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| SEXUAL DIFFERENCE AND PAIN: A CONSTRUCTIVE ISSUE FOR THE MILLENIUM Karen J. Berkley, Ph.D., Program in Neuroscience, Florida State University, Tallahassee, Florida Sexual difference is biology's, that is, life's most potent experimental variable, affecting virtually every human function, including pain.1 To increase our understanding, the challenge here is not first to look for some mythical neurological entity called pain experience and then to find out how sexual difference modulates it. Rather it is to turn the question around and thus seek to understand the rules by which sexual difference impacts on all of biology's mutually modulatory factors, i.e., social, psychological, physiological, cellular, molecular and genetic factors, that together create the motivating circumstances we designate as pain. Female vulnerability to pain. It appears clear that these modulatory factors interact so that females are more vulnerable to pain-motivating circumstances than males. Thus, for experimentally-delivered bodily stimuli, about half the studies show that females have lower thresholds, greater ability to discriminate, higher pain ratings or less tolerance of noxious stimuli than males; few studies show the opposite. But the differences are small, exist only for certain forms of stimulation and are deeply affected by many situational and other variables such as presence of disease, age, reproductive condition, culture, past experience, response bias, experimental setting and even nutritive status, to name just a few. For endogenous pains, women generally report more multiple pains in more body regions than men- With no obvious underlying rationale, many painful diseases, particularly of visceral and muscular origin, are more prevalent among females; fewer have a male prevalence. For a number of common diseases (e.g., coronary heart disease), symptoms differ between females and males. Sexual differences in attitudes exist that affect not only reporting, coping and responses to treatment, but also measurement and treatment. So many variables are cooperatively and competitively operative that it may seem that the most striking feature of sexual differences in reported pain experience is that none of any consequence exist. But, overall, the burden, variance, and variability of pain experience is indeed greater for females than males. Female strength to deal with pain. Despite, or perhaps because of this vulnerability, females appear to have more varied and effective mechanisms for dealing with pain. Thus, females make more aggressive and effective use than males of various coping strategies, health-care facilities and social support services. More counteractive physiological mechanisms appear to exist in females than males, such as a wider variety of modulatory systems that act to dampen the impact of noxious bodily events. For examples, estrogens promote skin healing after injury, and the high progesterone environment during luteal phase, pregnancy and lactation can increase some pain thresholds and is associated with reductions in incidence or severity of many painful diseases. These mechanisms provide lessons for males. Mechanisms. Deductive reasoning from known physiological and sociological sexual differences suggests powerful differences in the operation of pain mechanisms that might lead to greater female vulnerability, variations, and strengths. Five examples are as follows; First, the vagina may provide an additional route in women for internal trauma, infection and invasion by pathological agents that puts them at greater risk for developing hyperalgesia in multiple body regions. Second, sex differences in the actions of all three sex hormones in both sexes suggest pain relevant differences in the operation and metabolism of many neuroactive and analgesic/anesthestic agents, growth factors/cytokines, and the autonomic nervous system. Third, the structure and function of nearly every portion of the central nervous system studied so far is affected by sexual factors both hormonal and non-hormonal, genomic and non-genomic in ways that could affect pain experience and expression; e.g., spinal cord, dorsal column nuclei, inferior olive, cerebellum, central grey, striatum, parts of hypothalamus, amygdala, hippocampus and parts of neocortex. Fourth, sex differences in chronobiology are likely to give rise to sex differences in how pain is "learned" and stimuli are interpreted, a situation that could lead to a greater variability and wider range of pains without obvious peripheral pathology among females. Fifth, and perhaps most important, sociological and cultural factors impose societal roles that predispose females more than males towards multiple actions that minimize rather than maximize threats to bodily integrity or societal danger, and towards cooperation more than competition. Clinical relevance. Are these sexual differences applicable clinically? The answer seems obvious: yes, they must be. Unfortunately, because that answer has only just recently been vigorously acknowledged, there are at present few clear answers on how to apply what we know so far to specific clinical situations. Happily, however, as we approach the millenium, details about sexual difference at all levels biological (social to genetic) are emerging in a rapidly accelerating literature, some of which we will discuss here, that holds great promise for applying the information to the individual person, female or male, in pain. 1 'Gender' is the genetic 'sex' with which an individual identifies. The phrase 'sexual difference' refers to differences in both.
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