Analog SFF, September 2010 (7 page)

However, levels of some hormones fall not because of a clearly pathological process, but as a “normal” part of aging. These include dehydroepiandrosterone (DHEA), a hormone produced by the adrenal glands, and growth hormone. Although further studies might change this assessment, so far research has not definitively shown that replacement of these hormones to “youthful” levels produces a clinically significant improvement in health.

In women, levels of the female sex hormone estrogen fall dramatically at menopause. The higher level of estrogen present in premenopausal women compared to men is associated with a significantly lower risk of these women developing coronary artery disease (CAD). Roughly speaking, the risk of a woman developing CAD prior to menopause is about the same as a man ten years younger with similar risk factors (e.g. high blood pressure, an abnormal blood cholesterol level, diabetes, or tobacco use). The drop in estrogen level that occurs with menopause is associated with a significant increase in the risk of a woman developing CAD.

The “logical” conclusion was that, if a woman's estrogen level were restored to what it was before menopause, her risk of developing CAD would fall. The possibility that giving estrogen replacement might have effects that reduce the risk of developing CAD seemed to support this idea. These potentially beneficial effects include lowering low-density lipoprotein (LDL) cholesterol, increasing high-density lipoprotein (HDL) cholesterol, and reducing blood sugar. Some known effects of giving estrogen, such as raising the blood level of triglycerides (another component of cholesterol) and increasing the risk of developing blood clots, were recognized as being potentially harmful. However, these bad effects were not thought to be as significant as estrogen's good effects.

Some small studies done in the early and mid-1990s did in fact suggest that estrogen replacement was, overall, beneficial for preventing CAD in postmenopausal women. These studies contributed to the expanded use of estrogen for this indication and an unsuccessful attempt to have the FDA give official approval for it. In general, post-menopausal women were prescribed “hormone replacement therapy” (HRT) as a combination of estrogen and either another female sex hormone, progesterone, or a chemical with progesteronelike effects called a “progestin,” such as medroxyprogesterone. Giving estrogen by itself increases a woman's risk of developing cancer involving the lining of her uterus (endometrial cancer). Using estrogen with a progestin reduces this risk significantly. If a woman had a hysterectomy (removal of the uterus), she could receive estrogen alone.

However, large studies conducted in the late 1990s and in this century reached different conclusions about the effects of HRT on cardiovascular disease. They showed that using estrogen and a progestin together didn't reduce the risk of myocardial infarction or death from CAD in postmenopausal women either with or without known heart disease. HRT also didn't reduce how rapidly blockages in the arteries of the heart associated with CAD got worse.

In fact, some studies found HRT might increase risk to the heart, especially in the first year after this therapy was started. The
W
omen's
H
ealth
I
nitiative (WHI) study randomized 16,608 postmenopausal women between 50 and 79 years of age without known CAD to receive either an estrogen- medroxyprogesterone combination as HRT, or placebo. The women who received HRT had a 24% higher risk of having a myocardial infarction or dying from CAD than those receiving placebo.[14]

Another group of 10,739 women in WHI who'd previously had a hysterectomy were randomized to either estrogen therapy alone or placebo. In these women, treatment with estrogen showed no significant benefit or harm regarding CAD compared to placebo, but it was associated with an increased risk of stroke.[15]

Current guidelines recommend that HRT should not be used in postmenopausal women to prevent heart disease.[16] Here again, an idea that was once conventional wisdom and supported by preliminary research was not confirmed by further studies.

But the final word on this subject might not have been written yet. It's been suggested that giving HRT to younger postmenopausal women, such as those ages 50 to 59, or using a lower dose of estrogen in women age 60 or older may not be associated with increased cardiovascular risk and might still turn out to have a protective effect regarding CAD. HRT can also have good and bad effects on other parts of the body. Potential benefits include preventing osteoporosis (thinning of bones) and treating symptoms associated with menopause, such as “hot flashes.” Possible risks of HRT with an estrogen-progestin combination include increasing the chance of getting breast cancer. The overall decision whether or not to use HRT in individual postmenopausal women remains complex and hopefully will be clarified by further research.

Pills and Pregnancy

A dramatic example of how inadequate research can result in tragedy involves a woman's use of medications during preg- nancy. Both the mother and the developing baby (called an embryo from about the first four days through the eighth week after conception, and afterward a fetus until birth) share a single blood supply. During most of pregnancy, blood and nutrients are supplied to the baby through the placenta (specialized tissue attached to the inner wall of the uterus) and the umbilical cord. If the mother takes a medication, the baby can, to some degree, receive it too.

Thalidomide is a medication marketed from the late 1950s through 1961 as a treatment for morning sickness and a sleeping aid for pregnant women.[17] However, by 1961 it was belatedly recognized that use of thalidomide was associated with a high risk of serious birth defects in children born to women who'd taken it. These included severe shortening of the arms and legs—"phocomelia,” in which the hands or feet are connected to the trunk by only abnormally short or even absent long bones.

Over 10,000 children affected by thalidomide-induced malformations were born worldwide. An application to market thalidomide in the United States was submitted to the FDA in 1960. However, the physician who reviewed the application, Frances Kelsey, delayed approval pending further evaluation of the drug's safety and effectiveness. Because of her concerns, thalidomide didn't become available for general use in the United States before its “teratogenic” (birth defect-producing) effects were recognized.

As a result of these events, the FDA received increased authority and responsibility to ensure that drugs were both safe and effective. The thalidomide tragedy also showed that an idea commonly held before then, that medications given to the mother did not cross the placenta to her embryo or fetus, was wrong. It's now recognized that medications can adversely affect the developing baby in different ways throughout pregnancy.

For example, medications can cause death of the embryo soon after conception. The brain, internal organs, and limbs are most vulnerable to injury from about the first two weeks to two months following conception, when they are beginning to form and develop. Later in pregnancy, the major body parts of a fetus are better developed and mainly just growing larger. However, medicines taken at that time can cause harm by having too strong an effect on the fetus, due to its much smaller size compared to the mother, as well as interfering with normal growth and function of its organs.

The FDA has five categories for medications regarding risk to the embryo or fetus. Some medications fall into more than one category, with increased risk early in pregnancy but not later, or vice versa.

Category A medications have the lowest level of risk. Scientific studies in human mothers have not shown that these medicines cause harm when taken during pregnancy. They include ferrous sulfate (iron) tablets for treating anemia and standard doses of vitamins B and C.

Category B medications have either not been shown to harm the embryo or fetus in animal studies, or if they have been shown to cause harm in animals, studies have not shown them to be harmful in humans. Category C medicines are those known to cause harm in animal studies, but there are no studies to assess their safety in humans.

Category D medicines are known to sometimes cause harm in humans, but they may be used in certain circumstances when the overall benefit to the mother—and, perhaps, indirectly the baby—outweighs that risk. Category X medications are known to cause harm to a developing human embryo or fetus, and their risks outweigh any potential benefit to the mother.

Because of these risks, clinical trials involving investigational medications routinely exclude pregnant women from study. Only women who are incapable of pregnancy (e.g. postmenopausal or surgically sterilized) or, in some cases, potentially fertile but using effective birth control are typically included in these trials.

As a postscript to the serious harm it caused, further research found that thalidomide is actually helpful for some diseases. In 1998 the FDA approved it for treatment of erythema nodosum leprosum, a painful skin problem associated with leprosy, and in 2006 for treating multiple myeloma, a cancer involving a type of blood cell called a plasma cell. Of course, thalidomide remains in Category X, and its use is tightly regulated.

Nothing Ever Comes Easy

Clinical medical research has other limitations. It's not unusual for two or more large research studies investigating the same new medication or device to produce contradictory results. For example, one study may show a study medication is significantly better than placebo while another study doesn't find that to be so. Clinical trials typically exclude patients at the extremes of age (e.g. children), unless the trial is aimed specifically at those age ranges. Patients who have significant kidney or liver disease, cancer, or other serious medical problems in addition to the disease an investigational medication is designed to treat may also be excluded from trials due to these patients potentially having increased risk and decreased benefit from using that medicine. Individuals who participate in trials are also self-selected, in that they must agree to participate and give informed consent for treatment and follow-up.

Funding for clinical trials comes from many sources. These sponsors include government agencies such as the National Institutes of Health and Department of Veterans Affairs, as well as private medical institutions and foundations. Many trials are also sponsored by companies that make pharmaceuticals and medical devices. When a promising new class of medication or type of medical device is identified, these different companies often vie with each other to produce better versions. Sometimes this results in development of new medications and treatments that truly are improvements on older ones. However, it can also result in “me too” medicines being approved for use—new drugs that are medically not definitely better than the previous “gold standard” or each other, but which can cost significantly more than older, less expensive alternatives.

Economic, legal, and other nonmedical issues may also influence medical research. Pharmaceutical companies play an important role in developing new medicines and devices to improve medical care. However, questions have been raised about whether the results of unfavorable research concerning new or approved medications have been suppressed or at least argued against by them in ways that don't seem to make patient safety and well-being the most important considerations.[18] Also, these companies may not consider finding new treatments for rare diseases as being intrinsically profitable, thus delaying or curtailing research in those areas. Financial incentives for developing these so-called “orphan drugs” may include subsidies from governments, foundations, and other sources, as well as tax credits and special patent and marketing rights.

On the other hand, these companies can also suffer major financial losses due to product liability issues whose scientific validity is questionable at best. While these controversies are too complex to detail here, perceived adverse effects from vaccines and silicone-gel-filled breast implants have resulted in lawsuits against the manufacturers. For example, Dow Corning, a major manufacturer of silicone breast implants, filed for bankruptcy in 1995 due to lawsuits claiming that its products were responsible for an increased risk of adverse events, including breast cancer and other diseases. Subsequent studies found no significant association between silicone breast implants and those medical problems.[19]

Future Directions

The landscape of basic and clinical medical research is constantly shifting. Medications and other products that are currently approved undergo continued reappraisal regarding their uses and safety. Many medicines have significant “off-label” uses—indications that are not officially approved by the FDA, but are considered appropriate based on other research and clinical practice. Many new ways to diagnose and treat diseases continue to be evaluated. While some may turn out to be dead ends or need much more work before they're routinely available, others appear particularly promising for improving medical care in the near future.

For example, medical care individualized to a particular person's genotype—"genomic” or “personalized” medicine—has the potential to significantly increase the ratio between benefit and risk of using available medications. There is variability among individuals regarding the presence of certain genes that predispose or protect against certain diseases, or that influence how the body metabolizes and responds to medications for good or ill. Genetic profiling can help identify which medicines would be most beneficial and least likely to harm a particular individual. This would potentially be a significant improvement to the heuristic and probabilistic methods physicians employ based on known average risks and benefits for patients in general.

But every silver lining has a cloud. There's the potential risk that employers, insurance companies, or governments could use that genetic information against people who have a genetic predisposition to diseases and who therefore may be more “costly” regarding their medical care. For the individual, knowing he or she is susceptible to certain health problems can be beneficial if this information leads to improved prevention or treatment. It might also be more information than a person wants to know if the disease or other problem in question is one that's currently impossible to prevent or cure.