How are the human genetics of obesity influenced by gender? Women have approx. 40% higher levels of leptin, the product of the ob gene, than men do, which does not appear to be due to reproductive hormone differences. A rodent model of obesity shows that female Zucker rats, which are heterozygous for the fatty (fa) gene have a survival advantage early in life compared to those that do not carry the gene. However, this effect is not observed in male rats. These findings may explain the survival of obesity genes in the population and provide another example of gender-based biological differences in obesity.

Lung cancer is the number one cancer killer in women, followed by breast cancer and colorectal cancer. Given the same level of lifetime exposure to cigarette smoke, the risk for developing lung cancer is 20% to 70% higher in women than men at every level of exposure to cigarette smoke, indicating that women are more susceptible to the carcinogens in cigarettes. In fact, women with a shorter smoking history than men appear to be at increased risk for lung cancer. This is despite the facts that women tend to smoke lower tar and nicotine cigarettes than men, and that women smokers, on average, inhale less deeply than men do. Women who smoke have a higher level of specific DNA adducts than do men, indicating a higher risk of lung cancer in women with similar levels of smoking. Cardiovascular disease remains the number one cause of death in the United States and the leading killer of women, causing nearly half of all deaths in women.

Research findings indicate differences in the regulation of heart muscle growth and vascular structure between men and women. Angiotensin converting enzyme (ACE) generates angiotensin II, a small hormone with several functions in the cardiovascular system, including regulating blood pressure and cell growth. In men, alterations in the ace gene are associated with an increase in cardiovascular risk, in particular an increase in the size of the heart. The same genetic alterations in women, however, are not associated with increased cardiovascular risk. Despite the numerous roles of estrogen in cardiovascular health, data from the Heart and Estrogen/Progestin Replacement Study (HERS) show no statistically significant differences in heart disease between postmenopausal women who do and do not take hormone replacement therapy.

The action of sex steroid hormones on the brain is postulated as the biological basis behind many gender differences in neurological functioning, as the data on pain, mental abilities, neuromuscular diseases, and addiction indicate. However, newer research is hinting at gender differences not solely based on the action of sex steroids or the fluctuations of the menstrual cycle. Men and women metabolize food, alcohol, medications, and atmospheric toxins differently. Basic biological sex differences affect the pharmacokinetic and pharmacodynamic profiles of the multitude of drugs we use. Laboratory and clinical research emerging in the past few years is showing gender differences in virtually all areas of drug research. The biological factors of drug abuse, the antecedents and consequences of drug use and abuse, and prevention and treatment strategies all show gender-based differences.

Sex steroid hormones appear to be of significant importance in the prevalence of many mental disorders. Research is examining gender-related differences in the mechanisms of neurotransmission and the metabolism of neurotransmitters in the brain. In addition, researchers are seeking to identify the genetic components of major mental disorders. For example, it has been known for years that women are 2-3 times more likely to suffer from depression than men. Findings published in 1998 using PET imaging of human brains shows that the average rate of serotonin synthesis is 52% greater in male than in female subjects. This is "one of the largest differences between brains in males and females that is not related to hormone binding sites". Also "the lower rate of serotonin synthesis in women may be related to the higher incidence of unipolar depression".

Immunology is an area of striking gender differences. Women have enhanced levels of immunoreactivity compared to men, which increases women’s resistance to many types of infection, but also makes them more susceptible to autoimmune diseases. Women constitute 75% of those afflicted with autoimmune diseases. Women’s immunologic reactions to infectious disease have also been shown to be different than men’s. Rheumatoid arthritis is three times more frequent in women than in men. Lupus disproportionately affects young women of childbearing age, but the biological factors that predispose women to the condition are unknown. Multiple sclerosis (MS) is also more common in women, and the immune system plays a strong role in this neuromuscular disorder.

The recognition of gender as an important variable in scientific investigation has grown among a variety of disciplines. However, for a multitude of disease and conditions we may know only half of what we [need to] because our knowledge is from male subjects only. In recent years, an increasing number of requests for applications from the federal government have been released in the area of gender-based research. Additionally, a number of large private pharmaceutical and research companies have begun investing in research and analyzing gender differences in response to pharmaceuticals and other therapeutics.

Thompson PM and Wolf JL. J. Inves. Med. 47:106-113, 1999.

Last modified: August 13, 2003