Author ORCID Identifier
https://orcid.org/0000-0002-9841-0416
Date Available
7-15-2027
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Pharmacology
Faculty
Dr. Misung Jo
Abstract
Successful ovulation is a pivotal process for achieving fertilization and pregnancy. Defects in the ovulatory process are a leading cause of female infertility, affecting 25% of infertile women, underscoring the critical role of ovulation in reproductive success. A hallmark of the ovulatory process is the hormonal shift within ovarian follicles in response to the luteinizing hormone (LH) surge or human chorionic gonadotropin (hCG) stimulation. Two major hormonal shifts triggered by LH/hCG include the transition from estradiol to progesterone and the conversion of cortisone to its active form, cortisol. These hormonal changes activate their respective receptors – progesterone receptor (PGR) and glucocorticoid receptor (NR3C1) – which regulate the expression of genes essential for ovulation and subsequent luteinization. However, the precise molecular mechanisms by which these receptors function as transcription factors in the ovulatory process remain unclear. This dissertation aims to investigate the transcriptional regulatory role of PGR and NR3C1 in ovulation.
PGR is considered one of the most essential transcription factors for successful ovulation. To determine its transcriptional role in human ovulatory follicles, multi-omics analyses were conducted using a human granulosa cell (hGLC) model that recapitulates the in vivo ovulatory phenomenon. RNA-Seq and ChIP-Seq analyses identified numerous PGR-regulated genes in response to hCG treatment, including those involved in metabolism, steroidogenesis, signaling activation, cell cycle regulation, and transcriptional control. Comparative analysis with existing sequencing data from Pgr knockout mouse models revealed both conserved and species-specific PGR-regulated genes. Notably, this led to the identification of a human-specific, hCG-induced PGR-target gene, SOX9, in hGLCs. Further characterization of SOX9 using dominant follicle samples collected before and at different times after ovulatory hCG administration from regularly cycling women demonstrated that SOX9 expression is predominantly induced in the granulosa cells of ovulatory follicles and persists in the developing corpus luteum. Functional studies showed that SOX9 knockdown by siRNA reduced progesterone production and the expression of steroidogenesis-related genes (STAR and CYP11A1) in hGLCs, suggesting that SOX9 is a novel PGR-downstream mediator critical for progesterone biosynthesis.
While PGR is a key regulator of ovulation, emerging evidence suggests NR3C1 plays a crucial role in this process. However, the expression, regulation, and function of NR3C1 in human ovulatory follicles remain to be elucidated. This study revealed that the expression of NR3C1 and key genes involved in glucocorticoid receptor signaling actions are induced and regulated by LH/hCG in granulosa cells of human ovulatory follicles, both in vivo and in vitro. The functional role of NR3C1 was further determined in hGLCs, which showed that inhibition of NR3C1 activity resulted in the downregulation of genes involved in glucocorticoid receptor signaling, steroidogenesis, and the key ovulatory process. Together, these data demonstrated that NR3C1 plays a critical role in the human periovulatory process, functioning as a crucial transcription factor that regulates the expression of genes essential for ovulation and luteinization in the human ovary.
In summary, this study provides the first complete list of preovulatory PGR-downstream genes in human granulosa cells and unveils SOX9 as a novel human-specific ovulatory transcription factor with potential roles in steroidogenesis. It also presents the first evidence of the functional role of NR3C1 as a potential mediator of ovulation and luteinization in humans. Altogether, these findings enhance the understanding of the roles of PGR and NR3C1 in reproductive physiology, which could contribute to the development of novel and improved contraceptives and treatments for women’s fertility.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.292
Funding Information
This study was supported by the National Institutes of Health (P01HD71875 to M.J., T.E.C., and M.B.; R01HD096077 to M.J.) and the BTPSRF of the University of Kentucky Markey Cancer Center (P30CA177558).
Recommended Citation
Jeon, Hayce, "THE MOLECULAR MECHANISMS BY WHICH THE PROGESTERONE RECEPTOR (PGR) AND GLUCOCORTICOID RECEPTOR (NR3C1) REGULATE OVULATION IN HUMAN OVARIAN FOLLICLES" (2025). Theses and Dissertations--Pharmacology and Nutritional Sciences. 63.
https://uknowledge.uky.edu/pharmacol_etds/63
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