Pain 132 (2007) S22–S25

www.elsevier.com/locate/pain

Topical review

Pain and endometriosis

Susan Evans a, Gila Moalem-Taylor b, David J. Tracey b,*

a
Endometriosis Care Centres Australia, Adelaide, SA 5067, Australia
b
School of Medical Sciences, University of New South Wales Sydney, NSW 2052, Australia

Received 10 May 2007; received in revised form 27 June 2007; accepted 16 July 2007

1. Introduction persistent nociceptive input from endometrial tissues

Endometriosis is the commonest cause of chronic
pelvic pain in women (Fauconnier and Chapron,
2005). It is characterized by the presence of uterine
endometrial tissue outside of the uterus, most com-
monly in the pelvic cavity. The disorder mainly affects
women of reproductive age. Symptoms of endometri-
osis include recurrent painful periods, painful inter-
course, painful defecation during menstruation,
chronic lower abdominal pain and hypersensitivity,
chronic lower back pain and infertility (Farquhar,
2007). For many women, endometriosis has a negative
impact on the ability to work, on family relationships
and self-esteem (Huntington and Gilmour, 2005).
Many women with endometriosis describe a progres-
sion of symptoms over their menstrual life, which
may include a mix of different pains and abnormal
visceral sensations, indicative of viscero-visceral hyper-
algesia and suggestive of neuropathic pain (Horowitz,
2007). Current medical treatments for endometriosis
include oral contraceptives, progestogens, androgenic
agents, gonadotrophin releasing hormone analogues,
as well as laparoscopic surgical excision of the
endometriotic lesions. However, management of pain
in women with endometriosis is currently insufficient
for many women. Here we review the involvement
of the nervous system, immune cells and inflammatory
response, and hormones in endometriosis as well as
current practice in pain management. We suggest that
* cytochemical labelling of substance P and calcitonin
Corresponding author. Tel.: +61 2 9385 2471; fax: +61 2 9385
8016.
E-mail address: d.tracey@unsw.edu.au (D.J. Tracey).
might lead not only to peripheral sensitisation, but
also to central sensitisation resulting in increased
responsiveness of dorsal horn neurons innervated by
viscera and somatic tissues.
2. Visceral nociceptors
Nociceptors are found in most kinds of tissue, includ-
ing the viscera (Cervero and Laird, 1999). However,
their existence in viscera including the reproductive
organs was disputed for some time. One reason for this
was that clinicians found it difficult to elicit pain from
internal organs. For example, Lewis said ‘‘The body of
the uterus can be cut or burnt; the broad ligaments
can be dissected painlessly’’ (Lewis, 1942). It may be
that many nociceptors in the internal organs are ‘silent
nociceptors’ (Gebhart, 2000). These nociceptors do not
normally respond to intense mechanical or thermal stim-
uli, but when the surrounding tissue is inflamed, they
become sensitised and will respond to stimuli such as
pressure, distension or heat. This means that some noci-
ceptors may only respond to stimuli when tissue pathol-
ogy is present. For example, a normal appendix can be
cut without causing pain, but becomes painful when tis-
sue pathology is present. It is no longer in doubt that
nociceptors are present in the viscera, including the
reproductive organs, and there is good evidence that
nociceptors are present in the uterus and cervix. This
evidence is based on electrophysiological recordings
(Berkley et al., 1988; Berkley et al., 1990) and immuno-
gene-related peptide in uterine nerve fibres (Tong
et al., 2006).

0304-3959/$32.00 Ó 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2007.07.006
 S. Evans et al. / Pain 132 (2007) S22–S25
3. Nociceptors and endometriosis
There is increasing evidence that endometriosis elicits
changes in the population of uterine nociceptors. For
example, women with endometriosis have many small
unmyelinated nerve fibres in the functional layer of their
endometrium. These nerve fibres are probably nocicep-
tors, and are not present in women without endometri-
osis (Tokushige et al., 2006a). Nociceptors invade
peritoneal endometriotic lesions in women (Berkley
et al., 2005), and are also found invading endometriotic
cysts in experiments on rats (Berkley et al., 2004; Tok-
ushige et al., 2006b). This suggests that in women with
endometriosis, there is abnormal sprouting of nocicep-
tors in the endometrium and in peritoneal endometriotic
lesions. Such nerve sprouting might be caused by
increased levels of nerve growth factor (NGF), since
expression of NGF in endometriotic tissue is reported
to be higher than in eutopic endometrium (Anaf et al.,
2002; Tokushige et al., 2006b).
4. Immune and inflammatory factors in endometriotic pain
Endometriosis has been described as a pelvic inflam-
matory process with altered function of immune cells
and increased number of activated macrophages in the
peritoneal environment that secrete various local prod-
ucts, such as growth factors and cytokines (Agic et al.,
2006; Siristatidis et al., 2006). Endometriotic lesions
themselves secrete pro-inflammatory cytokines such as
interleukin-8 (IL-8), which recruit macrophages and T
cells to the peritoneum and mediate inflammatory
responses. The concentration of some chemokines (e.g.
MCP-1; monocyte chemoattractant protein 1) is
increased in the peritoneal fluid of patients. These obser-
vations could explain the presence of inflammatory cells
in endometriosis (Giudice and Kao, 2004). Immune cells
such as mast cells and macrophages, growth factors such
as NGF, and pro-inflammatory cytokines such as
tumour necrosis factor (TNF) and IL-6 have all been
shown to contribute to persistent pain, particularly neu-
ropathic pain (Moalem and Tracey, 2006). Increased
numbers of activated and degranulating mast cells have
been found near endometriotic lesions, often close to
nerve fibres (Anaf et al., 2006), and activated macro-
phages are present at significantly increased concentra-
tions in the peritoneal fluid of women with
endometriosis (Agic et al., 2006). It has been suggested
that neutrophils and macrophages contribute to angio-
genesis and the development of endometriotic lesions
(Lin et al., 2006).
Intense immunoreactivity for NGF has been reported
near endometrial glands in peritoneal endometriotic
lesions (Tokushige et al., 2006b), although the increase
in expression of NGF in peritoneal endometriotic tissue
over that in eutopic endometrium does not appear to be
S23
very marked (Anaf et al., 2002). NGF is known to con-
tribute to persistent inflammatory pain (Pezet and
McMahon, 2006).
The evidence on IL-6 is inconsistent – increased con-
centrations of IL-6 have been found in peritoneal fluid
of women with endometriosis (Punnonen et al., 1996),
but others did not find a difference in IL-6 concentra-
tions in peritoneal fluid between women with and with-
out endometriosis (Rapkin et al., 2000).
Concentrations of TNF in peritoneal fluid are higher
in women with endometriosis than in patients with nor-
mal pelvic anatomy (Eisermann et al., 1988), although
the concentrations of cytokines in peritoneal fluid are
not correlated with pain symptoms or severity of endo-
metriosis (Overton et al., 1996). However, it has been
suggested that TNF is one of the essential factors for
the pathogenesis and maintenance of endometriosis
(Bullimore, 2003), and its role in chronic pain is well
documented (Sommer and Kress, 2004).
Given the significant presence of inflammation in
endometriosis, one could expect that non-steroidal
anti-inflammatory drugs (NSAIDs) would relieve pain
in patients. Unfortunately, NSAIDs are of only partial
benefit; dysmenorrhoea may improve but chronic pelvic
pain is less responsive. In this respect chronic pain in
endometriosis is similar to neuropathic pain, in which
NSAIDs are equally disappointing.
It has been suggested that endometriosis is an auto-
immune disease (Nothnick, 2001; Thomson and Red-
wine, 2005). This idea is supported by findings of
abnormal polyclonal B-cell activation (Gleicher et al.,
1987), increased numbers of T and B lymphocytes in
peritoneal fluid and peripheral blood compared with
controls (Badawy et al., 1987) and high serum concen-
trations of IgG and IgM autoantibodies and antibodies
to the endometrium (Wild and Shivers, 1985). Endome-
triosis shares many features with autoimmune diseases
including elevated levels of cytokines (Nothnick, 2001),
and pain is a common symptom of such diseases. Initial
studies of immune modification with methotrexate and
hydroxychloroquine in women with chronic pelvic pain
and abnormal serum inflammatory markers have been
positive (Thomson and Redwine, 2005).
5. Pain and hormones in endometriosis
Endometriosis is estrogen-dependent, and traditional
treatments have aimed to decrease production of estro-
gens such as estradiol. However, the exact mechanism
by which estrogens promote endometriosis is unclear
and suppression of estrogens has variable effects. Reduc-
ing estrogen levels with gonadotrophin hormone ana-
logues may improve pain symptoms (Moghissi et al.,
1998) even when used concurrently with hormone
replacement therapy. Aromatase inhibitors which pre-
vent estrogen biosynthesis within the endometriotic
S24 S. Evans et al. / Pain 132 (2007) S22–S25
lesion have been shown to be effective (Attar and Bulun,
2006). However, trials of raloxifene (a selective estrogen
receptor modulator) were closed due to unfavourable
outcome and trials of fulvestrant (an estrogen receptor
antagonist) have remained unreported (Guo and Olive,
2007).
Estrogens do not have direct effects on nociceptors,
so how might suppression of endogenous estrogen pro-
duction relieve endometriosis pain? There are several
possible mechanisms. Estrogens stimulate production
of prostaglandins (Giudice and Kao, 2004), whose role
in pain is well known. Estrogens also increase levels of
NGF in the uterus (Shi et al., 2006). NGF promotes
sprouting of nociceptors and can contribute to persis-
tent pain in several other ways (Pezet and McMahon,
2006).
6. Involvement of the central nervous system in
endometriosis
Recent study of a rat model of endometriosis, in
which pieces of uterine horn are auto-transplanted into
the abdomen where they form cysts, showed that vaginal
hyperalgesia depends upon the cysts (Cason et al., 2003).
These cysts (like the uterus) are robustly innervated by
both sympathetic and sensory C and Ad fibres (Berkley
et al., 2004). This supply connects the implants directly
with the central nervous system via the splanchnic and
vagus nerves suggesting that the vaginal hyperalgesia
in this rat model involves central neural mechanisms
(Berkley et al., 2005). These studies suggested that this
hyperalgesia involves viscero-visceral interactions and
is likely centrally mediated because the cysts were
located in sites remote from the vagina. A further indi-
cation that central sensitisation may contribute to
endometriotic pain is the demonstration that patients
with endometriosis experienced increased pain intensity
and larger pain areas than control patients after saline
was injected into a hand muscle – a site distant from
regions normally experienced as painful by patients.
This could be a manifestation of central hyperexcitabil-
ity and may explain the extensive pain in endometriosis
patients (Bajaj et al., 2003). Central sensitisation is
known to play an important role in neuropathic pain
(Campbell and Meyer, 2006).
7. Pain management of endometriosis
Laparoscopic excision of endometriosis and pharma-
cological treatments with GnRH agonists, synthetic pro-
gestational hormones or danazol (an androgen-like
synthetic steroid) are all more effective than placebo
(Fauconnier and Chapron, 2005). However, these med-
ications, which aim to lower estrogen levels, do not effec-
tively manage pain in many women and have significant
side effects. The recurrence of painful symptoms is high
both after medical treatments and after laparoscopic
surgery (Fedele et al., 2004), and pain may persist or
recur even after complete excision of endometriotic
lesions (Abbott et al., 2003). In addition, the severity
of endometriosis as judged by visual laparoscopy corre-
lates poorly with pain (Vercellini et al., 2007).
These factors strongly suggest that other pain factors
are present. We suggest that in many women with endo-
metriosis, an inflammatory process has caused sensiti-
sation of nociceptors and central neurons. Surgical
excision and suppression of estrogens will not be suffi-
cient to manage their pain, and management with treat-
ments for inflammation and neuropathic pain should be
considered. Amitriptyline and gabapentin are widely
used in the treatment of neuropathic pain, and have
been shown to be effective pain therapies in women with
chronic pelvic pain refractory to surgery, tramadol and
metamizol (Sator-Katzenschlager et al., 2005).
8. Conclusions
It seems that several mechanisms contribute to the
pain of endometriosis. One is simply the activation of
nociceptors by inflammatory mediators in the endome-
triotic tissue. A second possible mechanism is that
‘silent’ or ‘sleeping’ nociceptors present in normal endo-
metrium or peritoneum are sensitised by their inflamma-
tory environment, while a third mechanism would be
contributed by sprouting of nociceptors, leading to a
greater number of nociceptive nerve terminals. All of
these mechanisms could lead to an increased barrage
of action potentials in nociceptors and greater activation
of spinal neurons, leading to central sensitisation. These
are also the mechanisms that underlie neuropathic pain
– so it may be useful to regard the pain of endometriosis
as having a neuropathic component, even if a primary
lesion or dysfunction of the nervous system is not
obvious.
Acknowledgment
We thank Dr. Silke Collins for constructive
suggestions.
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