LA JOLLA, CALIF. — It's time to rekindle enthusiasm for postmenopausal hormone therapy, Dr. Leon Speroff said at the annual meeting of the Association of Reproductive Health Professionals. “In my view, postmenopausal hormone therapy is in a stalled position and it's time to move forward,” said Dr. Speroff, professor of obstetrics and gynecology and reproductive endocrinology at Oregon Health and Science University, Portland.
“The initial negative impact of the Women's Health Initiative is over, we know the study's limitations, we know that some of the conclusions promoted in the media were not correct, and we know that the risks that have been promoted by the Women's Health Initiative are incredibly small and perhaps not real,” Dr. Speroff said in an interview.
Dr. Speroff pointed out several problems surrounding the WHI, including diagnostic and selection biases, high drop-in and drop-out rates, poorly presented media reports, sound-bite interpretations by “experts,” epidemiologists giving clinical advice, and the writing of position papers by various medical organizations that, in Dr. Speroff's opinion, “were profoundly influenced by medical-legal fears.”
While data from the WHI suggested that estrogen with progestin increased the risk of breast cancer, Dr. Speroff said that he believes the therapy may actually be beneficial when used early in menopause. He said that his suspicion was fueled by paradoxical findings from worldwide observational studies showing that while hormone users had an increased risk of breast cancer, they had reduced risk of mortality.
One explanation was that hormone users had more mammograms and their cancers were detected earlier. Subsequent studies corrected for this, looking only at women who were having mammography, and reports emerged documenting that estrogen-receptor positive hormone users who developed breast cancer had lower-stage, lower-grade disease, said Dr. Speroff, a consultant with Warner Chilcott, which markets Femtrace, and a recipient of research grants from Wyeth, Organon USA Inc., and Barr Laboratories Inc. “That struck me as the answer to the apparent paradox … that what we are seeing is earlier detection of less-aggressive disease, and thus the tumors of hormone users have better outcomes.”
However, surgeons at the University of Utah, Salt Lake City, have given Dr. Speroff a different explanation: “They argued that mammography doesn't detect the tumor itself … that imaging detects the stromal reaction around the tumor and … that hormone exposure causes differentiation of the tumor and slower growth, allowing more time for the stromal reaction and thus earlier detection.”
In any case, he added, both explanations add up to earlier detection. “All the studies find the increased risk fast, and it takes about 10 years for a malignant breast cell to become clinically detectable. Every single study has found the increased risk only in current users. After discontinuation, the risk returns to baseline and, to this day, not a single study has found an increase in hormone users in noninvasive, in situ disease,” Dr. Speroff said at the meeting.
Dr. Speroff added that the latest report on breast cancer from the WHI was issued this summer, and for the first time, all of the risk factors that influenced breast cancer had been taken into account and adjustments had been made. “The increased overall risk of breast cancer in the canceled estrogen-progestin arm after adjustments is no longer statistically significant,” said Dr. Speroff, adding that in the updated results, patients who adhered to treatment throughout the study had a significant reduction in the risk of breast cancer.
Physicians are warned, however, not to automatically conclude that the difference in results in the two arms reflects the effect of progestational agents, because the participants in the two arms were not identical.
“In terms of both cardiovascular disease and breast cancer, there are major differences comparing the two arms, and therefore it's not appropriate to conclude that the difference represents a progestational effect,” he said. “So where we are today with breast cancer is we're not sure whether there truly is an increased risk or whether we're seeing an impact on preexisting tumors, and the possibility remains that exposure to estrogen and progestin may actually be beneficial, causing greater differentiation and earlier detection and better outcomes.”
Dr. Speroff continued, “I tell clinicians that until we have definitive randomized trial data—which we may never have—whatever the patient wants to do is the correct decision. It takes about 10 minutes talking to a patient to know what she wants. However, it's important to point out to her that in case series involving over a thousand patients, whether your tumor receptor was positive or negative, it didn't make any difference.”