Ann. N.Y. Acad. Sci.

ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S
Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases I

Aromatase and endometriosis: estrogens play a role

Simone Ferrero,1 Valentino Remorgida,1 Carlo Maganza,1 Pier Luigi Venturini,1
Stefano Salvatore,2 Enrico Papaleo,2 Massimo Candiani,2 and Umberto Leone Roberti
Maggiore2
1
Department of Obstetrics and Gynecology, San Martino Hospital and National Institute for Cancer Research, University of
Genoa, Genoa, Italy. 2 IRCCS San Raffaele Hospital and Vita-Salute, San Raffaele University Hospital, Department of
Obstetrics and Gynecology, Milan, Italy

Address for correspondence: Simone Ferrero, M.D., Ph.D., Department of Obstetrics and Gynecology, San Martino Hospital
and National Institute for Cancer Research, University of Genoa, Largo R. Benzi 1, 16132 Genoa, Italy. [email protected]

Endometriosis is an estrogen-dependent inflammatory disease defined by the growth of endometrial stroma and
glands outside of the uterus. Epidemiological and clinical studies show that estrogen is essential for the growth of
endometriosis. There are several molecular links between estrogen production and inflammation in endometriosis.
The enzyme aromatase P450 is expressed aberrantly in endometriosis and is stimulated by prostaglandin E2 , resulting
in production of estrogen that induces prostaglandin E2 expression within endometriotic lesions. Furthermore,
estrogen promotes the secretion of several inflammatory cytokines and growth factors, which contribute to the
progression of endometriosis and stimulate estrogen production. On the basis of the local estrogen biosynthesis
in endometriotic implants, nonsteroidal aromatase inhibitors have been successfully used to treat pain symptoms
caused by endometriosis. These agents do not cause the disappearance of endometriosis; they cannot be considered
routine treatment and should only be administered in adequately controlled clinical studies.

Keywords: aromatase; endometriosis; estrogen; inflammation

Introduction bances) or less severe disturbances mimicking ir-

ritable bowel syndrome. Endometriosis is also as-
Endometriosis is a benign gynecological disease
sociated with infertility. In fact, endometriosis not
characterized by the presence of endometrium-like
only causes anatomic distortion of the pelvic vis-
tissue outside the uterine cavity. Endometriotic le-
cera and fallopian tubes, but it may also affect
sions may have various locations; they are found
the quality of oocytes and endometrial receptiv-
more frequently on the pelvic peritoneum, ovaries,
ity, impair the ciliary activity of the fallopian tubes,
and uterosacral ligaments, and in the rectovaginal
and promote alterations to the peritoneal immune
septum and vesico-uterine fold; they are found more
environment.
rarely in the bowel, diaphragm, umbilicus, peri-
The most widely accepted theory on the patho-
cardium, pleura, and even in the brain. Severe dis-
genesis of endometriosis is the retrograde menstru-
ease may result in deformation of pelvic anatomy
ation theory. In the mid-1920s, Sampson noticed
and extensive pelvic adhesions. Endometriosis is
the low frequency of endometriosis in amenorrheic
typically associated with pelvic pain and infertility;
or hysterectomized women, and observed the retro-
however, women with endometriosis may some-
grade menstrual reflux.1 On the basis of these obser-
times be asymptomatic. Pelvic symptoms include
vations, he proposed that endometriosis originates
dysmenorrhea, dyspareunia, noncyclic lower ab-
from retrograde menstruation of viable endometrial
dominal pain, lower back pain, and dyschezia. Deep
tissue through the fallopian tubes into the peritoneal
endometriotic lesions infiltrating the bowel wall
cavity where it implants on the peritoneal surface
cause gastrointestinal symptoms (e.g., obstructive
or pelvic organs.1 However, retrograde menstrua-
symptoms, severe pain, and heavy transit distur-
tion is a frequent event in all women;2 therefore,
doi: 10.1111/nyas.12411
Ann. N.Y. Acad. Sci. 1317 (2014) 17–23 
C 2014 New York Academy of Sciences. 17
Aromatase and endometriosis Ferrero et al.

endometriosis is believed to be caused by molecular Since the late 1990s, studies using polymerase
abnormalities that influence hormonal regulation chain reaction (PCR) and immunohistochem-
and inflammation. istry showed that the P450arom is expressed in
both eutopic and ectopic endometrium of pa-
Estrogen and aromatase in endometriosis
tients with endometriosis, while this enzyme is
Both epidemiological and clinical studies show not detectable in eutopic endometrium obtained
that estradiol (E2 ) plays a paramount role in from healthy women and in endometriosis-free
the maintenance of endometriosis. Endometrio- peritoneal tissue.9–13 Androstenedione of adrenal
sis affects at least 3.6% of women during the re- and ovarian origin is the primary substrate for
productive phase of life,3 while it regresses after P450arom activity that catalyzes its conversion to
menopause.4 However, the administration of hor- E1 in endometriotic tissue. Subsequently, E1 is con-
mone replacement therapy may cause relapse of verted to E2 by the activity of 17␤-hydroxysteroid
the disease in postmenopausal women.5 In pre- dehydrogenase 1. P450arom expression in en-
menopausal women, the suppression of E2 levels dometriosis is regulated by the nuclear receptor SF-
derived by gonadotropin-releasing hormone ana- 1, which is almost absent in normal endometrium
logues (GnRH-a) causes regression of endometri- and is highly expressed in endometriosis.14 The in-
otic lesions and improvement of pain symptoms; creased production of E2 in endometriotic lesions
however, the recovery of E2 levels after discontinu- is in line with the observation that higher concen-
ation of the therapy is associated with relapse of the trations of E2 have been detected in the peritoneal
disease.6 fluid of women with endometriosis than in that of
There are three mechanisms of E2 produc- normal controls.15 A recent study reported that the
tion during reproductive ages in women with endometrial and endometriotic tissue E2 levels do
endometriosis.7 Obviously, E2 is mainly produced not reflect corresponding serum concentrations.16
by the ovary in a cyclic fashion. E2 is secreted by During the proliferative phase, the local E2 con-
the preovulatory follicle when follicle-stimulating centration in the endometrium is higher than in
hormone (FSH) binds to its G protein–coupled serum samples, suggesting active local E2 produc-
receptor in the granulosa cell membrane; activa- tion. On the other hand, during the secretory phase
tion of the receptor causes an increase in intra- of healthy patients, the local E2 concentrations are
cellular cyclic adenosine monophosphate (cAMP), higher in serum, suggesting local inactivation of E2
which enhances the binding of two transcription in endometrium, shifting from an E2 -dominating
factors, steroidogenic factor-1 (SF-1) and cAMP proliferative phase to an E1 -dominating secretory
response element–binding protein (CREB) to the phase. Among patients with endometriosis, E2 lev-
promoter of the aromatase gene.8 Therefore, E2 els predominate over those of E1 throughout the
reaches endometriotic lesions by circulation. Fur- whole menstrual cycle. Therefore, the inhibition of
thermore, follicular rupture during ovulation causes local E2 synthesis plays a key role in decreasing local
the spillage of E2 directly onto pelvic endometriotic E2 concentrations in endometriosis lesions.16
implants. There are two rate-limiting steps in the The effects of E2 are mediated through the es-
production of E2 : the entry of cholesterol into the trogen receptors ␣ (ER-␣) and ␤ (ER-␤), which
mitochondrion, facilitated by steroidogenic acute are encoded by separate genes located on different
regulatory protein (StAR), and the conversion of an- chromosomes. Although both ER-␣ and ER-␤ are
drostenedione to estrone (E1 ), which is performed expressed in the eutopic endometrium, ER-␣ seems
by the aromatase P450 (P450arom). In addition, to be the most important mediator of estrogenic ac-
in peripheral tissues (such as fat, skin, and skele- tivity in this tissue.17 Endometriotic lesions express
tal muscle) there is conversion of circulating an- ERs and can undergo cyclical changes that, however,
drostenedione of adrenal origin to E1 , which reaches do not proceed as clearly or as uniformly as in the eu-
endometriosis via circulation and is converted lo- topic endometrium. Several studies investigated the
cally to E2 . Finally, while the normal endometrium expression of the two ER isoforms in the eutopic en-
does not biosynthesize E2 , endometriotic stromal dometrium and ectopic lesions of patients with en-
cells express the full enzymatic cascade required for dometriosis, using immunohistochemical staining
the production of E2 from cholesterol. and PCR. These studies reported higher expression

18 Ann. N.Y. Acad. Sci. 1317 (2014) 17–23 

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Ferrero et al. Aromatase and endometriosis

levels of ER-␤ and lower levels of ER-␣ in en- were proposed for the treatment of endometriosis.30
dometriotic tissue.18–20 Deficient methylation of the However, a randomized placebo-controlled trial
ER-␤ promoter and other accompanying epigenetic showed that raloxifene significantly shortens the
mechanisms may result in pathological overexpres- time to return of chronic pelvic pain after surgery
sion of ER-␤ in endometriotic stromal cells.20 High for endometriosis.31
levels of ER-␤ suppress ER-␣ expression.21 A study
Molecular links between inflammation and
using reverse transcription PCR (RT-PCR) quanti-
estrogen production in endometriosis
fied the mRNA levels of nuclear receptors in primary
endometrial and endometriotic stromal cells.21 E2 promotes inflammation in endometriosis
ER-␣ mRNA levels were found to be significantly (Fig. 1), and E2 not only has direct actions on
lower in endometriotic stromal cells compared with the endometrial or endometriotic tissues but also
endometrial stromal cells. ER-␤ mRNA was found has indirect actions on the inflammatory cells
to be significantly more expressed in endometri- within the peritoneal fluid. Under the influence
otic stromal cells, whereas it was much lower or of E2 , activated peritoneal fluid macrophages se-
nearly absent in endometrial stromal cells.22 In con- crete cytokines and growth factors (VEGF, HGF, and
trast with these observations, only one study group TNF-␣), which contribute to the development and
described a predominant expression of ER-␣ in persistence of endometriosis.26,32,33 Furthermore,
both glandular epithelial and stromal endometri- macrophage migration inhibitory factor (MIF)—
otic cells.23–25 a multifunctional cytokine with proinflamma-
Studies using RT-PCR showed that peritoneal tory, immunomodulatory, and growth-promoting
fluid macrophages of women with endometriosis effects—is expressed in endometriotic lesions34
contain the mRNA encoding ER-␣ and ER-␤.26,27 and has higher levels in the peripheral blood,35
More recently, it has been observed that peritoneal fluid,36 and eutopic endometrium37 of
macrophages obtained from peritoneal fluid of women with endometriosis compared with con-
women with endometriosis express significantly trols. There is a positive feedback loop between E2
higher levels of both ER subtypes than those ob- and MIF; E2 acts directly on ectopic endometrial
tained from women without the disease.28 Fur- cells to upregulate the expression of MIF, which, in
thermore, ER-␣ expression in peritoneal fluid turn, induces the expression of P450arom. The bi-
macrophages is positively correlated with the ex- ological effect of E2 on endometriotic stromal cells
pression of inflammatory cytokines (IL-1␤, IL-6, is mediated via binding and activation of ER-␣ and
TNF-␣) in women with endometriosis but not in ER-␤. Increasing the expression of either ER-␣ or
controls. In contrast, ER-␤ is positively correlated ER-␤ enhances E2 -mediated MIF expression in en-
with the expression of inflammatory cytokines both dometriotic cells, but a statistically significant in-
in women with and without endometriosis.29 crease in MIF expression in response to E2 is ob-
Some researchers tried to modulate or interfere served only with ER-␤.38
with ERs in order to develop new pharmacologic In endometriotic lesions, there is a positive
agents providing more efficacious therapeutic al- feedback loop between E2 and prostaglandin E2
ternatives and more acceptable side effects. Harris (PGE2 ) production. The enzyme cyclooxygenase
et al. observed that ERB-041, a highly selective ER- (COX) catalyzes the conversion of arachidonic
␤ agonist, causes the regression of 40–75% of en- acid to prostaglandin G2 (PGG2 ), which is then
dometriotic lesions in the nude mice model. This converted to PGE2 by the enzyme PGE2 synthase.
agent appears to be equally effective in gonad-intact Two distinct genes, referred to as COX-1 and
as in ovariectomized mice, suggesting that endoge- COX-2, encode the COX enzyme. COX-2 is
nous levels of E2 do not block the activity of an an inducible gene that is regulated by a whole
exogenous selective ER-␤ agonist. ERB-041 is in- host of factors; in particular, E2 stimulates the
active on classic estrogenic targets, but it has po- expression of COX-2 enzyme, thus increasing the
tent anti-inflammatory activity. Selective estrogen production of PGE2 . Therefore, in endometriotic
receptor modulators (SERMs) have tissue-selective stroma, COX-2 is upregulated in comparison with
agonist or antagonist activities and, on the basis normal endometrium.39 PGE2 is the most potent
of findings from studies with animal models, they stimulator of the expression of P450arom and other

Ann. N.Y. Acad. Sci. 1317 (2014) 17–23 

C 2014 New York Academy of Sciences. 19
Aromatase and endometriosis Ferrero et al.

Figure 1. Molecular pathways between inflammation and estrogen production in endometriosis.

steroidogenic genes, such as StAR, side-chain cleav- E2 activity, and have been shown to be associated
age (P450scc), 3␤-hydroxysteroid dehydrogenase with reduced peritoneal inflammation45–48 and
(HSD) type 2, and 17-hydroxylase/17–20-lyase decreased antibody titers.49 Aromatase expression
(P450c17), in endometriotic stromal cells.13 The and local E2 biosynthesis in endometriotic implants
PGE2 -dependent stimulation is higher for StAR prompted several investigators to target this
and P450arom compared with other steroidogenic enzyme in endometriosis using third-generation
genes.40 Although endometriotic stromal cells ex- nonsteroidal (type II) aromatase inhibitors (AIs),
press various subtypes of PGE2 receptors (EP1 , EP2 , such as anastrozole and letrozole. These drugs have
EP3 , EP4 ), only EP2 receptor is responsible for the been used to treat various forms of endometriosis,
PGE2 -mediated expression of StAR and P450arom including ovarian cysts,50,51 and rectovaginal,52,53
in endometriotic stromal cells.41 The activation bladder,54 and intestinal nodules.55,56 Ten years ago,
of EP2 causes a rapid increase in intracellular the first study suggested that AIs not only improve
cAMP.13 pain symptoms but also cause the disappearance
With regard to another link between inflam- of endometriotic lesions.57 Although subsequent
mation and E2 production, E2 regulates the syn- studies confirmed the beneficial effects of AIs on
thesis and secretion of a potent chemotactic pain symptoms,58 they also showed that endometri-
and activating factor for monocytes/macrophages otic lesions do not disappear during treatment50,52
(monocyte chemotactic protein-1, MCP-1) in en- and that pain symptoms quickly recur after dis-
dometrial cells of women with endometriosis.42 Fur- continuation of treatment.58,59 In premenopausal
thermore, IL-1␤, which is produced by peritoneal women, some form of ovarian suppression needs
fluid macrophages in women with endometriosis, to be added to AIs; otherwise, E2 depletion in
induces COX-2 in endometriotic and endometrial the hypothalamus causes FSH secretion, ovarian
stromal cells;43 this pathway further increases E2 lev- stimulation, and the development of functional
els in endometriotic tissue. Similarly, E2 stimulates ovarian cysts.60,61 Thus, AIs are administered
VEGF production by nonactivated and activated together with oral combined contraceptive pill,
macrophages, and VEGF induces COX-2 expres- progestin, or GnRH-a.52 No published study has
sion in uterine endothelial cells,44 thus promoting reported severe adverse effects associated with the
E2 production. administration of AIs to premenopausal women
with endometriosis. However, patients may suffer
Use of aromatase inhibitors to treat
bone and joint pain, muscle aches, and fatigue,
endometriosis
which may not be easily tolerated by young women
Conventional medical treatments of endometriosis suffering a benign disease. On the basis of these con-
aim to induce a hypoestrogenic state or to mitigate siderations, AIs should be administered to women

20 Ann. N.Y. Acad. Sci. 1317 (2014) 17–23 

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Ferrero et al. Aromatase and endometriosis

with endometriosis only in the setting of scientific 2. Halme, J., M.G. Hammond, J.F. Hulka, et al. 1984. Retro-
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combination with ovarian-suppressing agents have
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Conflicts of interest are determined by local metabolism rather than circulating
levels. J. Clin. Endocrinol. Metab. 97: 4228–4235.
The authors declare no conflicts of interest. 17. Brandenberger, A.W., D.I. Lebovic, M.K. Tee, et al. 1999. Oe-
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