Is hormone replacement therapy safe?

Enter the randomized clinical trial, which is less susceptible to this so-called “healthy-user” bias than observational studies. In a clinical trial, whose purpose is often to test a particular medical treatment, researchers actively intervene in participants’ lives by assigning them to the therapy under investigation or to a control group. The most rigorous type of trial — the “gold standard” by which all other studies are usually judged — is the randomized, placebo-controlled, double-blinded clinical trial. In these carefully controlled studies, half of a group of volunteers is assigned at random — via a figurative flip of the coin — to an active treatment (a drug, for example), and the other half is assigned to something that looks like the drug but is in fact an inactive placebo (often called a dummy or sugar pill). Neither the doctors conducting the trial nor the participants knows who is getting the medication and who is getting the placebo — hence the term “double-blinded.” The double-blinding ensures that the doctors do not treat the participants differently, and that the patients themselves do not behave differently, based on knowledge of their treatment status.

After a predetermined amount of time, the number of people in the treatment group who have developed the outcome (“endpoint”) being studied — for example, death, heart attack, hip fracture, or, as we saw in the last chapter, hot flashes and other symptoms — is compared with the number in the placebo group who have developed the same outcome. If the trial is large enough, the randomization process ensures that the people in the treatment group are virtually identical to those in the placebo group in terms of age, lifestyle, general health, menopausal status, and other possibly important factors. Because the only characteristic that differs between the two groups is the treatment under investigation, it is extremely likely that any difference in health outcomes found in the two groups is attributable to that treatment. This is the main advantage of a randomized clinical trial over an observational study.

Understanding the basic distinction between observational studies and clinical trials will take you a long way in interpreting epidemiologic data. But many other issues must be considered when evaluating scientific research. Indeed, a well designed observational study can be better than a poorly designed clinical trial for arriving at a sound scientific conclusion. Although this list is not exhaustive, the elements of a good study, whether an observational study or clinical trial, include the following factors.

• A representative study population: A study of a particular therapy may be of
  limited value if the study participants are not typical of the general public who use
  that therapy. As an extreme example, the first clinical trial of supplemental estrogen
  to reduce heart disease was actually conducted in men, not women. Because
  sex hormones differ dramatically between men and women, it’s unlikely that the
  results of such a study in one gender will apply to the other. (The trial showed
  clearly that estrogen didn’t help men, but the story is more complex in women.)
• Use of actual disease outcomes: Because it often takes many years for chronic
  diseases to develop, many studies look at intermediate changes, such as changes in
  blood levels of cholesterol, changes in bone density, or proliferation of the uterine
  lining, as proxies for the actual disease of interest, such as a heart attack, osteoporotic
  bone fractures, or endometrial cancer. However, these changes do not
  inevitably reflect or lead to changes in the actual disease outcome. Research looking
  at concrete disease outcomes such as heart attacks is more convincing and
  reliable.
• Large number of participants (size matters!): The larger the study, the smaller
  the possibility that its findings — whether positive, negative, or neutral — might have
  resulted by chance alone. The play of chance is such an important issue that scientists
  routinely employ sophisticated numerical methods to assess whether a study
  finding is “statistically significant” — that is, unlikely to have occurred simply by
  chance.
• Consistency of the evidence: Consistency is actually not a characteristic of one
  particular study, but rather of the whole body of research on any given topic. Perhaps
  the most convincing evidence that an effect may be real is consistent results
  from a number of researchers at different times, using different study designs, and
  involving different groups of people. An example would be the connection between
  cigarette smoking and lung cancer that’s been seen in so many different studies.
  But keep in mind that scientific research progresses in fits and starts, and there is
  rarely a straight-line path to the right answer or a complete absence of conflicting
  findings. Indeed, the progress of medical knowledge has been compared to the
  stock market — sometimes it goes up, sometimes down, but in the long run, the
  trend is (hopefully) in the right direction.
  

In the case of hormone therapy, a roller-coaster analogy, at first glance, might seem more appropriate because the ride ends up right back where it started. In a narrow sense, as we will see, this is true: the original reason for taking menopausal hormones — for relief of menopausal symptoms — is, for most women, still the only compelling reason for taking them today. In a larger sense, however, the rollercoaster analogy falls short, because researchers have made great strides, especially in the last decade, in understanding the impact of hormone therapy on many aspects of women’s health beyond the relief of symptoms. Incidentally, keeping these research principles in mind will help you be an educated consumer of the health news reported by the media, which tends to magnify the importance and implications of new studies, especially those that contradict common conceptions, while sometimes glossing over their limitations or failing to provide a context for the research.

Excerpted from “Hot Flashes, Hormones, and Your Health” by Dr. JoAnn Manson. Copyright 2007 by Dr. JoAnn Manson. Permission granted by The McGraw-Hill Companies.

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