Women in Balance

Progesterone & Breast Health

Chang KJ, et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 1995; 63(4):785-91.

The effect of transdermal estradiol (1.5 mg), transdermal progesterone (25 mg), and combined transdermal estradiol and progesterone (1.5 mg and 25 mg) on human breast epithelial cell cycles was evaluated in vivo. Results demonstrated that estradiol significantly increases cell proliferation, while progesterone significantly decreases cell replication below that observed with placebo. Transdermal progesterone was also shown to reduce estradiol-induced proliferation.
Cowan LD, Gordis L, Tonascia JA, et al. Breast cancer incidence in women with a history of progesterone deficiency. American Journal of Epidemiology 1981; 114:209. ,083.

Infertile women were followed for 14-34 years. Those who were deficient in progesterone showed a fivefold greater incidence of premenopausal breast cancer.
Desreux J, Kebers F, Noel A, Francart D, Van Cauwenberge H, Heinen V, Thomas JL, Bernard AM, Paris J, Delansorne R, Foidart JM. Progesterone receptor activation- an alternative to SERMs in breast cancer. Eur J Cancer 2000 Sep;36 Suppl 4:S90-1.

This review emphasizes progesterone’s role in supporting healthy breast homeostasis and opposing the proliferative effects of estradiol in the breast, unlike synthetic progestins.
Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S, de Lignieres B. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 1998 May;69(5):963-9.

In this double-blind randomized study, to evaluate the effects of estrogen and progesterone on normal breast cells, forty postmenopausal women received daily topical application of a gel containing either placebo, estradiol, progesterone, or estradiol + progesterone for two weeks prior to esthetic breast surgery or the excision of a benign breast lesion. The results showed that increased estrogen concentration increased the number of cycling epithelial cells, whereas exposure to progesterone for 14 days reduced the estrogen-induced proliferation of normal breast epithelial cells.
Formby B, Wiley TS. Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction of apoptosis. Mol Cell Biochem 1999 Dec;202(1-2):53-61.

This study sought to elucidate the mechanism by which progesterone inhibits the proliferation of breast cancer cells. Utilizing breast cancer cell lines with and without progesterone receptors (T47-D and MDA-231, respectively) in vitro, the authors looked at apoptosis (programmed cell death) in response to progesterone exposure as a possible mechanism. The genetic markers for apoptosis - p53, bcl-2 and surviving, were utilized to determine whether or not the cells underwent apoptosis. The results demonstrated that progesterone does produce a strong antiproliferative effect on breast cancer cell lines containing progesterone receptors, and induced apoptosis. The relatively high levels of progesterone utilized were similar to those seen during the third trimester of human pregnancy.
Formby B, Wiley TS. Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. Ann Clin Lab Sci 1998 Nov-Dec;28(6):360-9.

This study explored the mechanism by which progesterone inhibits breast cancer cell proliferation (growth). In progesterone receptor positive T47-D breast cancer cells, the mechanism of apoptosis appeared to be through the regulation of the genes p53 and bcl-2 by progesterone. These genes control the apoptotic process. It was demonstrated that at progesterone levels that approximate the third trimester of pregnancy, there was a strong antiproliferative effect in at least 2 breast cancer cell lines.
Laidlaw IJ, Clarke RB. The proliferation of normal breast tissue implanted into athymic nude mice is stimulated by estrogen, but not by progesterone. Endocrinology Jan 1995;136(1):164-71.

Normal human breast tissue was implanted subcutaneously into athymic nude mice. The mice were then treated with estradiol or progesterone such that serum levels approximated those seen in normal menstruating women. Immunocytochemical measures were made of proliferative activity and steroid receptor expression of the tissue implants. It was found that physiologic levels of estradiol significantly stimulated the proliferation of human breast epithelial cells and increased progesterone receptor expression 10-20-fold. Progesterone failed to affect proliferation alone or after estradiol priming.
Lin VC, Ng EH, Aw SE, Tan MG, Ng EH, Chan VS, Ho GH. Progestins inhibit the growth of MDA-MB-231 cells transfected with progesterone receptor complementary DNA. Clin Cancer Res 1999 Feb;5(2):395-403.

Progesterone is mainly thought to exert its effects via the estrogen-dependent progesterone receptor (PR), the effects of which may be overshadowed by the presence of estrogen. In order to study the independent effects of progesterone on breast cancer cell lines, PR expression vectors were transfected into a PR and ER negative cell line (MDA-MB-231). The growth of these cells was then studied in response to progesterone and several progestins. Progesterone was found to significantly inhibit DNA synthesis and cell growth in a dose-dependant fashion. The results of this study indicate that progesterone and progestins independent of estrogen have an antiproliferative effect on breast cancer cells via the progesterone receptor. This suggests a possible role in the treatment of PR negative breast cancer via re-activation of the PR receptor.
Malet C, Spritzer P, Guillaumin D, Kuttenn F. Progesterone effect on cell growth, ultrastructural aspect and estradiol receptors of normal human breast epithelial (HBE) cells in culture. J Ster Biochem Mol Biol 2002; 73: 171-181.

In a culture system, progesterone was found to have an inhibitory effect on breast cell growth. When given following estradiol (E2), it limited the stimulatory effect of E2 on cell growth.
Mauvais-Jarvis P, Kuttenn F, Gompel A. Antiestrogen action of progesterone in breast tissue. Horm Res 1987;28(2-4):212-8.

In a review of international literature on the cellular effects of progesterone on both normal breast cells and breast cancer cell lines, the authors conclude that most data indicate progesterone and progestins have an antiestrogenic effect on the breast, as reflected in the decrease in estradiol receptor content, the decrease in cell proliferation, and an increase in a marker of cell differentiation, 17 beta-hydroxysteroid activity, which is mediated by the progesterone receptor.
Mohr PE, Wang DY, Gregory WM, Richards MA, Fentiman IS. Serum progesterone and prognosis in operable breast cancer. British Journal of Cancer 1996;73:1532-1533.

Higher blood levels of progesterone measured during surgical treatment of breast cancers were associated with significantly better survival, especially in women who were node-positive (P<0.01). There was no significant relationship between E2 levels and survival. This study demonstrated that a higher level of progesterone at time of excision is associated with improved prognosis in women with operable breast cancer.
Pasqualini JR, Paris J, Sitruk-Ware R, Chetrite G, Botella J. Progestins and breast cancer. J Steroid Biochem Mol Biol 1998 Apr;65(1-6):225-35.

This review article outlines the many functions of progestogens in hormone-dependent and independent breast cancer and suggests new clinical applications their use in the treatment of breast cancer.
Plu-Bureau G, Le MG, Thalabard JC, Sitruk-Ware R, Mauvais-Jarvis P. Percutaneous progesterone use and risk of breast cancer: results from a French cohort study of premenopausal women with benign breast disease. Cancer Detect Prev 1999;23(4):290-6.

This cohort study followed 1150 premenopausal French women diagnosed with benign breast disease. Topical progesterone cream, a common treatment for mastalgia in Europe, had been prescribed to 58% of the women. Follow-up accumulated 12,462 person-years. There was no association noted between progesterone cream use and breast cancer risk. Furthermore, women who had used both progesterone cream and an oral progestogen had a significant decrease in breast cancer risk (RR= 0.5) as compared to women who did not use progesterone cream. There was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. These results suggest there are no deleterious effects caused by percutaneous progesterone use in women with benign breast disease.

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