Sex-related differences in clinical drug response: implications for women's health.

Abstract

Increasing evidence suggests that women have different patterns of drug metabolism and responsiveness throughout their life cycle and that these differences may be clinically significant. It is argued that sex related pharmacologic variations deserve clinical and basic research attention. Recent evidence is presented that gonadal sex steroids affect drug response metabolism and toxicity or adverse side effects. Since drug interactions are routinely monitored including those for estrogens and oral contraceptives (OCs) this database was examined for evidence that might be pertinent to the endogenous gonadal sex steroids and hence to the question of possible sex related differences in drug response. A pharmacological model was developed as defined in terms of exogenous estrogens and OC pills of sex related differences in pharmacological responsibility. Based on a selective literature review that is summarized in a table it was found that estrogens and OCs affect the therapeutic response of a wide variety of commonly used drugs including antiepileptics and antianxiety agents antidiabetics antidepressants anti-Parkinsons agents and thyroid medication. Although the magnitude and prevalence of these pharmacological effects are unclear it appears that the clinical implications deserve further study. Evidence was found for sex related differences as well as menstrual and menopausal variations in a variety of neurochemical systems. 1 example concerns evidence of a premenstrual impairment in oral glucose tolerance that is paralleled by a decrease in insulin receptors hence the question of possible menstrual or menopausal related exacerbations in certain diabetics appears to warrant further investigation. It appears that not only daily but also monthly cycles in drug metabolism may occur and that these alterations may be reflected in menstrual cycle related alterations in blood and tissue levels of drugs. 1 index of drug metabolism capacity antipyrine is decreased with OCs suggesting possible sex related effects. The question arises as to what are mechanisms that give rise to sex related differences in drug response or toxicity. Although gonadal sex steroids affect drug metabolism other possibilities must also be explored ranging from genetic sex to developmental differences in brain differentiation and laterilization. The kind of careful work needed in order to elucidate sex related differences in pharmacologic response includes study of whether the sex related variation is age dependent abolished by the administration of estrogen to the male dependent on sexual differentiation of the brain dependent on sex differences in metabolic clearance rate or on lack of weight normalization or dose dependent on estrogen.