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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
The online version of this article can be found at:
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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British Pain Society
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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
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
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
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
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
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 
  
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
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
Modulate GABA
Promote myelination
Mediate male aggression towards
↑↓seizure threshold
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
Modulate dorsal horn response in
neuropathic pain
Sensitise uterine and cervical afferents
glutamatergic nociceptor activity
Neuroprotective Facilitate release of ACh
System T and B cell proliferation and
cytokine and immunoglobulin
Modulate immune response
cellular immune response
etal System bone deposition
muscle mass recovery following
bone deposition
Smooth muscle relaxant
bone density and strength
muscle mass
System NO synthesis
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.
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):
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-
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).
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-
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
... 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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Background: Postoperative symptoms and pain after laparoscopic cholecystectomy (LC) are common in women. However, there is no evidence of differences in incidence and severity among different age groups. We evaluated whether adverse postoperative symptoms were more common in younger than in older women after LC. Methods: One hundred and fifty premenopausal (mean age 37.6 ± 3.6 y) and 145 postmenopausal women (59 ± 5.2 y) were included in this retrospective cohort study. Clinical and anthropometric parameters were analyzed. Study endpoints were the incidences of postoperative nausea and vomiting (PONV) and pain, and the additional analgesics and antiemetics needed after surgery. Results: Body mass index was normal in 42.7% of patients in the younger group and 64.8% in the older group (P < 0.001). Reported pain was more frequent and intense in the younger group throughout the study period (P < 0.01). Additional narcotics were required in 18% of premenopausal versus 7.6% of postmenopausal women (P = 0.001), and the doses used to reduce pain were higher for premenopausal women (P = 0.02). PONV was more frequent in the younger group at 1 and 6 h after surgery (P < 0.005). Rescue antiemetics were required in 29 premenopausal and 13 postmenopausal women (P = 0.01). Hospital stay was shorter for the older patients (P = 0.01). Minor morbidity was observed in both groups (0.7% and 2.1%). There was no mortality. Conclusions: Early PONV and pain after LC were more frequent in premenopausal women, who also required more rescue analgesic and antiemetic medication.
... Demographic information for these participants can be found in Table 1. To reduce the influence of age-related changes or hormone use confounding the results, groups were matched on age (±5 years) and hormonal contraceptive use (yes or no) (26)(27)(28). Inclusion criteria for both groups included: older than 18 years of age or under 50; no magnetic resonance imaging (MRI) contraindications (e.g., metal implants); no major brain or spinal cord injury; no use of medications that substantially affect the central nervous system (e.g., antipsychotics); and not currently pregnant or breastfeeding. In addition, women with PVD had to report idiopathic, provoked pain to the vaginal entrance during sexual and non-sexual activities involving vaginal penetration. ...
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The most common subtype of vulvodynia (idiopathic chronic vulvar pain) is provoked vestibulodynia (PVD). Previous imaging studies have shown that women with vulvodynia exhibit increased neural activity in pain-related brain regions (e.g., the secondary somatosensory cortex, insula, dorsal midcingulate, posterior cingulate, and thalamus). However, despite the recognized role of the spinal cord/brainstem in pain modulation, no previous neuroimaging studies of vulvodynia have examined the spinal cord/brainstem. Sixteen women with PVD and sixteen matched Control women underwent a spinal cord/brainstem functional magnetic resonance imaging (fMRI) session consisting of five runs with no painful thermal stimuli (No Pain), interleaved randomly with five runs with calibrated, moderately painful heat stimulation (Pain). Functional connectivity was also assessed in periods before, during, and after, pain stimulation to investigate dynamic variations in pain processing throughout the stimulation paradigm. Functional connectivity in the brainstem and spinal cord for each group was examined using structural equation modeling (SEM) for both Pain and No Pain conditions. Significant connectivity differences during stimulation were identified between PVD and Control groups within pain modulatory regions. Comparisons of Pain and No Pain conditions identified a larger number of connections in the Control group than in the PVD group, both before and during stimulation. The results suggest that women with PVD exhibit altered pain processing and indicate an insufficient response of the pain modulation system. This study is the first to examine the spinal cord/brainstem functional connectivity in women with PVD, and it demonstrates altered connectivity related to pain modulation in the spinal cord/brainstem.
... T-tests were used for continuous variables and Fisher's exact tests were used for categorical variables to examine any demographic differences between women with PVD and Control women ( Table 1). Groups were matched on age (+/-5 years) to account for age-related changes in sensory processing and on hormonal contraceptive use (yes or no) to account for any potential effects (e.g., on pain sensitivity) of exogenous hormones (21)(22)(23). In order to be eligible, participants were required to be between the ages of 18 and 50; not currently pregnant, breastfeeding, or using medications that substantially affect the central nervous system (e.g., antipsychotics); and have no magnetic resonance imaging (MRI) contraindications (e.g., metal implants) or major brain or spinal cord injury. ...
Full-text available
Provoked Vestibulodynia (PVD) is the most common vulvodynia subtype (idiopathic chronic vulvar pain). Functional magnetic resonance imaging (fMRI) studies indicate that women with PVD exhibit altered function in a number of pain modulatory regions in response to noxious stimulation, such as in the secondary somatosensory cortex, insula, dorsal midcingulate, posterior cingulate, and thalamus. However, previous neuroimaging studies of PVD have not examined periods of time before and after noxious stimulation or investigated functional connectivity among pain modulatory regions. Fourteen women with PVD and 14 matched Control participants underwent five fMRI runs with no painful stimuli interleaved randomly with five runs with calibrated, moderately painful heat stimuli applied to the thenar eminence. As recent findings indicate that pain processing begins before and continues after painful stimulation, 2-min periods were included in each run before and after the stimulus. Functional brain connectivity was assessed during both trials of Pain and No Pain stimulation for each group using structural equation modeling (SEM). Analyses of variance (ANOVAs) on connectivity values demonstrated significant main effects of study condition, and group, for connectivity among pain modulatory regions. Most of the differences between the Pain and No Pain conditions found only in the PVD group take place before (i.e., thalamus to INS, ACC to S1, thalamus to S1, and thalamus to S2) and after pain stimulation (i.e., INS to amygdala, PPC to S1, and thalamus to S2). Such differences were not observed in the Control group. These findings further support previous results indicating that women with PVD have altered pain processing compared to pain-free women.
... Moreover, some studies underlined specific mechanisms of ovarian steroids exerted on opioid systems directly, depending on the treatment duration (Ratka and Simpkins, 1991). However, it is also clear that the relationship between sex steroid hormones and pain is complex, modulating the nervous system functioning, as well as the pathophysiological processes themselves (Vincent and Tracey, 2008). Regarding the maintenance of plasma LTZ concentrations, previous studies described LTZ concentrations as being more persistent in females than in males, following single oral administration (Liu et al., 2000), and pharmacokinetic studies highlight that LTZ concentration steady state (2.5 mg daily doses) was reached after 4 weeks of treatment (Pfister et al., 2001). ...
Among postmenopausal women with estrogen receptor-positive breast cancer, more than 80% receive hormone therapy including aromatase inhibitors (AIs). Half of them develop chronic arthralgia - characterized by symmetric articular pain, carpal tunnel syndrome, morning stiffness, myalgia and a decrease in grip strength - which is associated with treatment discontinuation. Only a few animal studies have linked AI treatment to nociception, and none to arthralgia. Thus, we developed a new chronic AI-induced nociceptive disorder model mimicking clinical symptoms induced by AIs, using subcutaneous letrozole pellets in ovariectomized (OVX) rats. Following plasma letrozole dosage at the end of the experiment (day 73), only rats with at least 90 ng/mL of letrozole were considered significantly exposed to letrozole (OVX + high LTZ group), whereas treated animals with less than 90 ng/mL were pooled in the OVX + low LTZ group. Chronic nociceptive disorder set in rapidly and was maintained for more than 70 days in the OVX + high LTZ group. Furthermore, OVX + high LTZ rats saw no alteration in locomotion, myalgia or experimental anxiety during this period. Bone parameters of the femora were significantly altered in all OVX rats compared to Sham+vehicle pellet. A mechanistic analysis focused on TRPA1, receptor suspected to mediate AI-evoked pain, and showed no modification in its expression in the DRG. This new long-lasting chronic rat model, efficiently reproduces the symptoms of AI-induced nociceptive disorder affecting patients' daily activities and quality-of-life. It should help to study the pathophysiology of this disorder and to promote the development of new therapeutic strategies.
... 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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Rücken- und Nackenschmerzen sind in der Bevölkerung weit verbreitet und können die Lebensqualität bei einem Teil der Betroffenen deutlich mindern. Zum Zweck einer validen Schätzung der Prävalenzen von Rücken- und Nackenschmerzen wurde zwischen Oktober 2019 und März 2020 eine telefonische Querschnittbefragung unter Erwachsenen in Deutschland (N=5.009) durchgeführt. Neben der Häufigkeit und Intensität von Rücken- und Nackenschmerzen, wurden dabei auch Angaben zur Lebensqualität und zu Begleiterkrankungen erhoben. Es zeigt sich, dass 61,3% der Befragten in den letzten zwölf Monaten von Rückenschmerzen berichten. Schmerzen des unteren Rückens sind etwa doppelt so häufig wie Schmerzen des oberen Rückens. 15,5% der Befragten berichten von chronischen Rückenschmerzen. Des Weiteren geben 45,7% an, dass sie im vergangenen Jahr Nackenschmerzen hatten. 15,6% der Befragten berichten, im letzten Jahr sowohl Schmerzen im unteren und oberen Rücken als auch im Nacken gehabt zu haben. Frauen sind von allen Schmerzarten häufiger betroffen als Männer. Etwa die Hälfte der Befragten schätzt ihre Rücken- und Nackenschmerzen als mäßig stark ein; ältere Befragte geben deutlich mehr Schmerzattacken je Monat an als jüngere Befragte. Die Ergebnisse zeigen ein umfangreiches Bild zu den bevölkerungsbezogenen Beeinträchtigungen durch Rücken- und Nackenschmerzen. Sie werden im Rahmen der Studie BURDEN 2020 genutzt, um zentrale Indikatoren der Krankheitslastrechnung zu quantifizieren.
Chronic pain affects 20% of adults and is one of the leading causes of disability worldwide. Women and girls are disproportionally affected by chronic pain. About half of chronic pain conditions are more common in women, with only 20% having a higher prevalence in men. There are also sex and gender differences in acute pain sensitivity. Pain is a subjective experience made up of sensory, cognitive, and emotional components. Consequently, there are multiple dimensions through which sex and gender can influence the pain experience. Historically, most preclinical pain research was conducted exclusively in male animals. However, recent studies that included females have revealed significant sex differences in the physiological mechanisms underlying pain, including sex specific involvement of different genes and proteins as well as distinct interactions between hormones and the immune system that influence the transmission of pain signals. Human neuroimaging has revealed sex and gender differences in the neural circuitry associated with pain, including sex specific brain alterations in chronic pain conditions. Clinical pain research suggests that gender can affect how an individual contextualizes and copes with pain. Gender may also influence the susceptibility to develop chronic pain. Sex and gender biases can impact how pain is perceived and treated clinically. Furthermore, the efficacy and side effects associated with different pain treatments can vary according to sex and gender. Therefore, preclinical and clinical research must include sex and gender analyses to understand basic mechanisms of pain and its relief, and to develop personalized pain treatment.
Nanotechnology has enabled many interesting novel applications in all scientific and technological fields. Biomedicine is one of these fields, which has exploited nanotechnological advancements extensively in wound dressings, transdermal patches and tissue engineering scaffolds. In order to achieve desired functionalities, one or more therapeutic agents are generally embedded in the related structures. Hormones could also be used as therapeutic agents for different health purposes since they are known to be crucial for maintaining daily functions of the human body. For these facts, hormones and hormone-balancing agents have been given a special emphasis in biomedical applications both for maintaining health and well-being in youth and senescence and for treating diseases and wounds stemming from surgery and/or injury. It is also striking that hormonal therapies have gradually shifted from oral to topical route of administration, in which nanofibers have gained a special importance. Despite the increased attention in this field, there is no review present in literature regarding nanofibrous structures for the purpose of hormonal therapies. To fulfill this gap, this review article is devoted to summarizing the developments in nanofibrous structures for health and well-being applications and to addressing associated potential opportunities in wound dressings, transdermal patches, and tissue scaffolds.
This chapter explores the prevalence, clinical symptoms, diagnosis, and management of complex regional pain syndrome (CRPS) in pregnant patients. The etiology of CRPS in this patient population is unique due to the changes in anatomy and pathophysiology of pregnancy. Management of CRPS symptoms becomes challenging when considering the health of the patient and the unborn fetus. This chapter serves to outline the current recommendations and guidelines for treatment.
According to the National Cancer Institute in 2020 there will be an estimated 21,750 new ovarian cancer cases and 276,480 new breast cancer cases. Both breast and ovarian cancer are hormone dependent cancers, meaning they cannot grow without the presence of hormones. The two most studied hormones in these two cancers are estrogen and progesterone, which are also involved in the modulation of pain. The incidence of pain in breast and ovarian cancer is very high. Research about mechanisms involved in modulation of pain by hormones are still being debated, as some studies find estrogen to be anti-nociceptive and others pro-nociceptive in pain studies. Moreover, analgesic treatments for breast and ovarian cancer-associated pain are limited and often ineffective. In this review, we will focus on estrogen and progesterone mechanisms of action in modulation of pain and cancer. We will also discuss new treatment options for these types of cancer and associated-pain.
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Back and neck pain are widespread and can significantly reduce quality of life. A cross-sectional telephone survey (N=5,009) was carried out between October 2019 and March 2020 to gain a valid estimate of the prevalence of back and neck pain among adults in Germany. In addition to the frequency and intensity of back and neck pain, the study collected information about quality of life and comorbidity. The findings showed that 61.3% of respondents reported back pain in the last twelve months. Lower back pain was reported about twice as often as upper back pain, with 15.5% of respondents stating that they experienced chronic back pain. 45.7% reported neck pain, and 15.6% of respondents have experienced lower and upper back pain in addition to neck pain in the past year. Women are affected by all types of pain more often than men. About half of the respondents categorise their back or neck pain as moderate; older respondents report significantly more pain episodes per month than younger respondents. The results described here provide a comprehensive picture of the population-related limitations associated with back and neck pain and are used within the framework of the BURDEN 2020 study to quantify key indicators of burden of disease calculation.
The purpose of the present studies was to determine the role of either the organizational or activational sex steroids in mediating the sex differences observed in morphine-induced antinociception in the rat. To examine the organizational aspects, male pups were castrated at postnatal days 1 and 2; females were masculinized by large doses of testosterone on postnatal days 1 and 2. Adult male and female rats were also castrated over a period of 2 months to examine the role of the acute activational effects of the opiates in the already sexually differentiated adult rat brain. The results of these studies demonstrate that there were no alterations in the sex differences in opiate analgesia in castrated adult male and female rats; thus, male- and female-specific responses to opiate-induced antinociception were maintained even in the absence of the acute membrane-mediated effects of sex steroids. On the other hand, in male rats, castrated at postnatal days 1 and 2, the morphine dose-response curve shifted markedly to the right and, in fact, was almost identical to that observed in untreated females. Conversely, in female rats, masculinized by large doses of testosterone early in prenatal life, the morphine dose-response curve shifted to the left, yielding a dose-response curve that resembled that in normal males. These results strongly suggest that the sex differences that have been observed in morphine-induced analgesia are due to the organizational effects of sex steroids in the developing rat brain, rather than their acute activational effects in adulthood.
Background: We have previously shown that the menstrual cycle has no effect on rectal sensitivity of normal healthy women, despite them having looser stools at the time of menses. Patients with irritable bowel syndrome (IBS) often report significant exacerbation of their IBS symptoms with menses, raising the possibility that IBS patients may respond differently to the menstrual cycle. Aim and methods: Rectal responses to balloon distension during days 1–4 (menses), 8–10 (follicular phase), 18–20 (luteal phase), and 24–28 (premenstrual phase) of the menstrual cycle were assessed in 29 female IBS patients (aged 21–44 years), diagnosed by the Rome I criteria. During the course of the study patients completed symptom diaries to assess abdominal pain and bloating (visual analogue scale), and frequency and consistency of bowel habits. In addition, levels of anxiety and depression were assessed using the hospital anxiety and depression questionnaire. Results: Menses was associated with a worsening of abdominal pain and bloating compared with most other phases of the menstrual cycle (p<0.05). Bowel habits also became more frequent (p<0.05) and patients tended to have a lower general well being. Rectal sensitivity increased at menses compared with all other phases of the cycle (p<0.05). There was no associated change in rectal compliance, wall tension, or motility index. Neither was there any difference in resting anal pressure or the distension volumes required to relax the internal anal sphincter during the menstrual cycle. Conclusion: These data (1) confirm that IBS symptomatology is exacerbated at menses and (2) show for the first time that in contrast with healthy women, rectal sensitivity changes with the menstrual cycle. These cyclical changes in sensitivity suggest that women with IBS respond differently to fluctuations in their sex hormonal environment or its consequences compared with healthy females.
In their Focus article, Drs. Fillingim and Maixner have reviewed data on gender differences in responsive­ ness to experimental noxious stimuli, interpreted those data as indicating that women are more sensi­ tive to noxious stimuli than men, and proposed a model of how a range of biological and psychological factors might contribute to these gender-associated differences in pain sensitivity. The model is intriguing and is well grounded in the animal literature on sex differences in pain transmission and pain modulation systems. How­ ever, because the authors' stated motivation for assess­ ing gender-related differences in pain responsiveness is that certain pain conditions (e.g., migraine headache, fibromyalgia, temporomandibular disorder pain) are more prevalent in women than in men, and that persons with these predominantly female pain conditions exhibit enhanced sensitivity to laboratory pain procedures, additional perspectives from clinical and epidemiologic pain research may be relevant. Specifically, this commentary will introduce an epi­ demiologic approach to the issue of gender differences in pain that may be useful for exploring alternative inter­ pretations of the data presented and identifying strengths and weaknesses of the model proposed. Epi­ demiology is the study of the distribution and determi­ nants of diseases or conditions in populations. ' ° The science of epidemiology is grounded in three important perspectives: the population perspective, the ecological perspective, and the developmental perspective. Else­ where, we have presented an extensive discussion of the application of these perspectives to the study of pain: This article focuses 'more specifically on what these three perspectives have to offer in terms of
Moderate to severe functional bowel disease results in debilitating abdominal pain, nausea, intermittent vomiting, early satiety, bloating, abdominal distension, and/or altered bowel habits. Because it occurs 20–30 times more frequently in women than in men and its symptoms often coincide with the menstrual cycle, we hypothesized that reproductive steroids may antagonize diseased nerves of the gastrointestinal tract, enhancing the expression of symptoms. No effective or consistent therapy has existed for these patients. We prospectively investigated the effect of a gonadotropin-releasing hormone analog, leuprolide acetate, in 30 women with symptoms of moderate to severe functional bowel disease. The study was phase II, randomized, double blind, and placebo controlled. Lupron Depot 3.75 mg (which delivers a continuous low dose of drug for one month) or placebo were given intramuscularly monthly for three months. Symptom scores were assessed at each four-week visit. Follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone levels were assessed before and after therapy. Patients treated with low-dose leuprolide improved progressively and significantly in scores for nausea, vomiting, bloating, abdominal pain, and early satiety, and for overall symptoms (PPP=0.054).
Responses to vibrotactile stimuli were examined in men as a function of chronic exposure to either exogenous or endogenous androgens. Psychophysical techniques were used to evaluate thresholds to stimulus detection and perceived stimulus intensities in response to mild vibration applied to either the finger or the penis. Normal men were compared to the following groups: (a) untreated hypogonadal men, (b) androgen-replaced hypogonadal men, or (c) infertile men with androgen levels in the low normal range. Among the four groups, untreated hypogonadal men perceived vibrotactile stimuli as most intense and were slightly more sensitive to touch than were men with higher levels of androgen. Chronic treatment with testosterone enanthate was associated with a decline in the perceived intensity of vibrotactile stimuli in hypogonadal men. The lowest levels of sensitivity to tactile stimuli were observed in the infertile men.
Pain threshold for thermal stimulus was studied in male albino rats before and after three days of treatment with testosterone. It was also determined 15 days after castration and three days after testosterone treatment of castrated rats. There was a significant reduction in pain threshold after testosterone treatment and a marked increase in pain threshold after castration. This increase disappeared after administration of testosterone to the castrated rats.
Moderate to severe functional bowel disease results in debilitating abdominal pain, nausea, intermittent vomiting, early satiety, bloating, abdominal distension, and/or altered bowel habits. Because it occurs approximately 20-30 times more frequently in women than in men and its symptoms often coincide with the menstrual cycle, we hypothesized that reproductive steroids may antagonize diseased nerves of the gastrointestinal tract, enhancing the expression of symptoms. No effective or consistent therapy has existed for these patients. We prospectively investigated the effect of a gonadotropin-releasing hormone analog, leuprolide acetate, in 30 women with symptoms of moderate to severe functional bowel disease. The study was phase II, randomized, double blind, and placebo controlled. Lupron Depot 3.75 mg (which delivers a continuous low dose of drug for one month) or placebo were given intramuscularly monthly for three months. Symptom scores were assessed at each four-week visit. Follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone levels were assessed before and after therapy. Patients treated with low-dose leuprolide improved progressively and significantly in scores for nausea, vomiting, bloating, abdominal pain, and early satiety, and for overall symptoms (P < 0.01-0.05). All hormone levels decreased significantly (P < 0.05) except luteinizing hormone (P = 0.054).
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.