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SEX DIFFERENCES IN PAIN

Keywords

male; female; sex hormones; sympathetic nervous system; nerve growth factor; neuroactive peptides; GABA.

Abstract

Are there sex differences in pain? For experimentally-delivered somatic stimuli, females have lower thresholds, greater ability to discriminate, higher pain ratings and less tolerance of noxious stimuli than males. These differences, however, are small, exist only for certain forms of stimulation and are affected by many situational variables such as presence of disease, experimental setting and even nutritive status. For endogenous pains, women report more multiple pains in more body regions than men. With no obvious underlying rationale, some painful diseases are more prevalent among females, others among males, and, for many diseases, symptoms differ between females and males. Sex differences in attitudes exist that affect not only reporting, coping and responses to treatment, but also measurement and treatment. So many variables are operative, however, that the most striking feature of sex differences in reported pain experience is the apparent overall lack of them.

On the other hand, deduction from known biological sex differences suggests powerful sex differences in the operation of pain mechanisms. First, the vaginal canal provides an additional route in women for internal trauma and invasion by pathological agents that puts them at greater risk for developing hyperalgesia in multiple body regions. Second, 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. Third, sex differences in the actions of sex hormones suggest pain-relevant differences in the operation of many neuroactive agents, opiate and non-opiate systems, nerve growth factor and the sympathetic system.

Thus, while inductive analysis of existing data demonstrate more similarities than differences in pain experience between females and males, deductive analysis suggests important operational sex differences in its production.

Are there sex differences in pain? Ask the opinion of almost anyone and the answer will usually be yes (McCaffery and Ferrell, 1992; Bendelow, 1993). In fact, when carefully reviewed, evidence can be found for sex differences in virtually every sensory realm (Velle, 1987). Consensus disappears, however, on what the differences are.

A number of psychophysical studies in humans have been carried out over the years on sex differences in the attribution of intense somatic stimulation as painful (e.g., see reviews in Procacci et al., 1972; Goolkasian, 1985; Velle, 1987; Lander et al., 1990; Feine et al., 1991; Maixner and Humphrey, 1993; Lautenbacher and Rollman, 1993; Ellermeier and Westphal, 1994; Fillingim and Maixner, 1995). When differences are observed under these carefully controlled experimental circumstances, it is often the case that women have lower thresholds or rate similar stimuli as more painful or have less tolerance for intense stimuli.

Of interest is that certain parameters may be important for observing such differences. One such parameter is the type of stimulus (Lautenbacher and Rollman, 1993). Thus, ratings of electrical and pressure stimuli are more reliably observed to exhibit sex differences than are ratings of thermal stimuli. The timing characteristics of the stimulus are also important, sex differences being more readily observed with less temporal summation (Hogeweg et al., 1992; Lautenbacher and Rollman, 1993). Spatial aspects may also be important, including the size or bodily locus of the stimulus (Lipman et al., 1990; Hogeweg et al., 1992; Lautenbacher and Rollman, 1993; Lee and Essick, 1993;).

Factors other than stimulus characteristics are also relevant. Situation variables are important. For example, the sex of the experimenter can affect sex differences in pain estimates when this factor is exaggerated by selecting "attractive" experimenters (e.g., compare results of Levine and DeSimone, 1991 with Feine et al., 1991). The setting is also relevant. Somatic stimuli that are delivered in clinical settings (such as venipuncture and post-operative incisional cleaning) fail to show sex differences (Lander et al., 1990).

Other variables impact differently on males and females in a manner that would affect conclusions about the nature of any sex differences in pain. Thus, the presence of other disease conditions can affect pain ratings. In dysmenorrheic women, pressure-pain estimates are decreased during the follicular phase of their menstrual cycle (Hapidou and DeCatanzaro, 1988), whereas abdominal muscle becomes hyperalgesic throughout the cycle (i.e., pain thresholds are decreased), with maximum hyperalgesia appearing premenstrually (Giamberardino et al., 1995). Pressure pain thresholds are elevated in women suffering from bulimia nervosa (Faris et al., 1992).

Menstrual phase and reproductive status also affect pain ratings (Tedford et al., 1977; Goolkasian, 1980; 1985; Cogan and Spinnato, 1986; Hapidou and DeCatanzaro, 1988; Whipple et al., 1990; Procacci, 1993), although the actual nature of the variations is inconsistent and variations are not always observed, especially if thermal or ischemic stimuli are used (e.g., Dunbar et al., 1988; Amodei and Nelson-Gray, 1989). Sex differences in sugar and fat consumption are also likely to impact pain ratings (Frye et al., 1994a; Krahn et al., 1994). And finally, willingness to report is also a likely factor in pain ratings, but the issue is difficult to resolve because of the difficulty in separating sensory from response factors (see discussions in Chapman, 1977; Rollman, 1977; Lander et al., 1990; Ellermeier and Westphal, 1994; Clark, 1994).

Data on sex differences in nociception in animals also exist (i.e., in their responses to stimuli that produce or threaten to produce injury). As reviewed by Bodnar et al. (1988), there are sex differences in basal nociceptive thresholds in rodents and these differences can be hormonally modulated and shown to vary with estrous condition, a result also recently observed by others (Forman et al., 1989; Ginzler and Bohan, 1990; Frye et al., 1992; 1993; Martinez-Gomez et al., 1994). Similarly, chronic and acute sucrose consumption affects nociceptive responses differently in female rodents (Frye et al., 1992; 1993).

Thus, overall, experimental studies using exogenously-delivered somatic stimuli indicate that sex differences in pain reports do exist, with females generally reporting lower thresholds, higher ratings and less tolerance. However, the differences are small and inconsistently observed, being most prominent for pressure or electrical stimuli. Furthermore, even under these rigidly controlled experimental circumstances, the presence and direction of the differences are influenced by situational, health status, hormonal, motivational and nutritional factors.

The issue of sex differences becomes even more complex for clinical situations when one considers reports by humans of their own endogenous pains (i.e., pains not evoked by others via experimentally-delivered noxious stimuli) or of the endogenous pains of others. The literature is immense (see review in Unruh, 1996), in large part because there is a wider range and much less control over the research conditions. In addition, relevant information is often buried in the results sections of studies directed at other questions.

Many variables enter into any attempts to make sense of the available data (Mendelson, 1991; Turk and Melzack, 1992). These variables include what is measured, where the measures are being taken, who is being studied, when they are studied and how they are studied. As examples, for "what," clearly relevant to the results is whether it is physiological or psychological measures that are being made. For "where," the setting in which measures are taken are of clear importance (e.g., hospital, home, college classroom, survey in clinic waiting room, etc.). For "who," clearly significant is the age (Bodnar et al., 1988; VonKorff et al., 1988), ethnicity (Bates, 1987) and health condition (Basoglu, 1992) of the subjects. Also significant is the population from which the subjects are drawn; e.g., the general population or a clinical one (Crook et al., 1989). For "when," time of day is of importance, as is the interval over which (e.g., days, weeks, months, etc.) the pain is being studied, as is whether subjects are being asked to estimate current or previous pains (e.g., VonKorff, 1992). And, finally, for "how," pain diaries clearly differ from various scales (such as VAS), from brain imaging techniques, from verbal reports, from questionnaires, etc. A good example is the current debate not only about the value of but also what the best approaches are to assessing "pain behavior" (Keefe and Dunsmore, 1992a, b).

Given all of these interacting variables, it is at present possible to derive only a few general conclusions on the nature of sex differences in endogenous pain. Overall, health surveys in both North America and Europe show that women's morbidity and use of health care is higher than that of men (Gijsbers van Wijk et al., 1991). Of importance, however, is that much of the increased morbidity in women can be accounted for by specific gynecological or obstetrical problems (Gijsbers van Wijk et al., 1992). Another important factor may be an increased willingness on the part of women to perceive and report physical symptoms as indicative of illness (Grove and Hughes, 1979; Gijsbers van Wijk et al., 1991), although, as discussed above, it is difficult to separate these response and sensory factors.

This same sex difference appears to hold true, but considerably less so for pain complaints, many of which are musculoskeletal or visceral, and persistent, episodic or chronic, unlike the acute somatic stimuli studied experimentally. In general, when large-scale studies of pain prevalence are carried out, overall, chronic pain prevalence is not always higher in women than men (Andersson et al., 1993). However, women do report more multiple or recurrent pains than men, particularly more in certain body regions and at certain ages (VonKorff et al., 1988; 1990; James et al., 1991; Andersson et al., 1993; Eggen, 1993; Ektor-Andersen et al., 1993; Klonoff et al., 1993), although, as noted in some of these studies, some of the differences appear to be related specifically to gynecological or obstetric problems (see review in Unruh, 1996).

Studies on specific disorders in which pain is a prominent component provide additional information on the nature of sex differences in pain. The recently published "Classification of Chronic Pain" (Merskey and Bogduk, 1994) describes about 500 such disorders and provides information about sex prevalence for about 85 of them. This information is summarized in Table 1.

FEMALE PREVALENCE	MALE PREVALENCE	NO SEX PREVALENCE
migraine headache with aura	6migraine without aura	acute tension headache
chronic tension headache	cluster headache	cluster-tic syndrome
post-dural puncture headache	post traumatic headache	"jabs" and "jolts" syndrome
hemicrania continua	SUNCT syndrome	secondary trigeminal neuralgia
cervicogenic headache	Raeder's paratrigeminal syndrome	neuralgia of nervus intermedius
tic douroureux	Pancoast tumor	painful ophthalmoplegia
temporomandibular joint disorder	thromboangiitis obliterans	maxillary sinusitis
occipital neuralgia	brachial plexus avulsion	toothache due to dentino-enamel defects
periapical periodontitis and abscess	7pancreatic disease	toothache due to pulpitis
atypical odontalgia	duodenal ulcer	cracked tooth syndrome
burning tongue	abdominal migraine	dry socket
carotidynia	lateral femoral cutaneous neuropathy	vagus nerve neuralgia
chronic paroxysmal hemicrania	postherpetic neuralgia	stylohyoid process syndrome
temporal arteritis	hemophilic arthropathy	thoracic outlet syndrome
carpal tunnel syndrome	ankylosing spondylitis	brachial plexus tumors
Raynaud's disease		esophageal motility disorders
chilblains		chronic gastric ulcer
2reflex sympathetic dystrophy		Crohn's disease
hemicrania continua		diverticular disease of colon
chronic venous insufficiency		carcinoma of the colon
fibromyalgia syndrome		familial Mediterranean fever
esophagitis		hereditary corproporphyria
reflux esophagitis with peptic ulcer		acute herpes zoster
slipping rib syndrome		burns
twelfth rib syndrome
gallbladder disease
post-cholecystectomy syndrome
irritable bowel syndrome
3interstitial cystitis
acute intermittant porphyria
proctalgia fugax
4chronic constipation
pyriformis syndrome
peroneal muscular atrophy
5multiple sclerosis
rheumatoid arthritis
pain of psychological origin

Table 1a: Sex prevalence of various painful disorders
1All listings from Merskey and Bogduk (1994) except those footnoted 2-7. 2 Also called complex regional pain syndrome, Type I, the female-male ration for this disorder is 4:1 in children (Wilder, 1996) but not as large in adults (Baron et al., 1996). 3 Ratner et al, 1994). 4 MacDonald et al., 1993. 5 Moulin, 1989; Berkley, 1993. 6 Rasmussen et al., 1992. 7 Reviewed in Longnecker and Sumi, 1990.

FEMALE PREVALENCE	MALE PREVALENCE
gout (after age 60)	gout (before age 60)
osteoarthritis (after age 45)	osteoarthritis (before age 45)
livedo reticularis (after age 40)	coronary artery disease (before age 65)
2reflex sympathetic dystrophy (higest during childhood)	erythromelalgia (over age 50)

Table 1b: Age dependent sex differences

As discussed in Berkley (1993), the data on sex prevalence as shown in Table 1 are currently derived from such disparate, uncertain and often anecdotal sources that it is unclear at this time how to interpret them. Bush and colleagues (1993), in a detailed study of temporomandibular disorder, provide a strong argument that virtually all of the female predominance of that disorder can be explained by a "greater health awareness or interest in symptoms by women than by men." They go on to suggest that this explanation might also apply to other disorders. As discussed above, this explanation has logical problems, and, in any case, is difficult to apply to all of the conditions listed in Table 1, particularly those with a male predominance. Other tentative interpretations of the sex prevalence data are considered in the second section of this paper ("a switch from induction to deduction").

A factor that further complicates this issue are sex differences within individual disorders in the nature of the symptoms that are reported. For example, the diagnosis of irritable bowel syndrome (IBS) can be one of exclusion; i.e., "chronic abdominal pain with no apparent cause associated with alteration of bowel habit (Merskey and Bogduk, 1994)." To help reduce the number of investigative precedures and referrals, many gastroenterologists have followed a differential diagnostic process using as criteria for IBS the existence of some proportion of a set of six specific gastric symptoms described by Manning et al. in 1978. It has been shown, however, that these specific criteria are of diagnostic value only in women (correlation was 0.47 for women; 0.16 for men; Smith et al., 1991), which is one of the factors that led to the adoption of a different criteria set (Rome criteria; see Drossman, 1994).

Similarly, for acute appendicitis, while men and women share some similar symptoms (tenderness, rigidity, guarding, leucocytosis, location of pain at diagnosis), other symptoms differ considerably. For men, but not women, significant predictors include previous abdominal surgery, rectal digital tenderness, rebound and elevated body temperature, whereas for women, but not men, the absence of renal tenderness is a good predictor (Eskelinen et al., 1994). Migraine headaches comprise another example. Women show a prevalence of migraine without aura twice that of migraine with aura, while the opposite is true for men (Rasmussen et al., 1992) and these two types of migraine are now considered as different diseases (Merskey and Bogduk, 1994). In coronary artery disease, chest pain is a much poorer predictor in women of abnormal angiography or positive thallium-20 scans (Garber et al., 1992; Sullivan et al., 1994). Risk factors also differ, diabetes being more prevalent in women than men with cardiac disease, while external triggers (e.g., exceptional stress) or high weight are of higher prevalence in men than women with cardiac disease (Behar et al., 1993; Seeman et al., 1993; Sullivan et al., 1994).

An even further complication involves differences in the temporal aspects of pain between males and females. Females undergo large changes in hormonal status and other aspects of their lives as a function of changing reproductive status, including puberty, menstrual cycling, pregnancy and menopause. Hormonal and other conditions for males change as well, but differently. Males reach puberty at a different age and undergo more gradual changes in hormonal conditions with age. These differences have an as yet unclear impact on pain mechanisms (see below for hypotheses), but the incidence of some clinical pains are well known to vary with menstrual stage (e.g., migraine; Marcus, 1995), and others (reviewed in Berkley, 1993) vary in their incidence, disappearance and prevalence as a function of puberty, pregnancy, menopause and age.

Another major factor that enters into this issue comprises attitudes towards pain that can exert effects not only on a subject's report of her/his own pains but also on the experimenters or clinicians who carry out the assessments (Unruh, 1996). It is evident that cultural, religious, cognitive and sociological variables interact to give rise to attitudes about pain that affect the decision on the part of any given individual at any given moment to report the existence of endogenous pain (e.g., Bates, 1987; Mendelson, 1991; Strong et al., 1992; Roy, 1992). The possible differential impact of these variables on reports of pain by males and females has not been extensively studied directly, but when they have it is no surprise that sex differences in attitudes towards pain exist (Bendelow, 1993; Strong et al., 1992) and that such differing attitudes can give rise to sex differences in reports of endogenous pain. For example, one recent study (Bendelow, 1993) showed clearly that as a result of differences in attitude of the particular group of individuals she studied (those living in a inner city area of North London), women were more likely to give "holistic, integrated" reports of their pain, whereas men were more reluctant to classify pain associated with emotional suffering as "real" pain.

On the other hand, sex differences in attitudes might not always affect pain ratings. For example, Fowler-Kerry and Lander (1991) found that although female and male children and adolescents differ in their estimates of how painful an impending venipuncture might be (females overestimated; males underestimated), there were no sex differences in their ratings of the venipuncture pain that was actually produced. Whatever the circumstances with respect to ratings of pain, however, it has been shown that attitudes towards pain can affect coping behaviors and responses to treatment (e.g., see reviews in Edwards et al., 1992; Unruh, 1996). Relevent here are recent data showing that in certain specific situations women are more likely than men to benefit from behaviorally-based treatments (Jensen et al., 1994; Hapidou, 1994).

In addition to the impact of sex differences in attitudes towards pain on an individual's pain reports, coping behaviors and responses to treatment, attitudinal differences are likely to have an impact on the experimenters who carry out the assessments and the type of assessments that are made and treatments provided. Some even argue, for example, that the current major positive advance from a Cartesian biomedical model of illness towards a biopsychosocial one is due to the inclusion of a feminist point of view in science and health care systems in many parts of the world (Johnson, 1991; Rose, 1994).

Thus, another layer of factors that enters into the issue are sex differences in attitudes about how gender influences pain. In a recent study carried out by two female nurses (McCaffery and Ferrell, 1992), it was found that the majority of nurses (mostly female) have opinions about sex differences in pain that result in differential assessments of pain in female and male patients. It is not illogical to conclude from these results that sex differences in these opinions could give rise to a complex set of sex differences in the diagnosis and treatment of pain disorders in females and males (Unruh, 1996). There is in fact some evidence for this sex bias in the general health care system. For example, a number of studies have found evidence for a "less aggressive" management of acute nontraumatic chest pain in women that men (e.g., Heston and Lewis, 1992; Hsia, 1993), although this difference has been debated (Mark et al., 1994; Vacek et al., 1995), and such differences could relate to the sex of the physician (predominantly male in the case of cardiologists) as has been shown, but not always (Furman et al., 1993) in other realms of health care (Lurie et al., 1993).

In summary, studies of assessments of endogenous pain provide very little concrete information on the nature of sex differences, if any, in pain, be it acute, persistent or chronic. Women report more pain in more body regions and of more varied types than men. In addition, there is a female or male sex predominance for many painful diseases and the symptoms reported for them sometimes differ between the sexes. All of these differences, however, are subject to situational, temporal, attitudinal and social factors. The net result is that any sex differences that might exist in the amount of pain experienced or its impact on the life of the individual or its response to treatment represent only a small part of the vast array of other factors that impact on pain.

Thus, as discussed at length in the literature on sex differences in cognition (e.g., Halpern, 1992), it must be remembered that the differences observed so far are statistical and small. For the most part it is the similarities between the sexes that should be emphasized, particularly when it comes to using the data to form strategies for treatment. It is therefore inappropriate at this time to use data from a single limited experiment as a basis for recommending different overall treatment regimens for females and males. For example, in a recent paper published in the journal Pain (Jensen et al., 1994), the authors found significant sex differences in the coping strategies in their sample of 139 chronic pain subjects. From these differences, the authors recommend that "the management of each gender should be distinctive, focusing on observed differences of the determinants of outcomes and coping strategies. The message is of importance to primary care practitioners, rehabilitation specialist, clinical psychologists and occupational physicians (p. 171)." Although these authors go on to warn that "our findings could be easily over-interpreted and much caution is in order," such general recommendations are very clearly unwarranted by their data on a limited sample of patients. Furthermore, as pointed out clearly by McCaffery and Ferrell (1992), such recommendations, if acted upon in a clinical setting are dangerous because they could result in inadequate or inappropriate treatment.

Although the discussion above indicates that it is premature and indeed may be impossible to form definitive conclusions on the nature of sex differences in pain from an inductive analysis of the literature, this conclusion does not mean that the analysis of sex differences is irrelevant to improving our understanding of the mechanisms of and best array of treatments for various aspects of pain. Another strategy is to take a deductive approach. In other words, in addition to trying to determine the nature of sex differences in pain by analyzing the troublesome literature as above, it may prove useful as well to develop hypotheses from what is already clearly known about sex differences in general.

Few would disagree that females and males differ in many components of their socialization, psychology and biology. Although the actual differences are most often controversial or statistical, females and males do differ virtually absolutely and unarguably in three aspects of their reproductive biology. Their pelvic reproductive organs differ and their hormonal conditions differ chronobiologically and compositionally. How then might these three biological differences operate to affect pain?

Although many aspects of body structure, such as height, weight, muscle composition, fat distribution and so forth differ in females and males, those differences are statistical, not absolute. With the exception of a number of relatively infrequent intersex states, females and males differ absolutely in the characteristics of their reproductive organs. Females have a vagina, clitoris, cervix, uterus, fallopian tubes and ovaries; males have a penis, vas deferens, epididymis, prostate organ, seminal vesicles and testes.

These differences create major differences in the organization of the entire pelvic region, including muscles, skeletal structures and the relationship between reproductive urinary and alimentary tract organs. The impact of these structural sex differences on the functioning of non-reproductive pelvic organs (e.g., bladder) in females and males is only just beginning to be appreciated (Chalker and Whitmore, 1990; Bavendam, 1992). However, except for the fact that some of the increased use of health care and morbidity in women compared to men can be accounted for by gynecological and obstetrical problems (Gijsbers van Wijk et al., 1992), little is known about the possible impact of structural differences in pelvic organs on the mechanisms of pain.

As discussed by Slocumb (1984), one factor that could contribute to sex differences in pain derives from the fact that the vagina and cervix provide ready access to internal pelvic structures. Such access is of course important for sperm, but, like the mouth (and anus), that access also provides a route for the entrance of viral and other pathological agents. Susceptibility is high in the vagina because of its continual invasion by potentially damaging objects such as the penis during copulation, tampons during menstruation and various instruments during gynecological and obstetrical procedures. Phrased in another way, the vaginal canal and cervix increase the vulnerability in women of the T10-L1 (innervates uterus and cervix) and S2-S4 (innervates vagina and cervix) segments to morbidity (Bonica, 1990).

The consequences of such increased vulnerability and morbidity could be far reaching. To understand these potential consequences, it is necessary to consider five sets of evidence from the animal research literature. First, recent evidence in animals has shown that (a) peripheral pathological events can alter response characteristics of neurons within the dorsal horn of the spinal cord to produce a long-lasting state of hyperexcitability or "central sensitization" of those neurons and (b) that this state is probably part of the mechanism underlying certain chronic pain conditions that outlast their initial pathology (Woolf, 1984; McMahon, 1992; Coderre et al., 1993; McMahon et al., 1993). Second, input from C-fibers (which is the predominant type of fiber innervating the vaginal canal and cervix; Berkley et al., 1993) is particularly efficient at producing such states and probably does so not only by increased electrical activity but also by changes in the axonal transport of neuroactive substances induced by pathological events. (See discussions in Wall, 1989; Donnerer et al., 1992; Lewin et al., 1992; McMahon et al., 1993; Kitchener et al., 1994; Woolf et al., 1994). Third, viral agents have access via axonal transport in peripheral C-fibers not only to their spinal cord segment of entry but also transneuronally sequentially across several synapses to other parts of the spinal cord and brain (Card et al., 1990). Fourth, virtually all spinal dorsal horn neurons receive convergent input from local and distant sources, the input from distant sources arising both from diverging long-range peripheral afferent fibers (Wall and Shortland, 1991) and from multiple intraspinal linkages (see discussion in Wall et al., 1993; Berkley and Hubscher, 1994). Indeed, neurons in the C1-C2 segments of the spinal cord have recently been shown to receive input from and then provide a possible major influence back on neurons located throughout the entire length of the spinal cord (reviewed by Foreman, 1994; 1995). Fifth, dorsal horn neurons that have been provoked into a hyperexcitable state by peripheral pathological events appear to be able in turn to produce inflammatory changes and sensitize peripheral afferents back out in the periphery by a variety of efferent mechanisms both direct and indirect via sympathetic fibers (see discussions in Dubner and Basbaum, 1994; Levine and Taiwo, 1994; McLachlan et al., 1993; Rees et al., 1994; Sluka et al., 1994).

Taken together, these actions---central sensitization induced by alterations in C-fiber activity and transport, viral access via peripheral afferents across synapses in spinal cord and brain, intraspinal divergence and convergence and, finally, "retrograde" inflammation and hyperexcitability---produce a situation in which an initial noxious or pathological event at one locus could initiate a sequence of events that would eventually give rise to morbid conditions referred to multiple regions remote from the original site. Certain aspects of this scenario have indeed been postulated as the basis of referred hyperalgesia that occurs in association with many visceral pathological conditions (Vecchiett et al., 1993) sometimes to more than one locus (Slocumb, 1984; 1990) and as the basis for certain aspects of fibromyalgia (Goldenberg, 1993). The most common region of referral is to somatic loci within the same segments that receive input from the organs initially (but not necessarily currently) involved. However, multiple and long-range divergence-convergence patterns within the spinal cord and transneuronal transfer of viral agents clearly indicate the opportunity for a cascade of referrals to more distant ones, including the C1-C2 segments.

It is thus quite possible that a woman's vaginal canal provides her with an additional bodily entrance that puts her at increased risk relative to that of men for multiple sites of referred pain and hyperalgesia. Examples include fibromyalgia (because of multiple convergence patterns within the spinal cord; see Goldenberg, 1993) as well as certain types of headache and other facial/trigeminal pains as listed in Table 1 (because of the possible involvement of C1-C2). The clinical implications of this possibility are obviously significant.

What is important to remember about the scenario described above is that it would apply to males as well as females. In other words, although a woman's increased vulnerability could be at least part of the basis for the huge female predominance of certain forms of pain and for the fact that, overall, women report more multiple pains than men, the lesson to be derived from the analysis above applies to both sexes. That is, as discussed in the example of chest pain at the end of this article, diagnostic power and appropriate treatment in both sexes would be advanced by a more persistent pursuit and analysis of patterns of multiple symptomology (e.g., Fachinetti et al., 1993) and past history of pathological conditions (e.g., Laws, 1993).

Because of the importance of all three sex hormones (i.e., estrogen, progesterone and testosterone) to many aspects of life in both sexes (McEwen, 1991), how sex differences in those hormones affect pain is obviously unlikely to be straightforward. One obvious difference between the sexes, however, is in the temporal characterisitcs of estrogen and progesterone and testosterone levels (Goodman, 1994). All three change cyclically on a monthly cycle throughout most of a female's reproductive lifetime and episodically at puberty, during and after pregnancy and at menopause as well as gradually afterwards. Levels of these hormones in males also exhibit chronobiological changes, particularly with aging, but overall they are more stable than they are in females. Regardless of the compositional changes (to be discussed below), how might simply the temporal differences affect pain?

Much of the research on the impact of temporal hormonal characteristics on non-reproductive functions has focussed on menstrual or estrous cyclicity, although other biological rhythms obviously exist (e.g., Procacci et al., 1972; Moore-Ede et al., 1982; Binkley, 1992). In women, numerous conditions can be demonstrated to vary with menstrual cycle. Twelve examples include the following: memory (Phillips and Sherwin, 1992), creativity (Krug et al., 1994), mood disorders (Endicott, 1993), affective state (Johnston and Wang, 1991), thermoregulation (Kolka and Stephenson, 1989; Frascarolo et al., 1992), CO2 sensitivity (Dutton et al, 1989), caffeine elimination time (Lane et al., 1992), gastrointestinal transit time (Wald et al., 1981), wrist activity (Binkley, 1992), epilepsy (Newmark and Penry, 1980), the tics of Tourette syndrome (Schwabe and Konkol, 1992) and the symptoms of multiple sclerosis (Giesser et al., 1991; Smith and Studd, 1992).

Similar temporal variations are observed in female rodents. Nine examples include: binding of mu opioid receptors in the hypothalamus and GABAB receptors in the cerebral cortex (Maggi et al., 1993; Al-Dahan et al., 1994); norepinephrine levels in cerebral cortex (Parada et al., 1991); cannabinoid receptors in the hypothalamus (Rodríguez de Fonseca et al., 1994); galinin-like immunoreactivity in the spinal cord (Newton, 1992); glial characteristics in dentate gyrus (Luquin et al., 1993); seizure susceptibility for certain types of seizures (Woolley and Timiras, 1962; Thomas, 1990); susceptibility to viral innoculation (Teepe et al., 1990); cutaneous receptive field sizes of ganglion cells and peripheral nerves (Adler et al., 1977; Bereiter and Barker, 1980) and potency of central morphine analgesia (Kepler et al., 1989).

It is important to note that it is also sometimes the case that temporal variations are not observed. For example, menstrual variations were not observed in cardiovascular responses to mild stressors (Stoney et al., 1990) or in certain verbal or spatial cognitive tasks (Gordon and Lee, 1993) and estrous variations were not observed in seizure susceptibility to certain kindling procedures (Wahnschaffe and Löscher, 1992) or in various parameters of hippocampal electrical activity in struggling or immobilized awake rats (Mead and Vanderwolf, 1992). As discussed earlier in this article, this same sort of conflict in evidence demonstrating or failing to demonstrate menstrual or estrous variations exists for various pain conditions. It is thus necessary to conclude that while menstrual and estrous periodicities clearly exist for many conditions, it is also likely to be the case that certain subsets of individuals are more vulnerable to the temporal aspects of hormonal status than others and that those aspects are relevent only under certain circumstances. What will be important in the future is to characterize these subsets and circumstances.

In the meantime, despite the seemingly confused state of current knowledge, some conclusions can in fact be derived from these wide-ranging data. One conclusion is that the regular cyclical changes that females undergo throughout much of their lifetime have the potential of affecting their overall pain conditions in at least two important ways.

First, one possible consequence of menstrual/estrous periodicity could be the production of periodic experiences that by associative learning eventually do not require the same exogenous stimuli that originally provoked them. For example, time alone could come to serve as a discriminitive stimulus for pain, so that simply the passage of one month could give rise to certain "appropriate" pains, as it does in some women after menopause who continue to suffer from "dysmenorrhea." Another example is that animal data have shown that the hormones estradiol, progesterone and testosterone possess distinct stimulus properties and can therefore serve as discriminative stimuli for conditioning (Peeters et al., 1992; Heinsbroek et al., 1987). Thus, although it is unknown whether these hormones can similarly serve as discriminative stimuli in humans, if they can, then if a particular noxious stimulus is paired for several menstrual cycles with, say, high progesterone and estrogen just before menses (Ferin et al., 1993) or with high testosterone and estrogen just before ovulation (Vermeulen and Verdonck, 1976; Ferin et al., 1993), then, by associative learning, the presence of these hormones alone would give rise to experiences similar to the ones evoked by the original noxious stimulus; that is, pain. The net result of both of these associative learning cues (time, hormones) would be a greater number of pain conditions without obvious peripheral pathology in females than males.

Second, in addition to the possible consequences of menstrual/estrous cyclicity on "learned pain," the fact that such cycles also regularly subject females to a regularly fluctuating affective drive (Johnston and Wang, 1991) might give rise to regular fluctuations in their responses to either nociceptive events or treatments or in their interpretation of experiences as being painful or benign. The fluctuations could produce a situation in which some females develop a greater tolerance for various painful states and others develop an enhanced response to various stimulus events or experiences. The end result would be a greater variability in female pain behaviors than males. Such a situation could be part of the explanation, for example, for the seemingly conflicting data on coronary disease indicating on the one hand that many women with chest pains wait too long before seeking health care (Moser and Dracup, 1993) while many others have chest pains without evidence of cardiac pathology (Hsia, 1993; Sullivan et al., 1994).

While one message from these considerations is that menstrual cyclicity could put women at more risk than men for developing a wider range of pains without obvious peripheral pathology, the most important message is that chronobiological factors in general; that is, all types of temporal factors in addition to menstrual ones, are likely to be much more important for pain in both sexes than has been realized (Procacci, 1993; Lautenbacher and Rollman, 1993; Berkley, 1993). In other words, more active consideration is needed both in research and treatment of the impact of when and how regularly either nociceptive events have occurred or pain is reported as having been experienced on whether or not any given set of circumstances or treatments will produce or affect pain.

All three main sex hormones estradiol, progesterone and testosterone are functionally active in both sexes (Goodman, 1994). What varies are their relative concentrations in various tissues, the receptors for them in various tissues, certain aspects of their metabolism and, as discussed above, their temporal fluctuations. It is thus inappropriate to consider estrogen and progesterone as purely "female hormones" and testosterone as purely a "male hormone." It is also inappropriate to assume that all sex differences and all functions that vary with estrous or menstrual stage are due to the action of hormones (Reisert and Pilgrim, 1991).

Nevertheless, given the large changes that occur in estrogen and progesterone levels over the ovarian cycle as well as with puberty, pregnancy and menopause, it is not unreasonable to hypothesize that these hormones are functionally involved when an activity fluctuates with estrous/menstrual stage or as a function of puberty, pregnancy or menopause (Van Goozen et al., 1995). Similarly, given the large differences in testosterone and, at certain times, estrogen and progesterone between the sexes, it is not unreasonable to hypothesize that these hormones might be functionally involved in activities that exhibit sex differences. And finally, conversely, because of these changes and differences, if one of these hormones is demonstrated to be important for some function, then it is not unreasonable to hypothesize that that there would be sex differences in that function.

Given this logic, a number of intriguing possibilities applicable to possible sex differences in pain mechanisms in humans present themselves from the recent animal literature. Four of these possibilities will be considered here, on the following topics: the action of gamma aminobutyric acid (GABA) and other neuroactive agents, mechanisms of opioid and non-opioid analgesia, mechanisms of nerve growth factor (NGF) operation and sympathetic nervous system function.

GABA and other neuroactive agents. Numerous studies have now clearly demonstrated a very definite association between sex hormones and the action of GABA not only in epilepsy but also in many other aspects of neural function (Maggi and Perez, 1986; Perez et al., 1986; Lambert and Peters, 1989; Smith, 1991; Carey, 1992; Weiland, 1992; Grattan and Selmanoff, 1993; Jussofie, 1993; McCarthy, 1995), including pain (Schwartz-Giblin et al., 1989; McCarthy et al., 1990; Duncan and Frye, 1994; Frye and Duncan, 1994). How this association could produce operational differences in females and males is likely to prove complex but should be studied. For example, Westerling et al. (1991), showed that estrous stage influences the potentiation by barbiturate but not by benzodiazepine of primary afferent depolarization in slices of cuneate nucleus. One clear area is in the use of various pharmaceutical agents that act on GABAergic mechanisms whose effects on pain as well as other functions would then vary as a function of various hormonal states.

In addition to GABA, sex differences exist in the action of a number of other neuroactive agents such as serotonin (Kojima and Sano, 1984; Mendelson, 1992), dopamine (Beyer et al., 1992; Zanin and Takahashi, 1994), thyrotropin-releasing hormone (Deshpande et al., 1987), calcium-dependent nitric oxide (Weiner et al., 1994) and various peptides (Micevych et al., 1988; Newton et al., 1990). Most of these sex differences (Biegon et al., 1980; Fischette et al., 1984; Fernandez-Ruiz et al., 1991; Peris et al., 1991; Demotes et al., 1993; Weiner et al., 1994), but not all of them (Beyer et al., 1992; Ovtscharoff et al., 1992) appear to be related to hormonal action.

Because all of these substances are variously involved in pain mechanisms, the sex differences in their action together with those associated with GABA are likely to be of importance for overall sex differences in the mechanisms of pain and its control. As highlighted in an elegant review of the mechanisms of migraine (Marcus, 1995), this important possibility currently cries loudly to be addressed.

Opioid and non-opioid analgesia. One arena where the sex and hormonally-associated differences in the action of neuroactive agents is of clear relevance is analgesia. Recently, a substantial number of animal studies have emerged demonstrating sex differences in many aspects of analgesia. For example, female rats show less analgesia to morphine than do males (Bodner et al., 1988). As thoroughly reviewed by Fillingim and Maixner, 1995, these differences have been shown to depend upon how the analgesia is induced and to involve a number of opioid and non-opioid mechanisms, many of which are modulated by the action of estrogen and other steroids (Romero and Bodnar, 1986; Bodnar et al., 1988; Ryan and Maier, 1988; Baamonde et al., 1989; Kepler et al., 1989; 1991; Kavaliers and Colwell, 1991; Ratka and Simpkins, 1991; Dawson-Basoa and Ginzler, 1993; 1995; Islam et al., 1993; Kavaliers and Innes, 1993; Mogil et al., 1993; Aloisi et al., 1994) as well as by various reproductive conditions such as multiparity (Mann and Bridges, 1992).

As discussed in a recent issue of The Journal of NIH Research (Touchette, 1993), although it is clear that sex differences in pain modulatory mechanisms exist in animals, the mechanisms at work to produce these differences are not yet understood. The potential for this difference being of importance in humans is obvious, where very few clinical studies on this issue exist (e.g., DeKock and Scholtes, 1991) and where currently only brief mentions are made of sex, hormonal or chronbiological factors that might affect anesthetic or other drug usage in humans (Collins, 1993; Hrushesky, 1994).

NGF. In addition to its action on nerve development and sprouting, nerve growth factor has recently been found to be actively involved in many aspects of nociception, including inflammation, hyperalgesia and the regulation of afferent activity (Fitzgerald et al., 1985; Donnerer et al., 1992; Lewin et al., 1992; McMahon, 1992; Lewin and Mendell, 1993; Woolf et al., 1994). In certain circumstances, e.g., in female rat vocalizations and rejection behaviors during mating, this NGF involvement has been shown to depend on estrogen and progesterone conditions (Gibbs et al., 1993). Sex hormones are potently involved in inflammatory mechanisms as well as immune system functions important for inflammatory effects in diseases such as rheumatoid arthritis (e.g., DaSilva and Hall, 1992; Lahita, 1992; Szekeres-Bartho, 1992; DaSilva et al., 1993). Furthermore, estrogen receptors are prevalent throughout the nervous system where they develop in a sexually dimorphic manner in some regions (Kornack et al., 1991) and co-localize with receptors for NGF, including parts of the spinal cord relevant to pain (Toran-Allerand et al., 1992a, b; MacClusky et al., 1987; Morrell et al., 1982; Keefer et al., 1973; Urschel and Hulsebosch, 1992). And, finally, estrogen regulates NGF receptor mRNAs in sensory neurons and GAP-43 mRNAs in various parts of the CNS (Shughrue and Dorsa, 1993; Sohrabji et al., 1994).

Taken together, these facts suggest that NGF may operate differently in females and males in circumstances important for both peripheral and central plastic changes associated with pain. It is difficult to predict from these fast emerging and sometimes confusing data (e.g., NGF can both alleviate and increase pain under different circumstances) what the sex differences might be, but they could have important implications for the mechanisms of persistent pain (e.g., an increased vulnerability in women for the development of sympathetically-maintained pain; see below), for temporal aspects of surgery (e.g., certain menstrual conditions might promote postoperative recovery better than others; Emerson et al, 1993) and for the use of pharmacological agents now under development that act on NGF (e.g., Apfel, 1992; some of these agents might act differently in males and females under different reproductive conditions).

Sympathetic Nervous System Function. It is evident from a perusal of Table 1 that a large proportion of the disorders that show differences in their sex prevalence characteristics involve the cardiovascular system and visceral organs, particularly gastrointestinal structures. As discussed above, further analysis of some of these disorders shows that their pain components are influenced by menstrual stage, reproductive status or hormonal treatments. These sex differences could therefore be due in part to sex differences in the operation of the autonomic nervous system.

Structural differences. Numerous studies have provided evidence for sex differences in the structural organization of many groups of neurons throughout the CNS, mainly in brain regions directly associated with reproduction. These differences occur as a result of both hormonal and non-hormonal influences during development (reviewed in Kelley, 1986; Reisert and Pilgrim, 1991; Tobet and Fox, 1992; Breedlove, 1994). Structural sex differences, however, also appear to be produced during development in neural systems associated more generally with other physiological functions. Thus, Calaresu and Henry showed in 1971 and 1972 that there were many fewer sympathetic preganglionic neurons in the spinal cords of female cats than male cats, with a female to male ratio of 0.78 (Calaresu and Henry, 1971; Henry and Calaresu, 1972).

The possibility of an overall sex difference in the structural features of the sympathetic supply to internal structures has a number of implications important for pain. Differences in afferent input from internal structures to the CNS via sympathetic nerves could not only produce different visceral pains in females and males (such as those referred to earlier in this article for various painful diseases), but, assuming the importance of visceral input for the perception of emotions (James, 1884; Lange and James, 1967), sex differences in visceral afferent input could also result in different emotional consequences of pain experiences. Differences in the efferent supply of different viscera through sympathetic nerves as demonstrated by Calaresu and Henry would affect the responses of these organs to various stimuli that would in turn affect the interpretation of those stimuli through afferent mechanisms.

Functional differences. Considerable evidence supports the possibility of important sex differences in the functional organization and operation of the sympathetic system. In humans at rest, overall integrated levels of resting sympathetic nerve activity to skeletal muscles through the right peroneal nerve are lower in women than men (Ng et al., 1993). On the other hand, higher sympathetic output to the skin in women than men appears to account for lower basic levels of skin blood flow and perfusion in women (Cooke et al., 1990). In response to various stressors, Morrison and Pickford showed in 1971 that sympathetic nerve activity was differentially sensitive in female and male cats and dogs to arterial pressure changes induced by angiotensin and noradrenalin. These effects occurred mainly at higher pressures and were attributed by the authors to sex differences in the state of the blood supply to arterial chemoreceptors. Along these lines, Maixner and Humphrey (1993) found clear sex differences in humans in cardiovascular responses to forearm ischemia, with males having greater blood pressure responses during post-exercise ischemia. Interestingly, only in males did pain assessments of the ischemia correlate with the cardiovascular responses. Similarly, sex differences in adrenergic sensitivity leading to different patterns of cardiovascular responses to various stressors have been observed in humans (e.g., Claustre et al., 1980; Girdler et al., 1993) and these differences have been shown in animals to have important consequences for the action of alpha 2 adrenoreceptor pharmacological agents, some of which, such as clonidine, are of value for pain control (e.g., Heal et al., 1989).

Evidence exists in other arenas of autonomic function as well. For example, gastrointestinal transport and absorption are influenced so powerfully by the menstrual cycle (McBurney, 1991; Wald et al., 1981) that certain gastrointestinal disorders occur almost invariably in females (MacDonald, 1993). Norepinephrine levels and release in the cerebral cortex are influenced by the estrous cycle in rats (Parada et al., 1991). Of relevance to possible sex differences in sympathetic functions related to cutaneous and muscle pain are results showing that sweating, skin blood flow and postural vasoconstriction reflexes are powerfully influenced by menstrual cycle in normal women (Frascarolo et al., 1992; Kolka et al., 1989; Bartelink et al., 1990; Hassan et al., 1990) and there are sex differences in peripherally reflexly-induced muscle atrophy produced by bone fractures (Urbancova et al., 1993). And finally, there are sex differences in the CNS, sometimes modulated by hormonal conditions, of responses to traumatic events such as hemorrahge, contusion and electroconvulsive shock (Heal et al., 1989; Öztas et al., 1991; 1992; Roof et al., 1992; Iyengar and Laycock, 1993; Emerson et al., 1993; Stein, 1995) that are of relevance to pain (Wiesenfeld-Hallin et al., 1993).

Another important realm in which sex differences in sympathetic function would be important for pain, particularly persistent or chronic pain, relates to plastic changes in sympathetic action induced by injury. Recently, McLachlan et al. (1993) observed large increases in noradrenergic fibers surrounding dorsal root ganglion cells in response to ligation of the sciatic nerve in rats. Although the authors stated that there were no sex differences in this sprouting response, their study did not directly address the issue. In other studies where the issue has been directly addressed, sprouting of sympathetic fibers into the hippocampus induced by neural injury has been shown to be more restricted in male than in female rats and to be affected by neonatal (but not adult) manipulations of testosterone levels (Milner and Loy, 1982). Evidence exists as well for the involvement of both estrogen and testosterone in plastic responses to injury under other circumstances (Kujawa et al., 1991; Jones, 1988; Demotes-Mainard et al., 1993). And finally, the associations discussed above between NGF's functions in injury-induced sprouting and inflammation and pain and the interactions between NGF and sex hormones together enhance even more the possibility of sex differences in the plastic changes of sympathetic action induced by injury.

One net result of such differences in humans could be that females might be either at a greater risk of developing more potent forms of a condition involving the sympathetic nervous system variously referred to as reflex sympathetic dystrophy, causalgia or sympathetically maintained pain (Roberts, 1986; Jänig et al., 1991; Jänig, 1992; Campbell et al., 1992), or their symptoms might vary as a function of these conditions or they might be affected differently than males by treatments for this condition, especially in certain hormonal conditions.

Very little evidence exists directly related to this hypothesis, but it is certainly the case that there is a large female predominance of subjects reported in most studies of sympathetically maintained pain, causalgia or reflex sympathetic dystrophy. Although in one study, no sex differences were reported in responses to guanethedine blocks for algodystrophy in humans (Eulry et al., 1991), Abelli et al (1993) reported that while sympathectomy abolishes corneal lesions produced by neonatal sensory denervation with capsaicin in female rats, it only reduces those lesions in male rats. Similarly in another study currently underway at Johns Hopkins (e.g., see Shir et al., 1993), so far the ratio of females to males whose pains are greatly reduced by phentolamine (e.g., those classified by the authors as suffering from sympathetically-maintained pain) is greater than the female to male ratio of patients whose pains are only slightly reduced or unaffected (e.g., those classified as suffering from another form of pain; Campbell, personal communication).

Thus, women may have a better response than men to certain forms of therapy that address pathological alterations in sympathetic function or they might respond differently to such therapies under different hormonal conditions. For example, this possibility could relate to the fact that men are more at risk of developing duodenal ulcers than women (Schubert et al. , 1993). Clearly, the issue warrants further study.

Taken together, inductive analysis of the available literature indicates that for experimentally-induced acute somatic (usually skin) stimulation, females often have lower thresholds, greater ability to discriminate, higher pain ratings and less tolerance of noxious stimuli than males. The evidence also indicates, however, that these differences are inconsistently observed, relatively minor, exist only for certain forms of stimulation and can be affected by numerous situation variables in daily life such as the presence of disease, the setting of the experiment, the characteristics of the experimenter and even nutritive status.

The relevance of these minor differences to the clinical situation seems questionable (Berkley, 1995), because, in contrast to experimentally-induced pain, endogenous pains most often involve pains that are episodic, persistent or chronic (as well as acute) and that are more likely to involve muscles and internal organs than skin. However, results from studies of endogenous pains do indicate some sex differences. Thus, women report more multiple pains in a greater number of body regions than men. Some painful diseases are more prevalent among females, while some are more prevalent among males, with no basis yet evident for these differences. For many diseases, symptoms differ between females and males, again with no obvious rational basis. Some pains vary with hormonal status of females or males, once again with no clear basis for the variability. And finally, substantial differences in attitudes exist not only in the individual experiencing pain and thereby affecting her/his reporting and coping behaviors and responses to treatment, but also in the individual taking the measures and thereby affecting how and what measures are made and what treatments are carried out.

Taking all of this information together, the major consequence of so many diverse factors being operative in both experimental and clinical settings is that the most striking feature of sex differences in reported pain experiences is the overall apparent lack of them.

On the other hand, deductive analysis of the available literature gives rise to a number of possible factors that could operate differently to affect pains in females and males. Three examples are discussed here. First, the existence of a vaginal canal vulnerable to trauma or invasion by pathological agents in females and not males together with the existence of neural mechanisms of sensitization and divergence that operate to give rise to referred hyperalgesia in regions remote from the initial source of the problem could put females at greater risk than males of developing hyperalgesia in multiple regions remote from the initial problem. Second, differences in temporal patterns of many aspects of life produced by differences in temporal patterns of sex hormones could give rise to sex differences in how pain is "learned" and how various sensory experiences are interpreted, the net result being a greater variability and wider range of pains without peripheral pathology in women. Third, differences in compositional aspects of hormones give rise to a number of hypotheses associated with the actions of estrogen, progesterone and testosterone. Thus, there are sex and hormonally-dependent differences in the operation of GABA and other neuroactive substances that could produce both sex differences and hormonally-dependent differences in pain modulatory situations where those substances are operative and in the actions of their agonist and antagonist pharmacological agents. Along these lines, recent evidence is emerging on the existence of fundamental sex and hormonally-dependent differences in both opioid and nonopioid mechanisms of analgesia, the potential clinical implications of which are substantial but as yet unclear. In another arena, potential sex and hormonally-dependent differences in the organization and operation of the sympathetic nervous system give rise to the possibility of sex and hormonally-dependent differences in visceral symptomology for various diseases and the cardiovascular and emotional sequelae of noxious events. These differences also are relevent to pain situations in which the sympathetic system may be involved in the production of hyperalgesic states as a result of injury. This relevance is strengthened by evidence suggesting that sex and hormonal factors are likely to be involved in the operation of NGF both centrally and peripherally.

It is not immediately evident how conclusions such as these derived from inductive and deductive approaches to the literature might be applied to future research and current treatment of humans and animals. It is clear, however, that when patient A appears in a health care facility to report that she or he is experiencing, say, chest pain, a large number of variables have already contributed to that report that may have only a seemingly remote relation to the cause of A's pain. On the other side of the scene, a large number of seemingly remote factors also enter into the response of the health care worker B, who is faced with A's report of chest pain. These remote factors operate together to have a large impact on A's overall health.

It is also evident, moreover, that both A and B's sex is one of the more important factors that must be considered in this scenario. In fact, the issue of sex and hormonal factors in the significance, diagnosis and treatment of cardiac pain and cardiac disease is currently under intense scrutiny and on the verge of important findings (Cabral et al., 1988; Ditrich et al., 1988; Dewhurst et al., 1991; Harris and Weissfeld, 1991; Garber et al., 1992; Heston and Lewis, 1992; Behar et al., 1993; Chae et al., 1993; Hamilton and Seidman, 1993; Hsia, 1993; Karlson et al., 1993; Moser and Dracup, 1993; Seeman, 1993; Mark et al., 1994; Puntillo and Weiss, 1994; Sullivan et al., 1994; Vacek et al., 1995). Perhaps then it is not an exaggeration when modern philosophers make statements such as the following:

"Sexual difference is one of the major philosophical issues, if not the issue, of our age....Sexual difference is probably the issue in our time which could be our 'salvation' if we thought it through (Irigeray, 1993, p. 5)."

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