Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis

22 Nov.,2022


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We included two cohort studies and one population-based case-control study out of 3410 citations identified by the search. The included studies enrolled 86,881 postmenopausal women with mean age of 59 years and follow-up range from 3 to 20 years. The overall risk of bias of the included cohort studies in the meta-analysis was moderate. There was no data on cardiovascular events. Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55–0.81.

We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus through 17 May 2016 for studies that enrolled postmenopausal women using progesterone vs. synthetic progestins and reported the outcomes of interest. Study selection and data extraction were performed by two independent reviewers. Meta-analysis was conducted using the random effects model.

Use of menopausal hormonal therapy (MHT)-containing estrogen and a synthetic progestin is associated with an increased risk of breast cancer. It is unclear if progesterone in combination with estrogen carries a lower risk of breast cancer. Limited data suggest differences between progesterone and progestins on cardiovascular risk factors, including cholesterol and glucose metabolism. Whether this translates to differences in cardiovascular outcomes is uncertain. We conducted a systematic review and meta-analysis to synthesize the existing evidence about the effect of progesterone in comparison to synthetic progestins, each in combination with estrogens, on the risk of breast cancer and cardiovascular events.


Menopausal hormone therapy (MHT) is highly effective for the treatment of symptoms related to menopause [1]. MHT regimens typically include estrogen and, for women with an intact uterus, a progestin to protect the endometrium from hyperplasia caused by unopposed estrogen. A number of US Food and Drug Administration (FDA)-approved hormone preparations are available for treatment of women with menopausal symptoms [2]. The biochemistry, metabolism, and both beneficial and harmful effects of the various synthetic progestins differ widely from native progesterone and from each other [3].

Micronized progesterone is a bioidentical hormone with a molecular structure identical to that of endogenous progesterone produced by the ovary. Synthetic progestins have a different chemical structure from progesterone. These compounds mimic some of the effects of progesterone but may have different actions on progesterone receptors [4]. Synthetic progestins may be structurally related to progesterone (e.g., medroxyprogesterone acetate (MPA), dydrogesterone) or to testosterone (e.g., levonorgestrel, drospirenone) with differing potency and pharmacokinetics. The physiologic effects of a particular progestin depend not only on these properties but also on receptor binding. In addition to binding to progesterone receptors, these compounds may also have an affinity for androgen, glucocorticoid, and mineralocorticoid receptors [5].

Although some data suggest that MHT increases the risk of breast cancer [6], the risk of breast cancer may differ depending on the type of MHT used. For example, MHT containing conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) has been associated with increased risk of breast cancer compared to CEE alone [7]. Further, breast cancer risk may vary between regimens containing different progestins, with some synthetic progestins exhibiting greater risk than others [8]. The effects of progesterone have been shown to be growth-promoting, neutral, or anti-proliferative in breast cells, whereas in women, synthetic progestins, especially the combination of CEE and MPA, have been found to be growth-promoting [9]. In contrast to progestins, progesterone in combination with estrogen has not been associated with increased breast cancer [8]. Emerging evidence suggests that the progesterone receptor acts as a modulator of estrogen receptor α (ERα) binding and transcription, blocking estrogen-mediated cell proliferation. The presence of progesterone receptors in breast cancer that are positive for ERα is associated with positive clinical outcomes [10].

Progesterone and synthetic progestins also demonstrate varied effects on lipids, coagulation factors, glucose, and insulin and may therefore differentially impact cardiovascular risk, though data are sparse [11].

The PEPI trial previously demonstrated that, when combined with CEE, progesterone, unlike MPA, did not negate the positive effects of CEE on high-density lipoprotein cholesterol (HDL-C) [7]. A recent randomized, double-blind, placebo-controlled trial utilizing 300 mg of progesterone daily showed no adverse changes in endothelial function, blood pressure, weight, or markers of inflammation or coagulation. Although HDL-C was decreased on treatment, the change was not believed to be clinically relevant [12]. We conducted a systematic review and meta-analysis to synthesize the existing evidence about the effect of progesterone compared to synthetic progestins on the risk of breast cancer and cardiovascular disease.