Is HRT for Menopause Staging a Comeback?

A recent meta-study, which found that menopausal hormone replacement therapy (HRT) causes significant numbers of ovarian cancers, is highly misleading, say several hormone researchers.

Furthermore, other recent studies are showing estrogens in particular to be beneficial, causing not just reduction in hot flashes, but “reduction in coronary events, breast cancer, and mortality,” Columbia University endocrinologist Rogerio Lobo, M.D., told Bioscience Technology.

Lobo noted that 13 years have passed since the Women’s Health Initiative (WHI) clinical trial was halted prematurely due to some negative results. Longer term data from that study now find the situation to be “reversed in many cases,” he said. “It’s almost all very positive, particularly for younger populations.”

There were two WHI groups. One took Wyeth’s estrogen (Premarin) and synthetic progesterone (Provera) in a single pill called Prempro. The other group took Wyeth’s estrogen alone. “There was nothing significantly adverse in the estrogen-only group, and much that was beneficial,” Lobo said.

And among those taking both hormones, he said, over the 13-year follow up, “the only significant adverse thing was an association between long-term exposure and breast cancer. Even then, among women who never had hormones before, there was no increase over five years.” (There was a link to thrombosis, but this could be avoided by switching to patches.)

All told, the new WHI follow-ups, combined with results from new The Kronos Early Estrogen Prevention Study (KEEPS) and Early Versus Late Intervention Trial with Estradiol (ELITE) trials, have unveiled a clear bottom line: Wyeth’s synthetic progesterone Provera (aka MPA, or medroxyprogesterone acetate) was “the bad player. Few use it anymore...Hormones are coming back."

University of Southern California Atherosclerosis Research Unit chief Howard Hodis put it even more strongly. "The data looked this good 13 years ago. The negative shadow [was due to the] way the data was spun," he said. "But it is reassuring the effects of hormone therapy (HT) still look so good. HT as studied by the WHI and observational studies all show that it reduces overall mortality when initiated in young women in close proximity to menopause. In fact, data currently being published show that when women stop HT, death rates increase."

In general, Hodis told Bioscience Technology, "women are using HT more and more." But that "negative shadow" was for years "a real inhibitor."

The WHI

In 2002, the massive randomized, double-blind, placebo-controlled WHI clinical trial of Wyeth’s hormones was halted due largely to apparent small increases in breast cancer and heart problems. In an ensuing media panic, sales of all hormones plummeted.

Many researchers were frustrated. The WHI study had design flaws. Many of the women were older—average age 63—with existing heart disease. This mattered as, in nature, hormones are preventives, not combatant drugs. Older women’s results skewed the data. Protestors also noted Wyeth’s hormones were not physiologic (humanlike). Its synthetic progesterone clung to the wrong receptors. The estrogen was more physiologic, if made of many horse estrogens and other non-human elements. And Wyeth’s estrogen/progesterone was given in a daily pill continuously, hitting the bloodstream only after digestion alters them. Women’s hormones fluctuate, and are released directly into the bloodstream from the ovaries.

Two small clinical trials—ELITE and KEEPS—were launched to see if more physiologic hormone regimens would be beneficial, and to see if they should be given to healthy women shortly after menopause, rather than older women with existing disease.

ELITE and KEEPS

Results of the randomized, placebo-controlled, double-blind KEEPS show that, among younger (mean age 53) very healthy women, physiologic hormones do not harm the heart over four years. "KEEPS is solid proof that HT in recently menopausal women is not associated with serious adverse effects in the first four years of use," said Tel Aviv University menopause specialist Amos Pines, M.D., in a commentary.

The randomized, placebo-controlled, double-blind ELITE went further. Early results unveiled at a recent conference showed physiologic hormones “significantly” slow progression to atherosclerosis in women not as healthy as those in KEEPS, but younger (mean age 55) than the WHI average—as predicted by study leaders. ELITE physiologic hormones did not slow subclinical atherosclerosis progression in older (mean age 65) women starting HRT ten plus years into menopause—also as predicted.

“Estrogen may have an impact on progression of coronary atherosclerosis only when there is already some existing arterial plaque formation,” wrote Pines.

By the same token, there shouldn't be too much plaque. “The evidence does support the timing hypothesis,” wrote Harvard University hormone researcher Joanne Manson, M.D., in Medscape. “We need more research using other formulations of hormone therapy, such as transdermal (patch) estradiol (physiologic estrogen), and lower doses of hormones.”

HRT clearly impacts mortality rates

Hodis said mortality rate drops have been a standout almost across the board. The positive WHI results years after use testify "to the long-term safety of these products, especially in the correct women. Even in the face of 'risk' HT clearly reduces overall death," he told Bioscience Technology. That is, even when younger women used the Wyeth progesterone--which he agrees was problematic--death rates dropped. (There was a "possibly greater risk" for WHI women starting HT with Wyeth's progesterone at an older age.)

And a 2013 Hodis study found "when one considers primary prevention of coronary heart disease with other agents--statin or aspirin therapy--none improve mortality in women," he told Bioscience Technology. By contrast, much data find HT does. A 2006 meta-study of 23 trials, testing varied HT formulations in some 200,000 participants, found mortality and cardiovascular disease rates dropped significantly in younger women.

And of "immense importance," Hodis reported in 2013, was heart data from the 2012 Danish Osteoporosis Prevention Study (DOPS). In line with what so many experts now believe is the best way to do HT, women were only started on it at a young age (all 1006 were age 45 to 58). Only more physiologic hormones were used. HT use lasted 10 years; patients were followed for 16. Mortality, myocardial infarction, and heart failure combined were "significantly" lower --49 percent lower--among HT users even 16 years later. Mortality alone was 34 percent lower.

Recent ovarian meta-study

A recent ovarian study at first threatened to spoil the welcome-back party for HT. Published in a recent issue of The Lancet, it looked at several observational studies—not gold-standard clinical trials like WHI, KEEPS, DOCS, and ELITE—and found “significant” rises in ovarian cancer linked to HT. That is, the new study found an extra case of ovarian cancer per 5,000 HT users per year.

But many researchers said this shouldn’t worry clinicians and patients.

“It is important to realize this new study does not indicate cause-and-effect; no epidemiologic study can,” Hodis told Bioscience Technology. Hodis is involved with ELITE and KEEPS. “This study has many flaws, making interpretation of the results virtually impossible. Although this meta-analysis claims 52 epidemiologic studies, the results are driven primarily by two [the Million Women Study (MWS) and the Danish Sex Hormones Register Study (DaHoRS)], in which important adjustments for other associations of ovarian cancer could not be included because they either were not measured or not available.”

There are more “major internal inconsistencies...that cause one to have little confidence in the results,” Hodis said. “Other studies, such as the large randomized WHI designed to examine cause-and-effect of HT, found that HT does not cause ovarian cancer.”

Finally, Hodis told Bioscience Technology: “Even if one accepts the results of this new study, the number of new ovarian cancer cases is calculated to be two additional ovarian cancer cases per 10,000 women per year of HT. This is rare, and discriminating such a small number of additional cases of ovarian cancer in women who used, and did not use, HT in a study with the type of problems discussed is virtually impossible. All of the noise of the data and analyses would obscure such a rare and small difference in ovarian cancer....These facts, with the fact that the WHI showed no cause-and-effect between HT and ovarian cancer, indicate women should not be concerned."

Pines told Bioscience Technology: “The first issue is whether the MWS and the DaHoRS, the most influential studies included in The Lancet meta-analysis, give us a good estimation of ovarian cancer risk in postmenopausal HT users. The second issue is, taking the risk calculated as is, whether the results have a clinical significance....It is very well accepted that a huge observational study such as the MWS has many potential biases. It is impossible to gather all the needed data at baseline and during follow-up, and to control for so many variables in a cohort of more than one million women.”

Pines, former head of the International Menopause Society, continued: “Criticism of the MWS methodology, protocol, and analyses was published many times in the past....As for the estimated risk for ovarian cancer, it was in the range of 0.2 additional cases per 1,000 women per year of use, which is considered negligible. I believe that the old, good rule 'do not harm' is still the principal consideration....if the benefits of HT, especially in the first years of menopause, far outweigh the risks, it should be prescribed. Concerning HT, all the serious adverse consequences combined in the case of healthy peri-menopausal, or early postmenopausal, women do not exceed one extra case per thousand women per year of use. There should not be too much worry.”

Lobo agreed: “The MWS on ovarian cancer was soundly criticized because of flaws in design and statistical analysis. This analysis relied heavily on those data, as well those from DaHoRs. One major concern is they didn’t adjust appropriately in some cases. DaHoRs did not adjust for prior use of oral contraceptives, which are protective for ovarian cancer.”

Lobo also noted to Bioscience Technology that this was a European study. There have been criticisms it did not look at European patients given HRT for ailments turning out to be undiagnosed ovarian cancer.

“The main problem for me was the biological improbability,” Lobo said. “Estrogen/progesterone oral contraceptives decrease ovarian cancer. So how is it that, after menopause, estrogen and progesterone increase risk--at a lower dose? And the study claims that in the first five years, risk rises fast. This makes no sense. It would be cumulative.”

The future

Clinical trial funding plummeted after WHI, but there is hope that more is coming, given the recent positive developments.

ELITE may expand to look at cognition. WHI’s Wyeth (now Pfizer) hormones offered no benefit cognitively, but were only tested for cognitive effects in patients 65 years and older. Many animal studies have found hormones to be key for memory.

Physiologic hormones

Physiologic hormones often prescribed by M.D.'s are 17-beta estradiol patches like Climara and Vivelle, and micronized progesterone gels (Crinone) and pills (Prometrium).

Two papers that thoroughly analyze much of the new and old data are here and here.