Progesterone Actions and Resistance in Gynecological Disorders

Abstract

Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women’s lives. Because the menstrual cycle repeatably occurs during reproductive ages with dynamic changes and remodeling of reproductive-related tissues, these alterations can accumulate and induce chronic and recurrent conditions. This review focuses on faulty progesterone signaling mechanisms and cellular responses to progesterone in endometriosis, adenomyosis, leiomyoma (uterine fibroids), polycystic ovary syndrome (PCOS), and endometrial hyperplasia. We also summarize the association with gene mutations and steroid hormone regulation in disease progression as well as current hormonal therapies and the clinical consequences of progesterone resistance.

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

“…Spermatogenesis is also modulated at every level by estrogen, from the hypothalamus–pituitary–gonadal axis to the testis cells constituted by Leydig, Sertoli and germ cells [ 4 ]. In the ovary, estrogen and progesterone are key steroid hormones in the complex regulation of female reproductive functions [ 5 ].…”

Functional Implications of Estrogen and Progesterone Receptors Expression in Adenomyosis, Potential Targets for Endocrinological Therapy

“…Progesterone resistance resulting from the decreased expression of PGR, especially PGR-B isoform, has been reported in adenomyosis [ 38 ]. We showed PGR expression at both gene and protein levels in adenomyotic tissue.…”

Progesterone Resistance in Endometriosis

“…Suppression of PGR expression and activity in target cells may potentially take place due to interference in transcriptional, post-transcriptional, and posttranslational events, and at the level of protein stability. These events can reportedly be affected in endometriosis; 23,[57][58][59][60][61] however, progesterone receptor polymorphisms are not related to susceptibility to endometriosis. 62 Fundamentally, it depends on genetic background, natural history of development of the individual, and the organ and macro-to micro-environmental details.…”

“…It now appears that human endometrial fibroblasts display PGR resistance and an inflammatory phenotype, possibly due to epigenomic modifications in the endometrium during endometriosis. 10,23,30,31,40,61 Although PGR gene expressions and PGR actions are significantly dysregulated in both eutopic and ectopic tissues compared with control endometrium, the underlying epigenetic mechanisms for PGR suppression in the eutopic tissue are different from ectopic tissue. of reproductive age have endometriosis, with more than 70% of them affected by chronic pelvic pain.…”