Consideration of Sex Differences in Medicine to Improve Health Care and Patient Outcomes

(HealthNewsDigest.com) – Even though the observation that men and women are different is arguably as old as human life, women have been included in clinical trials for only a few decades. Women have a unique physiology and their experience of illness, and responses to therapeutic interventions are often significantly different from those of men. Recent regulations from the National Institutes of Health requiring grant applicants to consider sex as a variable in biomedical research are a welcome development.¹ However, despite increasing evidence that an individual’s sex is one the most important modulators of disease risk and response to treatment, consideration of the patient’s sex in clinical decision making (including the choice of diagnostic tests, medications, and other treatments) is often lacking. This is surprising given the increasing interest in precision medicine, which should begin with attention to sex differences in medicine.

In this Viewpoint, we highlight specific examples, focusing on biological sex differences in drug metabolism and cardiovascular risk that appear ready for clinical implementation. Clinicians receive minimal formal instruction about such sex differences, yet incorporation of sex-specific information into clinical practice will improve patient care.

Many medications are metabolized differently in women than men due to variances in body size and distribution volumes, sex hormone levels, activity of enzymes, and effects of routes of excretion on sex-specific responses to drugs.² For example, propranolol levels may be up to 80% higher in women, so dosage has to be adjusted to avoid adverse effects. This is important because survival benefits for women with heart disease who receive the drug are well documented.³ Zolpidem is more slowly metabolized in women, because of which the US Food and Drug Administration now recommends that the initial dose for women should be half the dose recommended for men.⁴ Digoxin, once a primary agent in the armamentarium of drugs used for heart rate control and the treatment of heart failure, has a different and relatively more hazardous effect on women, principally due to reduced distribution volume and the lower glomerular filtration rate in women.²Angiotensin-converting enzyme inhibitors reduce cardiovascular events in men but less so in women,⁵ and cough is a more frequent adverse effect in women.⁶ In contrast, angiotension receptor blockers are equally effective in both sexes.² In women, low-dose aspirin reduces the risk of stroke in women but has minimal effect on the risk of myocardial infarction (MI)²; whereas, in men the benefits of aspirin appear greater for preventing MI than stroke. Compared with men, women are more likely to experience bleeding after treatment with tissue plasminogen activator or warfarin,² suggesting that sex differences should be considered in dose adjustments.

Arrhythmias, particularly atrial fibrillation, have different consequences for women, who have higher mortality, more symptoms, and higher rates of recurrence following ablation procedures.² Women have a higher risk of atrial fibrillation–associated stroke than men (25% vs 10%) and experience significantly higher mortality after stroke (25% vs 19% at 6 months).^2,7Women’s unique electrophysiology (which produces a longer cQT interval than that of men) increases the risk of drug-related torsades de pointes (TdP)^8,9; risk of TdP associated with sotalol is higher among women than men (4.1% vs 1.0%). The observed vs expected prevalence ratio for TdP associated with amiodarone, dofetilide, and azimilide is at least twice as high among women as it is in men.⁹

Hypertension, dyslipidemia, smoking, diabetes, and obesity account for 80% of risk of acute MI in both sexes, but presence of diabetes is associated with a 6-fold increase in women’s risk of coronary artery disease (CAD), from 107 per 100 000 person-years to 651 per 100 000 person-years vs a 3-fold risk among men with diabetes (Box).^2,10 Moreover, women with diabetes and CAD have a 3-fold increased risk of heart failure; men with diabetes have minimal increase in risk.² Younger women with CAD have worse outcomes than men of similar age. Timely diagnosis of MI is often delayed in women because of their different symptom complex (shortness of breath, unusual fatigue, sleep disturbances, indigestion, and anxiety; almost one-half may not report chest discomfort). The results of diagnostic testing for CAD can be falsely reassuring in women: the standard stress test has lower specificity and sensitivity in women; stress echocardiography is preferred for women.²

Symptomatic women with normal coronary arteries on angiography may have microvascular disease, with metabolic abnormalities evident on magnetic resonance spectroscopy. Statins have a protective effect against CAD in both men and women, but adverse effects of statins (such as myalgias and statin-induced diabetes) may be more common in women than in men.² Moreover, women appear more susceptible to catecholamine-related dysregulation of vascular reactivity and to a reversible cardiomyopathy (takotsubo disease) that occurs in some women in response to profoundly emotional experiences.²

Diastolic dysfunction–producing heart failure with preserved ejection fraction is seen principally in women whose only symptom may be dyspnea.² Stress echocardiography is the appropriate initial test for diastolic dysfunction and will reveal normal ejection fraction in these patients. Coronary angiography in affected individuals may reveal no obstructive disease. Therapy depends on decreasing the cardiac rate, β-blockers, and nitrates and on reducing blood volume with diuretics and sodium restriction. Blunting the neurohumoral activation with aldosterone antagonists can mitigate fluid retention.²

Collection of information at the molecular level is rapidly increasing. The nascent ability to edit DNA may create entirely new diagnostic and therapeutic options for patients. Importantly, environmental modification of genomic expression through epigenetic changes clarifies how biological sex and the environment interact to produce the phenotype.^1,2 Biological “sex” and “gender” are no longer separate concepts but components of a unified process that is the consequence of modifications of the genome by individual experiences.

Sex-specific medicine should not be a separate specialty but rather should be integral to all medical educational efforts and clinical programs to support the importance and influence of sexual dimorphism in human physiology and health. This new awareness of the importance of sex differences in patient care is one of the richest features of 21st-century medicine. Research and clinical education in this vital area should be accelerated.

Corresponding Author: JoAnn E. Manson, MD, DrPH, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave, Third Floor, Boston, MA 02215 ([email protected]).

Published Online: October 31, 2016. doi:10.1001/jama.2016.13995

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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