Human Reproduction Vol.21, No.3 pp. 782–787, 2006 doi:10.

1093/humrep/dei368
Advance Access publication October 27, 2005.

High density of small nerve fibres in the functional layer of

the endometrium in women with endometriosis

N.Tokushige1,3, R.Markham1, P.Russell2 and I.S.Fraser1

1
Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants and 2Department of
Pathology, University of Sydney, Sydney, 2006, Australia
3
To whom correspondence should be addressed. E-mail: ntok0157@mail.usyd.edu.au

Downloaded from http://humrep.oxfordjournals.org/ at University of Wisconsin-Madison Libraries on February 2, 2015

BACKGROUND: Endometriosis is a common gynaecological disease and is frequently associated with recurrent
and serious pelvic pain such as dysmenorrhoea and dyspareunia, but the mechanisms by which these symptoms are
generated are not well understood. METHODS: Histological sections of endometrial tissue were prepared from
endometrial curettings and hysterectomies performed on women with endometriosis (n=25 and n=10, respectively) and
without endometriosis (n=47 and n=35, respectively). These were stained immunohistochemically for the highly spe-
cific polyclonal rabbit anti-protein gene product 9.5 (PGP9.5) and monoclonal mouse anti-neurofilament protein (NF)
to demonstrate both myelinated and unmyelinated nerve fibres. RESULTS: Small nerve fibres were identified
throughout the basal and functional layers of the endometrium in all endometriosis patients, but were not seen in the
functional layer of the endometrium in any of the women without endometriosis (P< 0.001). NF-immunoreactive nerve
fibres were present in the basal layer in all endometriosis patients but not in non-endometriosis patients, with one
exception (P< 0.001). CONCLUSIONS: Small nerve fibres detected in the functional layer in all women with endome-
triosis may have important implications for understanding the generation of pain in these patients. The presence of
nerve fibres in an endometrial biopsy may be a novel surrogate marker of clinical endometriosis.

Key words: endometriosis/endometrium/immunohistochemistry/nerve fibres/pain

Introduction
Endometriosis, defined by the presence of focal endometrium-
like tissue in sites outside the uterus (Binkovitz et al., 1991),
is a gynaecological condition which is being increasingly rec-
ognized in most societies, especially in developed countries.
Frequently it is associated with recurrent and disabling symp-
toms, primarily pelvic pain, yet little is understood about the
mechanisms by which symptoms are generated (Anaf et al.,
2000). Investigators have studied the presence of nerve fibres
in endometriotic plaques and, although there is some evidence
for the ingrowth of small nerve fibres into endometriotic
plaques (Tamburro et al., 2003; Berkley et al., 2004), no neu-
rofilament protein (NF)-immunoreactive nerve fibres could be
identified in the capsule of ovarian endometriomas (Al-Frozan
et al., 2004).
The multiplicity of molecular and cellular abnormalities
demonstrated in the eutopic endometrium of women with
endometriosis (Lessey et al., 1994; Ota and Tanaka, 1997;
Healy et al., 1998) suggests that primary abnormalities in this
tissue may have a role in the genesis of endometriosis and per-
haps even in the genesis of symptoms. We speculated that this
might include local growth factors or cytokines for nerve fibres
which, if also present in the ectopic endometrial-type tissue of
patients with endometriosis, could induce the growth of nerve
782 © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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fibres into the endometriotic foci and thus provide a mecha-
nism for lesion-specific pain. We therefore studied the pres-
ence of nerve fibres by immunohistochemistry in the basal and
functional layers of the endometrium from women with and
without visually and biopsy-proven endometriosis using highly
specific markers polyclonal rabbit anti-protein gene product
9.5 (PGP9.5) (Lundberg et al., 1988) and NF (Schlaepfer,
1987) for both myelinated and unmyelinated nerve fibres.
PGP9.5 is a highly specific pan-neuronal marker and it stains
both myelinated and unmyelinated nerve fibres (Aα, Aβ, Aγ,
Aδ, B and C fibres). NF is a highly specific marker for myeli-
nated nerve fibres and it stains Aα, Aβ, Aγ, Aδ and B fibres.
Aδ fibres are small myelinated fibres and transmit sharp, prick-
ing localized pain to the central nervous system. C fibres are
small unmyelinated fibres and transmit dull, aching, burning
poorly localized pain.
Materials and methods
Collection of tissue
This study was approved by the Human Ethics Committees of the
Central Sydney Area Health Service and the University of Sydney,
and all women gave their informed consent for participation.
Endometrial tissue (uterine curettage) was collected from 25
women with endometriosis (mean age, 27.5 years; range, 20–35) and

47 women without endometriosis (mean age 32.7 years; range, 28–38)
who underwent laparoscopy combined with hysteroscopy and
diagnostic curettage. The endometriosis patients all complained of
dysmenorrhoea and a range of related pain symptoms. The 47
endometrial curettage tissue samples collected from women without
laparoscopic evidence of endometriosis were from patients undergo-
ing tubal sterilization, assessment prior to tubal reanastomosis or
investigation of infertility. Full-thickness uterine blocks, which
included the endometrium and myometrium, were selected from 10
women with endometriosis (mean age 44.0 years; range, 42–46) and
35 women without endometriosis (mean age 46.0 years; range, 38–54)
who had undergone hysterectomy. The indications for hysterectomy
in the 35 women without endometriosis included multiple small uter-
ine fibroids, uterine prolapse, abdominal adhesions or abnormally
heavy menstrual bleeding.
Laparoscopic biopsies were collected from suspicious areas on the
peritoneum, and curettage samples of the functional layer of the
endometrium were carefully collected in single long strips allowing
orientation during paraffin embedding. The basal layer of the
endometrium was defined as 300μm above the endometrial–myometrial
interface (≤300μm) (Gambino et al., 2002) and the functional layer of
the endometrium was defined as the area from the epithelial surface to
the basal layer. The basal and functional layers were further divided
into two sublayers, namely superficial and deeper portions.
The severity of pain was not assessed systematically and prospec-
tively in this preliminary observational study, but detailed clinical
information was recorded in a standard format. All endometriosis
patients were staged according to the revised American Fertility Soci-
ety (AFS) score (American Society for Reproductive Medicine, 1996),
which ranged from 1 to 1V3. Eighty-six percent of the endometriosis
subjects had peritoneal endometriosis alone, while the remainder had
ovarian endometriosis with or without endometriosis in other sites.
Menstrual cycle staging was determined on all samples of
endometrium, by a single gynaecological histopathologist (P.R.), and
all phases of the cycle were represented: menstrual (days 1–7 of the
cycle), proliferative (days 8–14) and secretory (days 15–28) phases of
a normalized 28 day cycle. Of the 35 women with endometriosis, four
were assessed as being in the menstrual phase, 11 were in the prolifer-
ative phase and 20 were in the secretory phase, whereas of the 82
women without endometriosis, 12 were assessed as being in the men-
strual phase, 36 were in the proliferative phase and 34 were in the
secretory phase of the cycle. None of the women had received medical
therapy for endometriosis in the 3 months prior to endometrial or
hysterectomy sampling.
Immunohistochemistry
After resection, the specimens were immediately fixed in 10% neutral
buffered formalin for ~18–24h, processed and embedded in paraffin
wax according to a standard protocol. Each section was cut at 4μm
and routinely stained with haematoxylin and eosin (H&E). Antigen
retrieval techniques for PGP9.5 and NF were used. Serial sections,
also cut at 4μm, were immunostained using an antibody for polyclo-
nal rabbit anti-PGP9.5 (dilution 1:700; Dako Cytomation, Sydney,
Australia), a highly specific pan-neuronal marker (Lundberg et al.,
1988), and monoclonal mouse anti-human NF (dilution 1:200; Dako
Cytomation), a highly specific marker for myelinated nerve fibres
(Schlaepfer, 1987), for 30min at room temperature. Sections were
washed in Tris buffer, incubated with Envision-labelled polymer-AP
mouse/rabbit for 30min (Dako Cytomation) and stained with perman-
ent fast red chromogen (Dako Cytomation) for 10 min. All immunos-
taining was carried out on a Dako Autostainer Model S3400 (Dako
Cytomation Inc., Carpinteria, CA). Images of the sections were cap-
tured using an Olympus BX51 digital camera (Olympus, Tokyo,
Endometrial nerve fibres in women with endometriosis
Japan). We used normal skin as a positive control as it reliably
contains myelinated and unmyelinated nerve fibres expressing both
PGP9.5 and NF. Rabbit immunoglobulin fraction was used as a nega-
tive control, the concentration being matched with the concentration
of the PGP9.5 and NF antibodies.
Statistical analysis
The images were captured by using an Olympus BX51 digital camera,
and an assessment of nerve fibre density was performed by Image Pro
Plus Discovery (MediaCybernetics, Silver Springs, MD). Once the fea-
tures of the images were controlled, an orthogonal grid mask was
sketched above the original images. The sections of the grid were
250μm a side. Once the grid was in position, nerve fibres in the
endometrium and myometrium, and the total number of squares cover-
ing the sections of endometrium and myometrium were counted. The
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total number of nerve fibres was divided by the total number of squares
covering the endometrium to obtain an average of nerve fibres per
square (each square of 250×250μm). The results were expressed as the
mean (±SD) number of nerve fibres per mm2 in each specimen from all
endometrial and myometrial samples, stained with the polyclonal anti-
body against PGP9.5 and monoclonal antibody against NF. Nerve fibre
density between eutopic endometrium from endometriosis patients and
normal women was compared using the Mann–Whitney U-test. Differ-
ences were considered to be significant at P<0.05.
Results
Multiple small unmyelinated nerve fibres stained for PGP9.5
were present in the functional layer of the endometrium in all
endometriosis patients (Figure 1A). Most of the nerve fibres
were in the deeper portion of the functional layer; however,
some nerve fibres in the superficial portion were very close
(50–180μm) to the endometrial epithelial surface and they often
accompanied blood vessels and endometrial glands. In patients
without endometriosis, no nerve fibres were detected in the func-
tional layer of the endometrium (Figure 1B; Table I; P<0.001).
There were also NF-immunoreactive myelinated nerve
fibres in the deeper portion of the basal endometrium in all
endometriosis patients, while in patients without endometriosis
no myelinated nerve fibres were detected within the basal layer
of the endometrium, with one exception (Table II; P<0.001).
This exceptional patient did not have endometriosis, but she
had pelvic pain, menorrhagia, uterine fibroids and chronic
inflammation in the cervix. No NF-immunoreactive myeli-
nated nerve fibres were detected in the functional layer of the
endometrium in patients with or without endometriosis.
There were many more small unmyelinated nerve fibres
present throughout the basal layer (both deeper and superficial) of
the endometrium in women with endometriosis (Figure 1C) than
without endometriosis. Occasionally, small unmyelinated nerve
fibres were noted in women without endometriosis but only in the
deeper portion of the basal layer (four women out of 35; Figure
1D; Table II; P<0.001). In women with endometriosis, these
nerve fibres often formed obvious thick trunks in the basal layer
or at the endometrial–myometrial interface (Figure 1C). These
trunks were never seen in women without endometriosis. Thirty-
one women without endometriosis showed no nerve fibres
throughout the basal layer of the endometrium. All four women
without endometriosis who showed nerve fibres in the deeper
portion of the basal endometrial layer had uterine fibroids.
783
N.Tokushige et al.

Table I. Small unmyelinated nerve fibre density in the functional layer of

endometrium (per mm2, mean±SD) in women with and without endometriosis

n Mean±SD Range

Hysterectomy specimens: endometriosis

Menstrual 1 7 7
Proliferative 2 6 5–6
Secretory 7 15±5 9–23
Total 10 11±5
Hysterectomy specimens: no endometriosis
Menstrual 5 0 0
Proliferative 16 0 0
Secretory 14 0 0
Total 35 0
Curettage specimens: endometriosis
Menstrual 3 7±1 6–8

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Proliferative 9 5±1 3–6
Secretory 13 13±6 7–30
Total 25 10±7
Curettage specimens: no endometriosis
Menstrual 7 0 0
Proliferative 20 0 0
Secretory 20 0 0
Total 47 0 0

Nerve fibres were stained with PGP9.5.

P<0.001 for endometriosis versus no endometriosis.

Small and large nerve fibres including thick trunks stained

Figure 1. Nerve fibres in the functional and basal layers of the
endometrium from woman with and without endometriosis. (A)
Endometrium from the functional layer of a woman with biopsy-
confirmed endometriosis stained for PGP9.5 (magnification×400).
Arrows denote multiple small nerve fibres in the functional layer,
several within 100μm of the epithelial surface. (B) Endometrium
from the functional layer of a woman with no visible endometriosis
stained for PGP9.5 (magnification×400). No nerve fibres could be
identified. (C)Myometrial–endometrial interface from a woman with
biopsy-confirmed endometriosis stained for PGP9.5 (magnification
×200) showing thick nerve fibre trunks stained red. (D) Myometrial–
endometrial interface from a woman with no visible endometriosis
and with a small nerve fibre in the deeper portion of the basal layer
stained with PGP9.5 (magnification×200). (E) Myometrial–endometrial
interface from a woman with biopsy-confirmed endometriosis stained
for NF (magnification×400) showing several nerve fibres stained red.
Scale bars represent 100μm in (A), (B) and (E); and 200μm in (C)
and (D).
784
with PGP9.5 were present in myometrium in women with and
without endometriosis. There were more nerve fibres stained with
PGP9.5 in the myometrium in women with endometriosis than in
women without (Table III; P< 0.001). A small number of nerve
fibres stained with NF was seen throughout the myometrium of
all women with endometriosis (Table III), but only 16 out of 35
women (46%) without endometriosis showed a few nerve fibres
stained with NF throughout in the myometrium (P> 0.097).
There appeared to be a difference in the patterns of PGP 9.5
in the endometrium at different stages of the menstrual cycle.
There was a greater density of nerve fibres in the functional
and basal layers of the endometrium in the secretory phase than
either the menstrual or proliferative phases. The distribution of
nerve fibres was reasonably uniform throughout the functional
layer and basal endometrial layers in women with endometrio-
sis- (Figure 1A and C).
There was also a greater density of nerve fibres stained with
PGP9.5 in the functional and basal layers of the endometrium than
the myometrium in women with endometriosis (Tables I–III;
P<0.001).
Discussion
This study has demonstrated multiple small unmyelinated
nerve fibres in the functional layer of the endometrium in
35 women with confirmed endometriosis but in none of
82 women without endometriosis. There were also many more
nerve fibres in the basal layer of the endometrium in women
with endometriosis compared with women with no endometri-
osis. Some nerve fibres in the basal layer of the endometrium
in women with endometriosis were NF immunoreactive and
myelinated, but no NF-immunoreactive nerve fibres were
present in the functional layer of the endometrium in women
with or without endometriosis.
 Endometrial nerve fibres in women with endometriosis

Table II. Small unmyelinated and large myelinated nerve fibre densities in the basal layer of endometrium (per mm2, mean±SD) in women with and without
endometriosis

Endometriosis No endometriosis

n PGP9.5 NF n PGP9.5 NF

Mean±SD Range Mean±SD Range Mean±SD Range Mean±SD Range

Menstrual 1 12 12 1 1 5 0 0–1 0 0–1

Proliferative 2 11 9–18 2 1–2 16 0 0–1 0 0
Secretory 7 21±8 11–80 3±2 1–7 14 0 0–1 0 0
Total 10 18±8 2±2 35 0 0

Unmyelinated and myelinated nerve fibres were stained with PGP9.5; myelinated nerve fibres were stained with NF.
P<0.001 for endometriosis versus no endometriosis.

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Table III. Small unmyelinated and large myelinated nerve fibre densities in myometrium (per mm2, mean±SD) in women with and without endometriosis

Endometriosis No endometriosis

n PGP9.5 NF n PGP9.5 NF

Mean±SD Range Mean±SD Range Mean±SD Range Mean±SD Range

Menstrual 1 2.28 2.28 0.02 0.02 5 0.96±0.55 0.29–1.76 0.03±0.02 0.01–0.06

Proliferative 2 2.62 2.51–2.72 0.03 0.03 16 0.49±0.34 0.15–1.20 0.01±0.01 0.01–0.03
Secretory 7 3.58±1.36 2.21–6.24 1.00±0.03 0.96–1.03 14 1.12±1.06 0.17–3.13 0.03±0.02 0.01–0.09
Total 10 3.26±1.23 0.71±0.47 35 0.89±0.78 0.02±0.02

Unmyelinated and myelinated nerve fibres were stained with PGP9.5; myelinated nerve fibres were stained with NF.
P<0.001 for PGP9.5; P>0.097 for NF.

It has been known for some time that the myometrium, the
endometrial–myometrial interface and the deeper portion of the
basal endometrium can be innervated by nerve fibres, but that
nerve fibres are absent from the superficial two-thirds of the
endometrium (the functional layer) in the normal human uterus
(Coupland, 1969). The function of these nerve fibres in normal
basal endometrium is not well understood. However, some ace-
tylcholinesterase (AChE)-immunoreactive nerve fibres were
detected in the basal layer of normal human endometrium
(Coupland, 1969). Neuropeptide - (NPY), substance P- (SP),
vasoactive intestinal peptide- (VIP) and neurotensin (NT)-
immunoreactive nerve fibres were also present in normal human
endometrium (Heinrich et al., 1986). Yet little is known about
the functions of these nerve fibres in human endometrium.
Some researchers have studied nerve fibres in normal
endometrium in animals. Calcitonin gene-related peptide-
(CGRP) (Shew et al., 1990), AChE- and NPY-immunoreactive
nerve fibres were detected in rat endometrium (Papka et al., 1985)
and many CGRP-immunoreactive nerve fibres were near the sur-
face epithelium (Shew et al., 1990). SP and CGRP were also
localized in myometrial nerves in a rat model (Shew et al., 1990).
A variety of clinical conditions including endometriosis, pelvic
inflammatory disease, uterine fibroids, adhesions and uterine
contractions can cause pelvic pain. Various investigators have
demonstrated nerve fibres in endometriotic plaques, abdominal
adhesions and myometrium (Tulandi et al., 1998; Anaf et al.,
2000; Sulaiman et al., 2001; Tamburro et al., 2003; Berkley
et al., 2004). Endometriotic plaques in a rat model were inner-
vated by SP, CGRP (sensory C and Aδ fibres) and vesicular
monoamine transporter (VMAT) fibres (Berkley et al., 2004).
Nerve fibres were present in human peritoneal endometriotic
plaques, and transforming growth factor (TGF-β1) was
expressed in the nerve fibres only in red and white lesions
(Tamburro et al., 2003). Rectovaginal endometriotic nodules
from women with severe dysmenorrhoea and deep dyspareunia
showed the presence of nerve fibres staining with the non-
specific antibody, S-100 protein (Anaf et al., 2000). Human
peritoneal adhesions contained synaptophysin- CGRP-, SP-,
vasoactive intestinal peptide- (VIP)- and tyrosine hydroxylase
(TH)-immunoreactive nerve fibres (Sulaiman et al., 2001) and
78% of endometriosis-related adhesions showed NF-immuno-
reactive nerve fibres (Tulandi et al., 1998).
SP- and CGRP-immunoreactive nerve fibres were present in
human myometrium (Samuelson et al., 1985) and SP-induced
contractions were inhibited by CGRP. It has been reported that
women with endometriosis had uterine contractions with
higher frequency, amplitude and basal pressure tone during
menses (Bulletti et al., 2002); therefore, SP- and CGRP-immu-
noreactive nerve fibres may play a role in the pain of women
with endometriosis.
The pathogenesis of endometriosis is not well understood,
but there are numerous theories, including implantation of
endometrial fragments transported via the Fallopian tubes by
retrograde menstruation (Sampson, 1927, 1940), mechanical
transplantation (Allen et al., 1954; Levander and Normann,
1955), lymphatic and vascular metastasis (Halban, 1924;
Jubanyik and Comite, 1997), direct extension or invasion (Cullen,
1908), coelomic metaplasia (Ridley, 1968, Vasquez, 1984),
embryonic rests (Von Recklinghausen, 1896; Russell, 1899)
and a composite theory (Javert, 1949; Nisolle and Donnez,
785
N.Tokushige et al.
1997). Most researchers support variations of the implantation
theory, which postulates that peritoneal endometriotic lesions
result from the reflux of viable endometrial tissue fragments or
cells through the Fallopian tubes which then implant and grow
on the peritoneal surface and pelvic organs.
If the implantation theory is true, the nerve fibres in
endometriotic plaques may originate from nerve fibre progeni-
tors in the functional layer of the endometrium or, more prob-
ably, from ingrowth of local nerve fibres due to the secretion of
nerve growth factors (NGFs) and increased expression of two
NGF receptors, namely Trk-A and p75, by the implanting
endometrium. It is not yet clear what neural stimuli may initi-
ate the severe pain sensations which some women experience
with endometriosis. However, a number of molecules that are
capable of stimulating nerve fibres, such as tumour necrosis
factor-α (TNF-α) (Bergqvist et al., 2001), prostaglandin I2
(Ylikorkala and Viinikka, 1983), prostaglandin E2 and F2α (De
Leon et al., 1988), and NGF (Anaf et al., 2002) can be released
from endometriotic plaques. It seems highly probable that the
endometrium of women destined to develop endometriosis is
functionally abnormal (Lessey et al., 1994; Ota and Tanaka,
1997; Healy et al., 1998). It may also be programmed to
secrete large amounts of nerve trophic factors, resulting in the
remarkable ingrowth of unmyelinated small nerve fibres dem-
onstrated in this study. This may also be translated into
ingrowth of nerve fibres into new endometriotic plaques on the
peritoneum or ovary. These nerve fibres may have an import-
ant role in the mediation of pain symptoms. No other satisfac-
tory theory has yet been advanced for the genesis of pain
symptoms in women with endometriosis.
This demonstration of small nerve fibres in the functional
layer of eutopic endometrium of women with endometriosis is
so striking in the present study that we believe it could become
a relatively simple surrogate marker of this condition using
endometrial biopsies. It is even possible that an endometrial
biopsy may demonstrate nerve fibres in women destined to
develop the condition later in life. Much further research is
required to define possible roles and mechanisms of these
nerve fibres in endometriosis, as well as defining the presence
of uterine nerve fibres in other gynaecological conditions.
Acknowledgements
The authors thank Lawrence Young (Dako Cytomation,
Australia) for technical support. This study was supported by
research funding from the Department of Obstetrics and
Gynaecology, University of Sydney.
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