Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation

Abstract

Hormonal contraception exposes women to synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progesterone and progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect breast epithelial cell proliferation and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins induce the PR target and mediator of PR signaling-induced cell proliferation receptor activator of NF-κB ligand (Rankl), whereas progestins with anti-androgenic properties in reporter assays do not. We develop intraductal xenografts of human breast epithelial cells from 36 women, show they remain hormone-responsive and that progesterone and the androgenic progestins, desogestrel, gestodene, and levonorgestrel, promote proliferation but the anti-androgenic, chlormadinone, and cyproterone acetate, do not. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Androgen receptor inhibition interferes with PR agonist-and levonorgestrelinduced RANKL expression and reduces levonorgestrel-driven cell proliferation. Thus, different progestins have distinct biological activities in the breast epithelium to be considered for more informed choices in hormonal contraception.

Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1

“…The other progestins did not change tumour size or metastatic burden. It has been suggested that only progestins with androgenic effects stimulate the proliferation of mammary gland cells 49 . In this model, levonorgestrel which is also an androgen‐derived progestin as MPA, was not as stimulatory as MPA.…”

The Other Side of the Coin: May Androgens Have a Role in Breast Cancer Risk?

“…Nevertheless, these observations are in contrast with the findings that contraceptive progestins with androgenic activity, such as the T-related and widely used levonorgestrel, promote hyperproliferation of the breast epithelium with cytological changes, in a xenograft model obtained through intraductal injection of human mammary cells expressing hormone receptors [ 86 ]. Though limited by the fact that the hormonal milieu of human breast epithelial cells in mice is quite different to that in humans, these findings are consistent with a prospective study, involving 1,359,323 p-y from 1978 to 2002, that revealed an increased risk of IBC in postmenopausal women receiving estrogen/androgen hormone therapies compared with patients treated with estrogens alone [ 87 ].…”

RNA Sequencing-Based Single Sample Predictors of Molecular Subtype and Risk of Recurrence for Clinical Assessment of Early-Stage Breast Cancer

“…Included normal breast tissue was obtained from women undergoing mammoplasty surgery with no previous history of BC, who gave informed consent, and the tissue samples were examined by the pathologist to be free of malignancy and processed as described 24 . The study was approved by the Cantonal ethics committee, Commission Cantonale d’éthique de la recherche sur l’être humain, CER-VD, Avenue de Chailly, 1012 Lausanne, Switzerland (Approval number 183/10).…”