of mesenchymal-stem-cells (MSCs) in the models. In comparison, Grinodin had a plasma lifetime of 30 days and much lower GH release in mice. It significantly promoted the proliferation and activation of ovarian MSCs together with the development of follicles in the models by increasing Ki67 and GHS-R expressions, and decreasing GHRH-R expression in a dose-dependent manner. However, the high GH and excessive estrogen levels in the models showed a dose-dependent reduction in fertility. Therefore, unlike 2Y, the low dose of Grinodin specifically shows low GHS-R and high GHRH-R expressions thus evades GH and estrogen release and improves functions of organs, resulting in an increase of fertility. [Display omitted]