A French cohort study reported that
A French cohort study reported that micronized progesterone or didrogesterone used with oral or percutaneous estradiol showed no increase or decrease in the risk of breast cancer compared to synthetic progestins for at least 4 years of treatment  and even after 8 years . Although the results of the present study, except E2 plus P4, were completely opposite to those of the French cohort study, it demonstrates that various progestogens have different effects on breast cells, as well as on the expression of ERs and PRs. Significantly increased expression of ERβ and PRB was noted in E2 combined with MPA or NET, whereas a significant increase of ERα expression and decrease of PRB and/or PRA in the E2 combined with P4 or CPA was also noted. Because the major difference of these four progestogens in regards to biologic activity is the strong androgenic effects of MPA and NET and glucocorticoid effects of MPA and CPA, evident when compared with P4, further evaluation is needed to determine whether the androgen and glucocorticoid receptors also play important roles as additional cofactors on the expression of ERs and PRs, as well as on the effects of breast cell growth.
In this decade, although there have been many studies focusing on the effects of different progestogens plus E2 on breast cancer cell growth, the major differences in the present study were the concentrations of progestogens and E2 (Table 1) and the cell preparation. Because our goal was to examine the effects of E2, with or without progestogens commonly used for HT, on breast cells, breast PPT were cultured by serum deprivation and growth factors withdrawal to mimic an aging system. The clinically relevant blood concentrations of E2 for achieved HT range 50–200 pg/mL, equivalent to a concentration of 0.01–0.1 nM . However, it is well recognized that estrogens are synthesized in the breast tissue, and especially in tumor tissue, at concentrations that are remarkably higher than blood levels achieved under HT . In addition, the clinically relevant blood concentrations of progestogens in this study are in the region of 10 nM progesterone when administered in a dosage of 200 mg/day , and in the range of 4–10 nM for MPA  and around 10 nM for NET . Thus, 10 nM progestogens and higher concentration of 1 nM and 10 nM E2 were used in this experiment. Table 1 reveals that most of the other studies demonstrate similar results with higher pharmacological doses of progestogens. In addition, there are few data available to evaluate the effects of progestogens (especially CPA) plus E2 on breast cancer cell growth and the expression of sex steroid receptor subtypes simultaneously like the present study.
In conclusion, the present study demonstrates that E2\'s antiapoptotic effects are significantly reduced by coadministration of progestogens. The combination of E2 and progestogens resulted in diverging effects on the expressions of ERs and PRs, which induced different effects on the cell growth of MCF-7 cells. Our results in the MCF-7 cells showed that E2-abrogating apoptosis is mediated by ERα and that the regulated expression of PRA and PRB is critical to the breast cells\' response to synthetic progesterone. The effect of P4 on breast cells and the expression of ERs and PRs are different from that of synthetic progestins. Thus, the present study reveals that aberrant hormone activity, by way of altered receptor expression, may be an important factor in the malignant transformation of breast cells.
Acknowledgments This study was supported by the Medical Research Center (Chang Gung Memorial Hospital, Keelung) and a research grant from the Clinical Monitoring Research Program (CMRPG280072) of Chang Gung Memorial Hospital, Keelung.
Introduction At its inception in the 1960s, combined oestrogen–progestogen hormone replacement therapy (HRT) was believed to be an effective solution for the various symptomatic complaints attendant with diminished ovarian oestrogen production during menopause. Approximately one-fourth to one-third of women experience menopausal symptoms such as hot flushes and night sweats, vaginal dryness, and depression that are troublesome enough to seek medical advice , . Clinical trials consistently demonstrate that HRT effectively relieves menopausal symptoms in most women and provides clinically significant long-term beneficial effects as well. However, adverse effects contribute to reduced treatment compliance with HRT and are a major obstacle in maximising adherence to and long-term continuation with a regimen , , . Nuisance side effects, particularly cyclic or irregular uterine bleeding that occurs with sequential and continuous oestrogen–progestogen regimens, as well as fluid retention, breast tenderness, headaches, and mood changes are often given by women as the reason for discontinuing HRT , . Early discontinuation is a significant problem since continued HRT is required in order to produce some of the long-term benefits of hormone replacement such as protection against osteoporosis , .