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Sex differences have been ascribed mainly to hormonal and life-span factors, while neglecting chromosomal and socio-cultural determinants. Science is now reviewing the disregard for sex and gender as a potential explanation for the lack of expected outcomes in whole populations from clinical research. The medical research process begins with a hypothesis that is applied, generating results that can be disseminated. Many factors impact on this process that can be ascribed to sex, as a biological construct, and gender, as a psychosocial process involving experimental subjects, research- ers, funders and the public. Drug trial data analysis and publication of data from women and men have recently been scrutinized and found lacking, because expected clinical outcomes from ‘evidence-based’ guidelines are not being achieved. Hence visibility of sex and gender in all aspects of medical research is considered essential if personalized therapies are to bring benefits to both men and women.

Endometriosis is a painful disorder defined by extrauteral endometrial growths whose contribution to pain symptoms is poorly understood. Endometriosis is created in rats by autotransplanting on abdominal arteries pieces of either uterus (ENDO), which form cysts, or fat (shamENDO), which do not form cysts. ENDO, but not shamENDO induces vaginal hyperalgesia. We tested the hypothesis that the cysts are necessary to maintain vaginal hyperalgesia by assessing the effect of surgically removing them. Complete cyst removal eliminated ENDO-induced vaginal hyperalgesia up to four months post-operatively. Sham-cyst-removal in ENDO rats, in which cysts were not removed, or partial cyst-removal increased the ENDO-induced hyperalgesia. The decreases and increases both took three to six weeks to develop. Changes in ENDO-induced hyperalgesia did not occur in a control group of ENDO rats who had no surgery after ENDO. In a double-surgery control group, neither shamENDO surgery nor a subsequent sham surgery that mimicked “removal” of non-existent cysts influenced vaginal nociception. In a no-surgery control group, vaginal nociception remained stable for > six months. The increases in ENDO-induced hyperalgesia produced by the sham-cyst-removal surgery were smaller in proestrus than in other estrous stages. During the other stages (but not during proestrus), sympathetic innervation of the cysts increased. These results suggest that maintenance of ENDO-induced vaginal hyperalgesia requires continued presence of at least some ectopic endometrial tissue, and that surgical treatment that fails to remove ectopic endometrial tissue can exacerbate the hyperalgesia, possibly due in part to an increase in the cysts’ sympathetic innervation.

Endometriosis (ENDO) is a painful disorder defined by extrauteral endometrial growths. It is created in rats by autotransplanting pieces of uterus (which form cysts), or, for shamENDO, fat (no cysts). ENDO induces vaginal hyperalgesia, likely via central sensitization. The severity of this hyperalgesia correlates with estradiol levels during the estrous cycle, suggesting the hyperalgesia is estradiol-modulated. If so, then hyperalgesic severity should track estradiol changes during reproductive senescence (estropause) when estradiol levels initially decrease, then increase. Using psychophysical methods to assess vaginal nociception, we found that the severity of ENDO-induced hyperalgesia paralleled estradiol changes during estropause: hyperalgesia first decreased, then returned. Furthermore, the return occurred regardless of the presence of the cysts (excised in some rats). This finding provides further support for ENDO's likely centrally-mediated effects. Additionally, the results suggest that elimination of estradiol via ovariectomy (OVX) should alleviate ENDO-induced hyperalgesia and estradiol replacement should restore it. However, in healthy and shamENDO rats, OVX produces a vaginal hyperalgesia that is alleviated by estradiol, likely via estradiol's peripheral influences on the vagina. Hence, we tested the hypothesis that OVX in ENDO rats would trigger a different type of vaginal hyperalgesia dependent on the loss of estradiol. We predicted that the opposing influences of estradiol on ENDO- and OVX-induced hyperalgesia would cancel each other. As predicted, OVX had no effect on ENDO-induced hyperalgesia and estradiol replacement alleviated it. These results suggest that, in intact rats, ENDO-induced vaginal hyperalgesia is exacerbated by estradiol, and that different mechanisms underlie ENDO-induced versus OVX-induced vaginal hyperalgesia.

This study examined pseudoaffective responses elicited by vaginal distention in urethane-anesthetized rats, and tested hypotheses that responses would be increased by endometriosis (ENDO) and vary with the estrous cycle. Three groups were studied: ENDO, shamENDO, and Naïve. ENDO was induced by autotransplantating small pieces of uterine horn (or, for shamENDO, fat) on mesenteric arteries. Ten weeks later, rats in proestrus or metestrus were anesthetized with urethane. Distendable latex balloons were inserted into the vaginal canal. While an increasing series of vaginal distentions was delivered, changes in electromyographic activity of the external oblique musculature (visceromotor response, VMR) and mean arterial pressure (pressor) responses were simultaneously measured. Vaginal distention produced VMR and pressor responses in all groups. These responses were significantly greater in ENDO than in the other groups, and greater in proestrus than metestrus. Although the overall amount of cystic tissue was greater in proestrous than metestrous rats, there was no correlation between these amounts and VMR or pressor responses. Acute spinalization (T8-T9) and bilateral pelvic, but not hypogastric neurectomy attenuated both VMR and pressor responses, supporting the hypothesis that vaginal nociception involves suprathoracic spinal processing of information conveyed by the pelvic nerve. These effects on VMR and pressor responses to vaginal distention parallel behavioral escape responses to the same stimuli reported previously. The findings encourage continued use of VMR and pressor responses for further investigation of mechanisms underlying pain associated with ENDO and its potential treatment.

In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"

Studies have shown that the severity of bladder hyperreflexia induced by acute bladder inflammation varies with the ovarian cycle. These results suggest that the hyperreflexia is modulated by ovarian hormones. Other studies have suggested that such modulation involves the bladder's sympathetic innervation. These hypotheses were tested by assessing the development of bladder hyperreflexia in urethane-anesthetized rats subjected to different hormonal manipulations with or without bilateral hypogastric neurectomy (HYPX). The groups included sham ovariectomy (sham OVX), ovariectomy (OVX), OVX with estradiol replacement (OVX+E), OVX+HYPX, and OVX+HYPX+E. Assessments were performed using repeated cystometrograms (CMGs) to measure micturition thresholds (MT) before and hourly for 3 h after intravesicular treatment with 50% turpentine oil (or olive oil in an OVX+E control group). In the uninflamed bladder, treatment with estradiol increased MTs in the OVX+E group compared with the OVX group. As expected, bladder inflammation induced bladder hyperreflexia in sham OVX rats (studied in estrus). This hyperreflexia was eliminated by OVX and restored by either estradiol replacement or HYPX. Combining estradiol replacement and HYPX (i.e., OVX+E+HYPX) did not increase the severity of bladder hyperreflexia compared with either manipulation alone. These results indicate that the bladder hyperreflexia that is induced by bladder inflammation requires the presence of estradiol and suggest that this hormonal modulation is exerted via the sympathetic control of the bladder, possibly via an increase of β-adrenergic inhibitory actions on the detrusor muscle. Similar mechanisms may contribute to bladder disorders in postmenopausal women.

Pelvic pain associated with menstruation, i.e., dysmenorrhea, is a chronic pelvic pain that not only interferes with a woman's wellbeing for a large part of her life but also often co-occurs with other chronic painful conditions such as interstitial cystitis and irritable bowel syndrome and others. Little has been known about mechanisms underlying these chronic pelvic pains. This paper reviews 37 years of research in my laboratory at Florida State University on such mechanisms. Our research, mostly on rats, has contributed to the following findings: (1) Female reproductive organs are innervated in a topographic fashion by afferents in the pelvic (vagina/cervix) and hypogastric (cervix/uterine horn) nerves. (2) The input contributes to uterine and vaginal perceptions (nociception) that are modified by reproductive status. (3) Throughout the CNS, neurons responsive to stimulation of the reproductive tract also respond to stimulation of skin and other internal organs, in a manner modifiable by reproductive status and peripheral pathophysiology. (4) This dynamic physiological convergence may reflect extensive anatomical divergence of and interconnections between pathways entering the CNS via gateways through the spinal cord, dorsal column nuclei, and solitary nucleus. (5) The convergence also indicates the existence of extensive cross-system, viscero-visceral interactions within the CNS, that, while organized for coherent bodily functioning, serves as a substrate by which pathophysiology in one organ can influence physiology and responses to pathophysiology in other organs. (6) Some cross-system effects observed so far include: (a) Bladder inflammation reduces the rate of uterine contractions and the effects of drugs on the uterus. (b) Colon inflammation produces signs of inflammation in the otherwise healthy bladder and uterus. (c) A surgical model of endometriosis produces vaginal hyperalgesia, exacerbates pain behaviors induced by a ureteral stone, and reduces volume voiding thresholds if the bladder. These cross-system effects, which likely involve CNS mechanisms, likely also underlie co-occurrence of painful clinical conditions. Research continues on details of these mechanisms and their relevance for clinical diagnosis and therapy. None of this work could have been done without collegial support of colleagues and technical staff at Florida State University.

Endometriosis (ENDO) is a disorder in which vascularized growths of endometrial tissue occur outside the uterus. Its symptoms include reduced fertility and severe pelvic pain. Mechanisms that maintain the ectopic growths and evoke symptoms are poorly understood. One factor not yet considered is that the ectopic growths develop their own innervation. Here, we tested the hypothesis that the growths develop both an autonomic and a sensory innervation. We used a rat model of surgically induced ENDO whose growths mimic those in women. Furthermore, similar to women with ENDO, such rats exhibit reduced fertility and increased pelvic nociception. The ENDO was induced by autotransplanting, on mesenteric cascade arteries, small pieces of uterus that formed vascularized cysts. The cysts and healthy uterus were harvested from proestrous rats and immunostained using the pan-neuronal marker PGP9.5 and specific markers for calcitonin gene-related peptide (CGRP) (sensory C and Aδ fibers), substance P (SP) (sensory C and Aδ fibers) and vesicular monoamine transporter (sympathetic fibers). Cysts (like the uterus) were robustly innervated, with many PGP9.5-stained neurites accompanying blood vessels and extending into nearby luminal epithelial layers. CGRP-, SP-, and vesicular monoamine transporter-immunostained neurites also were observed, with CGRP and SP neurites extending the furthest into the cyst lining. These results demonstrate that ectopic endometrial growths develop an autonomic and sensory innervation. This innervation could contribute not only to symptoms associated with ENDO but also to maintenance of the ectopic growths.

Objecties: The loss of ovarian function in women through aging or oophorectomy is often associated with the development of vaginal hyperalgesia that can be alleviated with estrogen replacement. This study examined if ovariectomy in rats would similarly give rise to vaginal hyperalgesia, and, if so, whether estrogen replacement would alleviate it. Methods: Female rats were trained to perform an operant response to escape vaginal distention delivered by inflating a balloon located in mid-vaginal canal. Percent escape responses to eight different volumes of distention measured in normally cycling rats were compared with measures made in the same rats following ovariectomy (OVX) or sham ovariectomy (shamOVX), and then, in the OVX group, estrogen replacement (OVX + E2). Pressures exerted by the eight volumes on the vaginal wall were also measured, thereby permitting assessment of vaginal tone. Results: Whereas overall escape response percentages after OVX, but not shamOVX, were significantly higher to the largest six distention volumes compared with responses during cycling, there were individual differences in the amount of hyperalgesia. Following OVX +E2, escape response percentages decreased in all but one rat. Vaginal tone after OVX, shamOVX or OVX+E2 did not differ from overall vaginal tone in cycling rats. Conclusions: Ovariectomy in rats evokes a variable amount of vaginal hyperalgesia that can be alleviated by estrogen replacement in most cases. Thus, the ovariectomized rat appears to provide a useful model for the study of mechanisms underlying the dyspareunia that is associated with loss of ovarian function in women. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Endometriosis and urinary calculosis can co-occur. Clinical studies have shown that both painful and non-painful endometriosis in women are associated with enhanced pain and referred muscle hyperalgesia from urinary calculosis, but the mechanisms underlying this phenomenon are still poorly understood. The aim of this study was to develop an animal model adequate to explore this viscero-visceral interaction in standardized conditions. Using a model of endometriosis previously developed to study reduced fertility and vaginal hyperalgesia, endometriosis (endo) or shamendometriosis (sham-endo) was induced in rats by autotransplantation of small pieces of uterus (or, for sham-endo, fat) on cascade mesenteric arteries, ovary, and abdominal wall. After the endometrial, but not the fat autografts had produced fluid-filled cysts (3 weeks), urinary calculosis was induced by implanting an artificial stone into one ureter. Pain behaviors were monitored by continuous 24-h videotape recordings before and after stone implantation. Referred muscle hyperalgesia was assessed by measuring vocalization thresholds to electrical stimulation of the oblique musculature (L1 dermatome). The data were compared with previously reported data from rats that had received only the stone. Neither endo nor sham-endo alone induced pain behaviors. Following stone implantation, in endo rats compared to sham-endo and stone-only rats, pain behaviors specifically associated with urinary calculosis were significantly increased and new pain behaviors specifically associated with uterine pathology became evident. Muscle hyperalgesia was also significantly increased. To explore the relationship between the amount of endometriosis and that of ureteral pain behavior, two separate groups of endo rats were treated with either a standard non-steroidal anti-inflammatory drugs (ketoprofen) or placebo from the 12th to the 18th day after endometriosis induction. The stone was implanted on the 21st day. Ketoprofen treatment compared to placebo significantly reduced the size of the cysts and both ureteral and uterine pain behaviors post-stone implantation. The size of the cysts showed a significant linear correlation with the poststone ureteral pain behaviors. In conclusion, endo increased pain crises and muscle hyperalgesia typically induced by a ureteral calculosis, and the ureteral calculosis revealed additional pain behaviors typically induced by uterine pathophysiology; and this enhancement was a function of the degree of endometriosis. This result closely reproduces the condition observed in humans and could be due to a phenomenon of ‘viscero-visceral’ hyperalgesia, in which increased input from the cyst implantation sites to common spinal cord segments (T10-L1) facilitates the central effect of input from the urinary tract. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.

Recent evidence suggests that lower urinary tract functions may be influenced by reproductive status, particularly under pathophysiological conditions. This study used repeated cystometrograms via a transurethral catheter to investigate the influence of estrous stage on micturition thresholds before and after turpentine-induced bladder inflammation in urethane-anesthetized female rats. Whereas there were no estrous influences on micturition threshold in the uninflamed bladder, micturition thresholds after bladder inflammation were significantly lower in rats in proestrus or estrus than in rats in metestrus or diestrus. Furthermore, the risk that the initial urethral catheterization and preinflammation cystometrogram would produce hematuria was significantly lower in estrus than in the other stages. These estrous influences are not readily explicable by levels of ovarian hormones at the time of testing and may relate instead to dynamic interactions between these hormones and other neuroactive molecules. In addition, the results here have relevance to interpretations of cystometrographic findings in the clinic and basic research.

This study examined whether a rat model of surgically-induced endometriosis that reduces fertility also evokes vaginal hyperalgesia along with changes in vaginal compliance. In nine rats trained to escape vaginal distention, percent escape responses to different volumes of vaginal distention were measured for 2.5 months before and after endometriosis or sham surgery. Vaginal pressures were also measured simultaneously to provide an estimate of vaginal compliance. Endometriosis (or sham) was induced by autotransplantation of small pieces of uterus (or fat) on mesenteric cascade arteries, abdomen, and ovary. Escape responses were significantly increased only in rats whose autotransplants had formed cysts. Vaginal pressures, however, remained unchanged. This vaginal hyperalgesia may involve a process of viscero-visceral referred hyperalgesia.

Anatomical data indicate that the rat uterine horn is innervated primarily by afferent fibers in the hypogastric nerves, suggesting that hypogastric neurectomy, but not pelvic or pudendal neurectomy, should eliminate behavioral responses to uterine horn stimulation. To test this hypothesis, detection and escape responses of rats to different volumes of uterine horn distention (via an indwelling intrauterine balloon) were compared before and after bilateral hypogastric (n = 9), sham-hypogastric (n = 3), pelvic (n = 3), or pudendal (n = 2) neurectomies. As predicted, sham-hypogastric, pelvic, and pudendal neurectomies had no effect on the rats' responses. However, although hypogastric neurectomy completely eliminated responses in five rats whose postmortem evaluation revealed no signs that the uterine balloons had evoked any pelvic pathophysiology, the neurectomy had no effect on the responses of an additional four rats. Postmortem evaluation of these rats revealed gross signs of severe pathology in the vicinity of the balloon in two rats, and evidence that the balloon had shifted caudally so that it was stimulating the cervix rather than the uterine horn in a third. In the fourth rat, pathophysiology had been deliberately induced by the prior implantation of a small pellet that released approximately 1 microg/day of prostaglandin PF2alpha over the uterine horn. Similar findings have been reported in clinical studies on the efficacy of hypogastric ('presacral') neurectomy for dysmenorrhea. Together, the findings support the hypothesis that the major source of afferent innervation of the uterine horn in healthy rats and women is the hypogastric nerve but that the situation changes under conditions of pelvic pathology. Such changes could include additional activation of afferent fibers in nerves that supply other pelvic organs, activation by the uterine pathophysiology of latent uterine innervation from afferent fibers in the pelvic, vagus or ovarian plexus nerves, or some form of central sensitization.

B uried in the she-poetry and interpretation of the literature of the Focus article by AI-Chaer and colleagues is an emotional and potent threepoint message, as follows: First, compassion dictates that if we have strong reasons to believe that a treatment for pain can alleviate it, we should use that treatment, regardless of our ignorance of how it works or debates about the neural mechanisms of pain. Second, a small bilateral dorsal column lesion (limited myelotomy) can alleviate visceral pain with no permanent side effects. Third, the use of such a lesion to treat chronic visceral pain conditions is therefore encouraged. How could anyone disagree with the first message on the use of known effective remedies? Clinicians follow that dictum in many realms of healthcare, and we all follow it in our own personal lives. However, as I have argued recently [1] and will argue again here, such behavior does not mean that clinical approaches to treating patients and the success of those approaches are unaffected by our conceptualizations of treatment action or pain mechanisms. As for the second and third messages, evidence so far does indeed support the idea that limited myelotomy might alleviate certain visceral pains. Thus, to deny it in those cases simply because we do not yet understand how it works would be cruel indeed. However, we must remember that dorsal column lesions destroy forever one major route by which information about many bodily conditions (innocuous and nociceptive, occurring in somatic and visceral tissues), is conveyed from the periphery into the central nervous system, thence diverging to many parts of the brain to converge with information

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 that these are 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 temporal patterns 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 nonopiate 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.

Sex is one of biology's, that is, life's most potent experimental variables. So, are there sex differences in pain? And are these sex differences applicable clinically? The answer to both questions is decidedly yes, of course. But we still have a long way to go. We have much to learn from the study of females, making use of the lifelong changes in their reproductive conditions as experimental variables. We also have much to learn from animals, especially if we apply what we know about their social lives. However, the challenge in all of these studies is not first to look for some mythical neurological entity called pain experience and then to learn how sex modulates it, but rather to seek to understand the rules by which sex influences all of biology's mutually modulatory factors – social, psychological, physiological, cellular, molecular, and genetic – that collectively create the motivating circumstances we designate as pain. It appears almost beyond doubt that on the one hand these factors interact to make women more vulnerable to these circumstances than men, but on the other hand that women have more varied mechanisms for balance. Happily, the details of these sex differences at all levels biological (social to genetic) are now emerging in a rapidly growing body of literature that promises new insights into and applications for the individual person, male or female, in persistent pain.

Pain symptoms of many disorders are reported to vary with menstrual stage. This study investigated how pain thresholds to electrical stimulation of the skin, subcutis and muscle tissue varied with menstrual stage in normal women and compared these variations with those in women with dysmenorrhea and in healthy men at matched intervals. Thresholds of the three tissues were measured four times during the course of one menstrual cycle at four sites. Two of the sites were on the abdomen within the uterine viscerotome (abdomen-rectus abdominis, left and right) and two were outside it on the limbs (leg-quadriceps, arm-deltoid). Calculated from the beginning of menstruation (day 0), the menstrual phases studied were menstrual (days 2-6), periovulatory (days 12-16), luteal (days 17-22) and premenstrual (days 25-28). Spontaneous pain associated with menstruation was measured from diary estimates on a VAS scale. Whereas the highest thresholds always occurred in the luteal phase regardless of segmental site or stimulus depth, the lowest thresholds occurred in the periovulatory stage for skin, whereas those for muscle/subcutis occurred perimenstrually. Dysmenorrhea accentuated the impact of menstrual phase. For non-dysmenorrheic women menstrual trends were significant only in abdominal muscle and subcutis, but for dysmenorrheic women the trends were also significant in abdominal skin and in limb muscle and subcutis. Dysmenorrhea also lowered thresholds mainly in muscle and sometimes in subcutis, but never in skin, with the greatest hyperalgesic effects in left abdominis muscle. Abdominal sites were more vulnerable to menstrual influences than limb sites. Muscle thresholds, but not skin or subcutis thresholds, were significantly lower in abdomen than in limbs, particularly in dysmenorrheic women. The amount of abdominal muscle hyperalgesia correlated significantly with the amount of spontaneous menstrual pain. Only minor sex differences were observed for pain thresholds of the arm and leg, but there was a unanimous refusal by men, but not by women, to be tested at abdominal sites. These results indicate that menstrual phase, dysmenorrhea status, segmental site, tissue depth and sex all have unique interacting effects on pain thresholds, thus adding more items to the lengthy and still-growing list of biological factors that enter into an individual's judgment of whether or not a stimulus is painful.

This study examined responses of 35 neurons in the caudal intralaminar (IL) thalamic nuclei in 12 adult female virgin rats to mechanical stimulation of the skin (brush, pressure, pinch) and to 4 different visceral stimuli (noxious distension of the uterine horns and vaginal canal; gentle distension of the colon and probing the cervix). As in male rats and other species, many IL neurons ( 24 35 ) responded to frankly noxious somatic stimuli applied to several bodily regions. Some of these ( 16 24 ) also responded to one or more of the visceral stimuli (mainly the noxious ones), while 4 35 responded only to a visceral stimulus. Thus, unlike neurons in lateral thalamus studied under identical conditions, IL neurons appear to be signalling information primarily when intense somatic and visceral stimuli are frankly above the noxious threshold.

Information about bodily events is conveyed by primary sensory fibres to higher brain centres through neurons in the dorsal column nuclei (DCN) and spinal dorsal horn. The DCN route is commonly considered a ‘touch pathway’, separate from the spinal ‘pain pathway’, in part because DCN neurons respond to gentle tactile stimulation of small skin areas. Here we report that DCN neurons can additionally respond to gentle and noxious stimulation of viscera and widespread skin regions. These and other experimental and clinical data suggest that the DCN and spinal routes cooperate, rather than operate separately, to produce the many perceptions of touch and pain, an ensemble view that encourages novel approaches to health care and research.

The occurrence of knee osteoarthritis (OA) increases with age and is more common in women compared with men, especially after the age of 50 years. Recent work suggests that contact stress in the knee cartilage is a significant predictor of the risk for developing knee OA. Significant gaps in knowledge remain, however, as to how changes in musculoskeletal traits disturb the normal mechanical environment of the knee and contribute to sex differences in the initiation and progression of idiopathic knee OA. To illustrate this knowledge deficit, we summarize what is known about the influence of limb alignment, muscle function, and obesity on sex differences in knee OA. Observational data suggest that limb alignment can predict the development of radiographic signs of knee OA, potentially due to increased stresses and strains within the joint. However, these data do not indicate how limb alignment could contribute to sex differences in either the development or worsening of knee OA. Similarly, the strength of the knee extensor muscles is compromised in women who develop radiographic and symptomatic signs of knee OA, but the extent to which the decline in muscle function precedes the development of the disease is uncertain. Even less is known about how changes in muscle function might contribute to the worsening of knee OA. Conversely, obesity is a stronger predictor of developing knee OA symptoms in women than in men. The influence of obesity on developing knee OA symptoms is not associated with deviation in limb alignment, but BMI predicts the worsening of the symptoms only in individuals with neutral and valgus (knock-kneed) knees. It is more likely, however, that obesity modulates OA through a combination of systemic effects, particularly an increase in inflammatory cytokines, and mechanical factors within the joint. The absence of strong associations of these surrogate measures of the mechanical environment in the knee joint with sex differences in the development and progression of knee OA suggests that a more multifactorial and integrative approach in the study of this disease is needed. We identify gaps in knowledge related to mechanical influences on the sex differences in knee OA.

Viscerosomatic convergence is a surprisingly common inducible feature of the response properties of neurons throughout the central nervous system. It indicates an extensive potential overlap between neuronal domains that process interoceptive information and those that process exteroceptive and proprioceptive information. This potential for overlap suggests that responses of individual neurons serve different functions at different times depending on the current pattern of activity in other neurons throughout the nervous system. Within such a dynamic scheme, skin and skeletal muscle have access to interoceptive control mechanisms and take variable advantage of that access for different purposes, for example, for shunting blood supply to tissues that need it. Similarly, viscera have access to exteroceptive control mechanisms and use them flexibly as needed. One important use would be to employ the exteroceptive domain's efficient protective mechanisms when a viscus is under threat. Visceral and referred pain would thus be byproducts of this opportunistic tactic.

Background Many clinicians and patients believe that endometriosis-associated pain is due to the lesions. Yet causality remains an enigma, because pain symptoms attributed to endometriosis occur in women without endometriosis and because pain symptoms and severity correlate poorly with lesion characteristics. Most research and reviews focus on the lesions, not the pain. This review starts with the recognition that the experience of pain is determined by the central nervous system (CNS) and focuses on the pain symptoms. Methods Comprehensive searches of Pubmed, Medline and Embase were conducted for current basic and clinical research on chronic pelvic pain and endometriosis. The information was mutually interpreted by a basic scientist and a clinical researcher, both in the field of endometriosis. The goal was to develop new ways to conceptualize how endometriosis contributes to pain symptoms in the context of current treatments and the reproductive tract. Results Endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the CNS. This engagement provides a mechanism by which the dynamic and hormonally responsive nervous system is brought directly into play to produce a variety of individual differences in pain that can, in some women, become independent of the disease itself. Conclusions Major advances in improving understanding and alleviating pain in endometriosis will likely occur if the focus changes from lesions to pain. In turn, how endometriosis affects the CNS would be best examined in the context of mechanisms underlying other chronic pain conditions.

Multi-unit afferent nerve activity was recorded from branches of the hypogastric and pelvic nerves in virgin female rats on different days of the estrous cycle. In each rat, the response of hypogastric nerve fibers to uterine distention and the response of pelvic nerve fibers to vaginal distention was tested. The minimal pressure necessary to evoke a response was highest in diestrus for both the hypogastric and pelvic nerve fibers. For the hypogastric nerve, the minimal necessary pressures were significantly lower during both proestrus and estrus, whereas for the pelvic nerve, the pressure was significantly lower only on the day of proestrus. These results suggest that the overall response sensitivity of afferent fibers in the pelvic and hypogastric nerves are differentially affected by hormonal variations occurring across the estrous cycle in a manner that would enhance reproduction.

One commonly accepted idea is that affective aspects of pain sensation are derived from a flow of information from the spinal cord through the reticular formation to the intralaminar thalamus and subthalamus. Little is known, however, about the extent to which spinoreticular terminations and reticulodiencephalic neuronal cell bodies overlap. This study used a combination of anterograde and retrograde tracing techniques to compare these distributions in the cat. Whereas spinoreticular terminations were concentrated caudally and laterally, neurons projecting to intralaminar thalamus and subthalamus were concentrated rostrally and medially. Thus, information conveyed from the spinal cord to the reticular formation appears to have direct access to intralaminar thalamus and subthalamus only by way of a few widely scattered neurons. When considered with the results of others, these results encourage less emphasis on a putative spino-reticulo-diencephalic pathway for pain. Rather, the reticular formation's role in pain is more likely to involve its full complement of interconnected descending and ascending connections.

The issue of how sex and gender differences influence pain continues to be a focus of intense investigation at many levels of inquiry. Epidemiological studies consistently report a higher prevalence of chronic pain disorders in females in comparison to males. Indeed, very few persistent pain conditions show a higher male prevalence. Psychophysically, women will generally rate a stimulus as being noxious at a lower intensity level than males; however, there are many exceptions to this generalization, with individual and situational variations being greater than the sex differences. On the other hand, substantial sex and gender differences do appear to exist in the mechanisms by which pain is generated and relayed centrally. The many factors that underlie sex differences in pain mechanisms interact dynamically, and develop and change progressively throughout the life span of each individual. Sex differences in the actions of the gonadal steroids estradiol, progesterone, and testosterone have also been shown to contribute to these differences, affecting wide regions of the central and peripheral nervous system. However, despite their potency, gonadal steroids represent only one of many factors that influence the experience of pain. While these differences would appear to have potent clinical implications for the development of different strategies to diagnose and treat pain in women and men, it remains the case that such strategies are most effective when they are focused on the individual, with the sex of that individual being only one of many factors being considered.

Suspension of Neural Pathways for Pain and Nociception. This review traces the changing conceptualization of the biological mechanisms underlying pain sensation from the time of Descartes. The anatomical basis for the existence of a system dedicated to pain is discussed in the light of detailed neuroanatomical knowledge developed during the past quarter century. The adequacy of defining pain in terms of noxious stimulation is questioned. Instead, pain sensation might better be understood in the context of somatovisceral function, with its underlying neuroanatomical complexity and dynamic interactions between ascending and descending systems.

Projections from the spinal cord and solitary nucleus to the lateral parabrachial nucleus (PBN1) in the cat were directly compared using double anterograde tracing methods. The two inputs were found to overlap within a well-circumscribed zone in the rostral 2/3 of PBN1. This zone was flanked ventrally by a zone receiving only solitary nucleus input and dorsally by a zone receiving only spinal input. Other authors have shown that neurons within these three recipient zones (overlap area, solitary nucleus and spinal cord) project to different forebrain targets (hypothalamus, amygdala and thalamus, respectively). This orderly input-output organization is likely to provide part of the framework for PBN's complex involvement in the coordination of respiratory and cardiovascular activities and their association with pain, visceral sensation and emotion.

Foreword by Thomas R. Insel Preface by Sherry A. Marts PART ONE: STRATEGIES, METHODS AND BACKGROUND 1. Why are There Two Sexes? 2. Sex Differences in the Brain: What's Old and What's New? 3. Research and Methodological Issues in the Study of Sex Differences and Hormone-Behavior Relations 4. Methodological Issues in the Study of Hormone-Behavior Relations in Humans: Understanding and Monitoring the Menstrual Cycle 5. Sex Differences in Pharmacogenomics as a Tool to Study CNS Disorders 6. Sex Differences in HPA Axis Regulation PART TWO: SEX DIFFERENCES IN NEUROBIOLOGY AND BEHAVIOR 7. Steroid Hormone Receptors and Sex Differences in Behavior 8. Sex Differences in Affiliative Behavior and Social Bonding 9. Sex Differences in the Organization of Movement 10. Sex Differences in Motivation 11. Sex Differences in Neuroplasticity 12. Sex Differences in Cogntiive Function in Rodents 13. Sex Difference in Energy Metabolism, Obesity and Eating Behavior 14. Sex Differences in Children's Play 15. Sex Differences in the Neurocognition of Language 16. Endocrine Contributions to Sex Differences in Visuospatial Perception and Cognition PART THREE: SEX DIFFERENCES IN THE NEUROBIOLOGY OF DISEASE 17. Sex Differences in Infectious and Autoimmune Diseases 18. Sex Differences in Neuroimmunology 19. Sex Differences in Pain 20. Sex Differences in Anxiety Disorders 21. Hormones and Mood 22. Sex Differences in Brain Aging and Alzheimer's Disease 23. Sex Differences in Parkinson's Disease

Endometriosis is a poorly understood, estradiol-dependent condition associated with severe pelvic pains and defined by vascularized endometrial growths outside the uterus. Endometriosis is produced in cycling rats by autotransplanting pieces of uterus onto abdominal arteries where they develop into cysts. The surgery induces vaginal and abdominal muscle hyperalgesia, whose severity is greatest in proestrus and nearly absent in estrus. The cysts contain growth factors and cytokines and develop their own sympathetic and sensory C- and Aδ-fiber innervation. Here, we used quantitative immunostaining and protein array analyses to test the hypothesis that the innervation and growth factor/cytokine content of the cysts, but not uterine horn, contribute to proestrous-to-estrous changes in hyperalgesic severity. If so, these characteristics in the cysts, but not the uterine horn, should change with estrous stage. In cysts, the density of sympathetic (but not sensory) neurites and amounts of NGF and VEGF proteins (but not cytokines IL-1, IL-6, IL-10, or TNF-α) were greater in proestrus than estrus. These changes were accompanied by vascular changes. Both sympathetic and sensory fibers in both stages colabeled with TrkA, indicating that changes in NGF could act on both afferent and efferent fibers. In contrast with the cysts, no changes occurred in the uterine horn between proestrus and estrus. Together, these results suggest that coordinated proestrous-to-estrous changes in innervation and vascularization of the cysts contribute to similar changes in hyperalgesic severity. The findings also encourage consideration of endometriosis as a neurovascular condition.

En la decada pasada se ha acumulado cierta evidencia sobre las diferencias de sexo y genero en el dolor y en su alivio. Estimaciones de prevalencia de la enfermedad, estudios epidemiologicos y la investigacion psicofisica continuan mostrando que el problema del dolor es mayor, mas variado y mas variable en las mujeres que en los hombres, y que los hombres pueden infravalorar el dolor. Ademas, algunas enfermedades dolorosas se expresan de forma diferente entre hombres y mujeres, y ciertos tratamientos (farmacos, somaticos o situacionales) tienen una mayor eficacia en un sexo que en el otro. Esta cada vez mas claro que los factores interactivos geneticos, fisiologicos, anatomicos, neurales, hormonales, psicologicos, de estilo de vida y socioculturales contribuyen a estas diferencias a lo largo de la vida de cada individuo. Aunque los gobiernos y las agencias de investigacion cientifica se han percatado de la importancia de las diferencias de sexo y genero no solo para la salud sino tambien para la economia sanitaria, las diferencias todavia no estan totalmente reconocidas por los sistemas sanitarios en todos los paises. Sin embargo, esta situacion esta mejorando rapidamente, ya que la inclusion de los terminos sexo y genero aumenta no solo en el ambito de la investigacion basica y clinica sino tambien en las historias clinicas de dolor, el desarrollo de farmacos y los ensayos clinicos.

Central nervous system neurons process information converging from the uterus, colon, and bladder, partly via the hypogastric nerve. This processing is influenced by the estrous cycle, suggesting the existence of an estrous-modifiable central nervous system substrate by which input from one pelvic organ can influence functioning of other pelvic organs. Here, we tested predictions from this hypothesis that acute inflammation of colon, uterine horn, or bladder would produce signs of inflammation in the other uninflamed organs (increase vascular permeability) and that cross-organ effects would vary with estrous and be eliminated by hypogastric neurectomy (HYPX). Under urethane anesthesia, the colon, uterine horn, or bladder of rats in proestrus or metestrus, with or without prior HYPX, was treated with mustard oil or saline. Two hours later, Evans Blue dye extravasation was measured to assess vascular permeability. Extravasation was increased in all inflamed organs, regardless of estrous stage. For rats in proestrus, but not metestrus, either colon or uterine horn inflammation significantly increased extravasation in the uninflamed bladder. Much smaller cross-organ effects were seen in colon and uterine horn. HYPX reduced extravasation in the inflamed colon and inflamed uterine horn, but not the inflamed bladder. HYPX eliminated the colon-to-bladder and uterine horn-to-bladder effects. These results demonstrate that inflaming one pelvic organ can produce estrous-modifiable signs of inflammation in other pelvic organs, particularly bladder, and suggest that the cross-organ effects involve the hypogastric nerve and are at least partly centrally mediated. Such effects could contribute to cooccurrence and cyclicity of distressing pelvic disorders in women.

an institute of medicine (IOM) report in 2001 stated: “Sex matters. Sex, that is, being male or female, is an important basic human variable that should be considered when designing and analyzing studies in all areas and at all levels of biomedical and health-related research … .The study of sex

Objective To determine, in rats, how surgically induced endometriosis and a control surgery (partial hysterectomy; sutures in abdomen) affects micturition thresholds and bladder vascular permeability. Design Two animal studies, each performed in three groups of urethane-anesthetized rats in proestrus. Setting Academic facility. Animal(s) Seventy-three female, regularly cycling Sprague-Dawley rats studied in proestrus. Intervention(s) Surgical induction of endometriosis (ENDO), surgical control (shamENDO), intact control (NoSURG), and bladder inflammation via intravesicular turpentine in all three groups. Main Outcome Measure(s) [1] Micturition thresholds (MTs; volume voiding thresholds), as measured by repetitive transurethral cystometry before and after bladder inflammation and [2] bladder inflammation, as assessed by extravasation of Evans Blue dye. Result(s) In the uninflamed bladder, MTs were significantly lower and dye extravasation significantly higher in ENDO rats than in shamENDO and NoSURG rats. Bladder inflammation increased dye extravasation in all groups and reduced MTs in the NoSURG and ENDO rats, but not in the shamENDO rats. Conclusion(s) Endometriosis reduces MTs and produces signs of inflammation in the healthy bladder. Surprisingly, the control surgical procedure (partial hysterectomy; sutures on mesenteric blood vessels) protects bladder reflexes from the influence of bladder inflammation, a condition that is named silent bladder inflammation. Such cross-system inducing and masking effects have important clinical relevance.

This study examined sex and estrous differences in vocalization thresholds of rats to hindpaw and tail pressure stimulation tested daily throughout at least 3 weeks. When all the measures were pooled, compared to males, female rats had higher thresholds for tail pressure (499 +/- 6 g, n = 188 measures vs. 466 +/- 2 g, n = 144 measures, respectively), but equal thresholds for hindpaw pressure (321 +/- 6 g, n = 188 measures vs. 319 +/- 2 g, n = 144 measures, respectively). Thresholds of female rats in proestrus and estrus were lower than those of rats in metestrus and diestrus for both tail and hindpaw stimulation, whereas those of males did not vary systematically. Thresholds at the two stimulation sites covaried in females but not in males. These results add to the growing list of important interacting factors that underly behavioral sensitivity to noxious somatic stimulation.

Female and male brains differ. Differences begin early during development due to a combination of genetic and hormonal events and continue throughout the lifespan of an individual. Although researchers from a myriad of disciplines are beginning to appreciate the importance of considering sex differences in the design and interpretation of their studies, this is an area that is full of potential pitfalls. A female’s reproductive status and ovarian cycle have to be taken into account when studying sex differences in health and disease susceptibility, in the pharmacological effects of drugs, and in the study of brain and behavior. To investigate sex differences in brain and behavior there is a logical series of questions that should be answered in a comprehensive investigation of any trait. First, it is important to determine that there is a sex difference in the trait in intact males and females, taking into consideration the reproductive cycle of the female. Then, one must consider whether the sex difference is attributable to the actions of gonadal steroids at the time of testing and/or is sexually differentiated permanently by the action of gonadal steroids during development. To answer these questions requires knowledge of how to assess and/or manipulate the hormonal condition of the subjects in the experiment appropriately. This article describes methods and procedures to assist scientists new to the field in designing and conducting experiments to investigate sex differences in research involving both laboratory animals and humans.

The majority of patients with multiple sclerosis (MS) develop troublesome lower urinary tract symptoms (LUTS). Anecdotal reports suggest that cannabis may alleviate LUTS, and cannabinoid receptors in the bladder and nervous system are potential pharmacological targets. In an open trial we evaluated the safety, tolerability, dose range, and efficacy of two whole-plant extracts of Cannabis sativa in patients with advanced MS and refractory LUTS. Patients took extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD; 2.5 mg of each per spray) for eight weeks followed by THC-only (2.5 mg THC per spray) for a further eight weeks, and then into a long-term extension. Assessments included urinary frequency and volume charts, incontinence pad weights, cystometry and visual analogue scales for secondary troublesome symptoms. Twenty-one patients were recruited and data from 15 were evaluated. Urinary urgency, the number and volume of incontinence episodes, frequency and nocturia all decreased significantly following treatment (PB/0.05, Wilcoxon’s signed rank test). However, daily total voided, catheterized and urinary incontinence pad weights also decreased significantly on both extracts. Patient self-assessment of pain, spasticity and quality of sleep improved significantly (PB/0.05, Wilcoxon’s signed rank test) with pain improvement continuing up to median of 35 weeks. There were few troublesome side effects, suggesting that cannabis-based medicinal extracts are a safe and effective treatment for urinary and other problems in patients with advanced MS.

In september 2006 kwamen de leden van de belangengroepering (SIG) sekse- en genderspecifieke pijn van de International Association for the Study of Pain (IASP, de internationele associatie voor pijnonderzoek) bijeen om over de volgende onderwerpen te discussieren: 1) Wat is er bekend over sekse- en genderverschillen op het gebied van pijn en analgesie; en 2) Wat zijn de ‘best practice’-richtlijnen voor sekse- en genderspecifiek pijnonderzoek? Dit verslag is de consensus van deze bijeenkomst en omvat bijdragen uit algemeen wetenschappelijke hoek, van onderzoekers op het gebied van klinische en psychosociale pijn en van erkende deskundigen op het gebied van seksuele differentiatie en reproductieve endocrinologie.

A rat model of endometriosis, in which pieces of uterine horn (versus fat in controls) are autotransplanted into the abdomen where they form cysts, reduces fecundity and produces vaginal hyperalgesia. The cysts gradually enlarge over a 2-month period postsurgically and then plateau. Cysts regress with low estrogen levels and reappear when they rise. Based on the hypothesis that the vaginal hyperalgesia depends upon the cysts, this study tested two predictions: that (1) the hyperalgesia would develop postsurgically in parallel with the cysts, and (2) the hyperalgesia would vary with estrous, being greatest when estrogen levels are high (proestrus) and least when low (estrus). In rats trained to escape vaginal distention, percentage escape responses to different distention volumes were measured across the rat's 4-day estrous cycle for 2.5 months before and up to 4 months after autotransplantation of uterus (n = 9) or fat (n = 6) in abdominal sites. Vaginal pressures were also measured. In rats with uterine but not fat autotransplants, escape percentages increased postsurgically over a 2-month period and then plateaued. The increase was greatest in proestrus and failed to occur in estrus. Vaginal pressures were unchanged in all groups. These results strongly support the hypothesis that the vaginal hyperalgesia depends upon the cysts. Because the cysts were located in sites remote from the vagina, the hyperalgesia involves viscero-visceral interactions and is likely centrally mediated, whereas the estrous modulation could involve hormonal actions either on the cysts or, more likely, on vaginal afferent fibers, and/or on central neurons.

Responses of neurons in the gracile nucleus (NG) of female rats to tactile and visceral stimulation change across the estrous cycle [J. Neurosci. 20 (2000) 7722]. To investigate estrogen's role in these changes, responses of NG neurons to tactile and visceral stimuli were examined in three groups: ovariectomized (OVX), OVX with estrogen replacement (OVX+E2), or sham OVX (tested in diestrus; shamOVX-D). The stimuli were: gentle brushing of hindquarter skin, pressure on the cervix, and distention of the uterus, vagina, or colon. After OVX, the magnitude of multi-unit responses to brushing the perineum, hip and tail, but not the foot and leg, were significantly reduced relative to shamOVX-D. OVX+E2 restored this magnitude to the same level as shamOVX-D, but not, as expected, to levels as large as previously observed in proestrus. After OVX, responses of single neurons to stimulation of the uterus, cervix, and colon were more likely to be excitatory (versus inhibitory) than they had been in cycling rats in proestrus (uterus, cervix) or diestrus (colon); OVX+E2 did not restore the inhibitory responses. In contrast, whereas all responses to vaginal distention after OVX were also excitatory, OVX+E2 in this case significantly restored the inhibitory responses. These findings provide further support for the conclusion that response characteristics of NG neurons are influenced by the rat's hormonal milieu, but also indicate that the influences are not a simple reflection of estrogen levels. The findings further suggest that NG is a component of neural systems that contribute to both reproductive behaviors and vaginal nociception.

Previous research has shown that post-partum abdominal pain is greater in multiparous than primiparous women (Murray and Holdcroft, 1989). Although breast feeding in the immediate post-partum period induces uterine contractions and abdominal pain, it is unknown how parity influences the contractions. Here, a structured questionnaire that included the McGill Pain Questionnaire (total pain intensity index, TPI) and visual analog scales (VAS) was used to evaluate the intensity, location, referred tenderness (hyperalgesia), descriptor, and temporal characteristics of pain during breast feeding up to three days after uncomplicated vaginal delivery. Three groups of women were studied: primiparous (n=25); low parity (1-2 prior births; n=14); high parity (3-5 prior births; n=11). Uterine contractions during breast feeding were recorded using tocodynamometry in some women from each group (n=17, 6, 7, respectively). For comparison, an identical questionnaire was used to evaluate pains the women remembered experiencing during menstruation in the year immediately preceding the current pregnancy. During breast feeding, nearly all women (96%) reported deep pain primarily at three sites: lower abdomen, low back, and breast, with associated referred hyperalgesia in 62% of them. The intensity of these pains increased significantly with parity (P