Some Progestins May Hike Cancer; Some Estrogens May Ward it Off

A recent analysis of long-term after-effects of a specific hormone replacement therapy (HRT)—non-physiologic hormones created by Wyeth—finds that a pattern observed while women took the drugs during the famous Women’s Health Initiative (WHI) remains true years later.

That is, a persistent uptick in breast cancers was seen among those who had taken Prempro, which is a combination of Wyeth's estrogen Premarin (a composite of estrogens from pregnant mare’s urine) and its progestin Provera (a synthetic, non-physiologic form of progesterone called medroxyprogesterone acetate, or MPA).

Meanwhile, those taking only the estrogen saw a persistent decrease in breast cancers.

Many offer different explanations for this finding, which appeared in a recent JAMA Oncology. But one favored view comes from MD Anderson Cancer Center oncologist Craig Jordan, OBE, Ph.D, DSc, FMedSci, father of the breast cancer drug Tamoxifen. “MPA is the bad player,” Jordan told Bioscience Technology. It blunts “estogen-induced breast cancer apoptosis (cell death).”

Columbia University gynecology researcher Rogerio Lobo told Bioscience Technology he agreed. "MPA is known to behave differently, in part because it also has action on the glucocorticoid receptor," he said.

Howard Hodis, director of the University of Southern California’s Atherosclerosis Research Unit, told Bioscience Technology that clearly, “estrogen alone continues to show breast cancer reduction.”

The study

HRT use plummeted after the WHI trial was halted early in 2002, in part due to some increased breast cancers in the cohort of women taking both Wyeth’s estrogen and progestin. But while estrogen-plus-progestin was associated in the study with a small increase in breast cancer incidences and deaths, women who had had hysterectomies, taking the estrogen alone, experienced statistically significant fewer breast cancer incidences and deaths.

Years later, the team of Rowan T. Chlebowski, M.D., Ph.D., of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center compared trial results at the time, to those after a median follow-up of 13 years.

A total of 16,608 women with a uterus received Wyeth’s oral conjugated equine estrogens (CEE) (0.625 mg/d) plus MPA (2.5 mg/d), or placebo for a median of 5.6 years. A total of 10,739 women with prior hysterectomy were given the Wyeth estrogen alone, or placebo, for a median of 7.2 years.

For those taking both the estrogen and the (MPA) progestin, the increasing breast cancer risk occurring while they were taking the combo was followed by a substantial drop in risk in the early post-use phase (within 2.75 years of use). But those women experienced a higher breast cancer risk in later years after stopping therapy.

For those taking estrogen-only, reduced breast cancer risk occurring when the women were taking the estrogen lasted through the early post-use period. That reduced risk went away during the later post-use period.

Editorial

In a related editorial, the team of Rama Khokha, Ph.D., of the Princess Margaret Cancer Centre, wrote that the study seemed to implicate progesterones generally in the breast cancer risk. The team wrote that natural progesterones apparently have an impact on mammary stem cells—which can in turn cause many breast cancers—that should be more fully studied.

But in a December 2014 Cancer Research, Jordan suggested the problem was not all progesterones, just the MPA version.

MPA as culprit

“The current WHI paper completely conforms to our mechanistic explanation in the Cancer Research paper,” Jordan told Bioscience Technology. “Estrogen-induced apoptosis” in the estrogen-only group appears to have been “blocked by MPA, as it is really a weak glucocorticoid. It is as plain as the hand on ones face. The stem cell story in mice for progesterone does not address this blocking mechanism. If stem cells are important for the theory of tumor growth, then one has to explain how the killing effect on tumor cells is reversed.”

The Jordan team’s Cancer Research paper received a three-star “exceptional” rating on F1000 Prime, the Faculty of 1000’s stamp of approval. On that site, Henry Burger, emeritus director of the Prince Henry’s Institute of Medical Research wrote: “The findings have important therapeutic implications, suggesting that it may be preferable to use NETA in hormone therapy, rather than MPA.”

NETA is an oral contraceptive that, unlike MPA, does not have a glucocorticoid component that stops estrogen from causing apoptosis of breast cancer cells in post-menopausal women. NETA is also a synthetic progestin, but it possesses an estrogenic property that actually can add to the killing of breast cancer cells, according to Jordan, while protecting the postmenopausal uterus from the hyperplasia that estrogen-alone can cause.

Lobo explained to Bioscience Technology: “The [new JAMA Oncology] study is merely a rehash of old data already described in the 13-year-follow up. I know several people were going to send letters and were very surprised it got published. It is very common to mix up all progestogens and treat them the same way." MPA is known to be problematic, but "observational studies have found that natural progesterone does not increase the risk, although there are no prospective data. Various progestogens have been compared in basic science studies such as breast cancer cell lines, and there are clearly differences between progestogens.”

He added: “It is likely that with CEE/MPA there was a lagging effect, even after cessation, because those women in WHI who had never taken hormones and received CEE/MPA had no increase in breast cancer, while those who were on hormones in the past, then stopped, and then entered the trial... had the increase.”

Hodis said that, while MPA is a bad player, concerns even there have been overblown. Even in the original 2002 JAMA WHI report, he said, investigators said the breast cancer risk for the Provera/Premarin combo “`almost reached nominal statistical significance.’ Breast cancer was, and remains, clearly non-significant in the multi-adjusted statistic, which is the appropriate statistic to use anyway, as the WHI stats manual states.”

Hodis concluded to Bioscience Technology that the way some are “blurring the lines between MPA and progesterone" is a result of a lingering misunderstanding of their differences. And regardless, "there are several papers moving through the review process now that show that women who stop hormone replacement therapy (HRT) have a statistically greater chance of dying than women who continue to use HRT. But this is no surprise, since we have known that HRT reduces mortality for three to four decades.”

For information on more physiologic HRT, please see earlier Bioscience Technology story here.