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Menopause and Chronic Pain

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The relationship between menopause and musculoskeletal pain (MSP) is well-documented in the medical literature. The menopausal transition is associated with a significant increase in both the prevalence and severity of MSP. This is influenced by hormonal changes, particularly the decline in oestrogen levels.

Epidemiology

A systematic review and meta-analysis found that the overall prevalence of MSP among perimenopausal women is approximately 71%, with perimenopausal women having a higher risk of MSP compared to premenopausal women (OR: 1.63).[1] This risk remains elevated in postmenopausal women, who are also more likely to experience moderate to severe MSP compared to premenopausal women (OR: 1.45).[1]

Additionally, a longitudinal cohort study in Chinese women indicated that the prevalence and severity of muscle and joint pain increase as menopausal stages progress, with late menopausal transition being a critical period for the onset of MSP. Factors such as poor health status, high BMI, anxiety, and depression were independently associated with increased MSP.[2]

Pathophysiology

The International Menopause Society has introduced the term "musculoskeletal syndrome of menopause" to describe the collective musculoskeletal symptoms, including arthralgia, loss of muscle mass, and progression of osteoarthritis, which are largely influenced by estrogen deficiency during menopause.[3]

Estrogen modulates pain perception through several mechanisms. It influences the expression of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP), which are involved in nociceptive signaling. Studies have shown that estrogen deficiency, as seen in ovariectomized (OVX) models, leads to increased levels of SP and CGRP, contributing to heightened pain sensitivity. Estrogen also affects the endogenous opioid system, enhancing mu-opioid receptor-mediated neurotransmission, which can modulate pain perception.[4][5][6]

Postmenopausal women exhibit higher levels of inflammatory biomarkers such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) compared to premenopausal women.[7] Additionally, increased visceral fat mass, which is more common in postmenopausal women, is a strong predictor of elevated leukocyte counts and systemic inflammation.[8] The decline in estrogen during menopause disrupts immune homeostasis, leading to an increase in pro-inflammatory cytokines through pathways involving estrogen receptors and the NLRP3/NF-κB signaling pathways.[9] This systemic inflammation is also linked to menopausal symptoms such as hot flashes, which have been associated with higher levels of circulating IL-8 and TNF-α.[10]

Estrogen receptors (ERα and ERβ) in the spinal cord play a crucial role in modulating pain. OVX-induced hyperalgesia is associated with upregulated ERα and protein kinase B (AKT) in the spinal cord, which are reversed by estrogen supplementation. This indicates that estrogen's effects on pain pathways involve both genomic and non-genomic actions at the spinal level.[11]

Hormone Replacement Therapy

Human studies on the effects of HRT on pain have yielded mixed results, reflecting the complexity of estrogen's role in pain modulation and heterogenous pain conditions.

A study by Fillingim and Edwards found that postmenopausal women on hormone replacement therapy (HRT) exhibited lower pain thresholds and tolerances to thermal pain compared to those not on HRT and men, suggesting that HRT may increase pain sensitivity in certain contexts.[12]

Conversely, a double-blind, randomized, placebo-controlled trial by Stening et al. found that transdermal 17β-estradiol did not significantly affect self-estimated pain or experimental pain responses in postmenopausal women with fibromyalgia, indicating that ERT may not be effective for all types of pain conditions.[13]

The Women's Health Initiative (WHI) found that women with joint pain or stiffness at baseline were more likely to get relief with either combined oestrogen-progesterone or unopposed oestrogen than with placebo.[14][15]

References

  1. ↑ 1.0 1.1 Lu, Chang-bo; Liu, Peng-fei; Zhou, Yong-sheng; Meng, Fan-cheng; Qiao, Tian-yun; Yang, Xiao-jiang; Li, Xu-yang; Xue, Qian; Xu, Hui; Liu, Ya; Han, Yong (2020-11-25). Hu, Li (ed.). "Musculoskeletal Pain during the Menopausal Transition: A Systematic Review and Meta-Analysis". Neural Plasticity (in English). 2020: 1–10. doi:10.1155/2020/8842110. ISSN 1687-5443.
  2. ↑ Huang, Feiling; Fan, Yubo; Tang, Ruiyi; Xie, Zhuolin; Yang, Lingjin; Ma, Xiaonan; Liang, Jinghui; Chen, Rong (2024-11). "Musculoskeletal pain among Chinese women during the menopausal transition: findings from a longitudinal cohort study". Pain (in English). 165 (11): 2644–2654. doi:10.1097/j.pain.0000000000003283. ISSN 0304-3959. Check date values in: |date= (help)
  3. ↑ Wright, Vonda J.; Schwartzman, Jonathan D.; Itinoche, Rafael; Wittstein, Jocelyn (2024-09-02). "The musculoskeletal syndrome of menopause". Climacteric (in English). 27 (5): 466–472. doi:10.1080/13697137.2024.2380363. ISSN 1369-7137.
  4. ↑ Keita-Alassane, Sokhna; Otis, Colombe; Bouet, Emilie; Guillot, Martin; Frezier, Marilyn; Delsart, Aliénor; Moreau, Maxim; Bédard, Agathe; Gaumond, Isabelle; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne (2022-06). "Estrogenic impregnation alters pain expression: analysis through functional neuropeptidomics in a surgical rat model of osteoarthritis". Naunyn-Schmiedeberg's Archives of Pharmacology (in English). 395 (6): 703–715. doi:10.1007/s00210-022-02231-5. ISSN 0028-1298. Check date values in: |date= (help)
  5. ↑ Sarajari, Susan; Oblinger, Monica M. (2010-07). "Estrogen effects on pain sensitivity and neuropeptide expression in rat sensory neurons". Experimental Neurology (in English). 224 (1): 163–169. doi:10.1016/j.expneurol.2010.03.006. PMC 2885587. PMID 20303952. Check date values in: |date= (help)CS1 maint: PMC format (link)
  6. ↑ Smith, Yolanda R.; Stohler, Christian S.; Nichols, Thomas E.; Bueller, Joshua A.; Koeppe, Robert A.; Zubieta, Jon-Kar (2006-05-24). "Pronociceptive and Antinociceptive Effects of Estradiol through Endogenous Opioid Neurotransmission in Women". The Journal of Neuroscience (in English). 26 (21): 5777–5785. doi:10.1523/JNEUROSCI.5223-05.2006. ISSN 0270-6474. PMC 1808228. PMID 16723535.CS1 maint: PMC format (link)
  7. ↑ Pernoud, Laura E.; Gardiner, Paul A.; Fraser, Sean D.; Dillon-Rossiter, Kirsten; Dean, Melinda M.; Schaumberg, Mia A. (2024-12). "A systematic review and meta-analysis investigating differences in chronic inflammation and adiposity before and after menopause". Maturitas. 190: 108119. doi:10.1016/j.maturitas.2024.108119. ISSN 0378-5122. Check date values in: |date= (help)
  8. ↑ Abildgaard, Julie; Tingstedt, Jeanette; Zhao, Yanan; Hartling, Hans Jakob; Pedersen, Anette Tønnes; Lindegaard, Birgitte; Dam Nielsen, Susanne (2020-06-23). "Increased systemic inflammation and altered distribution of T-cell subsets in postmenopausal women". PLOS ONE. 15 (6): e0235174. doi:10.1371/journal.pone.0235174. ISSN 1932-6203.
  9. ↑ Zhang, Yuling; Tan, Xiying; Tang, Chaozhi (2024-06-19). "Estrogen-immuno-neuromodulation disorders in menopausal depression". Journal of Neuroinflammation. 21 (1). doi:10.1186/s12974-024-03152-1. ISSN 1742-2094.
  10. ↑ Huang, Wan-Yu; Hsin, I-Lun; Chen, Dar-Ren; Chang, Chia-Chu; Kor, Chew-Teng; Chen, Ting-Yu; Wu, Hung-Ming (2017-08-28). Proost, Paul (ed.). "Circulating interleukin-8 and tumor necrosis factor-α are associated with hot flashes in healthy postmenopausal women". PLOS ONE (in English). 12 (8): e0184011. doi:10.1371/journal.pone.0184011. ISSN 1932-6203. PMC 5573141. PMID 28846735.CS1 maint: PMC format (link)
  11. ↑ Li, Li-Hong; Ling, Dan-Dan; Lin, Hong; Wang, Zhe-Chen; Sun, Zhi-Rong; Zhang, Yu-Qiu; Yang, Liu; Zhang, Jun; Cao, Hong (2023-11). "Ovariectomy induces hyperalgesia accompanied by upregulated estrogen receptor α and protein kinase B in the rat spinal cord". Physiology & Behavior (in English). 271: 114342. doi:10.1016/j.physbeh.2023.114342. Check date values in: |date= (help)
  12. ↑ Fillingim, Roger B.; Edwards, Robert R. (2001-05). "The association of hormone replacement therapy with experimental pain responses in postmenopausal women". Pain (in English). 92 (1): 229–234. doi:10.1016/S0304-3959(01)00256-1. ISSN 0304-3959. Check date values in: |date= (help)
  13. ↑ Stening, K. D.; Eriksson, O.; Henriksson, K. G.; Brynhildsen, J.; Lindh-Astrand, L.; Berg, G.; Hammar, M.; Amandusson, A.; Blomqvist, A. (2011-03-01). "Hormonal replacement therapy does not affect self-estimated pain or experimental pain responses in post-menopausal women suffering from fibromyalgia: a double-blind, randomized, placebo-controlled trial". Rheumatology (in English). 50 (3): 544–551. doi:10.1093/rheumatology/keq348. ISSN 1462-0324.
  14. ↑ Barnabei, Vanessa M.; Cochrane, Barbara B.; Aragaki, Aaron K.; Nygaard, Ingrid; Williams, R Stan; McGovern, Peter G.; Young, Ronald L.; Wells, Ellen C.; OʼSullivan, Mary Jo; Chen, Bertha; Schenken, Robert (2005-05). "Menopausal Symptoms and Treatment-Related Effects of Estrogen and Progestin in the Womenʼs Health Initiative:". Obstetrics & Gynecology (in English). 105 (5, Part 1): 1063–1073. doi:10.1097/01.AOG.0000158120.47542.18. ISSN 0029-7844. Check date values in: |date= (help)
  15. ↑ Chlebowski, Rowan T.; Cirillo, Dominic J.; Eaton, Charles B.; Stefanick, Marcia L.; Pettinger, Mary; Carbone, Laura D.; Johnson, Karen C.; Simon, Michael S.; Woods, Nancy F.; Wactawski-Wende, Jean (2013-06). "Estrogen alone and joint symptoms in the Women's Health Initiative randomized trial". Menopause (in English). 20 (6): 600–608. doi:10.1097/GME.0b013e31828392c4. ISSN 1072-3714. PMC 3855295. PMID 23511705. Check date values in: |date= (help)CS1 maint: PMC format (link)
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