Out of the controversy over the link between hormone therapy and coronary heart disease (CHD) there has emerged a theme, or hypothesis, that it takes healthy cardiovascular endothelium to have a maximal beneficial response to estrogen exposure, continued Dr. Speroff.
For example, in the Nurse's Health Study, which looked at conjugated equine estrogens plus medroxyprogesterone acetate vs. placebo in more than 1,660 women, the only statistically significant reduction in CHD occurred in women who began estrogen early in their postmenopausal years, with no difference between the two treatment arms, he said.
At adjudication of WHI data, Dr. Speroff added, 10% of the coronary diagnoses were changed and CHD was no longer statistically significant—facts he said received no publicity whatsoever. “The only significant increase in coronary events in the WHI estrogen-progestin arm occurred in the women who were 20 or more years away from menopause; these were the oldest women in the study [N. Engl. J. Med. 2003;349:523]. When you subtract that group of women, there was no increase in coronary events … and after adjudication there was no increase in coronary disease in the estrogen-only arm [Arch. Intern. Med. 2006;166:357]. The WHI reported this as no beneficial effect, but if you read the report carefully, I believe you can find supporting evidence for a primary prevention effect” from hormone replacement.
Dr. Speroff concluded, “If there's one thing that's not going to change in coming years, it's the media, and it's time we become active in objecting to this policy where the major journals provide the publications to the media before they become available to you and me and the public. It's time that, as organizations and individuals, we begin to protest this particular policy.”
Dr. Steven Goldstein, who described himself as being “in the middle” on the issue of hormone therapy, agreed with Dr. Speroff.
“Some major journals [reporting WHI data] were in a frenzy to get air time,” Dr. Goldstein, professor of obstetrics and gynecology at New York University, said in an interview. Broadly speaking, reporting on the initiative represented a failure to educate the public on the difference between relative and absolute risk, he said.
“In this era of evidence-based medicine, people glom onto the randomized, controlled trial as being the gold standard of clinical evidence, and it should be. However, if you do that, you'd better be sure that the patient sitting opposite you in the consult room is exactly like the women in the study; otherwise, the results are not necessarily relevant,” he said.
“However, what Dr. Speroff has done I think is try to reslice the deck and reanalyze the statistics, which is no more valid than what he's accusing the WHI of doing,” said Dr. Goldstein, adding that he would rather get patients and physicians to recognize that “the 51-year-old woman who has 15 hot flashes a day and can't sleep can be helped with preparations that are not the same as those tested in the WHI, and that extrapolation from the WHI is unfair and inappropriate.”
Dr. Goldstein added that the information coming out of adjudication is not very valuable if suddenly “there's one less case so it's not statistically significant, or one more case and it is. That's tenuous information when you have thousands of people involved and people are fallible; so you're obviously dealing with a situation that is not clear cut.”
He said that the “pretty significant difference between the two arms of the WHI study” supports an epidemiologic study of over 46,000 postmenopausal women, in which those taking estrogen plus progestin were at greater risk for breast cancer compared with women taking estrogen alone (JAMA 2000;283:485–91).
“And the Million-Women study in England, whose flaws were somewhat overcome by the sheer number of women involved, showed three times as much breast cancer with estrogen plus progestin as with estrogen alone. And that wasn't just Prempro; that was any formulation,” Dr. Goldstein explained (Lancet 2003;362:419–27), adding that women are being overtreated with progestogen in an attempt to prevent uterine cancer. “If you look at the literature, unopposed Premarin for 6 months results in simple hyperplasia in 7% of women. We're treating 100% of women with a uterus to protect seven.”
Dr. Speroff's proposition that hormone therapy may actually protect women by causing greater differentiation and earlier detection “is an incredibly interesting hypothesis, but I can't in good conscience tell my patients that they should therefore take hormone therapy because if they're destined to get breast cancer this is going to make early detection more likely and improve their survival. I hope that's true, but it's not going to be my motivation for hormone therapy,” Dr. Goldstein said.