Maturitas 72 (2012) 214–219

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Maturitas
journal homepage: www.elsevier.com/locate/maturitas

Review

Potential mechanisms of postmenopausal endometriosis

Charlotte L. Bendon a,∗ , Christian M. Becker b
a
Department of Plastic and Reconstructive Surgery, Oxford University Hospitals, Headley Way, Oxford, United Kingdom
b
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Headley Way, Oxford, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Endometriosis is a chronic gynaecological disorder, the cause of which remains a subject of contro-
Received 2 April 2012 versy. Oestrogen dependence is considered central to development and progression, and endometriosis is
Accepted 24 April 2012 widely viewed as a disease of the premenopausal years, which normally regresses during the menopause.
Increasingly however, reports of cases of postmenopausal endometriosis challenge our current under-
standing of the pathophysiology and raise further questions concerning the processes involved. Exploring
Keywords:
the limited evidence available on postmenopausal disease we attempt to draw comparisons with pre-
Endometriosis
menopausal endometriosis, and in doing so to propose mechanisms for postmenopausal disease that are
Menopause
Postmenopausal
compatible with our current general understanding of the condition.
Pathophysiology © 2012 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
1.1. Features in common with pre-menopausal endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
1.2. Relationship to pre-menopausal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
1.3. Relationship to serum oestradiol levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
1.4. Role of local oestrogen production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
2. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

1. Introduction data demonstrating reduction in disease burden and symptoms

with oestrogen lowering medication, has lead to the widely held
Endometriosis is a common, chronic gynaecological disorder belief that endometriosis is a disease of premenopausal women
affecting an estimated 10% of women of reproductive age [1]. and ‘cured’ by menopause [7,8].
Defined morphologically by the presence of endometrial glands Several theories have been proposed to attempt to explain the
and stroma outside of the uterus, endometriosis is a cause of pathophysiology of premenopausal disease. Of these Sampson’s
chronic pelvic pain and infertility [2,3]. To date there is still no theory of retrograde menstruation and implantation is the most
single, unifying theory to explain the existence of endometriosis widely accepted [9]. However, the presence of endometrial cells
in all its various forms [4,5]. However, oestrogen dependence is in the abdominal cavity is frequently observed in women during
considered central to the pathophysiological process, and the per- menses [10], and this theory therefore fails to explain why some
sistence of these lesions [6]. This concept, combined with clinical women develop endometriosis while others do not [8]. It is likely
that additional factors determine the ability of these endometrial
deposits to implant, proliferate and persist. It has been suggested
that molecular aberrations in the eutopic endometrium of women
∗ Corresponding author at: Department of Plastic and Reconstructive Surgery,
with endometriosis [11] are likely to result in the activation of
John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United King-
dom. Tel.: +44 01865 741166; fax: +44 01865 231091. oncogenes [12], and progesterone resistance [13]. It is possible
E-mail address: charlottebendon@googlemail.com (C.L. Bendon). that alterations in the immune system resulting in failure to clear

0378-5122/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.maturitas.2012.04.010
 C.L. Bendon, C.M. Becker / Maturitas 72 (2012) 214–219
peritoneal implants might also play a central role in the pathophysi-
ology [14,15]. Additionally it has been proposed that endometriosis
is an angiogenesis-dependent disease, an imbalance in pro- and
anti-angiogenic factors facilitating the growth and establishment
of lesions [16–18].
In keeping with the concept of oestrogen dependence, high
levels of aromatase and steroidogenic acute regulatory protein
(StAR) expression and enzyme activity have been demonstrated
in cultured stromal cells taken from endometriotic lesions, under
prostaglandin E2 (PGE2) stimulation. In contrast aromatase activ-
ity was undetectable in eutopic endometrial stromal cells from
disease-free controls [8,19,20]. StAR facilitates the entry of choles-
terol into the mitochondrion, thus initiating oestrogen production
[8]. In fact in vivo studies have indicated that endometriotic lesions
express the full compliment of enzymes required for oestrogen
synthesis [21], and it is possible that locally produced oestrogen fur-
ther drives the disease process in endometriosis through paracrine
effects [6].
Contrary to popular belief, post-menopausal endometriosis is
thought to affect up to 2–4% of women [22]. However, the data on
postmenopausal disease is currently limited, and largely confined
to case reports and retrospective studies. Reports of disease arising
in post-menopausal women challenge current concepts and raise
important questions regarding the mechanisms by which these
lesions might develop and/or persist during the post-menopausal
years. Central to this debate are general issues regarding the nat-
ural history of premenopausal disease, and specifically whether
or not endometriosis can be considered progressive in nature. In
one study disease progression at 6 years was demonstrated in less
than 10% of women with asymptomatic, untreated, laparoscop-
ically confirmed rectovaginal endometriosis [23]. Furthermore it
has been suggested that mild endometriosis is not a disease at all,
rather a transient phenomenon occurring in healthy individuals,
which is capable of resolving spontaneously [2]. In a double-blind
placebo-controlled trial of treatment with oral gestrinone, infertile
women with laparoscopic evidence of asymptomatic endometrio-
sis were allocated to receive either oral gestrinone or a placebo and
followed-up with a second-look laparoscopy at 24 weeks. Remark-
ably even among women in the placebo group, disease appeared
to be eliminated in 24% and showed improvement in 29% [24]. It
is important to note however that high inter- and intra-observer
variability has been reported when disease severity is staged by
visual inspection [25,26].
If endometriosis can still be considered a progressive disease,
the detection of postmenopausal lesions does not directly contra-
dict Sampson’s retrograde menstruation and implantation theory
because lesions arising in this way during the premenopausal years
might simply progress and persist into the menopause. In contrast,
if endometriotic lesions arise de novo in postmenopausal women
in the absence of a functioning endometrium, it may be assumed
that these lesions develop as a result of alternative processes.
In this review, we will attempt to explore the pathophysiologi-
cal processes responsible for postmenopausal disease, and based
on current evidence, we propose potential mechanisms for post-
menopausal endometriosis.
1.1. Features in common with pre-menopausal endometriosis
There is evidence to suggest that post-menopausal endometrio-
sis is morphologically similar to pre-menopausal disease, albeit less
extensive and less active [7]. This evidence is derived from a ret-
rospective study on excised ectopic endometrial tissue from over
100 women, grouped according to age as ‘likely pre-menopausal
(<50 years) and ‘likely post-menopausal’ (≥50 years). The similar
distributions of oestrogen and progesterone receptors in ectopic
endometrial tissue taken from across age groups, suggests that
215
endometriotic lesions might have the potential to reactivate given
the appropriate hormonal stimulus [7,27]. Although unusual in
its approach, particularly in grouping patients by age rather than
by confirmed menopausal status, the study implies that post-
menopausal endometriosis is likely to share some of the features
normally associated with pre-menopausal disease.
However, lesions from women in the ‘likely post-menopausal’
group were found to be less haemorrhagic and less extensive com-
pared to women in the ‘likely pre-menopausal’ category. These
findings are in keeping with the concept that endometriotic lesions
should normally regress after the menopause. This forms the basis
of gonadotrophin-releasing hormone (GnRH) agonist therapy for
the management of endometriosis, which is thought to suppress
disease activity in affected individuals by generating an artificially
induced menopausal state. It is supported by studies demonstrating
reduced inflammation and angiogenesis, and increased apoptosis
in endometriotic lesions derived from women receiving systemic
GnRH agonists [28].
1.2. Relationship to pre-menopausal disease
Several cases of post-menopausal endometriosis described in
the literature identify a history of pre-menopausal disease. A post-
menopausal 53 year-old woman presenting with frank haematuria
was discovered to have a retroperitoneal mass compressing the
right distal ureter [29]. 8 years previously, during her pre-
menopausal years, the patient had undergone a total abdominal
hysterectomy and bilateral salpingo-oophorectomy (BSO) for uter-
ine fibroids and extensive pelvic endometriosis. Pelvic adhesions
involving the small bowel and right adnexa had been identified
at the time [29]. When surgical resection of the newly identi-
fied retroperitoneal mass was attempted, severe and extensive
endometriosis was once again identified, this time involving the
distal ileum, caecum, and inferior vena cava, with widespread adhe-
sions of the anterior abdominal wall, small bowel, sigmoid colon
and rectum [29].
In another report a 57 year-old woman who developed severe
and recurrent post-menopausal disease had already undergone a
hysterectomy and bilateral salpingo-oophorectomy (BSO) for con-
firmed endometriosis at the age of 35 [30]. It is possible that lesions
arising prior to the onset of the menopause might account for the
discovery of disease during the post-menopausal years, even in the
absence of a functioning endometrium providing a source of new
endometrial fragments. If all post-menopausal disease is indeed
associated with pre-menopausal disease, Sampson’s theory for the
pathophysiology of endometriosis [9] is not necessarily incompat-
ible.
There is, however, evidence to contradict this idea. Extensive
transmural intestinal endometriosis was discovered in a 74 year-
old woman presenting with symptoms of bowel obstruction, who
reported no premenopausal history of symptoms consistent with
endometriosis [31]. However, the patient had not undergone any
procedures during the pre-menopausal period, which could have
provided imaging or direct visualisation of the pelvic cavity prior
to the onset of the menopause. In another case, a 65 year-old
female who presented with haematuria and pelvic pain had devel-
oped post-menopausal vesical endometriosis, which was severe
and recurrent [32]. The patient had undergone a total abdominal
hysterectomy during the pre-menopausal years for uterine fibroids.
There was no mention of a diagnosis of endometriosis at the time;
however, this is not explicitly stated in the report [32]. It is therefore
possible that post-menopausal endometriosis might not be univer-
sally associated with pre-menopausal disease. However, as these
cases demonstrate, it is not always easy to establish a clear history
of pre-menopausal disease in affected women.
216 C.L. Bendon, C.M. Becker / Maturitas 72 (2012) 214–219
It has been suggested that endometriosis might be detected
laparoscopically in up to 7% of multiparous, asymptomatic women
[33]. Because the presence of endometriotic lesions can be symp-
tomless in some women, endometriosis can be an incidental
finding at surgery for other indications [33]. Therefore, if symp-
toms were to arise for the first time during the post-menopausal
years, a lack of pre-menopausal endometriosis might be incorrectly
assumed particularly in the absence of pre-menopausal investiga-
tions. Laparoscopic inspection of the pelvic cavity remains the gold
standard investigation for the diagnosis of endometriosis due to a
lack of biomarkers with sufficient sensitivity and specificity [34,35].
Women with post-menopausal disease who presented during the
premenopausal years with symptoms consistent with endometrio-
sis, but did not undergo laparoscopic investigation at the time, form
a group in whom pre-menopausal disease might be suspected but
cannot be confirmed retrospectively. Furthermore, while the natu-
ral history of endometriosis is poorly understood, there is strong
evidence to suggest that lesions might arise as a transient phe-
nomenon in some women [2,23]. The discovery of lesions in a
pre-menopausal woman does not guarantee their persistence up to
the age of onset of the menopause. Likewise the exclusion of pelvic
disease by laparoscopic visualisation at any given time does not
preclude the later development of lesions prior to the menopause.
Based on this evidence it is plausible that all observed cases of
post-menopausal endometriosis could have arisen in patients with
a pre-menopausal history of the disease.
1.3. Relationship to serum oestradiol levels
Regardless of the origins of the lesions themselves, endometrio-
sis is widely considered to be an oestrogen dependent disorder [6].
In women of reproductive age, cyclic ovarian oestradiol produc-
tion from circulating androstenedione and testosterone, catalysed
by granulosa cell aromatase activity, provides the major source
of serum oestrogen [6]. In the post-menopausal woman the skin
and adipose tissue become the main sites of oestrogen produc-
tion, once again catalysed by the aromatase enzyme, utilising
adrenal androstenedione as the substrate [6]. This endogenous
post-menopausal production is enhanced in obese individuals,
and may result in elevated serum oestradiol levels [6]. Additional
sources of endogenous oestrogen during the post-menopausal
years may include oestrogen-producing ovarian tumours [7]. Post-
menopausal women might also be exposed to exogenous oestrogen
sources, classically from hormone replacement therapy (HRT) and
phyto-oestrogens [7].
A clear source of excessive oestrogen has been identified in
several cases of post-menopausal endometriosis. A prospective
randomised study of 172 women implies a link between HRT
and post-menopausal disease recurrence. All women included in
the study had histological confirmation of endometriosis, and had
all undergone surgery for BSO, leading to a surgically induced
menopause [36]. Of the 172 women included, 115 were randomly
allocated to receive HRT in the form of controlled-release trans-
dermal oestradiol patches at a dose of 50␮g/day, and an orally
administered progesterone. All women underwent 6 month follow-
up by clinical examination, hormonal evaluation and transvaginal
ultrasound. Although statistical significance was not reached, of the
women allocated to receive HRT the incidence of endometriosis
recurrence was 0.91 per 100 woman years compared to a com-
plete lack of disease recurrence in the non-HRT controls [36]. Risk
factors for post-menopausal disease appeared to include previous
severe peritoneal disease and failure to perform total hysterectomy
at the time of BSO, the latter reaching statistical significance [36].
Taken together the evidence suggests a link between residual pre-
menopausal lesions and post-menopausal recurrence under HRT
stimulation. However it is important to mention that although
women included in the study were subject to 6-month hormonal
evaluation, mean serum oestradiol levels were not published in
the report [36]. Further to this, repeat laparoscopy, not ultrasound,
would be considered the gold standard for detecting disease recur-
rence [34] as lesions on the peritoneum might have been missed by
ultrasound alone. However, there are clearly ethical considerations
precluding the exposure of these women to an invasive procedure
such as a diagnostic laparoscopy.
It is possible that excessive endogenous oestrogen might also
play a causative role in post-menopausal endometriosis. A 69 year-
old female presenting with pelvic pain, constipation and weight
loss of 30 kg was discovered to have a sigmoid colon endometrioma.
The disease appeared to involve the uterus and bladder and was
managed surgically by colonic resection and a hysterectomy [37].
At the time of diagnosis the patient’s body mass index (BMI) was
within normal limits, while prior to the recent weight loss her BMI
had been 31.6. Analysis of the endometrium following uterine exci-
sion revealed evidence of pseudocystic hyperplasia consistent with
residual oestrogen stimulation [37]. However due to the nature of
her advanced disease and significant associated weight loss, evi-
dence of prior exposure to excessive endogenous oestrogen could
not be confirmed by serum oestradiol levels at the time of presen-
tation.
A case of post-menopausal cutaneous endometriosis in a 58
year-old female receiving HRT over a five year period challenges
a direct causative link between excessive oestrogen exposure and
post-menopausal disease. The woman had been postmenopausal
for 8 years, and had been exposed to 625 ␮g of oestrogen daily
over the latter 5 years, which she had been taking for the relief of
post-menopausal symptoms [38]. Three years prior to presentation
she had undergone a total abdominal hysterectomy and BSO for an
ovarian cystic teratoma and chronic cervicitis. She later developed
several erythematous plaques and papules on her back, confirmed
to be endometriosis on histological analysis [38]. Although the
cutaneous lesions resolved spontaneously within one month of ces-
sation of HRT, there was no evidence of disease recurrence within
6 months of re-starting hormone therapy [38].
Endometriotic lesions classically arise on the ovaries and pelvic
peritoneum, but reports of endometriosis in extra-pelvic locations
including the bowel, renal tract, the abdominal wall, lung and
pleura are relatively common [39]. In fact extra-pelvic disease
is thought to occur in up to 12% of cases of endometriosis [38].
Given the lack of continuity of these sites with the pelvic cavity,
the discovery of extra-pelvic disease is considered a contradiction
of Samson’s theory of retrograde menstruation and implantation
[9]. If cases of extra-pelvic endometriosis also arise during the
post-menopausal years, it is conceivable that post-menopausal,
and likewise pre-menopausal disease, does not rely on a function-
ing endometrium at any stage. If so, it is possible that another
theory for the pathophysiology of endometriosis is more compati-
ble. For example the coelomic metaplasia hypothesis suggests that
mesothelial cells of the ovary and peritoneal cavity may undergo
metaplasia to form endometrial-like tissue [40] perhaps under the
influence of hormonal stimulation [41]. However this theory could
only account for disease arising on the ovaries and peritoneal serosa
[42] and could not explain other forms of extra-pelvic disease.
Alternatively it has been suggested that endometrial tissue
from the uterine cavity might be transported to distant sites via
the veins or lymphatics [8,9], perhaps accounting for other extra-
pelvic manifestations of endometriosis, such as cutaneous deposits.
In fact, endometriotic lesions have been detected in the pelvic
lymph nodes of women with severe disease [43,44] suggesting
the possibility that dissemination of eutopic endometrium via
the lymphatics might contribute to disease spread. This theory,
however, still appears to rely on the presence of a function-
ing endometrium. Intriguingly, in the case of post-menopausal
 C.L. Bendon, C.M. Becker / Maturitas 72 (2012) 214–219
cutaneous endometriosis in a 58 year-old discussed previously [38],
the patient had undergone a total hysterectomy and BSO three
years prior to the appearance of the lesions. If endometriosis does
arise secondary to venous or lymphatic transport of endometrial
fragments, it is possible that the development of post-menopausal
cutaneous disease could have been the result of dissemination of
the endometrium at the time of the previous surgery [38]. Regard-
less of the origins of these lesions, the persistence of endometriotic
deposits is generally considered to be oestrogen dependent [6].
None of the theories discussed so far can therefore account for the
presence of active disease in the absence of serum oestradiol levels
in excess of the normal post-menopausal range [29,38].
1.4. Role of local oestrogen production
There is however new evidence to suggest that locally pro-
duced oestrogen plays a significant role in the pathophysiology
of endometriosis, perhaps negating the requirement for elevated
circulating oestrogen levels during the post-menopausal years [6].
High levels of aromatase and StAR expression and enzyme activ-
ity have been demonstrated in cultured stromal cells derived from
endometriotic lesions, and it has been suggested that PGE2 produc-
tion might further enhance localised oestrogen syntheses [8,19,20].
This is likely to form a positive feedback loop, whereby oestrogen
produced within lesions further promotes proliferation and dis-
ease progression through autocrine and paracrine effects, resulting
in more inflammation and localised PGE2 production, thus further
enhancing oestrogen synthesis [6,19]. If this picture is accurate,
it is possible that endometriosis is a self-perpetuating condition,
the lesions themselves driving local oestrogen production and dis-
ease progression, even in the absence of elevated serum oestradiol
as the stimulus. It is therefore conceivable that post-menopausal
disease might arise in cases where pre-menopausal lesions persist
and remain active into the post-menopausal years via local mech-
anisms and paracrine effects. This theory might explain cases of
post-menopausal endometriosis where a source of excessive cir-
culating oestrogen cannot be identified [32,45].
In keeping with this idea, it appears that aromatase
inhibitors provide an effective treatment for post-menopausal
endometriosis [6,22]. In the case of a 61 year-old, obese post-
menopausal female presenting with recurrent abdominal wall
endometriosis, serum oestradiol concentrations were found to
be elevated in excess of the normal postmenopausal range
at 39 pg/ml (pre-menopausal > 20 pg/ml), while FSH levels were
consistent with the post-menopausal status at 44 mIU/ml (pre-
menopausal < 40 mIU/ml) [22,29]. Following aspiration of the
abdominal wall endometrioma, oestradiol concentrations within
the cystic fluid of the lesion itself were recorded. Local oestra-
diol levels within the aspirate were found to be elevated in excess
of circulating oestradiol, at 89 pg/ml [22]. Initial treatment with
the aromatase inhibitor letrozole administered orally at 5 mg/day
resulted in a decrease in cystic fluid oestradiol levels to 28 pg/ml
[22]. Following 4 weeks of treatment with the aromatase inhibitor
(with the addition of medroxyprogesterone acetate at 10 mg/day
PO during the final week) the abdominal wall lesion had reduced
significantly in size and could be fully reduced following aspira-
tion, while serum and cystic fluid oestradiol levels had decreased
to <20 pg/ml and 22 pg/ml respectively [22]. This case demon-
strates the potential relevance of local oestradiol production in
post-menopausal endometriosis and, related to this, the efficacy
of aromatase inhibitors in treating post-menopausal disease.
2. Conclusion
Endometriosis is a common gynaecological disorder, which has
traditionally been considered a disease of the pre-menopausal
217
years [7]. For pelvic disease alone three clinically distinct forms
have been described, including superficial implants on the pelvic
peritoneum and ovaries, ovarian endometriotic cysts, and recto-
vaginal nodules [8]. Further to this, rare extra-pelvic disease has
been reported in the literature [39]. Of the theories proposed so
far, there is not a single one that is capable of explaining the
pathophysiology of endometriosis given all of its various forms
and presentations [4,5]. In fact it has even been suggested that the
three forms of pelvic endometriosis might arise through separate
pathophysiological mechanisms [4].
Reports of endometriosis developing during the post-
menopausal years have added to the confusion and controversy.
While our understanding of many pathomechanisms of pre-
menopausal endometriosis still remains elusive, it is virtually
non-existent for post-menopausal disease. Since we have not yet
determined a single mechanism for pre-menopausal disease, it
is highly unlikely that one single theory could account for the
post-menopausal lesions described. It is important to note that the
chronic pain symptoms associated with endometriosis appear to
correlate poorly with laparoscopic determinants of disease extent
[46]. Additionally it has been suggested that endometriosis might
be detected laparoscopically in up to 7% of fertile, multiparous,
asymptomatic females [33]. It is therefore conceivable that all cases
of post-menopausal disease could be preceded by pre-menopausal
lesions [29] regardless of whether the disease was symptomatic at
the time, or indeed confirmed by imaging or histology.
Further to this it is possible that once established, endometrio-
sis is a self-perpetuating condition. Local oestradiol production
by the endometriotic lesions might drive further disease activity
through autocrine and paracrine effects [6], despite the relatively
low circulating oestradiol levels of the menopause. It is conceiv-
able that this process might be further enhanced and accelerated in
post-menopausal women exposed to relatively higher levels of cir-
culating oestrogen, particularly in the form of HRT [36,47]. There is
data to suggest that rates of disease recurrence are not substantially
increased among women with endometriosis who are managed
surgically with bilateral oophorectomy and subsequently receive
low-dose HRT in order to provide bone protection and alleviate
adverse effects associated with the surgical menopause [48]. Fur-
ther to this there is evidence to suggest that various tissues differ
in their sensitivity to oestrogen, implying that a dose of oestrogen
sufficient to provide bone protection would not necessarily be high
enough to reactivate endometriosis [48,49]. This concept forms the
basis of the ‘oestrogen threshold theory’ [48]. According to this evi-
dence it is possible that a threshold dose of oestrogen exists, above
which endometriotic lesions might be stimulated and potentially
re-activated in postmenopausal women receiving HRT.
Finally, although normally considered a benign disorder, studies
suggest that endometriosis has the potential for malignant trans-
formation in some cases [50]. In particular low grade ovarian cancer
such as the clear cell and endometrioid subtypes are though to
be associated with endometriosis [51]. There is some evidence to
suggest that rates of malignancy associated with endometriosis
could be enhanced in cases of post-menopausal disease arising in
women who have also been exposed to HRT [47,52,53]. There is
clearly a need to improve our understanding of the pathophysio-
logical mechanisms involved, and the risk factors associated with
post-menopausal endometriosis. This should enable appropriate
decisions to be made regarding the use of HRT in post-menopausal
women with a prior history of endometriosis, and the appropriate
management of cases of confirmed post-menopausal disease [47].
Funding source
This work was supported by an MRC New Investigator Award
(G0601458; C.M.B.) and the Oxford Partnership Comprehensive
218 C.L. Bendon, C.M. Becker / Maturitas 72 (2012) 214–219
Biomedical Research Centre with funding from the Department of
Health’s NIHR Biomedical Research Centres scheme (C.M.B.).
The funding source had no role in writing the paper.
Contributors
C.L.B. and C.M.B. wrote the paper and approved the final version.
Competing interests
No conflicts of interest to declare.
Provenance and peer review
Commissioned and externally peer reviewed.
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