Progestagen component in combined hormone replacement therapy in postmenopausal women and breast cancer risk: A debated clinical issue

Abstract

The relevance of the progestagen component in combined hormone replacement therapy (HRT) for breast cancer risk has been long debated. In vitro studies have shown that progestins exert both genomic transcriptional and non-genomic effects that can enhance the proliferation, invasiveness and spread of breast cancer cells. According to a novel hypothesis, progestins can still activate cancer stem cells in patients with pre-existing, clinically undetected breast cancer. However, some experimental and clinical data suggest that different progestins may have a different impact on the pathophysiology of malignant breast cells. In vitro studies on estrogen receptor (ER)+ breast cancer cells have shown that the addition of medroxyprogesterone acetate (MPA) to estradiol (E₂) produces a significantly higher increase of the mRNA levels and activities of estrogen-activating enzymes aromatase, 17β hydroxysteroid dehydrogenase type-1 and sulfatase when compared with progesterone plus E₂. In randomised trial performed on ovariectomised adult female monkeys, oral E₂ plus MPA have resulted in a significantly greater proliferation of breast lobular and ductal epithelium when compared with placebo, whereas E₂ plus micronised progesterone have not. In the same experimental model, oral E₂ plus MPA have been found to induce the expression of genes encoding epidermal growth factor receptor (EGFR) ligands and downstream targets, whereas E₂ alone or E₂ plus micronised progesterone had no or modest effects on EGFR-related genes. In last years, some clinical studies on HRT users have shown that androgenic progestin- or MPA-based formulations are associated with an increased breast cancer incidence, whereas micronised progesterone- or dydrogesterone-based formulations are not. Further basic and clinical investigations on this topic are strongly warranted to elucidate whether the choice of the progestagen component in combined HRT could be of clinical relevance as for breast cancer risk.

Keywords:

• Breast cancer
• hormone replacement therapy
• growth factor
• progestin
• medroxyprogesterone acetate
• dydrogesterone
• micronised progesterone

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.