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Evolutionary considerations in the development of chronic pelvic pain John Jarrell, MD, MSc, FRCSC; Lars Arendt-Nielsen, DMSc, PhD, FRSM

Introduction hronic pelvic pain remains a major health problem for many women and a socioeconomic burden for societies.1,2 The problem of chronic persistent pain remains in spite of helpful medical approaches and surgical interventions.3,4 In this Viewpoint, we explore evidence that may support an evolutionary cause for development of some aspects of chronic visceral pelvic pain.5,6 Evolutionary medicine is made up of the intersections where “evolutionary insights bring something new and useful to the medical profession, and where medical research offers new insights, questions, and research opportunities for evolutionary biology.”7 Human beings and other organisms are molded by natural selection to maximize reproduction, not health, an imperative that causes unavoidable trade-offs. Disease can arise from the mismatch between our bodies and modern environments, given the slow pace of biological evolution and the relatively rapid pace of cultural change.7 Evolutionary theory indicates a need to study both proximal and evolutionary explanations of a disease.8 The former is associated with the physiological and pathological processes defining how the disorder affects individuals while the latter is directed to the definition of why the condition occurs. The proximal explanations of chronic pelvic pain are vast in number but include the presence of endometriosis, pelvic inflammatory disease, irritable bowel syndrome, fibromyalgia, and interstitial cystitis. Until now there has not been an evolutionary explanation identified to explain this common problem. Changes in human physiology may happen more rapidly that the processes of adaptation. The theoretical basis for why illnesses occur may be seen as a mismatch between our current human environment and selected traits. Evolutionary biology has been used to understand inflammatory disease among other conditions.9 We explore the strengths and weaknesses of the dramatic changes in the lifetime frequency

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From the Department of Obstetrics and Gynecology, University of Calgary, Calgary, Alberta, Canada (Dr Jarrell), and Center for SensoryMotor Interaction, School of Medicine, Aalborg University, Aalborg, Denmark (Dr Arendt-Nielsen). Received March 20, 2016; revised May 4, 2016; accepted May 10, 2016. Funding was provided by the Calgary Health Trust and the Department of Obstetrics and Gynecology, University of Calgary. The authors report no conflict of interest. Corresponding author: John Jarrell, MD, MSc, FRCSC. [email protected] 0002-9378/$36.00  ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2016.05.019

of menstruation with the maladaptive state of chronic pelvic pain. In 1976 Roger Short10 made the observation that in contemporary society, women are having many more menstrual cycles than the native !Kung hunter gatherer population and many more than women prior to the development of contraception. An evolutionary view supporting the role of increased menstrual frequency in the development of chronic visceral pelvic pain could be considered if: (1) lifetime menstruation has increased; (2) severe dysmenorrhea is common in the chronic pelvic pain population, particularly among those with pain sensitization; and (3) a potential biological mechanism can be identified.

Lifetime exposure to menstruation has increased Lifetime menstruation is a function of many factors including age at menarche, mortality, menopause, frequency of pregnancy and lactation, and presence of amenorrhea. There has been a dramatic nearly linear decrease in the age of menarche since 1860 when it was reported to occur at age 17 years.11 The changes in the age of menarche have been attributed to improved nutrition permitting increased fat availability. Based on the linearity of the data, it is possible that menarche may have occurred even >17 years among our ancestors due to nutritional limitations.12 Similarly, there has been a significant increase in life expectancy, from 40 years in 1860 to 86-90 years in 2010 in Western counties.13 Again, the linearity of the data may permit the projection that average mortality rates may have been much lower in our ancestors. For example, it is estimated that !Kung hunter gatherers have a life expectancy between 24-35 years.14 The average age of menopause historically is uncertain possibly due to earlier rates of mortality but has been noted currently to be approximately 52 years. The age of menopause has been noted to possibly be earlier among aboriginal communities.15 Pregnancy was much more common prior to effective contraception. Canadian and US population studies indicate the average number of births was 7-8 per family in the 19th century. Limited lifetime menstrual function is supported from studies of pre-Civil War populations in New York in 1840.16 Pregnancies were likely followed with lactational amenorrhea. There are no available data that would contribute additional amenorrhea due to spontaneous abortion. Short10 has indicated there would have been episodes of amenorrhea due to immaturity of the reproductive system in adolescence and perimenopause and has further provided estimates of reproductive function of the Hutterite population. AUGUST 2016 American Journal of Obstetrics & Gynecology

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Viewpoint The available information regarding the factors associated with menstruation is presented in the Figure. Contemporary estimates are based on menarche at age 12 years, average family size of 2 pregnancies, 1 year of lactation, menopause at age 52 years (in lieu of mortality rate), and 2 years of physiological amenorrhea. Data from 1840 use pre-Civil War information: menarche at age 17 years, 8 pregnancies and lactation, 2 years of physiological amenorrhea, and mortality at 40 years of age.16 Life expectancy of the !Kung hunter gatherers was estimated previously by Pennington.14

Severe dysmenorrhea is common among women with chronic pelvic pain An estimated 2-29% of women report dysmenorrhea.17 However, in women with chronic pelvic pain of >6 months’ duration, 62% reported severe dysmenorrhea and much greater in the presence of pain sensitization.18 In a process known as sensitization, visceral pain, such as dysmenorrhea, can initiate the viscerosomatic pain reflex and referred pain, resulting in chronic somatic pain and tenderness in the pelvic regions.19 This transition between acute and chronic pain is spurred by hyperalgesic priming: long-lasting latent hyperresponsiveness of nociceptors to inflammatory mediators following an inflammatory or neuropathic insult.20 Hyperalgesic priming is thought to be responsible at least in part for chronic back pain as well as other musculoskeletal pain conditions.21,22 The cellular and biochemical basis for this transition include protein kinase epsilon, alpha

FIGURE

Estimates of lifetime menstrual history over time

Estimates of lifetime menstrual frequency. Jarrell & Arendt-Nielsen. Chronic pelvic pain. Am J Obstet Gynecol 2016.

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ajog.org CaMKII,23 and isolectin B424 positive nociceptors.20,22 The process in human beings remains speculative but serves as a conceptual explanation for the shift from cyclic severe dysmenorrhea to persistent pain. In pelvic pain, clinical tests confirming sensitization include cutaneous allodynia and reduced pain thresholds primarily in the T1-L1 and S2-S4 dermatomes.25 In a population of 181 women with chronic pelvic pain, those who demonstrated pain sensitization using these tests were more likely to report severe dysmenorrhea compared to those with no sensitization (89% vs 63%).18 (While pain was selfreported, women were not aware of results of sensitization testing when they reported their pain histories.) There was also a greater duration of severe dysmenorrhea reported among women with sensitization compared to women without sensitization (12.6 vs 7.8 years).18 The negative correlation between the duration of severe dysmenorrhea and lower abdominal pain pressure thresholds suggests a temporal development of sensitization.18

Potential biologic mechanisms supporting the role of increased menstrual frequency in the development of chronic visceral pelvic pain Over centuries the menstruation frequency seems to have increased far beyond earlier populations as a function of earlier menarche, later age of menopause, and fewer pregnancy and lactation periods. The available data on the frequency of dysmenorrhea would indicate a substantial

ajog.org population of women are exposed to this condition. However, when the population of women with chronic pelvic pain are analyzed, the rates are much higher and are significantly higher in the presence of sensitization.18 There is a temporal relationship of pain pressure threshold reduction (greater sensitization) and years of severe dysmenorrhea.18 One particularly important observation is that the suppression of menstruation has been associated with the reduction in pain along with a reduction in allodynia and sensitization.26

Limitations to the evolutionary theory applied to chronic pelvic pain The limitations to this theory are substantial, however. There are no data about the incidence of chronic pelvic pain in earlier generations; our assumption that the rate was lower than currently is speculative. Similarly there are no available animal models that could evaluate hyperalgesic priming in relation to menstrual initiation of chronic pain. The temporal relationship of pain sensitization and duration of severe dysmenorrhea in our previous work is by necessity retrospective, however, the data were collected on the duration of severe dysmenorrhea prior to pain testing and determination of sensitized or nonsensitized state and our findings are consistent with other clinical pain states such as osteoarthritis.21 The observation that the severity of pain appears to be greater in younger women may actually reflect the normal processes of aging on the neuromuscular junction, so important for the viscerosomatic referred pain.27,28 Conclusion Recognizing an evolutionary cause of chronic pelvic pain permits an opportunity to consider study of preventive and treatment strategies, including possibly menstrual suppression. The cultural norms of the concept of the normal menstrual cycle might be better viewed from a wider evolutionary perspective. Chronic pelvic pain may also be viewed in part as a maladaptive state in which the biological evolution of pain physiology has not adapted to the faster-moving cultural evolution with its associated recurrent menstrual pain. REFERENCES 1. Mathias SD, Kuppermann M, Liberman RF, Lipschutz RC, Steege JF. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol 1996;87:321-7. 2. Zondervan K, Barlow DH. Epidemiology of chronic pelvic pain. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:403-14. 3. Vercellini P, Somigliana E, Vigano P, Abbiati A, Daguati R, Crosignani PG. Endometriosis: current and future medical therapies. Best Pract Res Clin Obstet Gynaecol 2008;22:275-306. 4. Vercellini P, Crosignani PG, Abbiati A, Somigliana E, Vigano P, Fedele L. The effect of surgery for symptomatic endometriosis: the other side of the story. Hum Reprod Update 2009;15:177-88.

Viewpoint 5. Nesse RM. Ten questions for evolutionary studies of disease vulnerability. Evol Appl 2011;4:264-77. 6. Williams GC, Nesse RM. The dawn of Darwinian medicine. Q Rev Biol 1991;66:1-22. 7. Stearns S, Nesse RM, Govindaraju DR, Ellison PT. Evolutionary perspectives on health and medicine. Proc Natl Acad Sci U S A 2010;107(Suppl):1691-5. 8. Nesse RM, Bergstrom CT, Ellison PT, et al. Evolution in health and medicine Sackler colloquium: making evolutionary biology a basic science for medicine. Proc Natl Acad Sci U S A 2010;107(Suppl): 1800-7. 9. Okin D, Medzhitov R. Evolution of inflammatory diseases. Curr Biol 2012;22:R733-40. 10. Short R. The evolution of human reproduction. Proc R Soc Lond B Biol Sci 1976;195:3-24. 11. Gluckman PD, Hanson MA. Changing times: the evolution of puberty. Mol Cell Endocrinol 2006;254-255:26-31. 12. Frisch RL. Ravell. Height and weight at menarche and a hypothesis of critical body weights and adolescent events. Science 2016;169: 397-9. 13. Weon BM, Je JH. Trends in scale and shape of survival curves. Sci Rep 2012;2:504. 14. Pennington R. Hunter gatherer demography. In: Panter-Brick C, Layton RH, Rowley-Conwy P, eds. Hunter gatherers: interdisciplinary perspectives. Cambridge: Cambridge University Press; 2001: 170-204. 15. Chadha N, Chadha V, Ross S, Sydora C. Experience of menopause in aboriginal women: a systematic review. Climacteric 2016;19:17-26. 16. Haines MR, Guest AM. Fertility in New York State in the pre-Civil War era. Demography 2008;45:345-61. 17. Ju H, Jones M, Mishra G. The prevalence and risk factors of dysmenorrhea. Epidemiol Rev 2013;36:104-34. 18. Jarrell J, Arendt-Nielsen L. Allodynia and dysmenorrhea. J Obstet Gynaecol Can 2016;38:270-4. 19. Giamberardino MA. Women and visceral pain: are the reproductive organs the main protagonists? Mini-review at the occasion of the “European Week Against Pain in Women 2007”. Eur J Pain 2008;12: 257-60. 20. Reichling DB, Levine JD. Critical role of nociceptor plasticity in chronic pain. Trends Neurosci 2009;32:611-8. 21. Arendt-Nielsen L, Nie H, Laursen MB, et al. Sensitization in patients with painful knee osteoarthritis. Pain 2010;149:573-81. 22. Dina OA, Green PG, Levine JD. Role of interleukin-6 in chronic muscle hyperalgesic priming. Neuroscience 2008;152:521-5. 23. Ferrari LF, Bogen O, Levine JD. Role of nociceptor alphaCaMKII in transition from acute to chronic pain (hyperalgesic priming) in male and female rats. J Neurosci 2013;33:11002-11. 24. Joseph EK, Levine JD. Hyperalgesic priming is restricted to isolectin B4-positive nociceptors. Neuroscience 2010;169:431-5. 25. Jarrell J, Giamberardino MA, Robert M, Nasr-Esfahani M. Bedside testing for chronic pelvic pain: discriminating visceral from somatic pain. Pain Res Treat 2011;2011:692102. 26. Jarrell J, Malekzadeh L, Yang H, Arendt-Nielsen L. Cutaneous allodynia as a differential diagnostic manifestation in chronic pelvic pain. J Obstet Gynaecol Can 2014;37:628-32. 27. Tintignac LA, Brenner HR, Ruegg MA. Mechanisms regulating neuromuscular junction development and function and causes of muscle wasting. Physiol Rev 2015;95:809-52. 28. Tudorascu I, Sfredel V, Riza AL, Danciulescu MR, Ianosi SL, Danoiu S. Motor unit changes in normal aging: a brief review. Rom J Morphol Embryol 2014;55:1295-301.

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ABSTRACT

Evolutionary considerations in the development of chronic pelvic pain Chronic pelvic pain is common among women of reproductive age and is associated with significant morbidity and comorbidities. In this Viewpoint, we explore the evolutionary cause of pelvic pain and summarize evidence that supports a menstruation-related evolutionary cause of chronic visceral pelvic pain: (1) lifetime menstruation has increased; (2) severe dysmenorrhea is common in the chronic pelvic pain population, particularly among those with pain sensitization; and (3) a potential biological mechanism can be identified. Thus, chronic pelvic pain may arise from the mismatch between the slow pace of biological evolution in our bodies and the relatively rapid pace of cultural changes that have resulted in increased menstrual frequency due to earlier menarche, later mortality, and lower fecundity. One possible mechanism that explains the development of persistent pain from repeated episodes of intermittent pain is

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hyperalgesic priming, a physiological process defined as a longlasting latent hyperresponsiveness of nociceptors to inflammatory mediators after an inflammatory or neuropathic insult. The repetitive severely painful menstrual episodes may play such a role. From an evolutionary perspective the relatively rapid increase in lifetime menstruation experience in contemporary society may contribute to a mismatch between lifetime menstruation and the physiological pain processes, leading to a maladaptive state of chronic visceral pelvic pain. Our current physiology does not conform to current human needs. Key words: chronic pelvic pain, dysmenorrhea, evolutionary cause, evolutionary medicine, hyperalgesic priming, pain sensitization, pain testing, proximal cause