Medicine and Synergism
Special Feature
Medicine and Synergism
By Sarah L. Berga, MD
Developing an appropriate management plan first requires that an accurate diagnosis be made. Then contributing factors must be identified and their effect size estimated. The practice of medicine is intimately linked to this exercise. Whether or not we are explicitly aware of it, every diagnosis and treatment plan involves an analytic component of this type. Therefore, one might suspect that we, as keepers of the applied side of the scientific method, are experts in analysis. But are we? Being more subject to the forces of our social milieu than we care to admit, I think we often fall into what I call the either/or trap. The either/or trap is herein defined as the relentless societal urge to attribute the cause of anything to one thing. Either/or thinking is seductive, common practice, supported by conventional wisdom, and often grossly misleading because it involves an unwarranted degree of reductionism. More often than not, the cause of anything, especially medical conditions, is multifactorial. Worse yet, the multiple factors are rarely additive. X% is not due to one factor and Y% to another in a simple additive fashion. Factors X and Y may interact to either diminish or amplify the effect of each other. The more contributing factors there are, the greater is the potential for complex interactions. As a general rule, we tend to ignore these interactions, but we do so at some risk. In this article, I outline some disorders commonly treated by gynecologists in which understanding the interactions is integral to developing and implementing an effective treatment plan.
The first condition that I would like to consider is polycystic ovary syndrome (PCOS). Here the "great debate" for the last few decades has centered on whether PCOS is due mostly to insulin resistance or mostly to an enzyme defect causing excess androgen secretion by the ovaries and/or adrenal glands. Some researchers have suggested that there may be an interaction between these proposed causal factors, but few have been able to demonstrate this interaction in an investigative or clinical setting. When treatment decisions are made, doctors frequently choose to prioritize either the insulin side of the story or to treat the hyperandrogenism as primary. Combined therapy targeting both factors has rarely been investigated. Further, treatment protocols often have not examined in any serious way the effect of one intervention on the other factor(s). Scientifically, we have generally been locked in an either/or model and patients have been held hostage to our myopia. When developing a treatment plan for a woman with presumed PCOS, it is important to gauge as best one can to what degree which of the potential causal factors seems to be operative in that patient. Then, these factors can be prioritized in the treatment plan. For instance, it seems reasonable to treat a PCOS patient with documented insulin resistance with metformin. It seems unreasonable to treat a patient with a fasting blood glucose of 65 and an insulin of 5 with metformin simply on the hypothetical basis that insulin resistance has been identified as one of the causal factors in the pathogenesis of this disorder. We need to keep in mind that there may be more than one pathway to PCOS and that insulin resistance may not predominate in all women with this condition. In some patients, however, combined therapies may be optimal. But as noted above, this type of approach has yet to be well studied. If combination therapy is undertaken in recognition of the underlying multifactorial etiology, then a safe rule-of-thumb is to initiate pharmacologic options in a stepwise fashion. Lifestyle alterations can be recommended as accompaniments to pharmacologic interventions at any point.
Let’s consider as our second condition cardiovascular disease (CVD). Here we know that multiple factors, including genetic predisposition, play a role. However, as gynecologists, we have often been placed in the position of advocating estrogen therapy for the prevention of this disorder. Although we know that estrogen is far from a panacea, it is less common for us to undertake screening, initiate statin therapy, or undertake dietary and lifestyle counseling. Even though we know that CVD is due to the interaction of multiple variables, we have owned only the estrogen part of the story. The unintended result? Patients often think that estrogen use will "make up" for all the other deleterious habits!
What about osteoporosis? Same trap. Estrogen is offered as the gynecologist’s panacea, absolving patients of the responsibility to exercise and monitor their diet. However, the few studies that have examined the effect of combined therapies have found that the simultaneous use of estrogen, vitamin D, and calcium is synergistic in terms of preserving or augmenting bone density. In other words, the benefit to bone is greater than the sum of the interventions. We should be explicit with our patients. Postmenopausal estrogen use does not obviate the need to exercise and eat well.
Sexual dysfunction is another complaint that is frequently multifactorial. It stands to reason that correcting hypoestrogenism will help with dysparenia. It will not necessarily repair a marriage on the rocks. I have seen countless women and even a few husbands who had the impression that estrogen therapy would "fix the problem," even when the problem was not obviously linked in time to any change in hormone levels. I wish it were this easy!
You might be wondering what prompted this essay. Let me confess. Years ago I was writing a grant on functional hypothalamic amenorrhea (FHA). I was a young unfunded assistant professor. I got lots of good advice on study design. One admonition was to keep the study group "clean." That meant excluding women who had more than one easily identified lifestyle variable as the cause of the FHA. I tried. It turned out to be impossible. Almost no one with FHA had a single cause such as just weight loss, only excessive exercise, or pure psychogenic stress. From that frustration came the study that helped to put the dilemma in perspective. We asked what would happen to menstrual cycles when we "added" metabolic and psychogenic stressors. So Dr. Judy Cameron did a study to look at what happens to menstrual function in female monkeys subjected only to a mild metabolic stress, only to a mild psychogenic stress, and to a combination of both stresses. Mild metabolic stress alone did not perturb menstrual function. Mild psychogenic stress was well tolerated by most monkeys and only a few had transient amenorrhea. However, the combination of psychogenic and metabolic stress induced amenorrhea in the majority! This is a classic demonstration of synergism in which each factor alone is relatively impotent. But which situation is most like our patient population? Combined stress. What are the clinical implications of this study? The results indicate that to correct FHA one must simultaneously address all contributing causes. Our initial results aimed at doing this have been extremely encouraging. Almost all patients with FHA exercise a lot, eat poorly, and have a set of unrealistic attitudes about self and other. Which of these variables needs to be addressed in treatment? All. So we have done just this, with stunning results. Almost all women with FHA willing to enter treatment were able to make minor adjustments in diet, exercise, and perspective. Doing so restored menstrual cyclicity. Our current conclusion is that addressing multiple contributors simultaneously has meant that no one factor needs to be corrected "completely." In this model, at least, it is seemingly easier and more efficacious to partially correct multiple factors than to completely correct one factor. I can only wonder if the same is true for the other conditions considered here.
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