Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women

Abstract

The largest-to-date randomized trial (Women's Health Initiative) comparing the effects of hormone replacement therapy (HRT) and a placebo concluded that the continuous use of an oral combination of conjugated equine estrogens (CEE) and medroxy-progesterone acetate (MPA) increases the risk of breast cancer. This conclusion may not apply to women taking other estrogen and progestin formulations, as suggested by discrepancies in the findings of in vitro studies, epidemiological surveys and, mostly, in vivo studies of human breast epithelial cell proliferation showing opposite effects of HRT combining CEE plus MPA or estradiol plus progesterone. To evaluate the risk of breast cancer associated with the use of the latter combination, commonly prescribed in France, a cohort including 3175 postmenopausal women was followed for a mean of 8.9 years (28 367 woman-years). In total, 1739 (55%) of these women were users of one type of estrogen replacement with systemic effect during at least 12 months, any time after the menopause, and were classified as HRT users. Among them, 83% were receiving exclusively or mostly a combination of a transdermal estradiol gel and a progestin other than MPA. Some 105 cases of breast cancer occurred during the follow-up period, corresponding to a mean of 37 new cases per 10 000 women/year. Using multivariate analysis adjusted for the calendar period of treatment, date of birth and age at menopause, we were unable to detect an increase in the relative risk (RR) of breast cancer (RR 0.98, 95% confidence interval (CI): 0.65-1.5) in the HRT users. The RR of breast cancer per year of use of HRT was 1.005 (95% CI 0.97-1.05). These results do not justify early interruption of such a type of HRT, which is beneficial for quality of life, prevention of bone loss and cardiovascular risk profile, without the activation of coagulation and inflammatory protein synthesis measured in users of oral estrogens.

Progesterone Inhibits the Growth of Human Neuroblastoma: In Vitro and In Vivo Evidence

“…Recently, several clinical trials found that, in hormone replacement therapy, the combination of estrogen with a progestin such as medroxyprogesterone acetate (MPA) increased the risk of breast cancer (15). Two cohort studies followed over mean durations of 7 and 9 years showed no increase in breast cancer risk when estrogen was combined with natural P4, but there was an additional risk when synthetic progestins were used (16,17). Further, MPA has differential effects on cell proliferation and growth inhibition in benign and malignant human breast epithelial cells (18).…”

Use of hormones in the menopausal transition period in the Netherlands between 1993 and 1997

“…It is, therefore, possible that the effect of European HT regimens is different from what has been observed in American studies. In a French cohort study HT users mostly received a combination of a transdermal estradiol plus either progesterone or progesterone-derivated progestins other than MPA and these women did not have an increased risk of breast cancer [39]. Although no large variations were seen between the effects of specific estrogens or specific progestagens in relation to breast cancer in the Million Women Study [12], a recent study by Fournier et al [40] showed that breast cancer risk differed according to the type of progestogen that was used.…”

Understanding the oestrogen action in experimental and clinical atherosclerosis

“…Even if this study raised the question of a potential role of the consequences of associated ovariectomy or the nature of the oestrogens used (potential protective role of conjugated equine oestrogens), most of the recent studies underline again the deleterious role of progestin. Indeed, a cohort study [74] and more recently the E3N INSERM study [75] showed no increased risk when HRT included natural progesterone, strikingly contrasting with an increased risk of breast cancer when oestrogen are associated with synthetic progestin having androgenic (19-nortestosterone) or anti-inflammatory (medroxyprogesterone acetate) properties.…”