MacLean, J. A., 2nd., & Hayashi, K. (2022). Progesterone Actions and Resistance in Gynecological Disorders. Cells, 11(4). https://doi.org/10.3390/cells11040647
MacLean JA 2nd, Hayashi K. Progesterone Actions and Resistance in Gynecological Disorders. Cells. 2022;11(4). doi:10.3390/cells11040647
MacLean, James A., 2nd., and Kanako Hayashi. "Progesterone Actions and Resistance in Gynecological Disorders." Cells, vol. 11, no. 4, 2022.
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RRM Academy Synopsis
Progesterone resistance is tied to endometriosis, adenomyosis and PCOS
A 2022 review reports that in endometriosis, adenomyosis and PCOS, the womb lining can respond poorly to progesterone. It also covers fibroids and overgrowth of the lining.
Key Findings
One study the review cites found KRAS mutations in 84% of adenomyosis lesions from women who responded poorly to dienogest, a progestin, and had a hysterectomy, against 26% without dienogest.
Approximately 30% of women with polycystic ovary syndrome (PCOS), now also called polyendocrine metabolic ovarian syndrome (PMOS), fail to respond to progesterone-based therapy.
Over 50% of women with endometriosis have a recurrence of symptoms within two years of GnRH agonist therapy. Hormonal therapies do not remove endometriosis lesions.
In a baboon model of endometriosis, progesterone resistance developed gradually and became evident at least 6 months after disease induction.
The review reports that progesterone and progestins stimulate fibroid growth, and approximately 70% of fibroids carry MED12 mutations, with a range of 48 to 92% across studies.
Interpretation
The paper is a narrative review. The authors summarize findings from cell cultures, mouse and baboon models and tissue samples, and report no new data of their own. Many proposed links between gene changes and progesterone resistance are described as likely or potential. The authors state that researchers still do not know how each disorder starts. Fibroids differ: progesterone and progestins are reported to promote their growth in cell and tissue studies. The review runs no trial of its own.
RRM Context
Restorative reproductive medicine looks for the cause of disease and works with the body's own cycle. Progesterone resistance gives that goal a biological target. The review names gene activity, epigenetic marks and mutations as likely contributors. The authors want personalized care that fits each patient's symptoms and fertility goals.
Our editorial summary of this paper, not the article's abstract.
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.
