Estrogen disorders: Interpreting the abnormal regulation of aromatase in granulosa cells (Review)

Abstract

Ovarian granulosa cells (Gcs) are the most important source of estrogen. Therefore, aromatase (estrogen synthase), which is the key enzyme in estrogen synthesis, is not only an important factor of ovarian development, but also the key to estrogen secretion by Gcs. disorders of the ovarian estrogen secretion are more likely to induce female estrogen-dependent diseases and fertility issues, such as ovarian cancer and polycystic ovary syndrome. Hence, aromatase is an important drug target; treatment with its inhibitors in estrogen-dependent diseases has attracted increasing attention. The present review article focuses on the regulation and mechanism of the aromatase activity in the Gcs, as well as the specific regulation of aromatase promoters. In GCs, follicle-stimulating hormone (FSH) is dependent on the cyclic adenosine monophosphate (cAMP) pathway to regulate the aromatase activity, and the regulation of this enzyme is related to the activation of signaling pathways, such as phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK). In addition, endocrine-disrupting substance and other related factors affect the expression of aromatase, which eventually create an imbalance in the estrogen secretion by the target tissues. The present review highlights these useful factors as potential inhibitors for target therapy.

FSH mediates estradiol synthesis in hypoxic granulosa cells by activating glycolytic metabolism through the HIF-1α–AMPK–GLUT1 signaling pathway

“…Estradiol synthesis has been described as an energy-consuming process ( 2 ). Under hypoxia, energy mainly comes from glycolysis metabolism.…”

“…Compared with oxidative phosphorylation, however, anaerobic glycolysis is significantly less efficient, providing a net production of only 2 ATP p er glucose molecule (versus 32 ATP per glucose molecule produced during oxidative phosphorylation) [30]. Since adenosine triphosphate (ATP) serves as an essential energy substrate and signaling molecule in FSH -mediated E2 synthesis [2], hypoxia seems to be detrimental for this process. Interestingly, when GCs were cultured under hypoxia, we observed no decrease in E2 production in FSH-treated cells.…”

“…cAMP in turn stimulates a protein kinase A–dependent activation of CYP19A1. In addition, the catalytic conversion of androstenedione to estradiol by CYP19A1 also requires the consumption of ATP ( 2 ). Therefore, ATP is indispensable for FSH-mediated E2 synthesis.…”

A Review on CYP11A1, CYP17A1, and CYP19A1 Polymorphism Studies: Candidate Susceptibility Genes for Polycystic Ovary Syndrome (PCOS) and Infertility

“…Likewise, in a similar case study, a population of Egyptian women with polycystic ovary syndrome, 53 patients and 53 controls in the rs4077582, were evaluated, which positively supported the occurrence of polymorphism and its association with PCOS [ 48 ]. In some research performed on the CYP11A1 promoter, It has been proposed that the regulation of the CYP11A1 promoter in granulosa cells is controlled by liver receptor homologue-1 (LRH-1) and Steroidogenic element-1 (SF-1) [ 49 ]. A 1999 study also supported this hypothesis, and it showed the loss of P450scc due to the knockout SF-1 [ 50 ].…”

Label-Free Quantitative Proteomic Study of The Effect of Dihydrotestosterone (DHT) On Rat Ovarian GCs

“…The ovarian androgens are mainly androstenedione and T; androgen is the source of estrogen in the body, and granulosa cells (GCs) can aromatize T into estrogen [4]. Unlike T, DHT cannot be aromatized into estrogen [5], but it can increase the activity of aromatase in GCs [6].…”