Daham Kim, Yoon Hee Cho, Min Jeong Kang, So Jeong Lee, Soohyun Lee, Bo Hyon Yun, Hyunjin Chi, Jeongsuk An, Kyungsun Lee, Jaekyu Han, Susan Chi, Moo Young Song, Sang-Hoon Cha, Eun Jig Lee
Received July 4, 2024 Accepted September 11, 2024 Published online December 4, 2024
Background Recombinant human follicle-stimulating hormone (rhFSH) is commonly used to treat female infertility, but its short half-life necessitates multiple doses. Even corifollitropin alfa, with an extended half-life, requires supplementary injections of rhFSH after 7 days. This study aimed to develop and evaluate a long-acting follicle-stimulating hormone (FSH) formulation using anti-serum albumin Fab-associated (SAFA) technology to avoid additional injections and enhance ovarian function.
Methods SAFA-FSH was synthesized using a Chinese hamster ovary expression system. Its biological efficacy was confirmed through assays measuring its ability to stimulate cyclic adenosine monophosphate (cAMP) production, estradiol synthesis, and the expression of human cytochrome P450 family 19 subfamily A member 1 (hCYP19α1) and human steroidogenic acute regulatory protein (hSTAR) in human ovarian granulosa (KGN) cells. To evaluate the effects of SAFA-FSH, we compared its impact on serum estradiol levels and ovarian weight increase with that of rhFSH in Sprague-Dawley (SD) rats using the modified Steelman-Pohley test.
Results The results indicated that SAFA-FSH induces cAMP synthesis in KGN cells and upregulates the expression of hCYP19α1 and hSTAR in a dose-dependent manner. Female SD rats, aged 21 days, receiving daily subcutaneous human chorionic gonadotropin injections for 5 days exhibited a significant increase in serum estradiol levels and ovarian weight when administered SAFA-FSH on the first day or when given nine injections of rhFSH over 5 days. Notably, the group receiving SAFA-FSH on the first and third days demonstrated an even greater rise in serum estradiol levels and ovarian weight.
Conclusion These findings suggest that SAFA-FSH presents a promising alternative to current rhFSH treatments for female infertility. However, further research is essential to thoroughly assess its safety and efficacy in clinical contexts.
Over the past years, pituitary hormones and their receptors have been shown to have non-traditional actions that allow them to bypass the hypothalamus-pituitary-effector glands axis. Bone cells—osteoblasts and osteoclasts—express receptors for growth hormone, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin, and vasopressin. Independent skeletal actions of pituitary hormones on bone have been studied using genetically modified mice with haploinsufficiency and by activating or inactivating the receptors pharmacologically, without altering systemic effector hormone levels. On another front, the discovery of a TSH variant (TSH-βv) in immune cells in the bone marrow and skeletal action of FSHβ through tumor necrosis factor α provides new insights underscoring the integrated physiology of bone-immune-endocrine axis. Here we discuss the interaction of each pituitary hormone with bone and the potential it holds in understanding bone physiology and as a therapeutic target.
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BACKGROUND FSH is a heterodimeric glycoprotein and is composed of alpha and beta subunits. alpha subunit is common to FSH and LH, while an unique beta subunit determines the biological specificity of each hormone. The synthesis of beta subunit is the primary rate-limiting step in the synthesis of each hormone. Although FSH plays a pivotal role in folliculogenesis and ovulation, very little studies have been performed on the regulation of FSH beta gene expression. Therefore, the present study attempted to examine the effect of GnRH or activin on the expression of FSH beta mRNA as well as FSH release and signaling pathway involved in their actions. METHODS: The primary cultures of rat anterior pituitary were used for this study. To determine FSH beta mRNA levels, northern blotting method was used. The concentration of FSH in the culture medium was evaluated by using a specific radioimmunoassay for rat FSH. RESULTS: PMA, an activator of PKC, increased FSH beta mRNA levels and FSH release, whereas forskolin, an activator of adenylate cyclase, showed no effect. The application of GnRH augmented FSH release, but not FSH beta mRNA levels. However, the administration of activin increased FSH beta mRNA levels as well as FSH release. Staurosporine, an inhibitor of PKC, suppressed activin-induced increment of FSH beta mRNA levels and FSH release. CONCLUSION: The present study demonstrated that activin rather than GnRH is a major regulator for FSH beta mRNA expression, and suggest that PKC-dependent pathway is also involved in the action of activin on the expression of FSH beta mRNA and FSH release.