In Reply Our Editorial provides insight into plausible biological phenomena that may underlie the menopausal hormone therapy influence on breast cancer risk in the Women’s Health Initiative randomized controlled trials reported by Chlebowski et al.1 We addressed the significant increase in breast cancer risk resulting from estrogen + medroxyprogesterone acetate (E+P) combination therapy and proposed, on the basis of experimental evidence, that stem and progenitor cells are likely to expand and promote cancerous lesions with E+P treatment. Gompel raises a distinction between “natural” and “synthetic” progesterones and progestogens in terms of androgenic, glucocorticoid, and mineralocorticoid properties. We acknowledge that medroxyprogesterone (a synthetic progestogen) has some distinct pharmacokinetics and targets compared with endogenous progesterone; however, in our Editorial we used the term “progesterone” to refer to a broad group of progesterone compounds that include the endogenous hormone as well as its exogenous structurally related synthetic derivatives. The reason for this is that these compounds can activate the progesterone receptor and increase expression of progesterone-induced mitogenic ligands such as RANKL, which exerts paracrine effects on breast progenitor cells2- 4—the mechanism that we discuss in our Editorial. Although not the focus of our Editorial, we recommend caution regarding the potential safety of oral micronized progesterone (OMP) therapy in relation to breast cancer risk suggested by Gompel. The E3N cohort study that she cited as evidence of the safety of OMP used an observational design that is susceptible to bias. It is concerning that the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, which used a randomized controlled design that reduces bias, reported that OMP therapy was associated with an increase in mammographic breast density,5 an independent risk factor for breast cancer. We believe that further research, using randomized designs, is warranted to investigate the long-term risk of breast cancer with menopausal hormone therapy that includes OMP.
Joshi PA, Goodwin PJ, Khokha R. Progesterone and Synthetic Progestin Controversies—Reply. JAMA Oncol. 2015;1(7):987-988. doi:10.1001/jamaoncol.2015.2294