Since clinical studies mostly involved cases
Since clinical studies mostly involved cases that used MPA, data from studies that examined other types of progestogens are very limited. While the WHI study examined the combination of conjugated equine estrogens plus MPA , the Million Women Study  that also demonstrated an increased risk of breast cancer with the combined use of estrogens and progestogens found little variation between the progestogens used (MPA, NET, or norgestrel/LNG). In a French cohort study of 3175 women , 83% of HRT users received mainly a transdermal E2 gel formulation, 58% received oral micronized P4, and fewer than 3% used MPA. Interestingly, this study failed to detect an increased risk of breast cancer. More data from both clinical and experimental studies are required to investigate the use of different progestogens in HRT.
Based on previous in vitro studies, the question as to whether progestogens are inhibitory or stimulatory has remained controversial. With regard to the effects of progestogens on estrogen-metabolizing enzymes, stimulation of the estrogen-activating enzyme 17βHSD1 by MPA, LNG, NET, NET acetate , and the synthetic progestogen ORG2058  have been reported. By contrast, Pasqualini et al. have claimed in a series of studies that various progestogens including MPA and P4 had inhibitory effects on STS and 17βHSD1 , . For the roles of progestogens on cell proliferation, Hofseth et al.  performed a cross-sectional observational study using benign breast biopsies and showed that postmenopausal HRT with BYL719 plus MPA was associated with greater breast epithelial cell proliferation and cell density than HRT with estrogen alone or no HRT. Also, of the studies using breast cancer cell lines, some have shown inhibition by progestogens and some have shown stimulation , , , , , , , . This inconsistency may be due to variations in culture conditions, cell types, and progestogens examined. For instance, when limited to the effect of MPA on E2-stimulated proliferation, most studies showed inhibition , , , , whereas Franke and Vermes  showed stimulation.
Seeger et al.  showed that for cell proliferation assays, various progestogens at relatively low concentrations showed inhibition in a CCR model but not in an SCR model, suggesting that the CCR was more favorable than SCR in reducing cancer risk. This discrepancy may be due to the apparently conflicting effects of progestogens on estrogen-activating enzymes and cell proliferation. In terms of clinical trials, few studies have been sufficiently well designed to compare SCR and CCR. The WHI study  showed an increased risk of breast cancer for CCR. The Million Women Study  also showed an increased risk, but with little difference between SCR and CCR. A prospective Danish study  showed an increased risk for current HRT use, with a significantly higher likelihood of developing estrogen-receptor positive breast cancer under a CCR than an SCR, and the Danish Nurse Cohort study  also showed that for current users of combined HRT with NET acetate/LNG, a CCR was associated with a higher risk of breast cancer than an SCR.
Introduction The expression of sex steroid receptors in breast cancer tissue has been recognized as being able to predict the clinical response to endocrine treatments. Knockout of the estrogen receptor (ER) and progesterone receptor (PR) genes prevents complete mammary gland development in mature mice , . Thus, the effects of estrogen and progesterone on the mammary gland are believed to be mediated by their ER and PR. However, the exact mechanisms by which estrogen and progestestogens regulate the proliferation and differentiation of human breast cells remains less known. It is generally accepted that female sex hormones are linked to the etiopathogenesis of breast cancer. Results from a large randomized clinical trial, the Women's Health Initiative, indicate a poorer outlook in users of combined estrogen-progestin therapy, represented by a larger proportion of tumors with lymph-node metastases and by differentiated tumors , . By contrast, observational studies have repeatedly reported fewer malignant clinical features and improved prognosis in hormone therapy (HT) users , . However, the impact of HT use on breast-cancer prognosis and clinical characteristics is not well understood. Just as the animal experiments and observations in women suggest, the treatment with estrogen/progestogen may have diverging effects on the expression of ER and PR isoforms in the breast epithelium .