Postmenopausal women with an intact uterus who use estrogen therapy should receive a progestogen for endometrial protection; this has led to much debate about the use of bioidentical hormones including micronized progesterone (MP). A panel of gynecologists and endocrinologists conducted a systematic review of the literature on the impact of HRT containing micronized progesterone on the mammary gland using two databases, Embase and Pubmed . Out of a total of 173 studies, 141 studies were the most relevant; of these 16 were selected for the systematic review. Breast density was evaluated in 6 randomized clinical trials (RCTs) lasting between 2-36 months, either by BI-RADS (3 studies) or by computerized methods (3 studies). Results of breast biopsies were reviewed in sixteen studies. Of a total of 16 studies, 6 studies were RCTs, one was a cohort study, 6 were prospective studies, one was a case-control study and two were systematic reviews of the literature. The periods of time of progesterone use analyzed in these studies ranged from 11 days to 11.2 years and, in addition, the demographic characteristics of the populations analyzed in these studies were heterogeneous. Different types of combined HRT at different dosages were used. The following recommendations were issued in conclusion: 1) estrogens combined with oral (approved) or vaginal (use not indicated on the label) MP does not increase the risk of breast cancer for up to 5 years of treatment duration, 2) there is limited evidence that estrogen combined with oral MP for more than 5 years is associated with an increased risk of breast cancer, 3) counseling on combined HRT should cover the risk of breast cancer, regardless of the progestin chosen. Women should also receive advice on other modifiable and non-modifiable breast cancer risk factors in order to balance the impact of HRT.
The systematic review  collected the evidence of the impact of MP on three outcomes: breast density, tissue changes (by breast biopsy) and breast cancer. The review found a tendency towards an increase in density to some degree with therapy. With regard to tissue results, the heterogeneity of the studies was very high, especially in the intervention, although the tendency towards a lower epithelial proliferation was observed. Of course the high heterogeneity of the studies added to the weakness of the systematic review; the level of evidence was low. With respect to the frequency of breast cancer, the evidence showed that MP does not increase the risk of cancer until 5 years. It is noteworthy that the evidence with respect to breast cancer was quite solid since it was obtained from cohort meta-analyses and RTCs. Studies indicate that progestins have potential effects on component 1 of the progesterone receptor membrane (PGRMC1), as documented in MCF7 breast cancer cells, inducing proliferation . Only a neutral effect, on the other hand, was found for progesterone, chlormadinone acetate and nomegestrol. Reviews have reported a lower cancer risk for progesterone compared to synthetic progestins when combined with estrogen in HRT (RR 0.67, 95% CI 0.55-0.81) [3-5]. However , data are reassuring only for the first 5 years of HRT use because this is the period of follow-up of most studies. We need to continue monitoring the literature for evidence and warn patients that the risk after 5 years of HRT use is not clear at the moment.
Camilo Rueda Beltz
IMS Board Member, Professor at Clinica Universidad de la Sabana, Colombia
Gina J. Arias
Resident in Obstetrics and Gynecology, Universidad de la Sabana, Colombia
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