Opinion

Menstruation pulls the trigger

for inflammation and pain in
endometriosis
Alexis Laux-Biehlmann1, Thomas dHooghe2, and Thomas M. Zollner1
1
2

Global Drug Discovery, Bayer Pharma AG, Mullerstrae 178, 13353 Berlin, Germany
Leuven University Fertility Center, University Hospitals, UZ Gasthuisberg, 3000 Leuven, Belgium

Endometriosis is a chronic, hormone-dependent, inflammatory disease, characterized by the presence and

growth of endometrial tissue outside the uterine cavity.
It affects 510% of the female population of reproductive
age and is frequently associated with moderate to severe pain, subfertility, and a marked reduction in healthrelated quality of life. Here, we propose a new pathophysiological concept of endometriosis, summarizing
recent findings in one unifying picture. We propose
menstruating tissue as the trigger for inflammatory pain
in endometriosis through the activation of innate immune cells and peripheral nerve endings. We speculate
how innovative treatment modalities beyond hormonal
treatment will improve patients lives.
The burden of endometriosis
Endometriosis is defined as the presence of uterine stroma
and glands outside the uterine cavity. It is one of the most
frequent disorders of the female reproductive tract, affecting
approximately 510% of women of reproductive age and
represents a significant disease burden [13]. Key symptoms are: (i) abdominal pain in different forms, such as
chronic pelvic pain (CPP), dysmenorrhea (see Glossary),
dyspareunia, or dyschezia (Box 1); and (ii) subfertility. More
than 50% of patients have these symptoms, which impact
their relationships, their work, and their health-related
quality of life [13]. Bleeding disorders, such as short cycle
length, heavier menstruation, and longer flow duration, are
also frequently observed and known as risk factors [4,5]. Endometriosis symptoms are also difficult for patients to handle because there is an average delay of 6.7 years between
disease onset and final diagnosis [5,6]. The burden of endometriosis has also significant economic consequences with
healthcare expenses and costs due to productivity loss similar to those of other chronic diseases, such as diabetes,
Crohns disease, or rheumatoid arthritis [3].
The pathophysiology of the disease is incompletely understood. The risk of developing endometriosis is greater in
women with increased quantity of menstruation due to
Corresponding author: Zollner, T.M. (Thomas.Zollner@Bayer.com).
Keywords: retrograde menstruation; inflammatory pain; neurogenic inflammation;
sensory nerves; endometriosis.
0165-6147/
2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tips.2015.03.004

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Trends in Pharmacological Sciences, May 2015, Vol. 36, No. 5

abnormal uterine bleeding [710]. Furthermore, the biology

of eutopic endometrium is different in women with endometriosis compared with controls [11,12], which probably is a
consequence of the development of endometriosis according
to preliminary evidence in baboons [13]. Among the different
hypotheses, Sampsons theory of retrograde menstruation is
the most widely accepted [14]. During menstruation, menstrual debris travels not only anterogradely to the vagina,
but also in a retrograde manner through the fallopian tube
into the peritoneal cavity [14]. Additional sources of tissue
debris are endometriotic lesions, which have been observed
to bleed during menstruation [15,16]. Here, we introduce the
term extra-uterine menstruation to combine bleeding endometriotic lesions and retrograde transfer of tissue from
uterine menstruation (retrograde menstruation). However,
retrograde menstruation occurs in most women, while only a
minority develops the disease. This implies additional causative factors, such as genetic susceptibility, autoimmunity,
or anomalies in the inflammatory response [8,1719]. As an
example, genetic susceptibility factors have been identified
in genome-wide association studies, although these currently cannot fully explain the disease in affected women [20].
Endometriosis has features of a hormone-dependent
disease, because its symptoms are usually restricted to
the reproductive period and are responsive to hormonal
treatment (Figure 1A). Sex hormones might influence the
disease through their proliferative, pro-nociceptive, and
proinflammatory effects [1,21,22]. However, beyond hormonal aspects, extra-uterine menstruation, inflammation,
and peripheral nerve endings have a major role in the
pathophysiology of the disease (Figure 1B,C). Recent
reviews focused on the interaction of immune cells and
sensory nerves in the generation of endometriotic pain
Glossary
Abnormal uterine bleeding: bleeding from the uterine corpus that is abnormal
in duration, volume, regularity, and/or frequency.
Deep infiltrating endometriosis: infiltration of endometriotic lesion into any
given structure to a depth of at least 5 mm (e.g., uterosacral ligaments, rectum,
rectovaginal septum, vagina, or urinary tract).
Dyschezia: painful defecation.
Dysmenorrhea: pain associated with menstruation.
Dyspareunia: painful sexual intercourse due to a medical condition.
Nociception: neural process of encoding noxious stimuli.
Nociceptive neurons: central or peripheral neurons of the somatosensory
nervous system that are capable of encoding noxious stimuli.
Progestin: natural or synthetic substance having progesterone-like activity.

Opinion

Trends in Pharmacological Sciences May 2015, Vol. 36, No. 5

Box 1. Pain in endometriosis

often claimed in the endometriosis field, we believe that neuropathic
pain aspects are not in general representative of the pathophysiology
underlying pain in the disease. Central sensitization is described in
women with endometriosis-associated pain, and this is often used as
an argument for neuropathic pain. In these patients, an increased
excitability of the CNS to normal and/or innocuous stimuli leads to
increased pain hypersensitivity and larger referred pain areas
[98,99]. However, central sensitization can arise in the context of
both neuropathic and inflammatory pain, and occurs in several
inflammatory-driven painful diseases, such as migraine and irritable
bowel syndrome [100]. The neurotrophic properties of endometriotic
lesions are also often used as argument for neuropathic pain in
endometriosis, but they are also strongly related to inflammatory pain
mechanisms, especially through NGF [101,102]. Finally, the positive
effect of the surgical removal of endometriotic lesions on pain
symptoms undermines that neuropathic pain mechanisms are key in
endometriosis [103]. Nevertheless, surgically induced neuropathic
pain occurs in 1040% of patients following general surgery [104]. It
may also be one of the causes of recurring pain following laparoscopic surgery in the absence of detectable lesions [105,106].
To summarize, endometriosis is a sterile inflammatory disease
within the peritoneal cavity and, as described here, there is abundant
evidence suggesting that endometriotic pain originates, to a large
extent, from inflammation.

(B)

(A)

(C)

Endometrioc cells

Pain
percepon

Thalamus

Secondary
sensory neuron

Gn
RH

Hormonal aspects of endometriosis

Hypothalamus

Dorsal root
ganglion

+
+
Anterior
pituitary
Spinal cord

FSH
LH

Immune
cells

Degenerang
ssue

Primary
sensory neuron

e
ron
ste
n
ge
ge
tro
Es

Pro

Endometrioc
lesions

Pro-nocicepve
mediators

Sensory nerve
acvaon
Neurogenic
inammaon

+
+

Pro-inammatory
mediators

Ovary
Uterus

Extra-uterine
menstruaon
Endometrioc
lesions

Per
iton
eum

Inammaon

To spinal
cord
Nocicepve
signal

Inammatory and nocicepve aspects of endometriosis

Endometriosis-associated pain, the main symptom of the disease, is

heterogeneous and complex. The most common symptoms are
dysmenorrhea, dyspareunia, and CPP. Two types of pain perception
system can be involved, depending on the localization of the lesions
in the pelvic cavity. Somatic pain comes from the stimulation of the
sensory nerves present in the skin or deep tissues, such as the parietal
peritoneum [91]. In opposition, pain arising from internal organs,
such as the uterus, bladder, or rectum, is called visceral pain [92]. The
mechanisms underlying the generation of pain are divided in two
main categories, nociceptive and neuropathic pain [93]. It is under
debate which of these is predominant in endometriosis [23]. Importantly, the involved pathophysiological mechanisms differ and,
consequently, the therapeutic strategies are not the same [93,94]. Neuropathic pain is a pathologic condition caused by a lesion or a disease
of the somatosensory nervous system that leads to an altered neural
processing [95,96]. Nociceptive pain arises from actual or threatened
damage to non-neural tissue and is due to the activation of
nociceptive neurons. When nociceptive pain is associated with
inflammation, it is called inflammatory pain [95,97]. Peripheral
sensitization of nociceptive neurons can occur in both, leading to an
increased responsiveness to noxious (hyperalgesia) and innocuous
(allodynia) stimuli.
Both neuropathic and inflammatory pain are often cited in the
context of endometriosis-associated pain [98]. In contrast to what is

Sensory nerves
Sensory nerve ending
TRENDS in Pharmacological Sciences

Figure 1. Schematic representation of the complex pathophysiology of endometriosis. Endometriosis is a complex, multifactorial disease. In this figure, hormonal aspects
(A) are opposed to inflammatory and nociceptive components (B,C). Endometriosis is a hormone-dependent disease characterized by the presence and growth of
endometrial tissue in various locations of the pelvic cavity, such as the peritoneal wall and ovaries. Its symptoms are modulated by sex hormones (e.g., estrogen and
progesterone). Sex hormones are under the control of the hypothalamicpituitarygonadal axis and gonadotropin-releasing hormone (GnRH) agonists have positive effects
on endometriosis-associated symptoms (A). Beyond hormonal aspects, bleeding endometriotic lesions and retrograde menstruation into the pelvic cavity (extra-uterine
menstruation) induce inflammation (B). Together, endometriotic cells, degenerating tissue, and immune cells release pro-nociceptive mediators, which activate sensory
nerve endings in endometriotic lesions. In response, sensory nerve endings contribute to neurogenic inflammation through the release of proinflammatory mediators (C).
Activation of primary sensory neuron endings leads to the generation of the nociceptive signal, which is conveyed to the central nervous system (CNS). The nociceptive
signal is then integrated in the spinal cord and carried by secondary sensory neurons to higher centers in the brain (B,C). Abbreviations: FSH, follicle-stimulating hormone;
LH, luteinizing hormone.

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Trends in Pharmacological Sciences May 2015, Vol. 36, No. 5

Endometrioc lesions

(B) Innate immune system

(C)

Peripheral nervous system

Dorsal root
ganglion

Sex hormones

Mast cells

Proliferang
endometrioc cells

NF-B

Innate immune
system acvaon

Nervous system
response
SP, CGRP

Primary sensory
neurons

Sensory nerve
smulaon

DAMPs, Iron (OS)

NGF, IL-1,
TNF-, PGE2

Spinal cord

(A)

NF-B

Nocicepve signal
Menstruang ssue

Cell death

Macrophages
Direct sensory
nerve smulaon
PGE2, Acidosis (H+),
Iron (OS)

Sensory nerve endings

TRENDS in Pharmacological Sciences

Figure 2. Main pathways involved in the pathogenesis of inflammatory pain in endometriosis. The three main players involved in the pathogenesis of endometriotic pain
are endometriotic lesions (A), the innate immune system (B), and the peripheral nervous system (C). Endometriotic lesions are under the control of sex hormones and
menstruation, proliferation of endometriotic cells, and cell death occur. Mediators released during this process, including prostaglandin E2 (PGE2), H+, and iron, directly
stimulate sensory nerve endings to generate the nociceptive signal. In addition, products released from tissue degeneration [e.g., damage-associated molecular patterns
(DAMPs) or iron] activate the innate immune system through the nuclear factor (NF)-kB pathway. Proinflammatory and pro-nociceptive mediators, such as nerve growth
factor (NGF), interleukin (IL)-1b, tumor necrosis factor alpha (TNF-a) and PGE2, released from activated mast cells and macrophages, are also able to stimulate sensory
nerve endings. In response to stimulation, sensory nerves further increase and maintain inflammation by secreting proinflammatory products, such as substance P (SP) and
calcitonin gene-related peptide (CGRP). Different mediators and receptors are illustrated: IL-1R (IL-1b), TNF-R (TNF-a), TrkA (NGF) and TRPV1 (H+). Abbreviation: OS,
oxidative stress.

[23,24]. However, the consequences of extra-uterine menstruation in the generation of endometriotic pain have not
been adequately addressed so far. Here, we propose that
tissue degeneration in extra-uterine menstruation has a
central role in the inflammatory response and the generation of pain in endometriosis. In particular, we draw a
novel pathophysiological picture of inflammatory pain in
endometriosis and summarize key immunological and
neurobiological findings in one unifying concept
(Figure 2). Although we focus our concept on endometriosis, similar pathophysiological principles may also be
active in other painful, inflammatory disorders in which
tissue degeneration represents a disease hallmark.
Menstruation causes innate immune activation
Similar to endometrium, endometriotic lesions are governed
by endocrine cycles, and cyclic bleeding occurs [15,16]. Menstruation has many features of an inflammatory process
and, during the late secretory phase, an increased number of
macrophages and activated mast cells is observed, which
persists during menstruation [25]. Moreover, the concentration of innate immune cells is increased in the peritoneal
fluid of women with endometriosis compared with controls;
furthermore, an increased number of activated mast cells
and macrophages is observed in endometriotic lesions
[18,2629]. In our opinion, the activation of the innate
immune system is the first important step in the pathophysiology of endometriosis. Here, we describe how retrograde
menstruation and the bleeding of endometriotic lesions
(extra-uterine menstruation) directly influence peritoneal
inflammation and activation of the innate immune system.
The highly regulated tissue breakdown occurring during
menstruation leads to necrosis and apoptosis of endometrial
272

cells. Numerous cellular products released during cell death

are well known to induce sterile inflammation by the activation of innate immune cells [3032]. Thus, menstrual
debris, arising from extra-uterine menstruation, releases
products occurring from cell death into the peritoneal cavity
and subsequently induces sterile inflammation [33,34]. The
family of damage-associated molecular patterns (DAMPs) is
the most well known among these products. DAMP molecules include the nuclear protein high-mobility-group box 1
(HMGB1), heat shock protein 60 and 70 (HSP60 and
HSP70), S100, nucleic acids, and soluble extracellular matrix components [35]. Several studies describe the presence
of DAMPs and suggest their implication in endometriosis.
For example, HSP70 levels are higher in the serum of
women with endometriosis compared with healthy
women, and HSP70 is detected in endometriotic lesions
[36,37]. Members of the S100 family of calcium-modulated
proteins (also known as calgranulins) are overexpressed in
endometriotic lesions (S100A13) and the peritoneal fluid of
women with endometriosis (S100A8), indicating a probable
role in the pathogenesis of endometriosis [38,39]. HMGB1 is
expressed in endometriotic lesions and its role in the activation of innate immunity in endometriosis has already
been suggested [51]. Extracellular DAMPs, such as fibronectin, fibrinogen, or hyaluronan, are also described to be
present in endometriotic lesions and in the peritoneal fluid
of women with endometriosis [33,41]. In addition, nucleic
acids are released during tissue degeneration and cell death,
and high amounts are found in menstrual blood [42].
In addition to DAMPs, iron and oxidative stress are also
major products of tissue degeneration and cellular injury.
Higher concentrations of iron have been detected in peritoneal fluid of women with endometriosis compared with

Opinion
controls, and iron is described as a main constituent of
endometriosis-associated inflammation [34,4345]. Interestingly, Escherichia coli is found in menstrual blood and
peritoneal fluid of women with endometriosis, indicating
not only a role of DAMPs, but also of pathogen-associated
molecular patterns (PAMPs) in endometriosis-associated
inflammation. This is supported by higher concentrations
of bacterial endotoxin in menstrual blood and peritoneal
fluid of women with endometriosis compared with those
without endometriosis [46,47].
Products arising from menstrual debris induce the activation of macrophages and mast cells through the predominant activation of the proinflammatory transcriptional
factor nuclear factor (NF)-kB. Indeed, reactive oxygen
species (ROS) produced subsequently to the iron overload
activate mast cells and macrophages through NF-kB
[40,48,49]. DAMPs and PAMPs are themselves able to
activate NF-kB through their actions on pattern recognition receptors (PRR), a family that includes, among others,
toll-like receptors (TLRs) [50]. As recently reviewed, the
interaction between DAMPs and TLRs has a major role in
the pathophysiology of endometriosis [33,51,52]. In endometrium, nine TLRs are expressed by immune, epithelial,
and stromal cells [53,54]. TLR2 and TLR9 are overexpressed in the peritoneal fluid of women with endometriosis, and there is an increased TLR4 expression in
endometriotic lesions of women during the secretory phase
[55,56]. TLR3 and TLR4 are expressed by dendritic cells,
monocytes, and macrophages in endometriotic lesions and
are increased in endometriotic lesions compared with endometrium [57]. As a consequence of innate immune activation, a range of proinflammatory and pro-nociceptive
mediators is released (see below for more detail).
In summary, there is likely to be a central role for
menstrual debris, more specifically DAMPs, as triggers
of innate immunity in endometriosis. The activation of
macrophages and mast cells by extra-uterine menstruation leads to the secretion of pro-nociceptive and proinflammatory mediators, which contribute to the generation
of nociceptive signals and the feed-forward loop, maintaining and strengthening the peritoneal inflammation
(Figure 2).
Peritoneal menstruation triggers sensory nerve
stimulation
Several products are released into the peritoneal cavity by
degenerating tissue during extra-uterine menstruation that
both activate the innate immune system and sensory
nerves. Here, we describe how these products can activate
sensory nerves, directly through tissue degeneration-related products or indirectly through innate immune cell activation. The activation of sensory nerve fibers that generate
and convey nociceptive signals to the central nervous system
(CNS) is an essential step in the pathophysiology of pain.
Sensory nerve endings are present in endometriotic lesions,
and a positive correlation between the amount of nerve
fibers and pain symptoms has been described in different
types of endometriosis [23,24], which strongly suggests their
significance in endometriosis-associated pain.
It is well known that tissue degeneration and cell death
lead to acidification of the tissue [58]. This pH decrease is

Trends in Pharmacological Sciences May 2015, Vol. 36, No. 5

sensed by several receptors expressed by the sensory nerve

fibers. Among them, the transient receptor potential vanilloid 1 (TRPV1) channel has been widely studied and its role
in inflammatory pain is well known [59]. Increased numbers of TRPV1-positive nerve fibers are found in endometriotic lesions of women with CPP compared with
endometriotic lesions of women without CPP, supporting
the implication of TRPV1 in endometriosis-associated pain
[60]. As described above, extra-uterine menstruation leads,
partially through iron overload, to an increased production
of ROS. ROS have a direct pro-nociceptive effect by sensitizing sensory nerve fibers, mainly by enhancing TRPV1
activity [6163].
Prostaglandins are produced and released upon cell
activation and tissue damage [64]. They directly activate
sensory nerve fibers. Prostaglandin E2 (PGE2) is abundantly detected in the peritoneal fluid of women with
endometriosis and its role in the pathophysiology of the
disease is well described [65]. Indeed, PGE2 is the most
well-known lipid mediator that contributes to inflammatory pain. PGE2 has a pro-nociceptive effect through the
sensitization of sensory nerve fibers [66]. Nonsteroidal
anti-inflammatory drugs (NSAIDs) suppress pain symptoms in inflammatory pain diseases, but they have numerous adverse effects upon chronic treatment [67].
In addition to the above-described direct effects, extrauterine menstruation can also indirectly stimulate sensory
nerves by innate immune activation. More inflammatory
cells are observed near nerve fibers in women with endometriosis and with more severe pain symptoms, suggesting
a direct activation of the sensory nerve afferents by immune cells and the inflammatory environment [6870]. Activated mast cells and macrophages synthesize and secrete
numerous proinflammatory and pro-nociceptive mediators. The concentrations of mediators, such as cytokines,
chemokines, complement components, prostanoids, reactive oxygen intermediates, hydrolytic enzymes, and growth
factors, are increased in the peritoneal fluid or in endometriotic lesions [18,51,71]. Among them, interleukin (IL)-1b,
tumor necrosis factor alpha (TNF-a), and nerve growth
factor (NGF) are able to directly activate sensory nerve
ending. Their implication in the generation of pain is well
described in several inflammatory diseases and has been
reviewed recently in endometriosis [23,24].
In contrast to other inflammatory pain disorders, the
underlying mechanism of endometriosis-associated pain
is still incompletely understood. Here, we have summarized evidence that extra-uterine menstruation activates
and sensitizes sensory fibers present in lesions through a
direct or an indirect action (Figure 2). Together, the
consequences of extra-uterine menstruation are likely
the first triggers for sensory nerve stimulation and,
subsequently, the generation of inflammatory pain in
endometriosis.
Nervous system response further increases peritoneal
inflammation
Nerve fibers themselves also have an active role in the
mechanism of inflammatory pain by secreting proinflammatory neuromediators. This mechanism, called neurogenic inflammation, is observed in several inflammatory
273

Opinion
painful conditions, such as complex regional pain syndrome, migraine, and arthritis [7274].
Neurogenic inflammation is also likely to be of relevance
in endometriosis [24]. The neuropeptide substance P (SP)
is present in the sensory nerve fibers of peritoneal and deep
infiltrating endometriotic lesions [75,76], and calcitonin
gene-related peptide (CGRP) is detected in peritoneal
endometriotic lesions [76]. Furthermore, the SP receptor
neurokinin 1 receptor (NK1R) is expressed in endometriotic lesions [77]. In addition, patients with the NK1R gene
polymorphism rs881 and high preoperative pain levels
have a higher disease free-survival probability compared
with patients with the wild type genotype [78]. Despite the
fact that the consequence of rs881 polymorphism on NK1R
function is not known, a loss-of-function could be speculated. This would further support a pathogenic role of SP/
NK1R and the existence of neurogenic inflammation in
endometriosis [78]. Neurogenic inflammation may cause a
vicious circle in endometriosis: SP stimulates mast cells
and macrophages and induces the release of proinflammatory cytokines, such as TNF-a, IL-6, and IL-8 [79]. CGRP
induces mast cell degranulation and edema by vasodilatory effects [72]. Interestingly, TNF-a concentration is
increased in the peritoneal fluid of women with endometriosis-associated nerves in lesions compared with women
with endometriosis but without associated nerve fibers
[70]. Therefore, the increased number of nerve fibers
may have proinflammatory effects, suggesting the existence of a neurogenic inflammatory process.
In summary, there is accumulating evidence for neurogenic inflammation in endometriosis. Proinflammatory
peptides released by sensory nerve fibers may complete
a vicious cycle between sensory nerve activation by extrauterine menstruation and the nervous system response,
which further increases and maintains inflammation
(Figure 2).
Concluding remarks
As outlined above, endometriosis is not only a hormonedependent disease, but also an inflammatory disease.
However, the current standard of care poorly reflects this
complexity because it mainly comprises combined oral
contraceptives, progestins, or short-term treatment with
gonadotropin-releasing hormone (GnRH) agonists. These
treatment modalities only indirectly interfere with inflammatory pain by suppressing the lesions and/or modulating
the menstrual cycle and, consequently, the amount of
menstruating tissue, although anti-nociceptive and immune-modulatory effects of gonadal hormones have been
described (reviewed in [80,81]). Owing to the molecular
nature of endometriosis, the limited efficacy of currently
available hormonal drugs, and their potential adverse
effects, there is a high medical need for innovative and
better treatment.
What would such innovative treatment options look
like? What are the general treatment requirements and
which disease mechanisms could potentially be targeted?
Women with endometriosis are in general young, otherwise healthy women of reproductive age. Although some
women with endometriosis are asymptomatic, the prevalence of endometriosis in women with CPP and/or
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Trends in Pharmacological Sciences May 2015, Vol. 36, No. 5

infertility is high and varies from 30 to 50% [82,83]. These

symptomatic women are in need of safe and convenient
medical and/or surgical treatment, which is effective in the
long term. This includes ideally: (i) a lack of sex steroid
deprivation-linked adverse effects (e.g., hot flushes, reduction in bone mineral density, etc.); (ii) unchanged menstrual cycle; (iii) no negative impact on fertility; and (iv) no
toxicity to reproduction [84,85]. Given that the main trigger for endometriotic pain is extra-uterine menstruation
and the subsequent peritoneal inflammation (i.e., a peripheral stimulus), we think that interfering with the
peripheral nervous system is advisable. This would reduce
the risk of unwanted CNS effects, including potential
negative effects on neuroplasticity. In addition, acting
on peripheral targets has the potential to reverse central
changes (e.g., central sensitization) occurring in women
with endometriosis [86]. Peripheral input activity has an
important role in the maintenance of central changes in
chronic painful diseases and treatment modalities targeting peripheral causes of ongoing chronic pain might have
short-term benefits in patients (reviewed in [87,88]).
Besides safety, innovative drugs have to demonstrate
clinically meaningful efficacy. In controlled clinical trials,
the currently available treatment options, such as combined oral contraceptives, progestins, or GnRH agonists,
show a marked reduction in pain experience. However,
high mean surgery numbers per lifetime (2.8) and rather
low rates of patient satisfaction with the available compounds are indicators that efficacy in daily clinical practice may differ from that observed in controlled clinical
trials, indicating the need for improved efficacy [89]. In
addition, there is also a need for a faster response. Peak
efficacy following hormonal treatment of endometriosis is
currently only achieved with a delay of several weeks
[90], most likely due to the indirect mechanism of action
of sex hormone-based drugs. Compounds with the potential to rapidly improve patients symptoms within a few
days will likely further improve their quality of life
significantly.
Based on our opinion that extra-uterine menstruation
has a central role in inflammation and pain in endometriosis, we believe that compounds that act on more than
one of the above defined three pathways will have the
most significant therapeutic potential. In this way, a
promising target could be involved in both the stimulation of sensory nerve endings and the activation and/or
stimulation of innate immune cells. For example, this
could be achieved by dampening oxidative stress or blocking the action of proinflammatory and pro-nociceptive
cytokines (e.g., IL-1b or TNFa). The key next steps for
the scientific community is to identify effective and safe
compounds against the proposed pathways and to test
them in clinical trials to bring preclinically validated
targets to the next level.
Acknowledgments
We thank Jens Nagel and Damian OConnell for critical comments and
reviewing the manuscript.

Disclaimer statement
A.L-B and T.M.Z. are employees of Bayer AG; T.M.Z. is also a shareholder.

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Trends in Pharmacological Sciences May 2015, Vol. 36, No. 5

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