There is no current consensus on the role of sex steroid usage for women through and beyond the menopause. There is virtually no information on the impact of HIV/AIDS on the menopause or vice versa, and nothing regarding the benefits or risks of postmenopausal hormone therapy. The purpose of this brief review is to cover the current issues as they apply to all women.
Barely was the long-awaited follow-up of the HERS study on the secondary prevention of cardiovascular disease published1,2, than the NIH terminated the estrogen plus progestin arm (E+P Trial) in women with an intact uterus in the WHI3. Since then, there has been much water under the bridge, and the following is an attempt to provide some perspective.
To summarize the data, out of HERS II the conclusion on coronary heart events was that ‘postmenopausal HRT should not be used to reduce risk for coronary heart disease events in women with coronary heart disease’1. In a second paper, HERS II concluded that hormone replacement therapy (HRT) in ‘older women with coronary disease increased the rates of venous thromboembolism and biliary tract surgery. Trends and other disease outcomes were not favorable and should be assessed in larger trials and in broader populations’2.
In short, older women with established coronary heart disease were at an increased risk of further complications if treated with combined-continuous HRT. There was no statistical power to determine the impact of secondary factors such as the rate of osteoporotic fractures.
Correctly, authors and reviewers suggested that the effect of HRT in a preventative mode on a younger non-clinical diseased population should await further studies, such as the WHI. The wait was not long. The NHLBI of the NIH announced the ‘earth moving’ news on 9 July 2002 that it had stopped early a major clinical trial of the risks and benefits of combined-continuous conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) in healthy postmenopausal women because of an increased risk of invasive breast cancer. The large multicenter trial, a component of the WHI, also found ‘increases in coronary heart disease, stroke, and pulmonary embolism in study participants on estrogen plus progestin compared to women taking placebo pills. There were noteworthy benefits of estrogen plus progestin, including fewer cases of hip fractures and colon cancer, but on balance the harm was greater than the benefit’4.
Although the merits and demerits of the data and the wisdom of the decision to terminate this arm of the WHI study will be debated for years, the manner in which the study was terminated was poorly planned, abrupt and a cause of unnecessary confusion. Predictably, the media response was enormous, ranging from thoughtful to sensational. Panic was caused, numerous women discontinued therapy, and women and their health providers alike were thrown into a state of uncertainty, distrust and quandary about what to do next.
The NHLBI conclusion that harm was greater than benefit was clearly magnified by its concentration on percentiles of relative risk, rather than the pertinent issue to women of absolute risk. Indeed, a review of the JAMA article demonstrates absolute risk to be low, invariably a fraction of 1%3. Thus, the 26% relative increase in invasive breast cancer translates into 38 cases among hormone therapy users versus 30 cases among placebo users per 10 000 WY. The 29% increase in coronary heart disease to 37 cases on hormone therapy versus 30 cases on placebo out of 10 000; stroke increased 41% with 29 versus 21 out of 10 000, and venous thromboembolism doubled at 34 versus 16 out of 10 000. On the benefit side, the 33% reduction in hip fracture was 10 on hormone therapy versus 15 on placebo out of 10 000, and the 37% reduction in colorectal cancer was 10 versus 16 out of 10 000. There was no difference in total mortality.
This arm of the WHI provides a wealth of information and opens many new questions. The challenge is to translate the meaning of all this to the individual woman sitting on the opposite side of the desk, confused and wanting a balanced recommendation.
Initial Conclusions from the Heart and Estrogen/Progestin Replacement Study and the Women's Health Initiative
Continuous-combined CEE+MPA is of no value in reversing established coronary heart disease or preventing it in apparently healthy women. Continuous-combined CEE+MPA increases the risk of myocardial infarction, deep venous thrombosis and thromboembolism, particularly in the first 12–18 months of therapy. The slight increase in invasive breast cancer may occur earlier than anticipated from observational studies (i.e. within 5 years), but data subsequently presented verbally suggest that the increase occurs only in women already on hormone therapy at the time of entry into the study, i.e. users for more than 5 years. Does this suggest that hormone therapy provides a growth-promoting rather than a causative role in breast cancer? With the premature termination of the study, this question may never be answered.
All of the above problems are more likely to be related to the attenuating effect of continuous MPA on CEE, as the groups using CEE alone in the WHI so far have not demonstrated these problems. Whether there is any role at all for the long-term regimen of any combined-continuous HRT in current standard doses is highly doubtful. At present, when long-term therapy is being utilized, a continuous-cyclic regimen (i.e. adding progestogen cyclically every one or 2 months) may be more favorable, but this needs to be proved. This regimen would reduce exposure to progestogen.
Continuous-combined CEE+MPA has shown early benefit in the reduction of hip fracture and colorectal cancer.
Estrogen alone may well still be proved to have a favorable benefit-to-risk ratio as the CEE-only arm still continues in the WHI.
Current Clinical Practice
The optimal approach necessitates ‘back to basics’.
Menopause is a normal physiological phase in the female life cycle. The hormonal changes through the menopause transition may result in symptoms, specifically vasomotor and vulvovaginal, and increase the risk over time of certain pathological processes such as osteoporosis. Coincidentally, age, environmental and genetic-related problems also begin to escalate beyond the usual age of menopause. The menopause transition is therefore the ideal time for a health screen for risk factors for both hormone-related and coincidental diseases, as well as for early evidence of the actual presence of pathology.
Therapy is broad based, with ‘good living practices’ (healthy diet, exercise, smoking cessation, seat belts, safer sex, moderation in alcohol, drug avoidance, etc.) being the anchor. Under this scenario, some women may benefit from pharmacotherapy, with the latter being prescribed for either prevention or treatment indications. In the broad range of pharmacotherapy available, hormones are only one option, and must be considered if there is a specific indication and the decision to use is based on an adequate risk-to-benefit assessment. It cannot be overemphasized that WHI is a prevention project, and that hormones can be prescribed for preventative or clinical indications, or both. Both the consumer and the provider must clearly understand why hormones are being considered and prescribed. The importance of the individualization of care for each patient has long been emphasized. Never has it been more important than now. Before prescribing hormone therapy, there must be a clear and strong indication for therapy, and the risks versus benefits carefully considered. Short-term therapy for symptoms still necessitates careful monitoring. Longer term therapy, now probably defined as beyond 2 years, mandates even more rigorous monitoring and an annual risk-to-benefit evaluation.
What does this mean in practical terms? The NAMS Hormone Therapy Advisory Panel Report provides some guidance in this respect5. However, the dilemma for the health provider is highlighted by the areas in which the NAMS panel could not reach consensus. Women are demanding specific answers to questions for which we can only provide superficial answers. Largely, truth is opinion, but for what mine is worth, the following is my personal take from the literature to the NAMS panel unanswered questions:
How Long Should Hormone Therapy be Continued for Symptom Relief?
The problem, irrespective of how long therapy is prescribed, is that symptoms often recur. What then, return to hormones, alternatives with less efficacy, or tough it out? I generally recommend 2–3 years and then an attempt at cessation.
What About Dose?
Current suggestions are to use the lowest dose possible.
Do Reasons Exist for Extended Hormone Therapy?
Possibly. I certainly have patients with a risk–benefit profile such that therapy can be justified, or so impacted by ‘quality of life’ benefits that they will not discontinue. Under these circumstances, it remains our responsibility to explain the risk data as it currently stands. I repeat the conversation at every visit.
Does Premature Menopause/Ovarian Failure Justify Long-term Hormone Therapy?
In my opinion it does, at least until the expected median age of menopause at approximately 50 years.
Is There a Best Way to Discontinue Therapy?
Certainly not that anyone has published to this time. Tailing would seem to make sense, but how? We all have our own clinical approach, but it is unlikely there will ever be a ‘one size fits all’.
Do the Conjugated Equine Estrogen and Medroxyprogesterone Acetate Data Implicate Other Estrogen/Progestogen Combinations, Dosages, or Routes of Administration?
We can theorize, but without adequate trials there is no answer. The million dollar question is whether the FDA changes guidance for product development and the pharmaceutical industry steps to the plate to meet the challenge.
Are Alternative Bone-sparing Products Safe and Effective for Extended Use in Younger Women?
The data are positive for 4–7 years, but what about 10–15 years? Up to 5 years of standard hormones for osteoporosis prevention makes sense, most especially in the symptomatic woman. After that a conversion would seem to be most appropriate course of action.
At this time estrogenic and progestogenic hormones remain a valuable component within our therapeutic armamentarium with short-term (less than 5 years’) use for specific indications presenting a favorable benefit-to-risk profile. In usual aged perimenopausal women (45–55 years) the prevalence of thromboembolism and coronary heart disease is low, an increased risk of breast cancer with less than 5 years’ therapy appears to be very low and non-significant, and the symptomatic benefits are considerable. This is even more so for women experiencing ovarian failure at an earlier age. Beyond the age of 55 years, and for specific problems such as increased cardiovascular or osteoporosis risk, all other options need to be considered, again taking the individual risk-to-benefit into account.
Finally, the lack of data regarding the impact of HIV/AIDS on all of the above issues is apparent and in need of urgent address. A call is therefore made immediately to set in place mechanisms for following current cohorts in a scientific manner so that data can be rapidly accumulated and applied to this population.
1. Grady D, Herrington D, Bittner V, et al
, for the HERS Research Group. Heart and estrogen/progestin replacement study follow-up (HERS II): Part 1. Cardiovascular outcomes during 6. 8 years of hormone therapy. JAMA 2002; 288:49–57.
2. Hulley S, Furberg C, Barrett-Connor E, et al
, for the HERS Research Group. Heart and estrogen/progestin replacement study follow up (HERS II): Part 2. Non-cardiovascular outcomes during 6. 8 years of hormone replacement therapy. JAMA 2002; 288:58–66.
3. Writing Group for WHI. Risks and benefits of estrogen plus progestin in healthy menopausal women. Principal results from the Women's Health Initiative Randomized Controlled Trial. JAMA
. 2002; 288:321–333.
4. NIH News Release. NHLBI stops trial of estrogen plus progestin due to increased breast cancer risk, lack of overall benefit. NHLBI Communications Office; Tuesday, 9 July 2002.
5. NAMS Report. Amended report from the NAMS Advisory Panel on Postmenopausal Hormone Therapy. Menopause
. 2003; 10:6–12.