Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

Abstract

Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide, with a prevalence of up to 80% in premenopausal women, and can cause heavy menstrual bleeding, pain, and infertility. Progesterone signaling plays a crucial role in the development and growth of UFs. Progesterone promotes the proliferation of UF cells by activating several signaling pathways genetically and epigenetically. In this review article, we reviewed the literature covering progesterone signaling in UF pathogenesis and further discussed the therapeutic potential of compounds that modulate progesterone signaling against UFs, including selective progesterone receptor modulator (SPRM) drugs and natural compounds. Further studies are needed to confirm the safety of SPRMs as well as their exact molecular mechanisms. The consumption of natural compounds as a potential anti-UFs treatment seems promising, since these compounds can be used on a long-term basis—especially for women pursuing concurrent pregnancy, unlike SPRMs. However, further clinical trials are needed to confirm their effectiveness.

A Systematic Review on Uterine Leiomyoma: From Pathogenomics to Therapeutics

“…Oestrogen and its receptor, ERα, play a pivotal role in controlling the expression of PR. Notably, oestrogen alone does not function as a mitogen in vivo [62]. Leiomyoma proliferative activity increases with combined oestrogen and progesterone level in postmenopausal women but does not show enhancement alone with oestrogen replacement [82].…”

“…Mature myocytes show much more oestrogen receptor α (ERα) and progesterone receptor (PR) expression then stem cells. So, sex hormones dependent cell proliferation is regulated by steroid hormone receptors present on these mature cells [62]. Self-renewal and proliferation of stem cells is induced by paracrine factors like WNT ligands, released from mature myocytes.…”

“…Oestrogen stimulates fibroid cells proliferation by ATP-sensitive potassium channels opening. Oestrogen stimulates fibroid expansion by suppressing normal p53 functions [62]. Leiomyoma proliferation requires oestrogen, however it is not adequate on its own [78].…”

“…Progesterone is primary maintainer of fibroid extension and volume maintenance while oestrogen mainly induces PR expression [62]. Progesterone shows its effects through progesterone receptors.…”

Levels of melatonin and some indicators of angiogenesis, antioxidant system and lipid peroxidation in blood plasma in women with uterine leiomyoma

“…Leomyoma of the uterus is undoubtfully a hormone-dependent tumour. It is believed that in the early stages, its development occurs with the involvement of physiological �luctuations in the concentration of hormones during the menstrual cycle [4]. The modern model of pathogenesis of uterine leiomyoma includes the genetic transformation of myometrial stem cells into tumour.…”