Hormone replacement therapy (HRT) is one of those subjects where many have a strong opinion either way and I suspect even if we have another dozen trials evaluating at the pros and cons, those opinions won’t change very much.
That said, the latest large randomised, double blind, placebo controlled study from the Women’s Health Initiative (WHI) in postmenopausal women with a prior hysterectomy (n=10,739) taking conjugated equine estrogens (CEE) such as Premarin has just reported their health outcomes analysis.
The original goal of the trial was to examine health outcomes after a mean of 10.7 years of follow-up. The study was stopped, however, after a mean of 7.1 years of follow-up because there was an increased risk of stroke. LaCroix et al., (2011) provided some context:
“The Women’s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.”
The baseline characteristics looked well balanced between the two arms, so I took a quick look at the hazard ratio plots to see which factors favoured placebo and noted not only stroke, but also deep vein vein thrombosis (DVT) and pulmonary embolism. It was easy to see why the trial was stopped early based on those results, especially as there were no significant differences in statin or aspirin use between the two groups.
Interestingly, looking at the topline hazard ratios on the cancer side, invasive breast cancer was lower on the treatment side, but colorectal cancer was more favourable in the placebo arm. Previous trials have shown an increase in treatment related breast cancers. Part of this reason may lie in the type of hormone treatments given (estrogens only versus combination therapy) and variations in the patient groups. Of course, the news media instantly picked up on the cancer issue rather than the cardiovascular effects.
Things started to get interesting, however, as I noticed that in the abstract, LaCroix et al., (2011) clearly stated:
“Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.”
Eh? That’s not what you see in the hazard ratio plots, so I went back to re-read the paper and discussion in more detail.
The differences can be explained in the long term follow-up after treatment:
“Among postmenopausal women with prior hysterectomy who stopped taking CEE after a median of 5.9 years of use, several patterns of health risks and benefits seen during the intervention period were not maintained during the postintervention period, while other trends persisted.”
In other words, you often lose an effect post treatment, which can be a good or bad thing depending upon the parameter itself.
With the stroke and cardiovascular events seen in the intervention period on treatment, for example, in the post intervention period those effects “rapidly dissipated” during the postintervention period.
No doubt we will see future subgroup analyses emerge from this trial, it would be interesting to see, for example, whether mammogram screening was higher in either group and whether that impacted the findings or not. Certainly that has been suggested in the past as one reason for the higher incidence of breast cancer in HRT users in other studies – in other words if you got looking for it more often you may well find it.
That said, the HRT story is likely to run and run as will emotions and opinions.
For some different perspectives, I can highly recommend checking out blog posts on the subject from Medical Lessons for a physician’s take and Flash Free for a science writer’s thoughts. There was also an insightful commentary (open access) in Cancer Prevention Research from Craig Jordan and Leslie Ford (see references), who noted:
“Administration of estrogen replacement therapy (ERT) to hysterectomized postmenopausal women decreases the incidences of breast cancer. Though paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances.”
Personally? I wouldn’t take it and I’m too young anyway, but I would like to see more granular research on which subpopulations are most likely to benefit, something that is not really that clear even now. I’ll leave you with a striking insight from Jordan and Ford:
“The important issue for the decision of breast cancer cells to survive or die in response to estradiol depends entirely on the cell populations present in an estrogenized environment or following estrogen deprivation.”
Maybe we need more cowbell.
LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD, Howard BV, Lewis CE, Wactawski-Wende J, & WHI Investigators (2011). Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA : the journal of the American Medical Association, 305 (13), 1305-14 PMID: 21467283
Jungheim ES, & Colditz GA (2011). Short-term use of unopposed estrogen: a balance of inferred risks and benefits. JAMA : the journal of the American Medical Association, 305 (13), 1354-5 PMID: 21467291
Jordan, V., & Ford, L. (2011). Paradoxical Clinical Effect of Estrogen on Breast Cancer Risk: A “New” Biology of Estrogen-Induced Apoptosis Cancer Prevention Research DOI: 10.1158/1940-6207.CAPR-11-0185