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Chronic pain conditions are encountered more frequently in women compared to men. Prior to the 17th century, the spleen and uterus were deemed to cause a number of somatic and mood aberrations in women. In fact, the psychiatric term hysteria originates from the belief that the uterus migrated about the body, releasing “humours” causing various “nervous disorders”) [1]. In our more enlightened scientific era, gonadal sex hormones are established to play a variable role in perception, intensity, and modulation of pain as well as mood [2-4]. Female sex hormones, including testosterone, are integral in programming multiple domains of brain development in utero [5]. In the context of pain perception, estrogen and progesterone regulate inhibitory and excitatory responses in the central and peripheral nervous systems. Chronic pain conditions increase in prevalence during the reproductive years but tend to abate in menopause [3, 6]. Migraine headache is a prototypical example of this trend. Headaches tend to diminish in frequency and intensity (or disappear altogether) at the onset of menopause [3]. Altogether, this would implicate a role for ovarian hormones in pain perception and regulation.

Two recently published literature reviews detail the relationship between endogenous sex hormones, pain perception, and chronic non-cancer pain disorders during the menstrual cycle [2, 4]. Both human and applicable animal data are detailed. Experimental methodologies have improved over the past decade, allowing a clearer understanding between gonadal hormone levels, ratios, and fluctuations and pain perception.

Iacovides and colleagues review observations and physiological mechanisms involved in pain processing and perception across the menstrual cycle [4]. Both experimental pain stimulation and clinical pain disorders are discussed. The authors point out that our present understanding of pain pathways and perception in the context of the hormonal milieu is incomplete and, at times, contradictory. Murine models may not translate directly into the human pain model, particularly given obvious differences in reproductive physiology. Gonadal hormones influence production of multiple neurotransmitters including serotonin, norepinephrine, GABA, substance P, dopamine, and μ-opiate system in the central and peripheral nervous system. The specific role and effect of estrogens and progesterone on pain sensitivity remain inconclusive.

Estrogen receptor (ER) α and β receptors are richly present in brain areas involved with transmission and inhibition of painful stimuli. Estrogen influences both pronocireception and antinocireception, but this must be understood in the context of the counterbalance between sensitization and inhibitory feedback systems in the central nervous system (CNS). In general, higher doses of estrogen may have antinocireceptive and anti-inflammatory effects while lower concentrations appear to be pronocireceptive [7]. In part, absolute serum or intracellular concentrations of estrogen, dynamic variants (fluctuations) in serum/tissue levels, and ratios between estrogen and progesterone may each play a part in response to noxious stimuli. Progesterone appears to influence antinocireceptive and anti-inflammatory properties in the nervous system. Iacovides and colleagues conclude that the totality of gonadal hormones on pain perception is a summation of all pronocireceptive and antinocireceptive factors at any given time in the menstrual cycle, and that some women, particularly those who suffer chronic pain disorders, have a differential response to painful stimuli compared to normal women without painful conditions.

Testosterone is briefly addressed, and androgens appear to proffer analgesic effects. This may explain, in part, differences in cognitive pain between the genders.

It is important to note that gonadal hormones are only a part of the story in pain perception. Well-designed studies demonstrate no effect of the menstrual cycle on pain-free women, validating the physiological concept of CNS sensitization to clinical pain generators [8].

In the second review, Hassan and colleagues assess specific pain conditions which predominate in the reproductive (premenopausal) years [2]. Pain associated with fibromyalgia, rheumatoid arthritis, temporomandibular disorder (TMJ), irritable bowel syndrome, and low back pain seem to correlate with low circulating estrogen levels (perimenstrual days and menopause). The presence of cognitive pain associated with migraine headache is also most pronounced around the menses (low estrogen state) and, not surprisingly, frequency and severity of migraine headache tend to improve with menopause.

Author(s)

  • Robert P. Kauffman
    Professor, Department of Obstetrics and Gynecology, Texas Tech University School of Medicine, Amarillo, Texas, USA

Citations

  1. Hare E. The history of “nervous disorders” from 1600 to 1840, and a comparison with modern views. Br J Psychiatry 1991;159:37-45
    http://www.ncbi.nlm.nih.gov/pubmed/1888978
  2. Hassan S, Muere A, Einstein G. Ovarian hormones and chronic pain: A comprehensive review. Pain 2014;155:2448-60
    http://www.ncbi.nlm.nih.gov/pubmed/25172822
  3. Meriggiola M, Nanni M, Bachiocco V, Vodo S, Aloisi A. Menopause affects pain depending on pain type and characteristics. Menopause 2012;19:517-23
    http://www.ncbi.nlm.nih.gov/pubmed/22334057
  4. Iacovides S, Avidon I, Baker FC. Does pain vary accross the menstrual cycle? A review. Eur J Pain 2015;19:1389-405
    http://www.ncbi.nlm.nih.gov/pubmed/25899177
  5. Berenbaum S, Beltz A. How early hormones shape gender development. Curr Opin Behav Sci 2016;7:53-60
    http://www.ncbi.nlm.nih.gov/pubmed/26688827
  6. Martin VT. Ovarian hormones and pain response: a review of clinical and basic science studies. Gend Med 2009;6 Suppl 2:168-92
    http://www.ncbi.nlm.nih.gov/pubmed/19406368
  7. Coulombe M, Spooner M, Gaumond I, Carrier J, Marchand S. Estrogen receptors beta and alpha have specific pro-and anti-nociceptive actions. Neuroscience 2011;184:172-82
    http://www.ncbi.nlm.nih.gov/pubmed/21377511
  8. Bolay H, Moskowitz M. Mechanisms of pain modulation in chronic syndromes. Neurology 2002;59(5 Suppl 2):S2-7
    http://www.ncbi.nlm.nih.gov/pubmed/12221149
  9. Gallicchio L, MacDonald R, Wood B, Rushovich E, Helzlsouer K. Menopausal-type symptoms among breast cancer patients on aromatase inhibitor therapy. Climacteric 2012;15:339-49
    http://www.ncbi.nlm.nih.gov/pubmed/22191462
  10. Peters M. Emotional and cognitive influences on pain experience. Mod Trends Pharmacopsychiatri 2015;30:138-52
    http://www.ncbi.nlm.nih.gov/pubmed/26436897
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