Kim, J. J., Kurita, T., & Bulun, S. E. (2013). Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocrine reviews. https://doi.org/10.1210/er.2012-1043
Kim JJ, Kurita T, Bulun SE. Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocrine reviews. 2013. doi:10.1210/er.2012-1043
Kim, J. J., et al. "Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer." Endocrine reviews, 2013.
Progesterone protects the endometrium and promotes fibroid growth
Progesterone restrains uterine lining growth but promotes fibroid growth, a 2013 review of lab, animal, and human studies concludes. In breast tissue it can promote cell growth, depending on cell context. The authors propose that supporting (stromal) cells with progesterone receptors may account for the split. The lining has many such cells, and fibroids and breast tissue lack organized ones.
Key Findings
In mouse uterine tissue combinations, progesterone slowed estradiol-driven growth of the lining cells only when the supporting stromal cells carried the progesterone receptor.
In endometriosis tissue, the progesterone receptor form PR-B was undetectable and PR-A was markedly lower than in endometrium.
In endometriosis stromal cells, inside and outside the uterus, the progesterone response was blunted and marker expression significantly lower. The authors read this as progesterone resistance.
In fibroid xenografts, growth required estradiol and progesterone together, and fibroid cell volume increased 3-fold with the combination compared with estradiol alone, progesterone alone, or no hormone.
In the Women's Health Initiative, an updated analysis of the estrogen-plus-progestin trial (n = 8506 versus 8102 on placebo) counted 245 versus 185 breast cancers after an average of 5.6 yr.
Interpretation
The article is a review from a Northwestern University research group. The authors draw on mouse experiments, cell cultures, tissue grafts, and clinical studies. The large breast cancer studies the authors cite found higher risk in postmenopausal women taking estrogen with a progestin than in those taking estrogen alone. The authors read this as a tumor-promoting role of progestins. The authors note that estrogen is active in each disease, which hides the effects of progesterone alone.
RRM Context
Fertility awareness charting follows ovulation. The corpus luteum forms after ovulation and makes most of the body's progesterone, the review states. The authors treat progesterone and synthetic progestins as different compounds. Progesterone acts differently in each tissue, so each condition calls for its own evaluation.
Our editorial summary of this paper, not the article's abstract.
Abstract
Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases.
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