ReviewThe role of female gonadal hormones in behavioral sex differences in persistent and chronic pain: Clinical versus preclinical studies
Introduction
Clinical and preclinical studies have found sex-specific differences in the discrimination and perception of nociceptive stimuli. The emerging picture suggests that the biological basis of these differences in pain perception resides in the regulatory activity of estrogen and progesterone in the central nervous system. Since others have recently reviewed sex differences and the role of gonadal hormones in responses to acute pain [3], [32], [45], this review focuses on sex differences and the role of gonadal hormones in the behavioral response to persistent inflammatory and chronic pain stimuli.
Section snippets
Experimental animal models for persistent inflammatory and chronic pain
The measurement of “pain sensation” in animals is largely indirect, relying on aversive behavior in response to stimuli, as opposed to assessing the quality of the pain [12]. Pain models are traditionally divided into acute, tonic/persistent inflammatory, and chronic categories, distinguished by the duration and mechanism of the pain. Generally, acute tests require a high-intensity stimulus (such as thermal, mechanical, or chemical). Tonic/persistent inflammatory pain tests, those of long
Clinical studies demonstrate sex differences in prevalence of persistent and chronic pain
As summarized in Table 2, epidemiological pain studies have found that women more frequently reported temporary and persistent pains than did men, and they were more likely to report pain of a longer duration [7], [10], [16], [18], [24], [34], [55], [58], [60], [86], [94], [97], [100], [109], [117], [123], [124], [128]. For example, women had higher rates of chronic tension headache and migraine than men [88], [89], [90], [92], [133]. Reports also demonstrated that women experienced more
Physiology of the menstrual/estrous cycle
During the menstrual/estrous cycle, serum levels of estrogen and progesterone fluctuate, as shown in Fig. 1. In women at the beginning of the cycle, levels of estrogen and progesterone are both relatively low (Fig. 1A). During the follicular phase, estrogen levels gradually increase, peaking prior to ovulation, and then moderately decrease during the luteal phase. Progesterone levels rapidly increase after ovulation, peaking during the middle of the luteal phase. Toward the end of the luteal
Clinical studies demonstrate that endogenous hormones affect persistent and chronic pain
Few studies have looked at how endogenous hormones affect pain perception and pain symptomatology in postmenopausal women. The 1994–1995 National Population Health Survey indicated that chronic pain was higher in women than males (20% versus 16%) and increased with age (aged 15 and over), with the most common types being back pain and arthritis/rheumatism [79]. For certain pain syndromes such as joint pain, chronic widespread pain, and fibromyalgia, prevalence rates were higher in cycling than
Clinical studies show that exogenous estrogen and progesterone administration affects persistent inflammatory and chronic pain responses
In postmenopausal women, exogenous estrogen or progesterone administration significantly increased reports of TMD [72]. Women receiving oral contraceptives had a 20% increase in the incidence of TMD and higher referral rates for treatment than did control groups [72]. Reports from open studies have shown an alleviation of symptoms of stomatodynia in a percentage of patients after hormonal supplements [9], [46], [131]. However, a recent study demonstrated no correlation between chronic
Gonadal hormone effects on acute versus persistent inflammatory and chronic pain models
The studies reviewed in this paper show that gonadal hormones play a key role in modulating behavioral responses to pain. However, the current data suggest that the interactions between estrogen and progesterone are complex and do not affect the behavioral outcome to chronic and tonic pain in a straightforward manner. The reviews of acute pain responses also have a plethora of results. For example, similar to the studies reviewed here, in acute pain studies the estrous cycle has shown
Potential mechanisms underlying gonadal hormonal effects on persistent inflammatory and chronic pain
Corticosterone, a steroid hormone secreted by the adrenal gland, is an essential component of stress adaptation [36], [39], [82]. Basally and after different stressors (e.g., physical stress [80] and drug abuse [29], [69] female rats have higher corticosterone levels than male rats [2]. Furthermore, in male rats, formalin administration significantly increases serum levels of corticosterone [116].
Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the conversion of arachidonic acid
Clinical implications of the current literature
Although a clearer picture is emerging, one suggesting that dynamic endocrinological changes during the female cycle affect chronic pain responses, further research is required regarding how hormone concentrations affect these responses. Both estradiol and progesterone are simultaneously present during the reproductive cycle, but the extent to which the presence of both hormones modulates nociceptive behavioral responses in humans and rats remains to be further examined. Studies are therefore
Acknowledgments
This work was supported by RR-03037, NIDA DA 12136, SCORE 506-GM60654, 1454-NS41073, and SNRP NF 39534.
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