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Hormones and Their Interaction with the Pain Experience

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•Sex differences in the prevalence of painful conditions appear after puberty•Variation in symptom severity across the menstrual cycle occurs in a number of clinical pain conditions•Sex steroid hormones act at a number of sites in both the peripheral and central nervous systems and in both reproductive and non-reproductive tissues•Sex steroid hormones have traditionally been thought to alter transcription; however, there is evidence that there are also non-genomic effects•Sex steroid hormones can have organisational effects from as early as in utero•The relationship between sex hormones and pain is complex
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Reviews in Pain
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DOI: 10.1177/204946370800200206
2008 2: 20Reviews in Pain
Katy Vincent and Irene Tracey
Hormones and Their Interaction with the Pain Experience
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 V. , N. , D 
  
Hormones and their interaction with the pain experience
Katy Vincent
Research Fellow
Irene Tracey,
Professor, Functional Magnetic Resonance Imaging of the Brain Centre, John Radcliffe Hospital, Oxford
 
Sex differences in the prevalence of painful conditions appear after puberty
Variation in symptom severity across the menstrual cycle occurs in a number of clinical pain conditions
Sex steroid hormones act at a number of sites in both the peripheral and central nervous systems and in
both reproductive and non-reproductive tissues
Sex steroid hormones have traditionally been thought to alter transcription; however, there is evidence
that there are also non-genomic effects
Sex steroid hormones can have organisational effects from as early as in utero
e relationship between sex hormones and pain is complex
Introduction
One of the most striking physiological differences between men and
women is in sex steroid hormones, both the absolute levels and the
occurrence of cyclical fluctuations in women (Fig.1). ese hormones
are known to be responsible for the embryological development of a
male or female phenotype and for successful reproductive function
after puberty. More recently, observations such as the marked
differences in pain symptoms between males and females in the period
between puberty and the menopause, and the cyclical variations in
many clinical pain symptoms in women have suggested that they may
also have a role in altering the pain experience. e aim of this review
is to examine the available evidence that sex steroid hormones have a
role in pain and to identify possible mechanisms of action for these
effects.
Clinical Pain
As well as the differences in hormonal status between males and females,
the different phases of female life (puberty, reproductive maturity,
pregnancy and the post-menopausal period) are also accompanied
Figure 1: Schematic illustrating how Estradiol and Progesterone vary over a 28 day menstrual cycle (adapted from (11)).
V. , N. , D  
  
conditions such as TMJ pain8. Rheumatoid arthritis patients (both
male and female) have been shown to have lower androgen levels than
sex-matched controls, and androgen administration improves their
symptoms, whilst female workers with lower testosterone levels have
more work-related neck and shoulder injuries9. However, investigation
of the specific effects of testosterone are complicated by the fact that
much is metabolised in vivo to estradiol by aromatase, and this is
therefore an issue which needs to be addressed in future studies.
Perhaps one of the more intriguing studies to be published recently
explored the effect of systemic hormone administration to both male
to female (MtF) and female to male (FtM) transsexuals (n=73) during
the process of sex reassignment10. ey observed that approximately
one third of the MtF subjects developed chronic pain during their
treatment with estrogen and androgens, and even those that did not,
reported a decreased tolerance to painful events and an enhanced
sensitivity to thermal stimuli (both warm and cold). Of those FtM
subjects who had chronic pain before the start of treatment, more than
half improved after commencing testosterone treatment, reporting
reduced numbers of painful episodes and shorter lengths of those
that did occur. Clearly, psychological effects cannot be ignored in
this group of subjects, however, this is the only situation where the
hormonal milieu in humans can be ethically altered to that of the
opposite gender and therefore gives us interesting insights.
Experimental Pain
It is possible that the effects of hormones on clinical pain are due to a
hormonal effect on pain sensitivity. If this were the case then we would
expect to see alterations in sensitivity to experimental pain across the
menstrual cycle. In fact, in healthy women, the results of the many
studies addressing this question have frequently been contradictory,
with some showing no change and others showing changes in differing
directions. Different methods of applying a painful stimulus (heat,
electrical, cold pressor etc.) have been used at different body sites
and tissue depths (skin, subcutis, muscle and viscera) and this may
be one of the reasons for the differences found. However, the largest
methodological problem is with the definition of cycle phase, which
differs between studies, is often too wide and does not account for
different cycle lengths and anovulatory cycles. A recent meta-analysis11
found that there is no evidence to conclude that a difference in
sensitivity to experimental pain across the menstrual cycle exists in
healthy women, except perhaps for electrical stimuli to subcutaneous
tissues.
Two brain imaging studies have looked at whether differences in
pain sensitivity in different hormonal states can be visualised. In one
painful heat was applied to the skin overlying the left masseter muscle
during a period of low estrogen and a period of high estrogen (no
significant difference in progesterone levels)12. ere was no significant
difference between pain ratings at these two time points, however,
different activation patterns were seen. In the other study13 a finger was
immersed in painfully hot water during the follicular (low estrogen/
progesterone) and the luteal (higher estrogen/progesterone) phases.
ey found significantly different pain and pain-related unpleasantness
by marked variation in hormone levels. Furthermore, many women
choose to alter their own hormonal status by the use of hormonal
contraception and HRT. Here we consider the evidence that clinical
pain conditions vary with hormonal state.
Dramatic changes in sex hormones occur around puberty and it is at
this point that sex differences in clinical pain conditions also begin
to be observed. Initial studies did not show correlations between age
and the development of painful conditions in girls or boys. However,
the timing of puberty is very variable between individuals and more
recent studies that control for the stage of pubertal development rather
than chronological age have shown an association with pain. For both
sexes, the probability of experiencing a painful condition increases
with increasing pubertal development1.
With the onset of regular ovulation and menstruation, it can be seen
that a number of clinical pain conditions show variation in symptom
severity across the menstrual cycle. Clearly the pain of dysmenorrhoea
is, by definition, associated with the menstrual cycle, however,
the symptoms of temperomandibular joint (TMJ) dysfunction,
fibromyalgia, Irritable Bowel Syndrome (IBS), Interstitial Cystitis (IC)
and migraine can also show cyclical variation2. e greatest reports
of pain symptoms appear to occur at times of low or rapidly falling
estrogen levels and the use of the combined oral contraceptive pill
(COCP) to give a more constant hormonal level can improve these
symptoms. Furthermore, complete abolition of hormonal fluctuation
with gonadotrophin releasing hormone agonists (GnRHa) (effectively
causing a reversible medical menopause) can improve the symptoms of
both IBS3 and IC4. is hypo-estrogenic state can worsen headaches
and migraine, although achieving a steady hormonal state with a
GnRHa and additional low-dose estradiol has been shown to improve
migraine5.
During pregnancy, the cyclical fluctuations in hormones cease and
instead a steady increase in the levels of both progesterone and
estrogen is seen towards term which fall rapidly after delivery. e
concentrations of a number of other steroid hormones also vary from
the non-pregnant state and may have an effect on painful conditions,
including prolactin and relaxin. Many clinical pain conditions improve
during pregnancy including arthritis, migraine and often pelvic pain
and there is an associated reduction in pain sensitivity a phenomenon
known as pregnancy-induced analgesia6. However, pregnancy itself
can be associated with the development of pain especially mechanical
back pain and symphysis pubis dysfunction (SPD). e painful
symptoms of systemic lupus erythematosus (SLE) usually worsen with
pregnancy7.
After the menopause, when levels of estrogen and progesterone are very
low, the sex differences in pain become much less marked. However,
the use of hormone replacement therapy (HRT) in postmenopausal
women has been associated with the development of pain conditions
including back and TMJ pain2.
From puberty onwards, men have significantly higher levels of
testosterone and its metabolites than women. Testosterone appears to
have an analgesic effect protecting against the development of painful
 V. , N. , D 
  
Emotion
In addition to its sensory aspect, pain is an emotional experience. It
is therefore of interest that the life time patterns in pain symptoms in
men and women are closely mirrored by those of mood disorders17,
though with the addition of a perimenopausal peak in mood disorders.
Comparing post-puberty with pre-puberty, rates of significant
depression increased two-fold for boys but more than four-fold
for girls1. In Premenstrual Dysphoric Disorder (PMD), there is no
evidence that abnormal levels of hormones occur (unlike in depression
associated with thyroid or pituitary dysfunction), rather, it appears
that some women are more sensitive to the mood destabilising effects
of these hormones18. It is not inconceivable therefore, that a similar
situation may exist for pain.
Possible sites and mechanisms of action
e traditional view of sex steroid hormones was that they act on
specific membrane receptors along the hypothalamic-pituitary-gonadal
axis to alter downstream transcription. ese effects would therefore
ratings and again differences in brain activation patterns between the
two phases. ese studies suggest that although pain sensitivity may
not vary with hormonal status in healthy women, the pain experience,
particularly the emotional-affective component, may well do.
In women with clinical pain conditions, however, cyclical variations
in pain sensitivity can be demonstrated. For example, although no
difference in rectal sensitivity to balloon distension across the cycle is
seen in healthy women, in those with IBS an increased sensitivity is seen
during the menstrual phase14. Similarly, variations in pain sensitivity
have also been demonstrated in women with IC, dysmenorrhoea and
fibromyalgia.
Although many studies have attempted to establish the effects of
hormones on experimental pain perception in women, few have
looked at their effects in men. One small study showed testosterone
to be associated with a reduced sensitivity to tactile stimulation, both
on the finger and the penis15, whilst in rats testosterone treatment is
associated with a reduction in pain thresholds16.
Table 1: Some non-reproductive actions of steroid hormones
Estrogen Progesterone Testosterone
Brain Mu-opioid receptor availability
Hippocampal excitability
5-HT
Noradrenaline
↑↓anxiety/stress
Anxiolytic
Sedative
Analgesic
Anticonvulsant
Modulate GABA
Promote myelination
Mediate male aggression towards
infants
Analgesic
↑↓seizure threshold
Noradrenaline
Mediate aggressive behaviour
Organisational effects on sexually
dimorphic behaviours
Modulate endogenous opioids
Regulate aromatase activity
Spinal Cord Modulate dorsal horn response to pain Mediate hypersensitivity after nerve
root damage
Neuroprotective
Modulate dorsal horn response in
neuropathic pain
Peripheral
Nerve
Sensitise uterine and cervical afferents
glutamatergic nociceptor activity
Neuroprotective Facilitate release of ACh
Immune
System T and B cell proliferation and
phenotype
cytokine and immunoglobulin
balance
Anti-inammatory
Modulate immune response
cellular immune response
Musculoskel-
etal System bone deposition
muscle mass recovery following
disuse
bone deposition
Smooth muscle relaxant
bone density and strength
muscle mass
Cardiovascular
System NO synthesis
vasodilation
vasodilation vasoconstriction
Abbreviations: 5-HT, 5- hydroxytryptamine; ACh, acetylcholine; NO, nitric oxide
V. , N. , D  
  
conditions. It is therefore important in future pain studies that both
the sex and hormonal status of the subjects are taken into account.
RefeRences
1. LeResche L, Mancl LA, Drangsholt MT, Saunders K, Korff MV.
Relationship of pain and symptoms to pubertal development in
adolescents. Pain 2005; 118(1-2): 201-9.
2. LeResche L. Epidemiologic perspectives on sex differences in pain.
In: Fillingim RB, ed. Sex, gender and pain. Seattle: IASP Press
2000: 233-49.
3. Mathias JR, Clench MH, Reeves-Darby VG, Fox LM, Hsu PH,
Roberts PH, Smith LL, Stiglich NJ. Effect of leuprolide acetate
in patients with moderate to severe functional bowel disease.
Double-blind, placebo-controlled study. Dig Dis Sci 1994; 39(6):
1155-62.
4. Lentz GM, Bavendam T, Stenchever MA, Miller JL, Smalldridge
J. Hormonal manipulation in women with chronic, cyclic irritable
bladder symptoms and pelvic pain. AJOG 2002; 186(6): 1268-
71.
5. Martin V, Wernke S, Mandell K, Zoma W, Bean J, Pinney S,
Liu J, Ramadan N. Medical Oophorectomy With and Without
Estrogen Add-Back erapy in the Prevention of Migraine
Headache. Headache 2003; 43(4): 309-21.
6. Carvalho B, Angst MS, Fuller AJ, Lin E, Mathusamy AD, Riley
ET. Experimental Heat Pain for Detecting Pregnancy-Induced
Analgesia in Humans. Anesth Analg 2006; 103(5): 1283-7.
7. Craft RM. Modulation of pain by estrogens. Pain 2007;
132(Supplement 1):S3-S12.
8. Fischer L, Clemente JT, Tambeli CH. e Protective Role of
Testosterone in the Development of Temporomandibular Joint
Pain. J Pain 2007; 8(5): 437-42.
9. Aloisi AM, Bonifazi M. Sex hormones, central nervous system and
pain. Horm Behav 2006; 50(1): 1-7.
10. Aloisi AM, Bachiocco V, Costantino A, Stefani R, Ceccarelli I,
Bertaccini A, Meriggiola MC . Cross-sex hormone administration
changes pain in transsexual women and men. Pain 2007;
132(Supplement 1): S60-S7.
11. Sherman JJ, LeResche L. Does experimental pain response vary
across the menstrual cycle? A methodological review. Am J Physiol
Regul Integr Comp Physiol 2006; 291(2): R245-56.
12. de Leeuw R, Albuquerque RJ, Andersen AH, Carlson CR.
Influence of estrogen on brain activation during stimulation with
painful heat. J Oral Maxillofac Surg. 2006; 64(2): 158-66.
take hours to days to appear. More recent work has challenged this
view. Rapid, reversible changes in neuronal excitability in the brain
and spinal cord have been demonstrated secondary to steroid
hormone administration which cannot be genomic effects19. Both
estrogen and androgen receptors have been identified throughout the
body, including in both the peripheral and central nervous systems,
supporting the idea that they have a role outside of reproductive
function. To further complicate matters these steroids can also be
synthesised within the central nervous system itself from endogenous
cholesterol9 and activation of different receptor sub-types (e.g. estrogen
receptor (ER) α and β) can exert different effects.
It is now known that the actions of sex steroid hormones on the brain
can be both organisational (during in utero development and early
neonatal life) and activational. Exposure to steroid hormones during
brain development has been shown to effect a variety of sexually
dimorphic behaviours in a number of species, including play patterns,
sexual behaviour, spatial learning, maternal behaviour and bird song20.
ese hormones can originate from the maternal circulation (either
endogenous or exogenous), the fetus itself or a twin/litter sibling.
Animal studies suggest that neonatal exposure to testosterone is
necessary to see a male response to pain7 and to morphine analgesia21
whilst early exposure to estrogens alters both the anatomy and
physiology of the hippocampus9. In the developed nervous system,
steroid hormones can modulate neurotransmission in the brain,
spinal cord and peripheral nerves, alter the excitability of specific
brain areas and influence the availability of receptors for themselves
and other ligands including opiates and serotonin7,9,22. Furthermore,
progesterone is well known to have GABAergic actions and thus is
likely to have an effect on pain7. We believe that these effects on the
CNS could have a substantial influence on pain perception.
Peripheral structures outside of the reproductive and nervous system
can also be affected by steroid hormones, including the immune system,
bone, joint surfaces, ligaments and blood vessels7. us alterations in
the structure or function of these “end-organs” secondary to variations
in sex steroid hormone levels could also increase or decrease the
sensation of pain and/or could be involved in the disease process itself.
It is likely, therefore, that hormones exert their effect on pain at a
number of sites (Table 1).
Conclusions
us it can be seen that there is copious evidence that sex steroid
hormones affect pain and that this may be, at least in part, responsible
for the differences in pain experience between men and women.
However, it is also clear that the relationship is not a simple one. It
is likely to involve dose-dependant organisational and activational
effects and actions at a number of sites outside the reproductive
system, including a wide variety in the nervous system, as well as
effects on disease processes themselves. Furthermore, there may be
interactions between the different hormones which also need to be
taken into account. More research is necessary to improve both our
understanding of this complex area and our management of painful
 V. , N. , D 
  
13. Choi JC, Park SK, Kim YH, Shin YW, Kwon JS, Kim JS, Ji-
Woong M.D, Kim, Soon Yul M.D, Sang Gyu M.D, Moo Sam
L . Different brain activation patterns to pain and pain-related
unpleasantness during the menstrual cycle. Anesthesiology 2006;
105(1): 120-7.
14. Houghton LA, Lea R, Jackson N, Whorwell PJ. e menstrual
cycle affects rectal sensitivity in patients with irritable bowel
syndrome but not healthy volunteers. Gut 2002; 50: 471 - 4.
15. Burris AS, Gracely RH, Carter CS, Sherins RJ, Davidson JM.
Testosterone therapy is associated with reduced tactile sensitivity
in human males. Horm Behav 1991; 25(2): 195-205.
16. Rao SSS, Saifi AAQ. Effect of testosterone on threshold of pain.
Indian J Physiol Pharmacol 1981; 25(4): 387-8.
17. Steiner M, Dunn E, Born L. Hormones and mood: from menarche
to menopause and beyond. J Affect Disord 2003; 74(1): 67-83.
18. Rubinow DR, Schmidt PJ. Gonadal steroid regulation of mood:
e lessons of premenstrual syndrome. Front Neuroendocrinol
2006; 27(2): 210-6.
19. Evrard HC, Balthazart J. Rapid regulation of pain by estrogens
synthesized in spinal dorsal horn neurons. J Neurosci 2004;
24(33): 7225-9.
20. Cooke B, Hegstrom CD, Villeneuve LS, Breedlove SM. Sexual
Differentiation of the Vertebrate Brain: Principles and Mechanisms.
Front Neuroendocrino. 1998; 19(4): 323-62.
21. Cicero TJ, Nock B, O’Connor L, Meyer ER. Role of Steroids in
Sex Differences in Morphine-Induced Analgesia: Activational and
Organizational Effects. J Pharmacol Exp er 2002; 300(2): 695-
701.
22. Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA,
Zubieta J-K. Pronociceptive and Antinociceptive Effects of
Estradiol through Endogenous Opioid Neurotransmission in
Women. J Neurosci 2006; 26(21): 5777-85.
coRRespondence t o :
Dr K Vincent
Clinical Research Fellow
Functional Magnetic Resonance Imaging of the Brain Centre
John Radcliffe Hopsital
Headley Way
Oxford OX3 9DU
Tel: 01865 222724
Fax: 01865 222727
email: kvincent@fmrib.ox.ac.uk
... Martin et al. asserted that ovarian hormones appear to have different effects on pain modulating systems [9]. Vincent et al. described a probable relationship between progesterone levels and pain perception [10]. Furthermore, in recent years, advanced age has been proposed as a contributing factor to developing a higher pain threshold as described, for example, by Tousignant-Laflamme et al. [11]. ...
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... Die höhere Betroffenheit von Frauen dürfte verschiedene Gründe haben [9,43]: Neben anatomischen Unterschieden wie der Muskelkraft nehmen Frauen ihren Körper häufig anders wahr als Männer und reagieren tendenziell sensitiver auf Schmerzen [9,43]. Weitere mögliche Gründe sind eine teilweise unterschiedliche zerebrale Schmerzverarbeitung, aber auch hormonell bedingte Unterschiede im Schmerzempfinden [44]. ...
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A wide variety of sexual dimorphisms, structural differences between the sexes, have been described in the brains of many vertebrate species, including humans. In animal models of neural sexual dimorphism, gonadal steroid hormones, specifically androgens, play a crucial role in engendering these differences by masculinizing the nervous system of males. Usually, the androgen must act early in life, often during the fetal period to masculinize the nervous system and behavior. However, there are a few examples of androgen, in adulthood, masculinizing both the structure of the nervous system and behavior. In the modal pattern, androgens are required both during development and adulthood to fully masculinize brain structure and behavior. In rodent models of neural sexual dimorphism, it is often the aromatized metabolites of androgen, i.e., estrogens, which interact with estrogen receptors to masculinize the brain, but there is little evidence that aromatized metabolites of androgen play this role in primates, including humans. There are other animal models where androgens themselves masculinize the nervous system through interaction with androgen receptors. In the course of masculinizing the nervous system, steroids can affect a wide variety of cellular mechanisms, including neurogenesis, cell death, cell migration, synapse formation, synapse elimination, and cell differentiation. In animal models, there are no known examples where only a single neural center displays sexual dimorphism. Rather, each case of sexual dimorphism seems to be part of a distributed network of sexually dimorphic neuronal populations which normally interact with each other. Finally, there is ample evidence of sexual dimorphism in the human brain, as sex differences in behavior would require, but there has not yet been any definitive proof that steroids acting early in development directly masculinize the human brain.