MPA: Medroxy-Progesterone Acetate Contributes to Much Poor Advice for Women

The article in this issue by Irwin and colleagues from the laboratory of Roberta Diaz Brinton extends a multipart investigation on the differences in the neural actions of medroxyprogesterone acetate (MPA) vs. progesterone (P4, pregn-4-ene-3, 20-dione). This issue became critically important after the Women's Health Initiative (WHI) trial. This trial, which used conjugated equine estrogens alone (Premarin^TR) or in conjunction with MPA to reduce the uterotrophic effect of equine estrogens (Prempro^TR), has turned women's health at menopause into a minefield. It is old news, but the combined hormone arm was ended prematurely because of increased incidence of breast cancer and the 11-year follow-up study found increased mortality attributable to breast cancer (1). Increased risk of dementia, stroke, and cognitive decline was also present in both arms relative to placebo in women aged 65 yr and older (2). While the WHI trial made a valuable contribution in revealing the risks associated with conjugated equine estrogens plus MPA treatment in postmenopausal women, it unfortunately generated considerable controversy in the field because it was interpreted as an indictment of postmenopausal hormone replacement, when in fact, it did not study hormone replacement at all: that would have required use of the natural hormones, estradiol and progesterone. The actions of the natural hormones are significantly different from those of Premarin and MPA. The Irwin et al. (3) study focuses on the progestin problem.

In previous studies, the Brinton laboratory demonstrated that 17β-estradiol and progesterone sustain and enhance brain mitochondrial energy-transducing capacity. In the current article, they show that the coadministration of MPA was detrimental to antioxidant defense, including superoxide dismutase activity/expression and peroxiredoxin expression. Accumulated lipid peroxides were cleared by estradiol treatment alone, but not in combination with MPA. Further, MPA abolished estradiol-induced enhancement of mitochondrial respiration in primary cultures of hippocampal neurons and glia. Hence, the effects of MPA differed significantly from the bioenergetic profile induced by progesterone, and overall MPA induced a decline in glycolytic and oxidative phosphorylation protein and activity. This means that MPA is potentially very detrimental to neuronal health.

But this is not the only evidence. Brinton and colleagues have also shown that progesterone, but not MPA, protects against glutamate toxicity in primary dissociated hippocampal neurons. In addition, progesterone, but not MPA, prevents the increase in intracellular Ca²⁺ levels consequent to glutamate exposure. Even though progesterone and MPA increase ERK phosphorylation, only progesterone caused the nuclear translocation of ERK, suggesting that nuclear translocation of the activated kinase is necessary for progesterone's protective effects (4). Furthermore, not only does MPA fail to mimic the ability of progesterone to increase the expression of the antiapoptotic protein, Bcl-2, but it actually inhibits ability of estrogen to do so (5, 6). Numerous studies from other respected laboratories have shown that progesterone has a wide range of neuroprotective actions, which are not shared by MPA (7–11). Altogether, progesterone has potent neuroprotective effects and MPA does not.

With respect to obvious mental health such as mood, anxiety, or depression, serotonin regulation is pivotal. We found that in nonhuman primates, estradiol or equine estrogens increase the expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis. Supplementation with progesterone was neutral and TPH remained elevated (12, 13). In contrast, supplementation with MPA completely blocked the effect of equine estrogens (14). Thus, MPA endangers brain cells and potentially facilitates stress and depression.

The negative effects of MPA are not limited to the brain. MPA reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery atherosclerosis, accelerates low-density lipoprotein uptake in plaque, increases the thrombogenic potential of atherosclerotic plaques, and promotes insulin resistance and its consequent hyperglycemia in primates (15), whereas progesterone does not (16, 17). In other studies, administration of estrogen and progesterone protected against coronary vasospasm, but the administration of MPA with estrogen eliminated the protection (18). Moreover, in humans, progesterone administration to postmenopausal women enhanced the protective effect of estrogen on exercise-induced myocardial ischemia, but MPA did not (19).

In breast tissue, the story is similar to that in the brain and cardiovascular system. Breast cancer continues to be the hobgoblin of hormone therapy, but studies are finally accumulating that show little effect of estradiol alone or estradiol plus progesterone on end points such as gene expression related to growth factors (20), proliferation and horizonal migration of breast cancer cells in vitro (21, 22), proliferation markers Ki67, cyclin B1, and TFF1 marker of estrogen receptor activity in macaque breast (23), as well as growth and metastasis of human breast cancer cells in nude mice (24). However, estrogen plus MPA significantly increased all of these parameters.

The rationale of the WHI was to use the most commonly prescribed combined hormone therapy in the United States for the trial, which was equine estrogens + MPA. However, failing to acknowledge that not all progestins are alike has done a disservice to the field. MPA is an androgenic progestin, and reducing the dose or using it intermittently in menopausal women is not a good solution. The WHI has led to a sharp decline in the use of hormone therapy at perimenopause and, oncologists argue, also breast cancer. But where are the studies that parse hormone use into the different formulations and then look at breast cancer incidence? A cardiovascular clinical trial is nearing completion [Kronos Early Estrogen Prevention Study (KEEPS)] that uses estradiol or equine estrogens and micronized progesterone at perimenopause (25). We will need information from those patients on breast cancer. In the meantime, a significant subset of women who might actually benefit from properly administered hormone replacement have instead been persuaded that it is intrinsically harmful, which may not in fact be the case. Most of the research papers showing significantly better outcomes in brain, breast, and cardiovascular parameters with estradiol plus progesterone instead of MPA end with rational statements to the effect that hopefully the data will lead to better hormone therapy. Is hope overcoming hype? Perhaps (26, 27); but many physicians remain under the misapprehension that all progestins are alike.

Striking differences exist among the progestins. Natural progesterone and some of its derivatives, such as the 19-norprogesterone molecules, and the new molecules drospirenone and dienogest, are not androgenic and, therefore, have no negative effect on lipid profiles. Depending on the progestin and the duration of application, breast cell differentiation and apoptosis may predominate over proliferation. Thus, it has little to do with the continuous treatment used in the WHI and has more to do with the specific properties of MPA (28, 29). It is entirely possible that new progestins will have neutral effects on the risk of coronary heart disease or breast cancer in younger postmenopausal women, while preventing uterine hyperplasia. Small trials with estradiol and alternative progestins are promising (30, 31).

Whether equine estrogens are a good substitute for estradiol is also questionable, and outcomes may vary with the target tissues. Nonetheless, it seems entirely possible that menopausal hormone replacement regimens may soon become available that will keep women healthy, without the risks identified by WHI: that is what we should be pushing for.