Can the increase in breast cancer observed in the estrogen plus progestin arm of the Women's Health Initiative trial be explained by progesterone receptor membrane component 1?

E ver since the estrogen-alone arm of the Women’s Health Initiative (WHI) trial showed a more balanced risk-benefit profile compared with the estrogen plus progestin arm of the trial, there has been considerable speculation as to why the estrogen-alone arm had a relatively more favorable outcome. The estrogen-progestin arm of the trial was discontinued first because of a statistically significant increase in invasive breast cancer and an increase in cardiovascular events. In contrast, in the estrogen-alone arm, there was an increased risk of stroke similar to that reported in the other arm of the trial, but there was no increase in breast cancer. It has been pointed out that the two arms of the WHI trial were actually two different trials with two different populations and treatments, making direct comparisons inappropriate. On risk factors for breast cancer, the women in the estrogen-only arm experienced more early births and bilateral oophorectomy and more and longer durations of previous hormone therapy. In addition, the women were more obese, less active, and had more pre-existing cardiovascular disease. It has also been suggested that the differential transcription activities of the various estrogen components of conjugated equine estrogens (CEE) that are mediated through estrogen receptor (ER)-> or ER-A may play a role in the findings of the estrogen-alone arm of the WHI trial. The main determinants of the transcriptional activity of ER-> and ER-A are the individual concentrations of the two ER subtypes in a target cell and the structure of the estrogen ligand. With respect to estrogen structure, it has been shown that the rank order of binding affinity and functional activity (transcriptional responses) of the various estrogen components of CEE are not directly related and are different for ER-> and ER-A. In addition, in contrast to estradiol (E2), the effects of equine estrogens such as equilenin are mediated mainly via ER-A. Depending on which estrogen is binding to it, ER-A can act as a dominant activator or dominant repressor of ER->. Therefore, the selectivity of equine estrogens for ER-A may play a protective role in breast cancer when CEE is administered alone, as was done in the estrogen-only arm of the WHI trial. Another explanation for the discrepant results of the two arms of the WHI trial pertains to the pharmacokinetics of medroxyprogesterone acetate (MPA) in the different age groups of postmenopausal women in the CEE/MPA arm of the trial. The pharmacokinetics of progestogens in older women (965 y) are altered compared with those in adult women and younger postmenopausal women. Older women have an increased oral bioavailability of drugs because of decreased hepatic cytochrome P450 content, which results in decreased hepatic firstpass metabolism. They also have a more extensive volume of distribution of lipid-soluble drugs, such as progestogens, and a less extensive volume of distribution of water-soluble drugs. Furthermore, perhaps the most important cause for altered pharmacokinetics of drugs in the older women is the decline in the renal clearance of drugs. It has been shown that after an oral administration of 1 mg or 2 mg of E2 valerate in combination with 2.5 or 5 mg of MPA to postmenopausal women daily for 12 or 14 days, the exposure of MPA, based on its area under the concentration-time curve, was, on average, 1.6 to 1.8 times higher in the oldest group of women (965 y) compared with the youngest group (G60 y). Therefore, high levels of MPA in older postmenopausal women may have adverse effects, especially if the women have pre-existing conditions. Exogenous progestins such as MPA may play a critical role in breast cancer risk. Although the key mediators of biologic effects of progestogens are the nuclear progesterone receptors (PRs) PR-A and PR-B, in recent years, it has become evident that many of the biologic actions initiated by some progestogens are mediated by nongenomic PRs, particularly progesterone receptor membrane component 1 (PGRMC1). PGRMC1, first described in 1998 as a putative progesterone-binding membrane receptor of approximately 22 kDa, is part of a multiprotein progesteronebinding complex that binds progesterone. It seems to have multiple functions, including the activation of cytochrome P450 enzymes that metabolize steroid hormones. PGRMC1 is expressed in a variety of tissues, including the breast, and is believed to be involved in progesterone signaling in the reproductive system and to mediate progesterone’s antiapoptotic effects. A recent study showed that PGRMC1 expression levels in peripheral nucleated blood cells did not vary significantly throughout the menstrual cycle, but a significant downregulation of PGRMC1 levels was observed in postmenopausal women and in patients with premature ovarian failure and polycystic ovary syndrome compared with the levels in the early follicular phase of healthy women. PGRMC1 is overexpressed in breast cancer, where it promotes cancer cell survival during chemotherapy. It has been shown to be more abundant in cancerous breast tissue than in normal tissue. PGRMC1 may play a critical role in tumorigenesis and may increase breast cancer risk. The study by Neubauer et al in the present issue of Menopause investigated the effect of E2, progesterone, and