Sex-related hormonal influences on pain and analgesic responses

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Abstract

Considerable evidence indicates sex-related differences in pain responses and in the effectiveness of various analgesic agents. Specifically, females are at greater risk for experiencing many forms of clinical pain and are more sensitive to experimentally induced pain relative to males. Regarding analgesic responses, nonhuman animal studies indicate greater opioid analgesia for males, while a limited human literature suggests the opposite. Though the mechanisms underlying these effects remain unclear, the influence of gonadal hormones on nociceptive processing represents one plausible pathway whereby such sex differences could emerge. The present article reviews the complex literature concerning sex steroid effects on pain responses and analgesia. First, nonhuman animal research related to hormonal effects on nociceptive sensitivity and analgesic responses is presented. Next, human studies regarding gonadal hormonal influences on experimental pain responses are reviewed. Several potential mechanisms underlying hormonal effects on nociceptive processing are discussed, including hormonal effects to both peripheral and central nervous system pathways involved in pain transmission. Finally, based on these findings we draw several conclusions and make specific recommendations that will guide future research as it attempts to elucidate the magnitude and importance of sex-related hormonal effects on the experience of pain.

Section snippets

Overview

The experience of pain is sculpted by multiple biological and psychosocial contributions. Indeed, there is substantial interindividual variability in responses to painful stimuli as well as responses to analgesic medications. One set of biopsychosocial variables whose influence on pain and analgesic responses has received considerable attention in recent years is sex- and gender-related factors. Specifically, several recent reviews indicate that both experimental and clinical pain responses

Hormonal influences on pain and analgesia

Gonadal hormones naturally fluctuate across the female menstrual cycle (discussed below). The analog to the human menstrual cycle in rodents is the estrous cycle, which is typically broken down into four stages: (1) metestrus, during which progesterone is elevated while estrogen and LH levels are low; (2) diestrus, characterized by relatively high levels of LH, increasing estrogen and decreasing progesterone; (3) proestrus, during which estrogen, progesterone, LH and FSH peak; and (4) estrus,

Human menstrual cycle physiology

The human female menstrual cycle is accompanied by a broad array of hormonal alterations, which produce wide ranging effects in both peripheral and central nervous system (CNS) structures (Fig. 1). Two gonadotropic hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), secreted by the pituitary gland control the female menstrual cycle. During the postmenstrual “follicular” phase of the cycle, both FSH and LH are secreted at relatively steady, low-to-moderate levels. Also,

Potential mechanisms underlying hormonal effects on pain and analgesia

The precise neuroanatomy and neurochemistry of pain processing is still far from established. Historically, theories of pain transmission have emphasized ascending pathways in which primary afferent nerve fibers activate neurons in the spinal cord and brainstem, which then simply relay the information to higher brain structures. More recently, the importance of central nervous system pain-modulatory systems has been recognized, and some investigators have proposed that the certain forms of

Clinical implications

The reviewed literature clearly demonstrates that sex-related factors, including gonadal hormones, produce multiple peripheral and central effects that can influence pain modulation; however, the practical import of these effects has yet to be determined. While it is possible that the effects of sex steroids on pain transmission are minimal compared to the influence of other factors, we believe that the potential clinical implications are substantial. First, menstrual cycle-related symptoms are

Summary and conclusions

The literature reviewed above clearly indicates that sex-related factors, including gonadal hormones, influence nociceptive processing and analgesic responses. The presence of contradictory findings can be partially attributed to multiple methodologic factors, including strain differences, timing of assessments in relation to hormonal cycling, and nociceptive assays used. It is also important to note that sex-related factors represent only one set of variables that can influence pain responses

Conclusions

  • 1.

    Sex steroids affect both peripheral and CNS pathways involved in nociceptive processing. The studies reviewed above depict the far-reaching effects of gonadal hormones both centrally and peripherally. The magnitude of these effects and the role that they play in the pathophysiology of clinical pain remains to be determined.

  • 2.

    The effects of gonadal hormones account partially but not completely for the differences in pain sensitivity between males and females. Meta-analytic reviews from human

Recommendations

  • 1.

    Investigators should determine menstrual cycle phase in pain-related studies. Historically, women were eschewed in biomedical research, partly based on assumptions that results derived from men were generalizable to women. When this proved an invalid assumption, the vagaries of controlling for the pesky female menstrual cycle were used as an excuse to exclude women (and female rats). While the menstrual cycle does present important challenges to biomedical research, it also provides rich

Acknowledgements

Supported by DE12261 (RBF) and DK51413 (TJN)

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