Hormone Replacement Therapy:  Another Nail in the Coffin

Regular readers of this column are already well educated on recent developments regarding hormone replacement therapy (HRT) for postmenopausal women.  The elaborate house of cards built around HRT since the end of World War II, by pharmaceutical companies and. Sadly, by many physicians, has been on very shaky ground since last summer’s Women’s Health Initiative update.  The landmark WHI, a large-scale prospective study, found that women using combined estrogenic and progestational HRT experienced an increased risk of several cancers, including breast cancer, in addition to heightened risks of stroke and cardiovascular disease.  The cardiovascular disease risks of combined HRT were particularly notable, as HRT has, for decades, been widely touted as cardiovascular protective therapy, in addition to its ability to eliminate the signs and symptoms of menopause.  The deleterious effects of combined HRT were so significant and worrisome in the WHI, this arm of the study was prematurely shut down in July of 2002.  Since HRT using estrogen alone increases the risk of uterine cancer, a progestational agent is added to the estrogenic component of HRT for women who have not undergone a hysterectomy.  Women without a uterus are generally prescribed conjugated estrogens alone.  )The arm of the WHI study that looks at estrogen HRT alone is still open, and a report on the results of this study have not yet been released.)

Another fundamental component of the folklore surrounding HRT has been that it improves the cognitive function of postmenopausal women, and reduces the risk of developing Alzheimer’s Disease and other dementias.  As with the other putative benefits of HRT, the dementia-reducing benefit of HRT was based mostly upon empiric observations and anecdotal reports of a reduced risk of dementia among women taking long term HRT.  New reports published under expedited circumstances in the current issue of the Journal of the American Medical Association (JAMA) have now called into question the ability of HRT to prevent dementia, and to protect cognitive function, in postmenopausal women.

The first study, from the WHI, looked at 4,532 postmenopausal women who were free of dementia when they volunteered for the study.  A total of 2,229 women received conjugated estrogens (Premarin) and medroxyprogesterone, while 2,303 women received placebos (sugar pills) only.  These women were followed for an average of 4 years.  At the time when the study was prematurely closed, 61 of the women had developed dementia.  Quite unexpectedly, 40 of the 61 women who developed dementia, or 66% of patients developing dementia, were in the combination HRT group.  The remaining 21 women with dementia (34%) were in the placebo group.  Following statistical analysis, the study determined that HRT usage, for an average of only 4 years, increased the risk of dementia two-fold.

The second study reported in JAMA, also from the WHI, looked at the issue of overall cognitive function between the same two groups of women who were evaluated in the previously mentioned study of combined HRT.  The study’s authors point out that the evidence supporting the theory that HRT improves cognitive function in postmenopausal women has been both sparse and contradictory. A total of 4,381 women completed at least one cognitive function evaluation during the average 4-year course of the study.  Using a previously validated test of overall cognitive function (the Modified Mini-Mental State Examination), the study found that the women in the combination HRT group had a substantial and clinically important progressive decline in overall cognitive function when compared with the placebo group.  Unlike the previous study, this second study did not look at the incidence of dementia.  Rather, it looked at more subtle indicators of overall cognitive function, including short-term and long-term memory.  Once again, however, women taking combination HRT fared worse in terms of significant cognitive decline than did the women who took the sugar pills.

Finally, the third study presented in JAMA, also from the WHI, updated the data on stroke incidence in women taking combination HRT.  As I have already mentioned, one of the adverse outcomes associated with combination HRT that resulted in the premature closure of this part of the WHI was an increase in the risk of stroke.  This part of the WHI involved whopping 16,608 postmenopausal women who were followed, until the closure of the combination HRT arm of the WHI study, for an average of 5.6 years.  A total of 151 WHI patients (1.8%) taking combination HRT developed strokes during the course of the study, while 107 (1.3%) of the women taking placebos experienced strokes.  When the study’s authors combined the two primary types of strokes (hemorrhagic and ischemic) in their analysis, there was a 31% increased risk of stroke in the group of women receiving combination HRT.    (When the authors excluded women who had not been compliant in taking either the HRT drugs or placebo pills assigned to them, the overall increased risk of stroke rose 50%.)  Ischemic stroke, caused by blockage of the brain’s arteries by atherosclerotic plaques and blood clots, was 44% more common among the women in the combination HRT group.  This is not surprising, as the two medications used for combination HRT are known to increase the propensity to form blood clots.  Also not surprising was the finding that the risk of hemorrhagic strokes, which are generally associated with high blood pressure, was not increased by combination HRT (indeed, the women taking HRT experienced a 12% lower risk of hemorrhagic stroke when compared to the placebo group of women).

These studies represent yet a further, and stunning, reversal in the decades-old mythology surrounding HRT; a mythology almost entirely contrived by the pharmaceutical industry and gullible physicians.  Until recently the most widely prescribed class of prescription drugs in America, the sales of Premarin and related HRT medications have plummeted since last summer’s WHI dramatic update.  (Unfortunately, the pharmaceutical industry continues to aggressively push other expensive prescription medications directly to the public and, often, using dubious clinical indications.)

I predict that the continuing maelstrom of bad news regarding the health effects of HRT will render combination HRT to the dustbin of medications that have, belatedly, been proven to cause more harm than good.  Stay tuned for a more detailed treatment of this subject when I am finished with a book underway on this subject.

Hospital Volume & Colostomy Rates for Rectal Cancer Surgery

There is growing scientific evidence that risks associated with certain complex surgeries are higher when they are performed by surgeons—and at hospitals—with a low volume of such cases.  The surgical treatment of cardiovascular disease, pancreatic cancer, liver cancer, stomach cancer, and esophageal cancer appears to result in fewer complications, including death, when performed by surgeons who treat relatively large numbers of such patients, and at hospitals accustomed to caring for patients undergoing operations for these diseases.  A new study in the Journal of the National Cancer Institute looked at the likelihood of patients leaving the hospital with a colostomy following surgery for rectal cancer.  Specifically, the study assessed the impact of rectal cancer surgery volume on colostomy rates.

Over the past 10 years, innovative surgical techniques have been devised that allow for the preservation of patients’ rectums and anuses when the cancerous tumors lie at least 2 inches above the external anal opening.  While a colostomy can still be technically avoided in patients with rectal tumors lower than 2 inches, most of these patients will experience profound difficulties with diarrhea and incontinence, and breakdown of the skin around the anus.  However, the treatment of low-lying rectal cancers, even those higher than 2 inches, requires highly specialized training and expertise in order to minimize serious complications.

In this new study, 7,257 California patients with a history of prior rectal cancer surgery were identified from a statewide cancer registry.  The relationship between hospital rectal cancer surgery volume and colostomy rates was then assessed using statistical analysis.  The role of surgical volume was also evaluated with respect to postoperative complications following rectal cancer surgery, including death. The study divided hospitals into 4 groups, based upon their rectal cancer surgery volumes.  The study determined that the lowest volume hospitals, when compared to the highest volume institutions, were associated with a greater than 7% increase in the likelihood of a patient receiving a colostomy.  Following statistical analysis of these findings, a 37% increase in the risk of receiving a colostomy was associated with surgery at low volume hospitals.  Death within 30 days of surgery occurred among 1.6% of rectal cancer patients at the highest volume hospitals, but in 4.8% of patients who received their surgeries at the lowest volume hospitals.  This translated into a nearly three-fold (odds ratio of 2.64) increased risk of death among patients treated in the lowest volume hospitals.   When the study’s authors looked at the 2-year mortality rates, which are a function of, primarily, recurrence of patients’ rectal cancers, the highest volume hospitals had a 7% lower death rate than the low volume facilities.  This represented a 28% relative increase in mortality at 2 years among patients treated at the lowest volume hospitals.  These results were consistent after controlling for stage of disease and coexisting health problems.  Thus, as with other complex surgical procedures, the treatment of rectal cancer at higher volume hospitals appears to be associated with a significantly reduced likelihood of receiving a colostomy, and a reduction in both early and delayed mortality. 

Before I leave this topic, I should point out that high volume alone is not a guarantor of good outcomes.  There are bad “high-volume” surgeons, just as there are “moderate-volume” surgeons who are highly skilled at performing many complex operations.  Although it used to annoy me when new patients grilled me on my training and my surgical experience, the growing body of research that associates higher levels of surgeon training, and higher volumes of complex surgical caseloads, has convinced me that such questions are both relevant and prudent.

Vindication for Dr. Atkins…?

The orthodox nutrition and diet scientific community was horrified when the late Dr. Robert Atkins proposed that a low-carbohydrate fat-rich diet could effectively help obese patients lose weight, and keep the excessive weight off.  When Dr. Atkins parlayed his counter-intuitive philosophy into highly lucrative writing and nutritional supplements careers, the resulting furor in the scientific community reached fever pitch.  Now, only weeks after Dr. Atkins accidental death (due to a head injury sustained when he slipped on an icy walkway), a new study in the New England Journal of Medicine looks at the Atkins Diet and comes to some surprising conclusions.

In a relatively small study, a total of 132 severely obese patients (average BMI of 43) were evaluated.  A total of 39% of these study participants had diabetes, and 43% had a pre-diabetic condition referred to as the “metabolic syndrome.”  The study volunteers were randomly assigned either to a low-carbohydrate diet or to the more traditional low-calorie low-fat diet.  Only 79 participants completed the 6-month study, however.  Among these 79 patients, the patients randomized to the low-carbohydrate diet lost more weight than those on the traditional diet (12.8 pounds, on average, versus 4.2 pounds, respectively).  Even more surprising was the finding that the blood levels of triglyceride fats were actually lower in the low-carbohydrate group than in the traditional diet group.  When sensitivity to insulin was tested (a measure of the body’s risk for developing diabetes) in the non-diabetic patients, the Atkins Diet group experienced a greater degree of improved sensitivity to insulin over that achieved by the traditional diet group (6% vs. 3%, respectively).  While the authors caution that the weight loss and insulin sensitivity differences between the two diet groups are relatively small among these morbidly obese people, and while the number of patients studied is too small to make sweeping recommendations, this study nonetheless suggests that, at a minimum, a low-carbohydrate diet is no more harmful than the more traditional low-calorie low-fat diet (at least in the short term).  A larger study, with a longer period of follow-up, needs to be performed before the findings of this small pilot study can be validated.  Moreover, the long-term impact of a high-fat low-carbohydrate diet on LDL and c-reactive protein levels, cardiovascular health, blood pressure, stroke and death must be fully studied before physicians and nutritionists can objectively recommend this approach to weight loss.

Dr. Robert A. Wascher