European Journal of Obstetrics & Gynecology and
Reproductive Biology 122 (2005) 144–150
www.elsevier.com/locate/ejogrb
Invited review
Aromatase inhibitors and cyclooxygenase-2 (COX-2) inhibitors
in endometriosis: New questions—old answers?
Andreas D. Ebert a,*, Julia Bartley a, Matthias David b
a
Charité Endometriosis Research Center Berlin, Department of Gynecology, Charité-Universitätsmedizin Berlin,
Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
b
Department of Obstetrics and Gynecology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Germany
Received 7 February 2005; received in revised form 14 April 2005; accepted 28 April 2005
Abstract
The medical treatment of endometriosis needs to be optimized. Therapeutic management strategies for endometriosis-associated pain or
recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial
implants. In this context, basic research is providing important results for the development of new, specific treatment modalities. Aromatase
overexpression has recently been detected in endometriotic tissue. Aromatase (p450arom) is responsible for converting C19 androgens into
estrogen in several types of human tissue. Aromatase activity causes local estrogen biosynthesis, which, in turn, stimulates prostaglandin E2
production by upregulating cyclooxygenase-2 (COX-2). Thus, a positive feedback cycle develops between the two systems. Another
abnormality in endometriosis, the deficient 17b-hydroxysteroiddehydrogenase type II (17b-HSD-Type-II) expression, impairs the inactiva-
tion of estradiol to estrone. In contrast to the eutopic endometrium, these molecular aberrations increase the amount of local estradiol and
prostaglandin E2 in endometriosis. In several human cell lines, prostaglandin and estrogen concentrations are associated with proliferation,
migration, angiogenesis, apoptosis resistance and even invasiveness. Consequently, aromatase and COX-2 are thought to be promising new
therapeutic targets. Thus, specific aromatase inhibitors (e.g. Letrozol/Femara1, Anastrozol/Arimidex1 or Exemestan/Aromasin1) or
selective COX-2 inhibitors (e.g. Celecoxib/Celebrex#, Rofecoxib/Vioxx#, Valdecoxib/Bextra#) are of great interest and should be studied in
clinical trials in premenopausal woman with endometriosis to expand the spectrum of currently available treatment options.
# 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Endometriosis; Aromatase p450; Cyclooxygenase-2; Estradiol; Prostaglandin
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2. New concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3. Aromatase and aromatase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3.1. Clinical data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3.2. Clinical problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
4. Cyclooxygenase-2 expression and COX-2 inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
1. Introduction
Drug treatment options in endometriosis are unsatisfac-
* Corresponding author. Tel.: +49 30 8445 2593; fax: +49 30 8445 4477. tory especially in the case of recurrence. New approaches to
E-mail address: (A.D. Ebert). optimize therapy are urgently needed. Taken together, the
0301-2115/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejogrb.2005.04.017
, A.D. Ebert et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 122 (2005) 144–150 145
following treatment strategies are currently available: open [35,55], which leads to a local increase in estrone and
or laparoscopic resection of endometriotic lesions including estradiol. Since there is no 17b-HSD-Typ2 activity in the
adhesiolysis and reconstruction of the pelvic anatomy, the secretion phase, progesterone is not stopping the estrogen-
use of GnRH analogues or GnRH antagonists, the dependent proliferation in endometriotic tissue. Thus, in
application of gestagens or their derivatives, oral contra- contrast to eutopic endometrium, transformation and
ceptives in the cyclic or nonstop mode (long-term cycle), desquamation are incomplete in endometriotic tissue
danazol, nonselective nonsteroidal antiphlogistics, and/or [62]. Moreover, it was shown that only the progesterone
the combination of treatment [9,33,57,58]. receptor A (PR-A) is expressed in endometriotic lesions,
while PR-B is found in eutopic endometrium as well
[3,35,47].
2. New concepts Furthermore, important steps in the molecular regulation
of the CYP19 gene (p450arom) have been described
In recent years, fresh impetus has been given to [12,14,15,35]. Simply, it can be assumed that the stimulating
endometriosis research by the in vitro detection of invasive transcription factor steroidogenic factor-1 (SF-1) competes
properties of endometriosis cells [30], by studies on with the inhibiting factor chicken ovalbumin upstream
angiogenesis [66], cytokines and chemokines, growth promotor transcription factor (COUP-TF), a dimer, for the
factors and steroid receptor modulators, by developments same DNA binding site of the aromatase promotor II
in genomics and proteonomics, and by establishing the [12,14,15]. While COUP-TF can be detected in both the
archimetra concept [27,47,48,50]. Numerous new and eutopic endometrium and endometriotic tissue, SF-1 is
treatment approaches developing out of basic research are obviously only expressed in endometriotic tissue. As a
currently being tested in clinical studies in different phases: result, SF-1 binds more often to the aromatase promotor II,
gonadotropin-releasing hormone antagonists, antigestagens which leads to the initiation of aromatase gene transcription
and selective progesterone receptor modulators, estrogen in endometriotic tissue. In the normal endometrium, only
receptor b-agonists, angiogenesis inhibitors, matrix metal- COUP-TF binds to the promotor and thus inhibits
loproteinase inhibitors, immunomodulators and TNF-a transcription. These processes are accompanied by the
inhibitors, aromatase inhibitors, and cyclooxygenase-2 interaction of the PGE2-induced cAMP with other co-
inhibitors [50,56,57]. repressors/stimulators [12]. The differential modulation of
Against this background, the detection of aromatase [12– SF-1 or COUP-TF expression may thus offer a perspective
15] and COX-2 overexpression [4,17,24,59] in endome- genetic treatment approach to the therapy of endometriosis.
triosis tissue seems to be important and extensively In this connection, it must be remembered that successful
developed clinically, since it appears for the first time that detection of aromatase expression (p450arom) in experi-
there are molecular targets for causal therapeutic mental ectopic endometriotic lesions was accomplished in a
approaches, whose clinical value will be clarified in primate model. Aromatase expression was, however, only
controlled, prospective randomized studies. evident 10 months after intraperitoneal inoculation of the
endometrium (menstruation phase), which may provide
information about the biology of aromatase metabolism in
3. Aromatase and aromatase inhibitors the sense of a survival pathway [25,41].
Modern steroidal and nonsteroidal aromatase inhibitors 3.1. Clinical data
(e.g. Letrozole1, Arimidex1 and Exemestan1) have been
intensively examined and are now an integral part of the As a clinical consequence of the human aromatase
endocrine therapy of postmenopausal breast cancer model (Fig. 1), the application of specific aromatase
[6,34,44,61]. inhibitors appeared relatively early as a new and causal
Recently the overexpression of aromatase [54,55] and a therapeutic approach under study conditions in patients
deficiency of 17b-hydroxysteroid dehydrogenase type 2 with extensive endometriosis (e.g. stages rASRM III
(17b-HSD-Typ2) were also detected in endometriosis tissue and IV) [22]. However, a problem was and still remains
[71,72]. Thus, the following pathophysiological model that endometriosis patients are women usually at the
requiring further evaluation seems to arise for endometriosis reproductive stage, who may still want to have a child or
[35]. In the eutopic endometrium, estrone is converted into who have not yet definitively completed their family
estradiol (E2) by 17b-hydroxysteroid dehydrogenase type I planning [61,64].
(17b-HSD-Typ1). A steady state between estradiol and Significant findings with the use of aromatase inhibitors
estrone is ensured by 17b-HSD-Typ2, which, in turn, converts in premenopausal breast cancer patients have not yet been
estradiol into estrone. On the other hand, 4-androsten-3, published, which is the reason why aromatase inhibitors
17-dion and testosterone are aromatized to estrone or estradiol have also not been approved for this patient group.
by the enzyme aromatase (p450arom). An overexpression Consequently, the aromatase concept was initially tested
of aromatase was detected in endometriotic lesions in one of the rare postmenopausal patients with aggressive
Reproductive Biology 122 (2005) 144–150
www.elsevier.com/locate/ejogrb
Invited review
Aromatase inhibitors and cyclooxygenase-2 (COX-2) inhibitors
in endometriosis: New questions—old answers?
Andreas D. Ebert a,*, Julia Bartley a, Matthias David b
a
Charité Endometriosis Research Center Berlin, Department of Gynecology, Charité-Universitätsmedizin Berlin,
Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
b
Department of Obstetrics and Gynecology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Germany
Received 7 February 2005; received in revised form 14 April 2005; accepted 28 April 2005
Abstract
The medical treatment of endometriosis needs to be optimized. Therapeutic management strategies for endometriosis-associated pain or
recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial
implants. In this context, basic research is providing important results for the development of new, specific treatment modalities. Aromatase
overexpression has recently been detected in endometriotic tissue. Aromatase (p450arom) is responsible for converting C19 androgens into
estrogen in several types of human tissue. Aromatase activity causes local estrogen biosynthesis, which, in turn, stimulates prostaglandin E2
production by upregulating cyclooxygenase-2 (COX-2). Thus, a positive feedback cycle develops between the two systems. Another
abnormality in endometriosis, the deficient 17b-hydroxysteroiddehydrogenase type II (17b-HSD-Type-II) expression, impairs the inactiva-
tion of estradiol to estrone. In contrast to the eutopic endometrium, these molecular aberrations increase the amount of local estradiol and
prostaglandin E2 in endometriosis. In several human cell lines, prostaglandin and estrogen concentrations are associated with proliferation,
migration, angiogenesis, apoptosis resistance and even invasiveness. Consequently, aromatase and COX-2 are thought to be promising new
therapeutic targets. Thus, specific aromatase inhibitors (e.g. Letrozol/Femara1, Anastrozol/Arimidex1 or Exemestan/Aromasin1) or
selective COX-2 inhibitors (e.g. Celecoxib/Celebrex#, Rofecoxib/Vioxx#, Valdecoxib/Bextra#) are of great interest and should be studied in
clinical trials in premenopausal woman with endometriosis to expand the spectrum of currently available treatment options.
# 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Endometriosis; Aromatase p450; Cyclooxygenase-2; Estradiol; Prostaglandin
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2. New concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3. Aromatase and aromatase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3.1. Clinical data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3.2. Clinical problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
4. Cyclooxygenase-2 expression and COX-2 inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
1. Introduction
Drug treatment options in endometriosis are unsatisfac-
* Corresponding author. Tel.: +49 30 8445 2593; fax: +49 30 8445 4477. tory especially in the case of recurrence. New approaches to
E-mail address: (A.D. Ebert). optimize therapy are urgently needed. Taken together, the
0301-2115/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejogrb.2005.04.017
, A.D. Ebert et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 122 (2005) 144–150 145
following treatment strategies are currently available: open [35,55], which leads to a local increase in estrone and
or laparoscopic resection of endometriotic lesions including estradiol. Since there is no 17b-HSD-Typ2 activity in the
adhesiolysis and reconstruction of the pelvic anatomy, the secretion phase, progesterone is not stopping the estrogen-
use of GnRH analogues or GnRH antagonists, the dependent proliferation in endometriotic tissue. Thus, in
application of gestagens or their derivatives, oral contra- contrast to eutopic endometrium, transformation and
ceptives in the cyclic or nonstop mode (long-term cycle), desquamation are incomplete in endometriotic tissue
danazol, nonselective nonsteroidal antiphlogistics, and/or [62]. Moreover, it was shown that only the progesterone
the combination of treatment [9,33,57,58]. receptor A (PR-A) is expressed in endometriotic lesions,
while PR-B is found in eutopic endometrium as well
[3,35,47].
2. New concepts Furthermore, important steps in the molecular regulation
of the CYP19 gene (p450arom) have been described
In recent years, fresh impetus has been given to [12,14,15,35]. Simply, it can be assumed that the stimulating
endometriosis research by the in vitro detection of invasive transcription factor steroidogenic factor-1 (SF-1) competes
properties of endometriosis cells [30], by studies on with the inhibiting factor chicken ovalbumin upstream
angiogenesis [66], cytokines and chemokines, growth promotor transcription factor (COUP-TF), a dimer, for the
factors and steroid receptor modulators, by developments same DNA binding site of the aromatase promotor II
in genomics and proteonomics, and by establishing the [12,14,15]. While COUP-TF can be detected in both the
archimetra concept [27,47,48,50]. Numerous new and eutopic endometrium and endometriotic tissue, SF-1 is
treatment approaches developing out of basic research are obviously only expressed in endometriotic tissue. As a
currently being tested in clinical studies in different phases: result, SF-1 binds more often to the aromatase promotor II,
gonadotropin-releasing hormone antagonists, antigestagens which leads to the initiation of aromatase gene transcription
and selective progesterone receptor modulators, estrogen in endometriotic tissue. In the normal endometrium, only
receptor b-agonists, angiogenesis inhibitors, matrix metal- COUP-TF binds to the promotor and thus inhibits
loproteinase inhibitors, immunomodulators and TNF-a transcription. These processes are accompanied by the
inhibitors, aromatase inhibitors, and cyclooxygenase-2 interaction of the PGE2-induced cAMP with other co-
inhibitors [50,56,57]. repressors/stimulators [12]. The differential modulation of
Against this background, the detection of aromatase [12– SF-1 or COUP-TF expression may thus offer a perspective
15] and COX-2 overexpression [4,17,24,59] in endome- genetic treatment approach to the therapy of endometriosis.
triosis tissue seems to be important and extensively In this connection, it must be remembered that successful
developed clinically, since it appears for the first time that detection of aromatase expression (p450arom) in experi-
there are molecular targets for causal therapeutic mental ectopic endometriotic lesions was accomplished in a
approaches, whose clinical value will be clarified in primate model. Aromatase expression was, however, only
controlled, prospective randomized studies. evident 10 months after intraperitoneal inoculation of the
endometrium (menstruation phase), which may provide
information about the biology of aromatase metabolism in
3. Aromatase and aromatase inhibitors the sense of a survival pathway [25,41].
Modern steroidal and nonsteroidal aromatase inhibitors 3.1. Clinical data
(e.g. Letrozole1, Arimidex1 and Exemestan1) have been
intensively examined and are now an integral part of the As a clinical consequence of the human aromatase
endocrine therapy of postmenopausal breast cancer model (Fig. 1), the application of specific aromatase
[6,34,44,61]. inhibitors appeared relatively early as a new and causal
Recently the overexpression of aromatase [54,55] and a therapeutic approach under study conditions in patients
deficiency of 17b-hydroxysteroid dehydrogenase type 2 with extensive endometriosis (e.g. stages rASRM III
(17b-HSD-Typ2) were also detected in endometriosis tissue and IV) [22]. However, a problem was and still remains
[71,72]. Thus, the following pathophysiological model that endometriosis patients are women usually at the
requiring further evaluation seems to arise for endometriosis reproductive stage, who may still want to have a child or
[35]. In the eutopic endometrium, estrone is converted into who have not yet definitively completed their family
estradiol (E2) by 17b-hydroxysteroid dehydrogenase type I planning [61,64].
(17b-HSD-Typ1). A steady state between estradiol and Significant findings with the use of aromatase inhibitors
estrone is ensured by 17b-HSD-Typ2, which, in turn, converts in premenopausal breast cancer patients have not yet been
estradiol into estrone. On the other hand, 4-androsten-3, published, which is the reason why aromatase inhibitors
17-dion and testosterone are aromatized to estrone or estradiol have also not been approved for this patient group.
by the enzyme aromatase (p450arom). An overexpression Consequently, the aromatase concept was initially tested
of aromatase was detected in endometriotic lesions in one of the rare postmenopausal patients with aggressive
