The Hormonal Sexual Dimorphism of Pain

RESEARCH ANALYSIS

The Hormonal Sexual Dimorphism of Pain

Emily Grieco, BS

Drexel College of Medicine

SUMMARY POINTS

-       Testosterone protects males from pain. On the other hand, fluctuating levels of estrogen increases pain in females.

-       Females display a more robust proinflammatory reaction.

-       Estrogen is pronociceptive and testosterone is antinociceptive.

-       Sex-hormone crosstalk with innate immunity seems linked to differences in analgesic effects of morphine.

ANALYSIS

Background

Pain is one of the most prevalent chronic conditions in the United States, affecting 1 in 5 Americans every day (1). Chronic pain can adversely affect quality of life by limiting physical function, causing emotional distress, and even potentially altering one’s lifestyle. Countless research efforts have been dedicated to elucidating the complexities of pain perception. Notably, epidemiological studies have found that females experience higher rates of clinical pain, lower pain threshold and tolerance, and more sensitivity and distress to pain compared to males (2). The literature has attributed these differences to a variety of factors: neuroanatomical, neuroimmunological, psychological, social, cultural, and hormonal. Although the sexual dimorphism of pain is multidimensional, this analysis focuses on the key hormonal differences that cause males and females to experience pain differently. 

Findings

Testosterone and estrogen are the two main sex hormones in men and women, respectively. Studies have shown that they not only contribute to the differences in pain perception but have rather opposing effects. Testosterone has protective capacities for men, but varying estrogen levels have been shown to increase pain in women. One study investigated the influences of sex hormones on hyperalgesia using capsaicin in a mouse model. Barret et al. (2003) found that male rats required a 3.0-fold higher dose of capsaicin to induce a pain level comparable to that of the female rats. Furthermore, after gonadectomies were performed, the potency of capsaicin increased in males and decreased in females, supporting the conclusion that estrogen does not have the same protective effects in women that testosterone does in males (3). This study, as well as many others, concludes that testosterone helps shield males from pain. However, the role of estrogen on pain in females has not been found to be as direct. Although studies have found conflicting effects of estrogen on pain perception, most determine that fluctuating levels of estrogen can lead to increased pain whereas stable levels protect females from noxious stimuli (4). This concept is most easily understood by analyzing pain throughout the menstrual cycle. A study conducted by Bajaj et al. (2001) showed that females feel the highest pain intensity during the ovulatory phase (days 13-15) and an increased pain sensitivity during the middle of the follicular phase (days 8-10) (5). The key to these findings is that both indications of increased pain are associated with a drastic rise or fall in estrogen levels (Figure 1).

The immune system, mainly through inflammation, is a key contributor to chronic pain states. As indicated earlier, females are known to have an increased prevalence of chronic pain. Additionally, they are also at a higher risk for autoimmune diseases than males. This association is most likely because females display a more robust pro-inflammatory reaction. Specifically, Nasser et al. (2019) demonstrated that, at a higher baseline estrogen level, Th1 immune response dominates, whereas higher testosterone leads to a Th2 dominated immune response. Testosterone was found to suppress pro-inflammatory mediators (IFN-γ, IL-5, and NO) and induce the production of the anti-inflammatory cytokine IL-10 (6). In contrast, the heightened inflammatory response in females leads to increased levels of mediators such as bradykinin and histamine, which irritate nerve fibers and transmit pain signals to the brain. Additionally, because inflammation and swelling are closely linked, the resulting edema can further aggravate nearby nerve endings and intensify pain.

Not only has testosterone been found to protect males from pain, but it has also been found to increase opioid antinociception. Terner et al. (2002) found that opioids were generally more effective in blocking the detection of painful stimuli in intact males compared to females. Furthermore, upon gonadectomy, the potency of opioids decreased in males and increased in females (7). This study suggests that testosterone enhances and estrogen reduces opioid antinociception in male and female mice, respectively. Another study that sheds light on sex differences of opioid analgesia delves into the crosstalk between the sex hormones and innate immunity. By investigating mu-opioid receptor expression in trigeminal ganglia, Zhang et al. (2014) found that inflammatory cytokines upregulated mu-opioid receptor expression only in male mouse cultures (8). To explore this further, they neutered the mice and administered hormone replacements. No receptor upregulation was observed in castrated male mice; however, the addition of testosterone restored receptor expression. In contrast, no significant differences were found between intact and gonadectomized females (8). These findings may help explain sex-based differences in the pain-reducing effects of opioids administered to patients.

Discussion

Pain is an integral part of the human experience. Physicians across all specialties routinely encounter and manage it in their patients. Despite decades of research, our understanding of pain continues to evolve, with new findings emerging to this day. In the current research landscape, the sexual dimorphism of pain has been at the forefront of recent developments. Although many studies are limited to mouse models, they still help to explain why men and women may have very different experiences when it comes to pain. Future studies may be able to explore the effects of hormones on pain perception through the transgender community, who serve as a population that commonly utilizes hormone replacement therapy. Although hormones play a large part in the sexual dimorphism of pain, one must not overlook the other physiological, psychological, and sociocultural factors that are also involved. Further research examining these differences in pain between males and females could allow for more individualized treatment plans for prescribing opioids.

REFERENCES

1.     Yong RJ, Mullins PM, Bhattacharyya N. Prevalence of chronic pain among adults in the United States. Pain. 2021;163(2). doi:10.1097/j.pain.0000000000002291

2.     Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL. Sex, gender, and pain: A review of recent clinical and experimental findings. The Journal of Pain. 2009;10(5):447-485. doi:10.1016/j.jpain.2008.12.001

3.     A.C. Barrett, E.S. Smith, M.J. Picker. Capsaicin-induced hyperalgesia and mu-opioid-induced antihyperalgesia in male and female Fischer 344 rats. J. Pharmacol. Exp. Ther., 307 (2003), pp. 237-245.

4.     Athnaiel, Onella, et al. “The role of sex hormones in pain-related conditions.” International Journal of Molecular          Sciences, vol. 24, no. 3, (2023), p. 1866.

5. Bajaj, P.; Arendt-Nielsen, L.; Bajaj, P.; Madsen, H. Sensory changes during the ovulatory phase of the menstrual cycle in healthy women. Eur. J. Pain 2001, 5, 135–144.

6.     Nasser SA, Afify EA. Sex differences in pain and opioid mediated antinociception: Modulatory role of gonadal hormones. Life Sci. 237, (2019).

7.     J.M. Terner, A.C. Barrett, E. Grossell, M.J. Picker. Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats. Psychopharmacology (Berl.), 163 (2002), pp. 183-193

8.     X. Zhang, Y. Zhang, J. Asgar, K.Y. Niu, J. Lee, K.S. Lee, M. Schneider, J.Y. Ro. Sex differences in mu-opioid receptor expression in trigeminal ganglia under a myositis condition in rats. Eur. J. Pain, 18 (2014), pp. 151-161.