Gender-Based Biology

Gender-based biology is a fascinating and growing area of research already reaping clinical benefits for both men and women. The exclusion of women from most clinical studies has resulted in substantial gaps in our knowledge about the effects of disease and treatments on women. Government guidelines now strongly encourage both the inclusion of women (including women of child-bearing age) in clinical trials and the analysis of research data by gender. Three of the papers in this month’s issue deal directly with gender issues. One is about the effects of an exogenous female hormone on cognition (“Enhanced Verbal Memory in Nondemented Elderly Women Receiving Hormone-Replacement Therapy,” by Pauline M. Maki, Ph.D., et al.). Two concern the differential effects of alcohol abuse on the brains of men and women (“Sex Differences in the Effects of Alcohol on Brain Structure,” by Adolf Pfefferbaum, M.D., et al., and “Evidence for a Gender-Related Effect of Alcoholism on Brain Volumes,” by Daniel W. Hommer, M.D., et al.)

First, a concern. Despite the emerging data about sex differences in the brain and about the differences between men and women in the average age at onset and clinical course of schizophrenia, “Structural Abnormalities in Frontal, Temporal, and Limbic Regions and Interconnecting White Matter Tracts in Schizophrenic Patients With Prominent Negative Symptoms,” by Thordur Sigmundsson, M.D., et al., included only three female subjects. Although this may have enabled the authors to make the groups as internally homogeneous as possible, it does not improve our understanding of crucial gender differences. “GABA Transporter-1 mRNA in the Prefrontal Cortex in Schizophrenia: Decreased Expression in a Subset of Neurons,” by David W. Volk, M.S., et al., matched comparison with study subjects by gender as well as other characteristics but, no doubt because of limited sample size, failed to analyze the data by gender. Emerging data indicate that the expression of some genes is affected by the sex of the parent from whom the gene is inherited and by the hormonal milieu in which the expression takes place. This would be an interesting area for follow-up to this research.

The article on hormone replacement therapy and cognition is an addition to a large and fast-growing field. Unfortunately, the literature on menopause is permeated by unwarranted assumptions. Those assumptions have deleterious effects on science, education, clinical care, and the status of women in society. Both researchers and the public conflate menopause with aging; many studies purportedly about menopause fail to establish the subjects’ actual hormonal and menstrual status. Cross-cultural studies reveal connections between a society’s attitudes toward older women and its fixation on menopausal morbidity. In the West, old women are perceived as crones, and women are symptomatic at menopause and afraid of aging. In the East, women gain respect and power as they age. There is no term for hot flashes in Japan; aging men and women report similar symptoms.

The long-standing Western assumption that menopause is associated with psychiatric morbidity has not survived empirical investigation, but fears that a woman in the White House would subject the world to “raging hormones” have not entirely subsided. Another assumption is that women are biologically programmed to die at menopause, so that the mere existence of postmenopausal women is a biological aberration. The average life expectancy of a newborn girl for many centuries was about the same as the age at menopause, but that average was a product of infant mortality, infectious diseases, and complications of childbirth rather than of some abrupt deterioration at age 45.

In fact, menopause is a normal physiological development that makes biological sense. Human children require considerable maternal energy, for many years, before they are ready to survive, prosper, and perpetuate the species by raising children of their own. If women were capable of bearing children until the ends of their lives, the last children born would have little chance of survival. There would be no grandmothers to help deliver and raise children. Whatever the substrate of traditions and misconceptions, menopause is a growth industry.

The ever-increasing population of postmenopausal women is a vast market for hormones. Reading either the popular or professional literature, one might reasonably conclude that the medical profession is determined to find some rationale for the administration of exogenous hormones to menopausal and postmenopausal women. Hormone levels considered normal in prepubertal girls are said to constitute a deficiency disease in adult women. When evidence for one indication (prevention of cardiovascular disease) dwindles, another indication (prevention of cognitive impairment, which is a terrifying eventuality to many women) takes its place. There must be something pathogenic about women’s changing hormone levels, whether the morbidity consists of involutional melancholia, osteoporosis, the empty nest syndrome, or myocardial infarction, and the pathology must be treated, the so-called deficiency replaced, with hormones. Alternative and effective approaches to disease prevention have received less attention from the medical community.

The study of gender differences in the substrate of alcohol abuse is a field where data are sparse and long overdue. Men’s drinking behaviors tend to be more public and to cause more visible damage than women’s. Paradoxically, men’s drinking is more socially acceptable, driving women’s alcohol problems underground. Most treatment programs are developed for, and serve, men, making men more readily available subjects for research and further widening the gender knowledge gap. Women have different susceptibilities, different clinical courses, and different treatment needs than do men. Confrontational models are less effective than approaches framed in terms of relationships. Mothers may avoid treatment for fear of provoking investigations by child welfare services and losing custody of their children or simply because there is no safe place for their children while they are in treatment. Governmental agencies are more likely to remove a newborn child from a mother with a drinking problem than to offer her treatment while she is pregnant. We do well to attack the problem from both ends of the medical spectrum: basic brain science and better access to better treatment. The articles by Pfefferbaum et al. and Hommer et al. are important contributions to that mission.