Modulation of pain by estrogens

Pain 132 (2007) S3–S12 www.elsevier.com/locate/pain

Comprehensive review

Modulation of pain by estrogens Rebecca M. Craft

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Department of Psychology, Washington State University, Pullman, WA 99164-4820, USA Received 21 September 2007; accepted 28 September 2007

Abstract It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men. Ó 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Estradiol; Nociception; Sex differences

1. Sexual differentiation of pain Sex differences in human pain perception have been reported in numerous studies, from laboratory experiments to epidemiological studies of clinical conditions. In laboratory tests of healthy subjects, pain thresholds and pain tolerance are generally lower in women than in men, using various stimulus modalities such as heat, pressure and chemical irritants (e.g., [23,43,92]). Moreover, a number of chronic pain conditions such as migraine, temporomandibular joint disorder, fibromyalgia, arthritis and interstitial cystitis are more prevalent in women than in men (for reviews, see [7,103]).

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Sexual differentiation of pain appears to rely on both organizational and activational effects of gonadal steroid hormones. As far as organizational effects of hormones, early (neonatal) exposure to testosterone may be necessary for the development of the adult male phenotype (lesser sensitivity to noxious stimuli); this has been demonstrated in animal studies of carageenaninduced mechanical allodynia [9], and lumbar nerve injury-induced mechanical allodynia and thermal hyperalgesia [60]. Sex differences in NMDA-mediated stressinduced antinociception [98] and morphine-induced antinociception [24,58] also have been shown to depend on testosterone exposure in the early neonatal period in rodents. In contrast, neonatal testosterone administration in female rat pups – sufficient to de-feminize them in terms of the reproductive system – did not result in a male phenotype in adulthood when tested on a

0304-3959/$32.00 Ó 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2007.09.028

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formalin test of inflammatory nociception [49]. There are several additional reports of failure of neonatal testosterone manipulations to eliminate or reverse sex differences in nociception in adulthood; however, it is not known whether these failures reflect sex differences that are sex-chromosome-linked (non-hormonal) in nature [3], or are simply failures to elucidate the time course of sexual differentiation of nociception. It is possible, for example, that sexual differentiation of some types of nociception begins prior to the early neonatal period (i.e., in utero). Regarding activational effects of gonadal hormones, an overwhelming number of studies implicate estrogens as key modulators of pain in adults. A hallmark of pain modulation by estrogens, however, is the complexity with which estrogens affect pain. It cannot be concluded that estrogens worsen or alleviate pain per se; rather, estrogens may do either, perhaps depending on the type and chronicity of pain, as well as estrogen level and stability. The clinical pain sections below primarily focus on a few types of pain for which we currently have the most evidence for modulation by estrogens. In most laboratory studies in which an estrogen was manipulated, only estradiol was examined, and many studies examining oral contraceptives or hormone replacement therapy (HRT) involve ethinylestradiol or conjugated equine estrogens, respectively, with or without a progestin. At this point there has been no systematic study of whether different estrogens affect pain differently. For a preliminary review of the different types of estrogens used for contraception, HRT and osteoporosis, the reader is referred to [26].

strual cycle are equally equivocal. Although some studies demonstrate that women in follicular phase show higher response thresholds and greater tolerance than women in luteal phase to experimental pain, more careful analysis suggests that these conclusions may be confounded by methodological factors such as how menstrual cycle phases are defined (for reviews, see [89,93]). If there are such cycle-related changes in acute pain sensitivity, it can be hypothesized that estradiol, which during the follicular phase increases while progesterone remains low, may ‘‘protect’’ against acute pain. One of the few studies in which estradiol was actually manipulated in a controlled manner provides some evidence for this hypothesis, albeit using a pain procedure that was more sustained than those typically used in the animal and human studies cited above. Using a hypertonic saline infusion into the masseter muscle to induce pain for 20 min, short-term estradiol treatment of early follicular phase women (who have relatively low endogenous estradiol) was associated with reduced pain ratings compared to the untreated control state [96]. Estradiol treatment also was associated with increased activation of the endogenous mu opioid system during exposure to the pain stimulus, whereas in the low estradiol state, this system appeared to de-activate when women were exposed to the pain stimulus [96]. Therefore, insofar as animal and human studies of relatively short-lived pain are concerned, current data suggest that estradiol primarily attenuates pain, or has no effect. 3. Modulation of pain by estrogens: clinical pain 3.1. Migraine

2. Modulation of pain by estrogens: healthy subjects In animals, estradiol modulation of acute nociception – that is, momentary exposure to a noxious stimulus – has been studied by innumerable investigators, with highly equivocal results. Although there are studies demonstrating longer latencies to respond to acute nociceptive stimuli in ovariectomized, estradiol-treated female rodents compared to hormone-depleted controls (e.g., [29,76,99,109]), there are many more studies reporting no effect of estradiol on acute nociceptive responses (though few report hyperalgesia [54]). Studies examining changes in nociceptive response latencies across the estrous cycle in rodents demonstrate a similar lack of agreement regarding which stage, if any, is associated with the lowest or highest acute nociceptive threshold (e.g., [12,57,76,78,100,106]). At present it must be concluded that in animals, other factors are more important than estradiol in terms of modulating responses to brief nociceptive stimulation, or that estradiol modulation of pain is highly specific to the type of nociceptive test. In humans, findings regarding women’s sensitivity to brief (experimental) noxious stimulation across the men-

Evidence supporting a role for estrogen modulation of migraine includes: (1) migraine is approximately 3 times more likely to occur in women than in men; (2) sex differences in migraine prevalence emerge at puberty, with prevalence in women peaking in the reproductive years and declining after menopause; (3) at least 50% of women migraineurs experience menstrually related migraine (migraines occurring within ±2 days of menstruation); (4) up to 80% of pregnant women migraineurs experience complete relief of migraines during the third trimester, and nearly all experience a return of migraines post-partum; (5) abrupt withdrawal of estrogens (via gonadotropin releasing hormone treatment in cycling women or termination of estrogen supplementation or replacement in peri- or post-menopausal women) may precipitate migraine attack [13,75,95]. Although cyclic use of estrogens (as in oral contraceptive regimens) may be associated with increased migraine frequency and severity in women who already suffer from migraine, it does not appear to cause headache per se [69], and there is clear evidence for decreased frequency and severity of migraines in

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women taking estrogen supplements continuously, or after complete hormone depletion via medical oophorectomy [13,27,75,101]. Thus, growing evidence supports the hypothesis that abrupt estrogen withdrawal (rather than estrogen levels per se) precipitates migraine, particularly in women who suffer menstrually related migraine. Mechanisms underlying estrogenic modulation of migraine include estrogen receptor (ER)-a-mediated increases in nitric oxide in vascular endothelial cells (modulating vasodilation), altered 5-HT signaling, and altered endogenous opioid tone [13,74,75]. It has been shown, for example, that estradiol enhances sensitivity to neuroendocrine [82] and mood-altering [35–37] effects of serotonin agonists. Given the utility of serotonin agonists such as triptans in the treatment of migraine, it will be important to determine whether combined manipulation of estrogenic and serotonergic function could be employed for more optimal treatment of pain. For more comprehensive discussion of ovarian hormones and migraine, readers are referred to excellent recent reviews by Brandes [13] and Martin and Behbehani [74,75]. 3.2. Temporomandibular disorders Similar to migraine, temporomandibular disorders (TMD) are approximately twice as prevalent (and more severe) in women than in men, and have their highest prevalence in women during the reproductive years, with onset of pain typically after puberty, and declining postmenopausally [68,107,108]. In a laboratory model of TMD pain, healthy women reported more pain than healthy men after glutamate injection into the masseter muscle [17], although there were no differences in pain between women taking oral contraceptives vs. those who did not [20]. In reproductive age women with TMD, temporomandibular joint (TMJ) pain is highest peri-menstrually, although in women not using oral contraceptives, an additional pain peak may occur in the peri-ovulatory period [64]. Use of oral contraceptives by reproductive age women, or HRT by post-menopausal women, is associated with higher prevalence of TMD [65,71], and serum estradiol levels have been reported to be higher in luteal phase women and in men who have TMD compared to healthy controls [62]. In contrast, women with TMD experience some amelioration of pain during pregnancy, with a return to baseline pain levels by 1 year post-partum [66]. These findings strongly suggest that ovarian hormones modulate pain in women with TMD, although the estrogen-TMD relationship is clearly not a simple one. To determine how estrogens modulate TMD pain, rodent models have been very useful. Three aspects of estrogenic effect that are most obviously relevant to TMD pain are its immune (inflammatory), skeletal (bone deposition), and nervous system effects.

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Ovarian hormone depletion via ovariectomy in rats has been shown to result in maladaptive changes to TMJ structure, which are prevented by estradiol replacement [115]. Femoral bone mineral density, an index of overall bone density, is also significantly reduced in ovariectomized female rats compared to gonadally intact controls when assessed 3–4 months after surgery [87]. Thus, in terms of structural aspects of the TMJ, estradiol has a protective effect. In regard to TMJ inflammation, estradiol-treated, ovariectomized female rats showed greater visually assessed swelling in the TMJ 24 h after inflammation was induced by intraTMJ injection of complete Freund’s adjuvant (CFA), despite the fact that estradiol also reduced the number of monocytes in the TMJ synovium [48]. The authors suggest that estradiol-treated rats may actually have experienced less pain than controls, based on the fact that they ate more than controls did within the first 24 h after CFA injection; thus, the increased masticatory activity may have increased TMJ inflammation. In agreement with this interpretation is another rodent study: using plasma extravasation as the measure of inflammation, estradiol-treated ovariectomized female rats showed significantly reduced plasma extravasation compared to untreated controls, at 72 h after intraTMJ CFA injection [42]. These authors suggest that the long-term consequence of lesser plasma extravasation would be greater joint damage. Thus, in contrast to its protective effects on bone/cartilage integrity, estradiol may reduce short-term TMJ inflammation while worsening it in the long-term. Greater inflammation in the long-term is likely associated with greater tissue damage (including bone degradation) and more pain. In regard to estrogenic modulation of nociceptive neurons in the area of the TMJ, acute TMJ inflammation induced by mustard oil injection produced greater fos-like immunoreactivity in proestrous compared to diestrous female rats at the subnucleus caudalis/upper cervical spinal cord junction – the major terminal zone for sensory afferents innervating the TMJ [4], indicating that TMJ inflammation produces greater neural activation when ovarian hormones are higher (suggesting that cycling females in higher hormone states may experience greater pain). Unfortunately, estrogenic modulation of TMJ nociception per se has been examined in anesthetized rats only, with jaw muscle and/or nociceptor activity serving as a proxy for pain. In these studies, estradiol treatment of ovariectomized rats increased digastric and masseter muscle activity towards that seen in intact females, after glutamate was injected into the TMJ [16]. Estradiol also dose-dependently increased trigeminal afferent discharge induced by NMDA injection into the masseter muscle or intra-TMJ CFA injection in ovariectomized rats [33,41], and increased NMDA receptor-mediated currents in cultured dorsal root ganglion neurons taken from female rats (more than in

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those taken from males: [77]). Interestingly, both endogenous and exogenous noradrenergic antinociception against TMJ pain are blunted in estradiol-treated rats [80,81]. Because there are a-adrenergic receptors on trigeminal afferents, estradiol-induced increases in trigeminal nerve activity during TMJ inflammation may reflect a decrease in endogenous antinociceptive mechanisms. Finally, it should be noted that mustard oil injected into the TMJ, which increases glutamate levels at the trigeminal subnucleus/upper cervical cord junction, was ineffective in increasing glutamate in high-dose estradiol-treated ovariectomized rats; these females also showed increased sensitivity to a glutamate transport inhibitor, suggesting enhanced glutamate reuptake [5]. Whether the results of this latter study in rats explain why TMD pain tends to remit during pregnancy in women is not yet known. Overall, replacement of estradiol to levels found in normally cycling rats, although important for maintaining healthy temporomandibular joints, appears to enhance glutamatergic neurotransmission at NMDA receptors after chemically induced TMJ inflammation, which may contribute to greater TMD pain observed in cycling women at ovulation, or in post-menopausal women taking HRT. 3.3. Arthritis and other auto-immune pain syndromes The prevalence of musculoskeletal pain syndromes such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus and fibromyalgia is 2–10 times greater in women compared to men; arthritis may be attenuated by pregnancy and by oral contraceptive use, and may worsen after menopause, whereas lupus appears to show the opposite relationship to ovarian hormones [14,34,85,112]. To indirectly address the hypothesis that estrogens increase or decrease these types of musculoskeletal pain, information may be gleaned from trials in which estrogens or aromatase inhibitors (to deplete estrogens) are administered for other reasons. For example, examination of a subset of data from the Women’s Health Initiative, including over 10,000 women who had hysterectomies and were randomly assigned to receive estrogens or placebo, showed that estrogen-treated women were significantly less likely than placebo-treated women to have undergone any type of joint replacement during the approximately 7 years they were followed [25]. Discontinuation of HRT in the Women’s Health Initiative study was associated with greater ‘‘pain or stiffness’’ compared to the placebo-treated group [84]. Similarly, emerging evidence indicates that estrogen deprivation via aromatase inhibitor therapy (for estrogen receptor-positive breast cancer) is associated with increased incidence of arthralgias [15]. Significantly lower early follicular-phase estradiol levels also have been observed in women who developed osteoarthritis compared to those who did not [97].

These studies support the hypothesis that estrogens tend to thwart the development of arthritis-type musculoskeletal pain. No such link between estrogens and fibromyalgia has been found, although few studies have examined this possibility [72,85]. In contrast to their ameliorative effects on arthritis, estrogens may exacerbate systemic lupus erythematosus: pregnancy tends to increase risk of developing or worsening the disease [34], and recently, a case of HRT-induced lupus was reported [19]. One hypothesis regarding the opposite effects that pregnancy exerts on rheumatoid arthritis vs. lupus is the differential exacerbation of the two diseases by different cytokines, which are oppositely modulated by estrogens during pregnancy [34]. At any rate, it cannot be concluded that estrogens simply alleviate all musculoskeletal inflammatory pain conditions; rather, as noted for TMD, different aspects of each disease process and associated pain are differentially enhanced or suppressed by estrogens via diverse actions on the central and peripheral nervous systems, as well as on the skeletal and immune systems (see Fig. 1). A growing number of animal studies more specifically address the question of estrogenic modulation of inflammatory pain. Using the formalin test, in which the ‘‘second (tonic) phase’’ of pain-related behaviors is associated with acute inflammation, systemically administered estradiol decreased the number or intensity of nociceptive behaviors during the tonic phase, in gonadectomized male and female rats [44,59,73] and in aromatase-knockout mice, which do not produce estradiol endogenously [79]. Other studies measuring inflammation rather than pain after adjuvant administration also demonstrate that estradiol decreases various indices of inflammation and immunoreactivity (and cartilage damage) in ovariectomized female rodents [30,52,91,114]. It should be noted, in contrast, that exacerbation of formalin-induced nociception was observed in two studies when estradiol was administered i.c.v. to male rats [2,21], perhaps indicating that CNS effects of estradiol are opposite to PNS effects on inflammatory pain. Several recent studies implicate ER-b activation in the ameliorative effect of systemically administered estradiol against inflammatory pain and inflammation. First, an ER-b-selective agonist was anti-hyperalgesic in tests of PGE2-, capsaicin- and carageenan-induced thermal hyperalgesia in the male rat [67]. Second, an ER-b-selective agonist dramatically decreased inflammation of CFA-induced arthritis in both male and female rats, as well as decreasing inflammation in a male rat model of inflammatory bowel disease [50]. Finally, female (but not male) ER-b knockout mice spontaneously developed an interstitial cystitis-like syndrome [53]. In contrast to studies examining an acute inflammatory episode (i.e., lasting up to several hours), studies examining estrogenic modulation of the thermal and mechanical hypersensitivities that develop days to weeks

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Fig. 1. Modulation of pain by estrogens depends on the diverse, tissue-specific actions of estrogens in multiple systems of the body. Shown is a sample of the mechanisms by which estrogens modulate pain via their effects in the peripheral nervous system (PNS), central nervous system (CNS), skeletal, immune and cardiovascular systems; in all cases there is at least preliminary evidence that estrogenic modulation of that system alters pain directly, or alters disease trajectory which likely affects pain.

after inflammation/injury demonstrate that hyperalgesia and allodynia may be facilitated by estrogens (but see [90]). For example, when peripheral neuropathy was induced by chronic alcohol consumption, mechanical hyperalgesia developed in gonadally intact and estradiol-replaced female rats but not in ovariectomized rats [32]. Estradiol also has been reported to facilitate the onset and progression of nociceptive responses to excitotoxic spinal cord injury in male rats [45]. Furthermore, in the weeks after induction of arthritis using CFA, females in proestrus (high ovarian hormones) showed the greatest thermal hyperalgesia [11], and females in proestrus and estrus showed the greatest mechanical hyperalgesia [28]. Male and female rats treated with estradiol also had significantly greater polyarthritis scores than untreated controls when examined weeks to months after streptococcal cell wall inoculation [1]. These long-term studies may explain why clinically women experience more musculoskeletal and other pains than men over their lifetime. It may also be significant that stress-induced facilitation of pain, which presumably plays an important role in the experience of chronic pain patients, is enhanced by estradiol (e.g., stress-induced visceral hypersensitivity to rectal distension in female rats [10]). That is, stress-induced facilitation of pain may be greater when estradiol is present. Taken together these studies suggest that estradiol may attenuate the immediate pain of inflammation, while possibly worsening the long-term trajectory of post-inflammation/injury processes leading to greater hyperalgesia and allodynia. However, further complicating the picture are data showing that estradiol sup-

presses hyperalgesic priming – the prolongation of hyperalgesia observed upon repeated incidents of inflammation – in both male and female rats [55]. This finding suggests that estradiol should temper the progressive increase in pain in inflammatory diseases that involve intermittent flare-ups. The sum total of estradiol’s effects on inflammatory pain and disease clearly reflects an intricate balance between its pro- vs. antinociceptive effects, as illustrated in Fig. 1. 4. Why is pain modulation by estrogens so complex? 4.1. Widespread distribution of ER in pain-relevant areas of the body Given the diverse actions of estrogens described above, it is not surprising that estrogen receptors are distributed in areas known to influence nociceptive transmission. For example, ER-a and ER-b are located on neurons of the trigeminal brainstem complex (trigeminal subnucleus caudalis), with similar distribution but greater density in female than in male rats, and with some cycle-related fluctuations in females [6]. Dorsal root ganglion cells express ER-a, and estradiol acting at membrane-bound ER-a rapidly attenuates ATPinduced Ca++ signaling in these cells [22]. ER-a and -b are also located in areas of the brain that mediate stress, anxiety and pain, such as the hypothalamus, amygdala, periaqueductal gray (PAG) and dorsal raphe nucleus [94]. The presence of ER in PAG suggests that estrogens influence the function of descending nociceptive modulatory pathways. This hypothesis is supported by studies

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demonstrating that estrous female rats are less sensitive than diestrous female rats to intra-PAG morphine antinociception, and irreversible blockade of l-opioid receptors in the PAG reduces morphine antinociception to a greater extent in females compared to males [8]. Additionally, morphine activates fewer PAG output neurons in females than in males [70]. In addition to altering opioid antinociceptive pathways, estrogens also can suppress adrenergic antinociception (e.g., [80,81]) while restoring sensitivity to serotonin agonists [82], and these are likely additional mechanisms by which estrogens influence various types of pain. As noted above, estrogens may also indirectly affect pain via their modulation of skeletal and immune systems. ER-a and -b are found in articular cartilage and subchondral bone of the TMJ [113] as well as in other joints (e.g., [86]); these receptors are clearly implicated in maintenance of normal joint structure by estrogens. ER-a and -b are also found in organs of the immune system, including the thymus, spleen and bone marrow; activation of each ER by estrogens differentially contributes to granulocyte-induced inflammation, Tlymphocyte proliferation and phenotypic shift, suppression of NK cell cytotoxicity, and B-lymphocyte suppression and increased differentiation [18]. The immunoregulatory mechanisms of estrogens that contribute to estrogenic modulation of musculoskeletal pain are only partially understood (for reviews, see [18,34,83]). Both membrane and nuclear estrogen receptors are likely to be important in pain modulation by estrogens. Although rapid effects of estradiol on nociceptive behavior have been observed [38], very few pain studies have attempted to distinguish between membrane and nuclear receptor-mediated effects, or between ER-a and ER-bmediated effects of estrogens. Activation of ER-a and -b can produce opposing effects, for example, on anxiety [111]; thus, the effects of a given estrogen likely reflect the balance between ER-a and -b activation, for some effects. How rapid vs. genomic (transcriptional) effects of estradiol interact to modulate pain is not yet known, nor is it known which estrogenic effects on pain might be mediated by the newly described estrogen receptor, GPR30 [39]. Interestingly, there is some evidence that certain ERa gene polymorphisms are associated with earlier onset of rheumatoid arthritis in women but not men, higher risk of osteoarthritis in women, and greater pain in women with TMJ osteoarthritis [56,104,105]. These studies confirm an important role for ER-a in the trajectory of at least some types of musculoskeletal pain disorders. Emerging evidence that ER-b-selective agonists have powerful anti-inflammatory and anti-hyperalgesic effects (see above), plus anti-anxiety and anti-depressant effects – while producing fewer effects on the reproductive system [111] – suggest that ER-b may be a fruitful

target for developing estrogenic medications for certain types of inflammatory pain. 4.2. Dose-dependency of estrogenic modulation of pain The extent to which pain modulation by estrogens is dose-dependent is not yet clear. There are some demonstrations of ‘‘drug-like’’ dose-dependency for estradiol’s effects on pain (e.g., [73]), but other studies demonstrate an all-or-none effect over a wide dose range (e.g., [81]), and still others demonstrate biphasic effects (effect present at intermediate but not low or high doses) (e.g., on opioid antinociception [29]). Compounds with estrogenic activity also have been shown to produce biphasic or other unconventional dose–effect curves in in vitro assays [110], demonstrating that estrogens are capable of exerting a wide variety of dose-dependent to relatively dose-independent actions, depending on the tissue examined. The diverse array of dose–effect functions observed thus far adds another level of complexity to the task of characterizing how estrogens modulate pain, as any particular clinical type of pain undoubtedly represents the integration of innumerable tissue-specific actions of estrogens. 5. Future directions 5.1. Methodological issues Sherman and LeResche [93] outline several important methodological issues for researchers studying hormone modulation of pain in cycling women, including accurately assessing cycle stage relative to ovulation, employing within-subject experimental designs (as a way to accommodate substantial individual variability in hormone levels), and avoiding small, underpowered studies. Other methodological issues to consider in human research on hormone modulation of pain are outlined in substantial detail in the consensus report of the Sex, Gender and Pain Special Interest Group of the IASP [47] (this issue). At this point, the greatest gap in human research on estrogenic modulation of pain is hormone manipulation studies. Although they are difficult to carry out, studies such as that conducted by Smith and colleagues [96] – in which estradiol was manipulated in a controlled manner – will greatly enhance our understanding of the impact of estradiol and other hormones on pain perception. In animal studies, one of the largest gaps at this point is time course assessments. First, the impact of waxing and waning estrogens over time has rarely been examined. In the case of migraine and some other types of pain, change in estrogen levels appears to be more relevant than absolute levels, yet most animal studies have examined nociception during steady-state estradiol exposure (established via capsule or pellet implant) or

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at a single time point after estradiol injection. Second, the possible difference in estrogenic modulation of shortvs. long-term pain has not been adequately addressed. Noted above are several cases in which estradiol’s effects appear to differ when assessed within the first few days vs. weeks to months after induction of inflammation or injury. Thus, examining the effects of fluctuating estrogens (e.g., [29]), as well as comparing short- vs. long-term pain trajectory in subjects treated with estrogens, will be necessary for a more complete, clinically relevant assessment of estrogenic modulation of pain. 5.2. Do other sex steroids modulate pain? Although this review focuses on estrogens (primarily estradiol), other sex steroids have been implicated in pain modulation. For example, progesterone has been shown to attenuate inflammation-induced thermal hyperalgesia [88] and nociceptive behavior after excitotoxic spinal cord injury [45]. Progesterone and two of its metabolites also have been shown to attenuate peripheral diabetic neuropathy [63], and there is limited evidence in humans that progestins decrease musculoskeletal symptoms [46]. Similar to estradiol, progesterone increases dramatically and steadily throughout pregnancy, and contributes to the shift in immune function during pregnancy [34]. To what extent progestins contribute to the remission or exacerbation of pain syndromes during pregnancy is not known. Given the well-documented GABAergic actions of progesterone metabolites (for review, see [61]), it is not surprising that they can modulate pain, and further research on the possible ameliorative effects of progestins on pain is clearly warranted. The combined effects of estradiol and progesterone may differ from the effects of estradiol alone: in some cases, progesterone reverses the effects of estradiol (e.g., formalin-induced nociception [59]), and vice versa (apoptotic injury in experimental allergic encephalitis [52]). Because many women frequently take estrogen– progestin combinations, it will be important to further elucidate the interactions of these ovarian hormones on various types of pain. Activational effects of testosterone also likely contribute to sex differences in pain, in part by providing relatively greater protective effects in men than in women. Testosterone has been shown to increase inflammation-induced plasma extravasation in the TMJ [42], prevent inflammation-induced cartilage damage [30,31], attenuate nociception after intraTMJ [40] and intra-paw [44] formalin injection, and decrease acute thermal nociception [51,100]. In most cases it is not known whether testosterone’s ameliorative effects on inflammation and pain are actually attributable to estradiol, as testosterone readily aromatizes into estradiol. Non-aromatizable androgens

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such as dihydrotestosterone, or aromatase inhibitors (or androgen receptor antagonists) in combination with testosterone, can be used to confirm whether effects are truly androgenic (e.g., [31,51]). Few studies have examined progesterone in males and testosterone in females (e.g., [44,63]); further work will be required to determine whether pain modulation by these hormones is sexually dimorphic. As noted in previous sections, estradiol sometimes produces similar effects in males and females (e.g., [1,44]), whereas in other cases males do not respond to estradiol as females do (e.g., [77]). Finally, there are other estrogens besides estradiol about which we know almost nothing insofar as their pain modulatory actions. Other endogenous estrogens such as estriol and estrone are sometimes used in contraceptives, and various synthetic estrogens are used in contraceptive and HRT preparations, and to treat osteoporosis [26]. There may be differences among the various estrogens that increase or decrease their likelihood to affect pain. For example, conjugated equine estrogens (often used for HRT) have substantially greater anti-inflammatory activity than estradiol [102], although whether they decrease pain to a greater extent than other estrogens is not yet known. Systematic comparisons of estrogens on a number of pain-related assays will help us to refine our use of these steroids in women, for example, to determine whether some might be preferable to others for treating osteoarthritis in women with a certain type of chronic pain. 6. Summary Considerable evidence now suggests that estrogens modulate at least certain types of pain, including menstrually related migraine, TMD and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad mechanisms by which estrogens ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.

References [1] Allen JB, Blatter D, Calandra GB, Wilder RL. Sex hormonal effects on the severity of streptococcal cell wall-induced polyarthritis in the rat. Arthritis Rheum 1983;26:560–3. [2] Aloisi AM, Ceccarelli I. Role of gonadal hormones in formalininduced pain responses of male rats: modulation by estradiol and naloxone administration. Neuroscience 2000;95:559–66.

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