TOPICAL REVIEW

Does pain vary across the menstrual cycle? A review S. Iacovides1, I. Avidon2, F.C. Baker1,3 1 Wits Dial-a-bed Sleep Laboratory, Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 2 Exercise Physiology Laboratory, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Human Sleep Research Program, SRI International, San Francisco, USA

Correspondence Stella Iacovides E-mail: [email protected] All work was carried out in the School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Funding sources None. Conflicts of interest None of the authors have conflicts of interest with respect to this work.

Accepted for publication 23 March 2015 doi:10.1002/ejp.714

Abstract Reproductive hormones are implicated in moderating pain. Animal studies support both pronociceptive and antinociceptive actions of oestradiol and progesterone suggesting that the net effect of these hormones on pain is complex and likely depends on the interaction between hormones and the extent of fluctuation rather than absolute hormone levels. Several clinical pain conditions show variation in symptom severity across the menstrual cycle. Though, there is still no consensus on whether the menstrual cycle influences experimental pain sensitivity in healthy individuals. Comprehensive literature searches on clinical and experimental pain across the menstrual cycle, as well as gonadal hormones and pain were performed using the electronic databases PubMed, Google Scholar and the Cochrane Library. Full-text manuscripts were reviewed for relevancy and reference lists were crosschecked for additional relevant studies. Most of the more recent, wellcontrolled studies show that menstrual cycle phase has no effect on the perception of pain in healthy, pain-free women. Although recent studies investigating pain-related brain activation have shown differential activation patterns across the menstrual cycle in regions involved with cognitive and motor function, even in the absence of a behavioural pain response, suggesting that cognitive pain and bodily awareness systems are sensitive to menstrual cycle phase. The interaction between the gonadal hormones and pain perception is intricate and not entirely understood. We suggest further investigations on the association between female reproductive hormones and pain sensitivity by exploring the interaction between clinical and experimental pain and the hormone changes that characterize puberty, post-partum and the menopause transition.

1. Introduction Clinical pain conditions are more common in women than men (Stewart et al., 1992; Marcus, 1995; Unruh, 1996; Berkley, 1997; LeResche, 2000; Pogatzki-Zahn, 2013) and, importantly, these conditions often affect women of reproductive age (Unruh, 1996; Craft, 2007). Epidemiological studies demonstrate menstrual cyclical exacerbations in several clinical pain conditions, suggesting that gonadal © 2015 European Pain Federation - EFICâ

hormones may influence pain perception. Furthermore, the various phases of a woman’s life, from puberty to the post-menopausal stage, which are accompanied by marked variation in hormonal levels, are also associated with discernable variation in the pain experience. While the exact mechanisms underlying these effects remain unclear, it is plausible that female gonadal hormones may alter endogenous pain modulation and analgesia (Fillingim and Ness, 2000; Craft et al., 2004; Aloisi and Bonifazi, 2006). In this review, we first briefly discuss the Eur J Pain 19 (2015) 1389--1405

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Database • PubMed, Web of Science, Google Scholar databases, and the Cochrane Library. What does this review add?

• After briefly discussing the literature investigating the impact of gonadal hormones on nociception in basic models, we review that of menstrual variation in clinical and experimental pain. • Though reviews are available prior to 2009, several more studies, with improved methodology, have since been conducted to investigate pain across the menstrual cycle; we critically discuss and present these findings in a tabulated form for easy reference. • We discuss the overall findings and propose future directions for research.

literature investigating the impact of female gonadal hormones on nociception in basic models (for more extensive reviews on this topic, see Craft et al., 2004; Aloisi and Bonifazi, 2006; Craft, 2007; Martin, 2009). Next, we review the literature about variation in clinical and experimental pain sensitivity across the menstrual cycle. Reviews are available on this topic (Riley et al., 1999; Sherman and LeResche, 2006; Martin, 2009), however, since the last review, published in 2009, several more studies, with improved methodology, have been conducted to investigate pain across the menstrual cycle. We present the major findings from studies in this area in tabulated form for easy reference to readers. Lastly, we conclude with a discussion of the overall findings and propose future directions for research.

2. Methods Using the electronic databases, PubMed, Google Scholar and the Cochrane Library, literature searches were conducted on clinical and experimental pain across the menstrual cycle in human and animal studies. A literature search on gonadal hormones and pain was also performed using the same electronic databases. A combination of the following keywords were used to obtain articles published in peer-reviewed journals only: pain, experimental pain, clinical pain, chronic pain, women, menstrual cycle, menstrual phase, gonadal hormones, sex hormones, oestrogen, progesterone, hyperalgesia, analgesia, pain threshold, pain tolerance, pain sensitivity, 1390 Eur J Pain 19 (2015) 1389--1405

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pain reactivity and pain perception. Full-text manuscripts were reviewed for relevancy and importantly, reference lists were cross-checked for additional relevant studies.

2.1 Pain and gonadal hormones Nociception involves dynamic and interactive events in the peripheral and central nervous systems. Although the exact neuroanatomy and neurochemistry of nociceptive processing and modulation remain unclear, the current notion of nociceptive processing describes an arrangement which, under normal circumstances, involves a counterbalance between sensitization and desensitization (by inhibitory feedback systems) of the system (Fillingim and Ness, 2000; Fields et al., 2006). Modulation of pain occurs at a variety of sites in the primary afferents, spinal cord, brainstem and cerebrum (Fields and Basbaum, 2005). As gonadal hormone receptors have been identified throughout the nervous system (Deroo and Korach, 2006), it is possible for these hormones to affect numerous sites to modulate the pain experience. Indeed, gonadal hormones have been demonstrated to interact with nociceptive processes at multiple levels of the peripheral and central nervous system (CNS) (Fillingim and Ness, 2000; Aloisi and Bonifazi, 2006; Puri et al., 2006; Roglio et al., 2008; Martin, 2009). However, the underlying mechanisms and the precise role of gonadal hormones in modulating nociception and pain are complex and not fully understood (Frye et al., 1992; Robbins et al., 1992; Gaumond et al., 2005; Kuba et al., 2006), and there is a lack of consistency regarding the relationship between these hormones and pain perception, such that oestrogen and progesterone have paradoxically been observed to generate both antinociceptive and pronociceptive effects on pain pathways (Craft et al., 2004; Martin, 2009). The hormonal effects on nociceptive processing likely are the result of actions at multiple levels, from peripheral nerves to the highest cortical response, and sex steroids may exert pronociceptive or antinociceptive effects, depending on the overall hormone profile. As reviewed by Martin (2009), most studies suggest that the hormonal milieu during the proestrous phase of the rats oestrous cycle (in which serum oestradiol concentrations peak during early proestrous and decline during late proestrous, and serum progesterone concentrations are low during early proestrous and peak during late proestrous) may be pronociceptive. It is, however, not known whether the fluctuating serum oestradiol

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concentrations are accountable for the pronociceptive effects during this phase, or whether progesterone might also influence pain perception during the proestrous phase (Martin, 2009). Also, it should be noted that the rodent oestrous cycle differs considerably from the human menstrual cycle, such that hormone influences observed in rodents may not translate directly to humans. Gonadal hormones have been found to alter various neuromodulators involved in spinal nociceptive processing, including substance P, the amino acids glutamate and gamma-aminobutyric acid (GABA), as well as various other neurotransmitters, including endogenous opioids, dopamine, noradrenaline and serotonin (Smith, 1994; Duval et al., 1996; Fields and Basbaum, 2005). Oestrogen is believed to be associated with nociception through modulatory effects on GABA receptors, mu (l) opioid receptors, and nerve growth factor receptors in the dorsal root ganglion (Woolf, 1996; Eckersell et al., 1998; Aloisi, 2003; Smith et al., 2006). High or fluctuating levels of oestrogen can also enhance afferent sensory input through glutaminergic mechanisms (McRoberts et al., 2007) or by increased synthesis of neurotrophins (Pezet and McMahon, 2006). Furthermore, there is evidence of pronociceptive actions of oestrogen via inflammatory and stress responses (Fillingim and Maixner, 1995; Martin, 2009). One suggested mechanism by which oestrogen enhances pain is via the release of peripheral cytokines, such as gamma interferon, which in turn, increases cortisol secretion. Prolonged increases in cortisol release may promote destruction of muscle, bone and neural tissue, thus establishing the foundation for various chronic pain conditions (Melzack, 1999). On the other hand, antinociceptive effects of oestrogen have also been displayed (Aloisi et al., 2010). It has been proposed that oestrogen may reduce sensory neurotransmission via down-regulation or inhibition of transient receptor potential vanilloid subfamily 1 receptors (Xu et al., 2008) and glutamate reuptake (Pawlak et al., 2005). In addition, oestrogen affects endogenous opioidergic processes at various levels; including the synthesis, absorption, distribution and metabolism of opioids (Craft et al., 2004), and has been shown to influence all three primary receptor types (mu, kappa and delta) mediating the effects of endogenous opioid peptides. Oestrogen activates spinal cord kappa- and delta-opiate receptors (Dawson-Basoa and Gintzler, 1998) and affects mu-mediated neurotransmission, with decreased neurotransmission in the CNS during © 2015 European Pain Federation - EFICâ

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periods of low oestrogen concentration (Smith et al., 2006). Negative associations also have been observed between circulating levels of oestradiol and CNS mureceptor availability during the follicular, compared with the luteal phase (Smith et al., 1998). The analgesic effects of oestrogen via the opioid system have also been well documented in animal studies (Maggi et al., 1989; Fillingim and Ness, 2000; Craft et al., 2004). Oestrogens bind predominantly to two nuclear receptors, oestrogen receptor-alpha and oestrogen receptor-beta, both of which are present throughout the CNS, but importantly are present in brain areas involved in both pain transmission and inhibition (Alves et al., 1998a,b; Papka et al., 2002; Vanderhorst et al., 2002; Mitra et al., 2003; Coulombe et al., 2011). Although both receptors are involved in pain transmission and modulation, they may act at very distinctive pain pathways, explaining oestrogen’s pronociceptive and antinociceptive actions. Indeed, the results of a study done on oestrogen receptor-alpha and oestrogen receptor-beta knockout mice support the distinct role of the two oestrogen receptors in nociceptive responses; formalin-induced pain supported the role of oestrogen receptor-beta in pronociception and that of oestrogen receptor-alpha in antinociception (Coulombe et al., 2011). Furthermore, investigation of inflammatory models of pain in animals has revealed oestrogen to exert anti-inflammatory effects (Leventhal et al., 2006; Ganesan et al., 2008; Coulombe et al., 2011). For example, oestrogen administration attenuates inflammatory collagen-induced arthritis (Ganesan et al., 2008), thermal-mediated hyperalgesia after the application of the inflammatory agent prostaglandin E2 (Leventhal et al., 2006), and lipopolysaccharide-induced microglial activation and release of inflammatory agents (Smith et al., 2011). Both oestrogen receptor-beta (Leventhal et al., 2006; Coulombe et al., 2011; Smith et al., 2011) and oestrogen receptor-alpha (Coulombe et al., 2011; Smith et al., 2011) have been implicated in the anti-inflammatory effects of oestrogen. Similar to oestrogen, the analgesic, neuroprotective and anti-inflammatory effects of progesterone in animals have been well documented (Ogata et al., 1993; Fillingim and Ness, 2000; Labombarda et al., 2002; Craft et al., 2004; El-Etr et al., 2005; Schumacher et al., 2007; Cai et al., 2008; Ishrat et al., 2009; Wang et al., 2010; Dableh and Henry, 2011). Progesterone modulates afferent sensory input through the inhibitory GABAergic system. GABA levels in the occipital cortex of humans have been Eur J Pain 19 (2015) 1389--1405

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found to decrease across the menstrual cycle, with a negative association between GABA and both oestrogen and progesterone levels (Epperson et al., 2002). As GABA is the main inhibitory neurotransmitter in the CNS, reduced GABA concentrations may result in reduced pain inhibition and hence, increased pain. On the other hand, progesterone and its metabolites have also been reported to exert antinociceptive effects, mainly via the GABAA receptor complex (Twyman and Macdonald, 1992; Frye and Duncan, 1994; Belelli and Lambert, 2005). In summary, the net effect of these hormones on pain sensitivity likely is dependent on the sum of their pronociceptive and antinociceptive effects (Martin, 2009), and/or the interaction between oestrogen and progesterone. Most (Frye et al., 1992; Frye et al., 1993; Kayser et al., 1996; Sapsed-Byrne et al., 1996; Vincler et al., 2001; Okamoto et al., 2003; Cook and Nickerson, 2005; Martin et al., 2007; Ji et al., 2008), but not all (Giamberardino et al., 1997a; Leer et al., 1988; Martinez-Gomez et al., 1994; Bradshaw et al., 1999; Fischer et al., 2008) animal studies suggest that sensitivity to pain peaks during the proestrous phase; a period characterized by fluctuating levels of oestrogen (peaking first and followed by a rapid decline) and progesterone (low levels followed by a peak). Whether or not it is the cyclical fluctuation in sex steroids, absolute levels of oestradiol and/or progesterone, or the ratio of these two hormones that modulates pain sensitivity across the oestrous cycle, remain to be determined. Finally, it is important to note that although less is known about the role of other sex hormones, such as testosterone, in the perception of pain, their possible contributing effects cannot be disregarded. Testosterone appears to have analgesic effects to experimental pain (Ceccarelli et al., 2003; Aloisi et al., 2004; Hau et al., 2004; Okifuji and Turk, 2006; Teepker et al., 2010; Bartley et al., 2014), which may be protective against painful conditions (Fischer et al., 2007). Furthermore, male and female patients with rheumatoid arthritis have been found to have lower levels of androgens compared with gender-matched controls, and androgen administration has been shown to improve their symptoms (Aloisi and Bonifazi, 2006). In addition, a recent study suggests that testosterone influences pain processing by affecting descending inhibitory pathways in women (Vincent et al., 2013). However, the study of the specific effects of testosterone are complicated by the fact that much of it is metabolized in vivo to oestradiol by aromatose, and the effects of testosterone in the above-mentioned study appeared to be 1392 Eur J Pain 19 (2015) 1389--1405

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dependent on oestrogen concentrations. It is, therefore, likely that hormone constellations are more important than individual hormone levels when considering their effects on pain.

2.2 Sex differences in clinical pain Epidemiological studies report that pain disorders including headaches/migraines, temporomandibular joint disorder, irritable bowel disorder, rheumatoid arthritis and osteoarthritis are more prevalent in women than in men (Dworkin et al., 1990; Verbrugge et al., 1991; Wolfe et al., 1995; Unruh, 1996; Schwartz et al., 1998; Lipton et al., 2001; Symmons et al., 2002; Mayer et al., 2004). In the clinical setting, women, compared with men, report a greater number of painful symptoms, higher ratings of pain severity and pain-related disability, and are more likely to consult physicians due to their pain complaints (Von Korff et al., 1988; Unruh, 1996; Rollman and Lautenbacher, 2001; Latinovic et al., 2006). Sex differences in the prevalence and experience of painful disorders may be a consequence of social (Unruh, 1996; Courtenay, 2000), neurophysiological (Craft, 2003), genetic (Mogil et al., 2003; Fillingim et al., 2005) or immunological (Berkley et al., 2006) influences independent of hormone effects, as well as organizational and activational effects of reproductive hormones (Craft et al., 2004). Symptoms often vary in predictable patterns in relation to hormonal status. For example, sex differences in clinical pain begin to manifest around puberty, at which time dramatic changes in reproductive hormones occur, pain disorders prevail during women’s reproductive years and symptom severity often displays cyclic variation across the menstrual cycle (Marcus, 1995; Unruh, 1996; Craft, 2007). Furthermore, sex differences in the prevalence of pain disorders become less noticeable in the postmenopausal period of a woman’s life, when oestrogen and progesterone levels are very low (Craft, 2007). In both genders, the probability of experiencing painful conditions, particularly back and facial pain, rises with advanced pubertal development (LeResche et al., 2005a). However, only in girls, this increased probability extends to include two other forms of pain, headache and stomach pain (Sillanpaa and Aro, 2000; LeResche et al., 2005a; Rhee, 2005). Given that pubertal development is a stronger predictor than age of the presence of pain in girls, it is believed that biological development during puberty may initiate changes that predispose women to experience pain (LeResche et al., 2005a). In an © 2015 European Pain Federation - EFICâ

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attempt to explain the clear gender difference in the prevalence of temporomandibular pain that is observed in adults (LeResche, 1997), the authors speculate that this phenomenon may be the result of a sufficient period of exposure to hormones; hence, as pubertal development advances and women are naturally exposed to ‘sufficient’ hormones, they may become more susceptible to developing pain (LeResche et al., 2005a). Subsequently, post-menopausal women have lower prevalence rates of particular forms of pain, namely, headache, abdominal and facial pain, compared with women of reproductive age (Von Korff et al., 1988; Stewart et al., 1992; Marcus, 1995). However, other pain conditions, particularly intestinal cystitis (IC), joint pain and fibromyalgia often persist into the forth decade of a woman’s life (Curhan et al., 1999; LeResche, 2000; Pamuk and Cakir, 2005). A recent study in postmenopausal women with fibromyalgia found that women with an early onset of menopause were more sensitive to experimental painful and nonpainful stimuli compared with women with a late onset of menopause, suggesting perhaps that an early transition to menopause, and hence exposure to oestrogen for a shorter period of time, may result in hyperalgesia (Martinez-Jauand et al., 2013). However, assessment of pain sensitivity across the menstrual cycle in women with fibromyalgia is limited and inconclusive (Carette et al., 1992; Ostensen et al., 1997; Alonso et al., 2004; Gur et al., 2004; Okifuji and Turk, 2006).

2.3 Clinical pain across the menstrual cycle The ovulatory menstrual cycle is characterized by regulated cyclic variations in reproductive hormone production (Fig. 1). In brief, the follicular (proliferative)

LH

Pituitary hormones (mlU/mL) FSH

Ovarian phases (days)

Oestrogen (pg/mL)

Menstruation (1–5)

Follicular (5–13)

Progesterone (ng/mL)

Ovulation 14

Ovarian hormones

Luteal (15–28)

Figure 1 Plasma hormone concentrations during a typical 28-day ovulatory menstrual cycle.

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phase lasts from the first day of menses, typically referred to as day 1, until ovulation, which occurs around day 14. During menstruation, concentrations of the four predominant reproductive hormones, namely luteinizing hormone (LH), follicle stimulating hormone (FSH), oestrogen and progesterone, are low. Oestrogen levels progressively increase from around day 5, and rapidly reach a peak towards the end of the follicular phase. The rise in oestrogen stimulates the secretion of LH leading to ovulation around day 14. While oestrogen predominates in the follicular phase, progesterone concentrations remain low. However, in the second half of the menstrual cycle, the luteal (secretory) phase, progesterone is secreted from the corpus luteum, and thus becomes the predominant steroid hormone (Vander et al., 1998). Several clinical pain conditions, including temporomandibular joint (TMJ) disorder, fibromyalgia, irritable bowel syndrome (IBS), IC, rheumatoid arthritis and migraine, all display variation in symptom severity across the menstrual cycle (Marcus, 1995; LeResche, 2000; Martin, 2009). For the most recent, comprehensive review on variation in musculoskeletal pain, migraine headache, TMJ disorder and pelvic pain across the menstrual cycle, see Hassan et al. (2014). Pain symptoms appear to be most severe at times of low, or rapidly falling, levels of oestrogen (Johannes et al., 1995; LeResche, 2000; LeResche et al., 2003; Martin et al., 2003; Pamuk and Cakir, 2005; Martin, 2009; Colangelo et al., 2011). For example, the highest and most severe incidence of headache during the menstrual cycle has been reported to be during menstruation (Johannes et al., 1995; Marcus, 1995; Stewart et al., 2000; Martin et al., 2005), while periods of lowest vulnerability to headache (less severe headaches) occur during the mid-luteal phase (Beckham et al., 1992; Martin et al., 2005), during which time oestrogen and progesterone levels are high. Similarly, compared with the late follicular, luteal and premenstrual phases, the menstruation phase has been associated with greater exacerbations of abdominal pain and bloating in patients with IBS (Houghton et al., 2002), and the pre-ovulatory phase has been associated with increased joint pain and morning stiffness in patients with rheumatoid arthritis, compared with the post-ovulatory phase (Latman, 1983). In one study, 45% of premenopausal women with fibromyalgia (n = 80) reported that their pain is most severe during menstruation (Pamuk and Cakir, 2005), and in a separate study, 51% of women with fibromyalgia experienced a flare immediately preceding menses (Colangelo et al., Eur J Pain 19 (2015) 1389--1405

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2011). However, it has also been reported that pain severity and number of tender points do not differ between the mid-to-late luteal phase and the earlyto-mid follicular in 125 premenopausal women with fibromyalgia (Alonso et al., 2004). Clinical temporomandibular disorders pain also varies systematically across the menstrual cycle, whereby the timing of higher pain intensity corresponds to a time of rapid changes in oestrogen levels (LeResche et al., 2003). Daily reports of temporomandibular pain intensity in women were highest towards the end of the menstrual cycle, and peaked during the first 3 days of menstruation. Interestingly, even in the women using oral contraceptives, pain intensity was highest just before and during menstruation, when the placebo pill replaced active medication. Further, women not using oral contraceptives, had a secondary peak pain, which occurred around the time of ovulation; also a period of rapid oestrogen fluctuation (LeResche et al., 2003). Similarly, periodontal pain, following supragingival and subgingival debridement, is reportedly the greatest during the peri-menstrual phase compared with the post-menstrual phase (Ozcaka et al., 2005). Such studies therefore suggest pain in several clinical pain conditions is worse when absolute levels of oestrogen are low or unstable. It has been proposed that some forms of clinical pain, such as menstrual migraines and temporomandibular pain, are triggered by the withdrawal of oestrogen (Somerville, 1975; Rasmussen, 1993; LeResche et al., 2003), or the effects of oestrogen withdrawal on pain neurotransmitters (Marcus, 1995). In fact, studies have found that supplementing oestrogen to prevent withdrawal is effective in preventing headaches associated with menstruation (Somerville, 1975; MacGregor et al., 2006). Similarly, though the oral contraceptive is not able to alleviate the symptoms of rheumatoid arthritis, it has been reported to have a protective effect in the development of rheumatoid arthritis (Bijlsma et al., 1987; Spector and Hochberg, 1990; Bijlsma and Van den Brink, 1992). Also, pregnancy, a time during which oestrogen (and progesterone) levels increase dramatically, is generally, though not always (Chancellor et al., 1990), associated with significant improvement in migraine headaches in women with a pre-pregnancy history of migraines (Somerville, 1972; Uknis and Silberstein, 1991; Granella et al., 1993; Rasmussen, 1993; Maggioni et al., 1997). Not surprisingly, during the postpartum period, when oestrogen levels fall, studies have reported increased headache (Stein et al., 1984). Clinical pain symptoms can be improved by 1394 Eur J Pain 19 (2015) 1389--1405

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generating more constant hormone levels, by means of combined oral contraceptives (Coffee et al., 2007; Craft, 2007; Sulak et al., 2007), gonadotrophinreleasing hormone agonist (Mathias et al., 1994; Lentz et al., 2002) or pregnancy (Da Silva and Spector, 1992; LeResche et al., 2005b). However, Martin et al. (2003) demonstrated that minimization of hormonal fluctuations alone is inadequate to prevent migraine headaches; oestrogen, administered at an appropriate dosage may additionally be required. In contrast to the studies described above, others have shown an association between high levels of female reproductive hormones and increased risk of migraine (Silberstein and Merriam, 1991). Also, the use of oral contraceptives and hormone replacement therapy (HRT) has been identified as risk factors for developing TMJ pain (LeResche et al., 1997) and back pain (Brynhildsen et al., 1998). Similarly, pain associated with fibromyalgia has been reported to be heightened the week before the onset of menstruation, when oestrogen and progesterone levels are high (Ostensen et al., 1997). Nevertheless, this study did not assess the women’s hormone levels. The ‘week before menstruation’ may comprise periods of high and falling levels of oestrogen. Since the authors do not state when in the week preceding menstruation, these women experienced more pain, we cannot conclude that the women reported heightened pain during periods of high oestrogen. The study’s results may, therefore, in fact, support the analgesic effects of oestrogen during a time of fluctuating concentrations. Furthermore, a study investigating the effect of systemic hormone administration to both male-tofemale and female-to-male transsexuals found that approximately 30% of the male-to-female subjects developed chronic pain during their treatment with oestrogen and anti-androgens, and those who did not develop chronic pain still reported less tolerance to pain and had heightened sensitivity to experimental thermal (warm and cold temperatures) pain (Aloisi et al., 2007). On the other hand, more than half of the female-to-male subjects who experienced chronic pain before the start of the androgen treatment had a reduced number of painful episodes, and shorter lengths of the painful episodes that did occur (Aloisi et al., 2007). However, interpretation of studies investigating the impact of exogenous hormones on pain is complicated by the different formulations available, the effects of exogenous hormones on levels of endogenous hormones and the variable doses of hormones used. © 2015 European Pain Federation - EFICâ

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2.4 Experimental pain across the ovulatory menstrual cycle Patients with clinical conditions may have other confounding factors that could influence their pain experience across the menstrual cycle. They also may have altered sensitivity to reproductive hormone changes. Human experimental pain models applied to healthy volunteers are useful tools for investigating various aspects of the pain mechanisms, as they create a situation in which healthy volunteers can be used to assess the sensory manifestations and sensory-motor interactions of a welldefined pain. Moreover, experimental pain models may be valuable in both pharmacological and clinical studies to quantify the sensitivity of the nociceptive system in pain patients, and in predicting clinical pain, and clinical pain outcomes (Riley et al., 1998; Arendt-Nielsen and Graven-Nielsen, 2008). Collectively, research on experimental pain compliments clinical research. Below, we review the studies on the perception of experimental pain in healthy painfree women. There is a relatively large body of literature on experimental pain perception across the menstrual cycle in normal healthy women. However, studies have been unable to agree on whether a cyclical influence on pain exists, let alone the direction of the effect, should it exist. Some studies suggest that responses to painful stimuli vary across the menstrual cycle, while others argue that experimental pain perception does not vary according to menstrual cycle phase. The details and results of each study on pain perception across the menstrual cycle in healthy women with normal menstrual cycles are presented in Supporting Information Table S1. In summary, studies have shown variable effects of the menstrual cycle on pain sensitivity. Enhanced sensitivity to pain has, e.g. been reported around the time of menstruation (Tedford et al., 1977; Hapidou and De Catanzaro, 1988; Giamberardino et al., 1997b; Hapidou and Rollman, 1998; Teepker et al., 2010; Ribeiro-Dasilva et al., 2011; Veldhuijzen et al., 2013), at the time of ovulation (Goolkasian, 1980, 1983; Cimino et al., 2000; Kowalczyk et al., 2010), during the luteal phase (Goolkasian, 1980; Hapidou and De Catanzaro, 1988; Tassorelli et al., 2002; Choi et al., 2006), during the premenstrual phase (Fillingim et al., 1997; Pfleeger et al., 1997; Isselee et al., 2001) and during the menstrual phases (Herren, 1933; Robinson and Short, 1977; Hellstrom and Lundberg, 2000; Isselee et al., 2001). In contrast, a number of studies suggest a lack of variability

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in response to pain across the menstrual cycle (Aberger et al., 1983; Veith et al., 1984; Kuczmierczyk and Adams, 1986; Kuczmierczyk et al., 1986; Amodei and Nelson-Gray, 1989; Fillingim et al., 1997; Hapidou and Rollman, 1998; Granot et al., 2001; Bajaj et al., 2002; Drobek et al., 2002; Oshima et al., 2002; Straneva et al., 2002; Kowalczyk et al., 2006; de Leeuw et al., 2006; Ring et al., 2009; Klatzkin et al., 2010; Teepker et al., 2010; Ribeiro-Dasilva et al., 2011; Vincent et al., 2011; Bartley and Rhudy, 2013; Balter et al., 2013; Iacovides et al., 2013; Bartley et al., 2014).

2.5 Methodological concerns The inconsistent findings in the current literature regarding pain sensitivity across the menstrual cycle have been attributed to various experimental methodological concerns including: differences in the choice of experimental pain stimuli, and where these are applied (Sherman and LeResche, 2006; Vincent and Tracey, 2010), as well as different outcome measures (thresholds vs. tolerance) used (Sherman and LeResche, 2006). Also, in the majority of studies, menstrual cycle phase was arbitrarily divided into functionally distinct phases, based either on the ovarian or endometrial cycle (Sherman and LeResche, 2006; Vincent and Tracey, 2010; PogatzkiZahn, 2013), which may not effectively capture the cyclical changes in reproductive hormones. Importantly, most studies did not measure plasma levels of gonadal hormones (see Supporting Information Table S1). Measurements of plasma gonadal hormone concentrations not only are needed to accurately determine the menstrual cycle phase and confirm ovulation but also are vital to determine the relationship between hormone levels and pain responses. Importantly, concentrations of the gonadal hormones during each phase vary markedly between women and there is a large inter- and intra-variability in menstrual cycle lengths. As shown in Supporting Information Table S1, studies that have determined gonadal hormone concentrations also differ in the method used to measure the gonadal hormones. Salivary hormonal assessments, e.g. appear to offer a reliable and sensitive alternative to plasma or serum sex hormone assessments (Ellison, 1993; Lu et al., 1997; Lu et al., 1999; Higashi, 2012). Salivary samples are easily collectable, inexpensive and non-painful and non-invasive to the patient (Higashi, 2012). However, their disadvantages also need to be considered, one of which is

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the influence of sample storage temperatures (Toone et al., 2013). We refer the reader to Higashi, 2012, for a review of the advantages and disadvantages. Further, approximately one in three or one in four menstrual cycles may be anovulatory in normal women (Metcalf et al., 1983). Confirming ovulation is therefore also imperative because if ovulation does not occur, the hormonal milieu in the second half of the menstrual cycle will be distinctly different from that which occurs in a normal ovulatory menstrual cycle. Other factors that have not always been considered in studies to date are whether women have severe premenstrual mood changes, such as with premenstrual dysphoric disorder (Straneva et al., 2002) or menstrual pain (dysmenorrhoea) (Iacovides et al., 2013) which may impact pain responses. 2.5.1 Experimental pain stimuli The diverse range of experimental pain stimuli also contribute to the inconsistent findings across the studies. The choice of experimental pain stimuli used in studies is fundamental for numerous reasons: when assessing pain, it is essential that the pain stimulus is (1) reproducible, (2) strong enough to elicit a measurable response, (3) moderate enough to display individual differences and (4) either meaningful enough to bear some resemblance to a natural physiological or clinical pain, or precise enough to elucidate the basic mechanism of a response to pain (Sherman and LeResche, 2006). As shown in Supporting Information Table S1, the pain induction procedures that have been used, include: pressure/ mechanical pain (Amodei and Nelson-Gray, 1989; Bajaj et al., 2002; Teepker et al., 2010; Balter et al., 2013; Bartley and Rhudy, 2013), thermal (Bajaj et al., 2002; Teepker et al., 2010), cold pressor stimulation (Hapidou and De Catanzaro, 1988), electrical stimulation (Giamberardino et al., 1997b; Teepker et al., 2010), ischaemia (Aberger et al., 1983; Bartley and Rhudy, 2013; Bartley et al., 2014), pinch (Bajaj et al., 2002), tactile stimulation (Bajaj et al., 2002), intramuscular injection of hypertonic saline (Smith et al., 2006; Iacovides et al., 2013), venipuncture and intravenous catherization pain (Ring et al., 2009), electrocutaneous stimuli (Bartley and Rhudy, 2013; Bartley et al., 2014), pain-evoked potentials by laser stimuli (Granot et al., 2001) and spinal nociception (Bartley and Rhudy, 2013; Bartley et al., 2014). It is likely that each painful stimulus results in differential processing of nociceptive afferents (Lynn and Perl, 1977). Electrical stimuli, e.g. used to

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induce muscle pain, activate all classes of afferent neurons, (i.e. both nociceptive and non-nociceptive fibres), hence producing both painful and non-painful sensations (Gracely, 1990; Keefe et al., 1991), which may be difficult to distinguish. Electrical stimulation also is confounded by concurrent activated muscle twitches (Arendt-Nielsen and Graven-Nielsen, 2008), and this modality has been shown to evoke pain sensations that are less natural than other pain stimuli (Gracely, 1990; Fillingim and Ness, 2000). Intramuscular injection of the algesic substance, hypertonic saline, also induces muscular pain; one that closely reproduces clinical musculoskeletal pain in both subjectively perceived pain quality and in its effects on motor performance (Graven-Nielsen et al., 1997). Hypertonic saline is believed to excite wide dynamic range neurons (Ro and Capra, 1999), possibly via activation of group III (thinly myelinated A-delta fibres) and group IV (unmyelinated C-fibres) muscle nociceptors to produce both a local area of transient pain and referred pain (Paintal, 1960; Iggo, 1961; Kumazawa and Mizumura, 1977; Graven-Nielsen et al., 1997; Graven-Nielsen et al., 2002). Another method of producing deep-muscle pain, used by several studies (shown in Supporting Information Table S1), is the induction of tissue ischaemia (Aberger et al., 1983; Amodei and Nelson-Gray, 1989; Fillingim et al., 1997; Pfleeger et al., 1997; Straneva et al., 2002; Sherman et al., 2005; Klatzkin et al., 2010; RibeiroDasilva et al., 2011). By occluding blood flow to a group of muscles using a tourniquet, and by voluntarily contracting the muscle group to increase the use of oxygen by the muscles, the muscles become ischaemic and pain is produced (Maixner et al., 1990; Svensson and Arendt-Nielsen, 1995). The involved mechanisms of deep-muscle pain after ischaemic contractions are complex and not fully understood. However, it has been suggested that ischaemic contractions result in the accumulation of various substances such as potassium, adenosine and lactate, which excite muscle nociceptors or sensitize nociceptors to respond to muscle contractions that are normally non-painful (Newham and Mills, 1999; Grace et al., 2001; Mense and Simons, 2001). In addition, theories on tourniquet-induced ischaemic pain support the role of C-fibres in the transmission of pain, while A-fibre conduction is believed to be abolished during an ischaemic event (Chabel et al., 1990; Loram et al., 2007). Thermal stimuli, in contrast, activate both A-delta and C-fibres (Keefe et al., 1991). Furthermore, some stimuli (e.g. ischaemic pain and cold pressor pain) produce a stress © 2015 European Pain Federation - EFICâ

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response, while others activate endogenous pain regulatory mechanisms (e.g. ischaemic pain) (Pertovaara et al., 1982; Maixner et al., 1990; Kirschbaum et al., 1999). Given that studies have shown enhanced hypothalamic–pituitary–adrenal responses to stress during the luteal phase compared with the follicular phase (Kirschbaum et al., 1999), a specific hormonal milieu is likely to affect one pain stimulus in a different manner compared with another pain stimulus. 2.5.2 Body site and tissue depth Body sites have included the thumb (Haman, 1944), index finger (Tedford et al., 1977; Kuczmierczyk and Adams, 1986; Kuczmierczyk et al., 1986; Amodei and Nelson-Gray, 1989), forearm (Goolkasian, 1983; Straneva et al., 2002; Kowalczyk et al., 2006; Teepker et al., 2010), arm (Fillingim et al., 1997; Giamberardino et al., 1997b; Pfleeger et al., 1997; Bajaj et al., 2002), leg (Giamberardino et al., 1997b; Bajaj et al., 2002), abdomen (Giamberardino et al., 1997b; Bajaj et al., 2002; Vincent et al., 2011), lower back (Bajaj et al., 2002), foot (Veldhuijzen et al., 2013), and masseter and temporalis muscles (Isselee et al., 2001; Drobek et al., 2002). Several aspects of pain assessment have been shown to vary according to body location, particularly with respect to the proximity to the reproductive organs (Robinson and Short, 1977; Klonoff et al., 1993; Giamberardino et al., 1997b). The tissue depth at which pain is applied is also likely to play a role in the inconsistent findings since hyperalgesia has been reported to differ in the skin compared with subcutaneous tissue and compared with deep-muscle tissue (Vecchiet et al., 1990; Giamberardino et al., 1993; Giamberardino et al., 2014). Furthermore, there is some evidence that nociceptive activity arising from deep tissues, such as muscle, is under greater inhibitory influence than activity from cutaneous sites (Mense, 1990). 2.5.3 Measurement of pain response Researchers have used various pain response outcomes, including: pain threshold, pain tolerance and visual analogue scales (VAS) to measure pain intensity. It has been argued, e.g. that tolerance measures may constitute a learnt component of pain which is a more sensitive index of psychological, motivational and cultural factors affecting the experience of pain, while measures of pain threshold constitute an unlearnt component of pain more reflective of pure physiological aspects of pain perception (Weisenberg © 2015 European Pain Federation - EFICâ

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et al., 1975; Wolff, 1978). The VAS is widely used as an effective method of assessing clinical and experimental pain, as it has been shown to produce consistent and reliable measures of pain intensity and pain unpleasantness (Revill et al., 1976; Price et al., 1983; Price et al., 1994; Coll and Ameen, 2006). Collectively, as seen in Supporting Information Table S1, differences in the methodology of the studies render it difficult to compare outcomes and to reach agreeable compatible conclusions about the influence of the menstrual cycle phase on pain perception in women with normal menstrual cycles. Even the two reviews that used forms of metaanalyses of several experimental studies about pain reactivity in healthy women across the menstrual cycle are not in agreement. Riley et al. (1999) concluded that there is increased pain sensitivity during the luteal compared to the follicular phase of the menstrual cycle, for almost every stimulus modality used, including pressure, cold pressor, thermal heat and ischaemic muscle pain (Riley et al., 1999). It is important to note, however, that the effect sizes in this meta-analysis were relatively small. In a more recent review of 19 studies, including studies conducted after 1999, Martin (2009) reclassified the menstrual cycle into early, mid-, and late follicular and luteal phases, since the hormonal milieus at the various stages of both the follicular and luteal phases vary vastly. Of the 19 studies examined, 7 reported increased pain perception during the late luteal or early follicular phases (low or declining serum oestrogen and progesterone concentrations), 5 reported increased pain sensitivity during the late follicular and early luteal phases (rising serum oestrogen and rising serum progesterone concentrations) and 6 studies reported no differences in pain sensitivity across the menstrual cycle (Martin, 2009). This meta-analysis therefore concluded that the literature about the impact of menstrual cycle phase on pain sensitivity is still inconclusive (Martin, 2009). There have been further studies conducted since 2009 (see Supporting Information Table S1). Most of these more recent studies have used hormone measures to confirm menstrual phase, have looked at more than two menstrual cycle phases and have used several different pain modalities. Most, though not all, report no difference in pain sensitivity across the menstrual cycle (Supporting Information Table S1). There is still nonetheless, no consensus; from the recent studies that did find a menstrual phase effect on pain sensitivity; two studies found decreased sensitivity to ischaemia (Ribeiro-Dasilva et al., 2011), pressure and electrical pain stimulation (Teepker Eur J Pain 19 (2015) 1389--1405

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et al., 2010) during the luteal phase, another found decreased sensitivity to mechanical pressure pain during the menstrual and late luteal phases compared to the follicular, ovulatory and luteal phases (Kowalczyk et al., 2010), and one found increased sensitivity to pressure pain during the follicular phase, compared with the menstrual, periovulatory and mid-luteal phases (Veldhuijzen et al., 2013). Few studies have investigated correlations between oestradiol and progesterone levels and pain sensitivity to experimental pain stimuli. One study reported a positive correlation between progesterone and oestradiol and venepuncture and intravenous catherization pain ratings across the menstrual cycle (Ring et al., 2009), whereas others found no correlation between hormone levels and pain sensitivity (Kowalczyk et al., 2006; Klatzkin et al., 2010; Teepker et al., 2010). Others still have reported mixed results depending on the menstrual cycle phase: during the ovulatory phase, oestrogen was found to be negatively correlated with thermal pain onset, while progesterone correlated positively with thermal and ischaemic pain onset. However during the luteal phase, progesterone was negatively correlated with thermal pain tolerance (Fillingim et al., 1997). Thus, it appears that if a relationship between gonadal hormones and pain sensitivity does exist, it is not a simple linear relationship. Studies involving functional imaging techniques, including positron emission tomography scans (Smith et al., 2006) and functional magnetic resonance imaging (Choi et al., 2006; de Leeuw et al., 2006), provide further insight into the possible involvement of gonadal hormones in the modulation of pain sensitivity. Functional imaging techniques offer objective information on brain activity during the perception of pain, even when behavioural differences in pain responses are not evident, such that interpretations can be made regarding central processing mechanisms (Vincent and Tracey, 2010). In all these studies, which used different noxious stimuli, pain-related cerebral activation patterns differed between phases of the menstrual cycle characterized by high and low oestrogen levels, even though behavioural responses to pain did not necessarily differ (Choi et al., 2006; de Leeuw et al., 2006; Vincent et al., 2011; Veldhuijzen et al., 2013). Brain regions involved were not associated with pain perception, but more with cognitive and motor function, and suggest that cognitive pain modulation and bodily awareness systems are susceptible to menstrual cycle effects (Choi et al., 2006; de Leeuw et al., 2006; Veldhuijzen et al., 2013). In one study, the changes in 1398 Eur J Pain 19 (2015) 1389--1405

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pain sensitivity and brain activation patterns in response to painful stimuli were marginally correlated with hormone levels (Veldhuijzen et al., 2013), suggesting that cycle-related changes in brain activation to pain were only partly explained by circulating hormone levels (Veldhuijzen et al., 2013). Few studies have investigated reactivity to experimental pain across the menstrual cycle in women with pain disorders. Experimental pressure (Sherman et al., 2005; Vignolo et al., 2008) and ischaemia thresholds (Sherman et al., 2005) were found not to vary across the menstrual cycle in women with TMJ disorder, although their pain responses were increased compared with controls. Similarly, no significant difference in ischaemic pain threshold or tolerance (Okifuji and Turk, 2006) and dolorimetry (Alonso et al., 2004) has been found across the menstrual cycle in women with fibromyalgia. Finally, no differences were found in pain sensitivity to ischaemic or hypertonic saline-induced pain in women with primary dysmenorrhoea, although they too showed heightened sensitivity to experimental pain at all menstrual phases tested compared with controls (Iacovides et al., 2013).

3. Conclusion As discussed in this review, conflicting results among studies that have evaluated the effect of the menstrual cycle on experimental pain have been attributed to various methodological concerns across the various studies. That said, the majority of the more recent, well-controlled studies show that menstrual cycle phase has no effect on the perception of pain in healthy, pain-free women (Granot et al., 2001; Bajaj et al., 2002; Straneva et al., 2002; Sherman et al., 2005; Kowalczyk et al., 2006; de Leeuw et al., 2006; Klatzkin et al., 2010; Rhudy and Bartley, 2010; Vincent et al., 2011; Iacovides et al., 2013). The lack of effect of menstrual cycle phase on pain sensitivity may be surprising, considering the dramatic fluctuations in reproductive hormones across the cycle and that studies in animals have shown that progesterone and oestradiol influence the pain response (Maggi et al., 1989; Fillingim and Ness, 2000; Craft et al., 2004). However, as shown by the few imaging studies conducted, there are differences in brain activation patterns in regions involved in cognitive pain modulation in association with the hormonal changes of the menstrual cycle even when behavioural pain responses have not changed. Further studies that evaluate brain activation responses to painful stimuli both under experimental pain conditions and clinical © 2015 European Pain Federation - EFICâ

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pain syndromes are warranted. We suggest the use of clinically relevant painful stimuli, such as intramuscular hypertonic saline injections and ischaemic pain, and given that hyperalgesia differs according to tissue depth, we recommend that experimental painful stimuli be applied at the deep-tissue/muscle-level in future studies. It would also be valuable to investigate pain sensitivity in girls and women at other stages of reproductive hormone changes: just before and following the onset of puberty, post-partum and during the menopause transition, to further evaluate the possible impact of reproductive hormone changes on pain sensitivity. As suggested in a recent review (Craft, 2007), gonadal hormones may affect some but not all forms of pain. For example, the decline in gonadal hormones at the end of the luteal phase is associated with a greater incidence of migraines, temporomandibular and back pain (Kuba and Quinones-Jenab, 2005), but not necessarily with pain associated with fibromyalgia (Alonso et al., 2004). It is also interesting to speculate that some women may be more vulnerable to the impact of reproductive hormones on pain sensitivity, leading to changes in clinical pain experiences across the menstrual cycle; clinical pain patients may react differently to fluctuations in gonadal hormones. Pain is a personal experience influenced by many factors including previous pain experiences; previous pain predicts future pain (Hunter, 2001; Katz and Seltzer, 2009). Pain is also impacted by mood (Weisenberg et al., 1984; Zelman et al., 1991; Zillmann et al., 1996; Weisenberg et al., 1998; Rhudy and Meagher, 2000; Meagher et al., 2001; Wunsch et al., 2003; Rainville et al., 2005; Rhudy et al., 2005; Rhudy and Bartley, 2010), prior night sleep amount and quality (Onen et al., 2001; Azevedo et al., 2011; Goodin et al., 2011). Also, given that pain not only is a sensory experience but also an emotional event (Taxonomy, IASP, 1979; Bromm, 1995), psychological distress (Von Korff and Simon, 1996; Bair et al., 2003), as well as cultural and social influences on pain (Riley et al., 1998; Anttila et al., 2002; Groholt et al., 2003; LeResche et al., 2005a), also need to be accounted for. A noteworthy distinction, therefore, must be made between the negative emotional-affective components of clinical pain compared with that of experimental pain. Although anticipation of experimental pain may cause some anxiety, its emotional component is distinct from that of clinical pain. For example, the amygdala is activated during chronic arthritic pain, but not during acute experimental pain (Kulkarni et al., 2007). In addition, affective VAS ratings of © 2015 European Pain Federation - EFICâ

unpleasantness have been reported to be significantly higher in patients experiencing various forms of clinical pain compared to experimentally induced pain (Price et al., 1987). In conclusion, the interaction between the gonadal hormones and pain perception is intricate and not entirely understood. Hormonal effects on nociceptive processing likely are the result of actions at multiple levels, from the peripheral nerve to the highest cortical response and may be pronociceptive or antinociceptive in nature, depending on the hormonal profile, as well as the sum of their pronociceptive and antinociceptive effects. While the majority of recent studies have found that pain sensitivity to several experimental pain modalities does not change according to menstrual cycle phase, there is evidence of underlying changes in brain responses. Also, clinical pain severity varies according to menstrual cycle phase for several pain syndromes. We therefore recommend that researchers and clinicians should continue to consider menstrual cycle phase as a potential variable that could impact pain responses for both experimental and clinical pain. Additional research is required to advance our understanding of the relationship between pain and hormonal status. Further knowledge of the mechanisms by which hormones modulate the pain response would develop our understanding of the gender difference in prevalence and clinical manifestations of pain disorders, and would also provide significant insight into the management of pain. Author contributions S.I. and F.B. conceptualized the rationale and design of the review article. S.I. drafted and edited the manuscript. All authors read, revised and approved the final manuscript.

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Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1. Summary of human studies, in chronological order, investigating the influence of the normal menstrual cycle on experimental pain responses in healthy, normally cycling women.

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Does pain vary across the menstrual cycle? A review.

Reproductive hormones are implicated in moderating pain. Animal studies support both pronociceptive and antinociceptive actions of oestradiol and prog...
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