estrogen biosynthesis and signaling in endometriosis

Molecular and Cellular Endocrinology 358 (2012) 146–154

Contents lists available at SciVerse ScienceDirect

Molecular and Cellular Endocrinology

journal homepage: www.elsevier .com/locate /mce

Review

Estrogen biosynthesis and signaling in endometriosis

Kaisa Huhtinen a,b, Mia Ståhle a, Antti Perheentupa a,b, Matti Poutanen a,c,⇑a Department of Physiology, Institute of Biomedicine, University of Turku, 20014 Turku, Finlandb Department of Obstetrics & Gynecology, Turku University Hospital, 20520 Turku, Finlandc Turku Center for Disease Modeling, University of Turku, 20014 Turku, Finland

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

Article history:Available online 22 August 2011

Keywords:SteroidogenesisPre-receptor regulationEstrogen receptorCoregulatorHydroxysteroid (17beta) dehydrogenaseAromatase

0303-7207/$ - see front matter � 2011 Elsevier Irelandoi:10.1016/j.mce.2011.08.022

⇑ Corresponding author at: Department of PhysioloUniversity of Turku, 20014 Turku, Finland. Tel.: +2502610.

E-mail addresses: [email protected] (K. [email protected] (A. Perheentupa), matti.pou

Endometriosis is an estrogen-dependent gynecological disease where endometrium-like tissue growsoutside uterine cavity. Endometriotic cell proliferation is stimulated by estrogens acting predominantlyvia their nuclear receptors. Estrogen receptors (ESR1, ESR2) are ligand activated transcription factorswhose activation is dependent on the cell-specific dynamic expression of the receptors, on the interactingproteins and on the ligand availability. The different types of endometriotic lesions, peritoneal, deep, andovarian endometriosis, may respond to estrogens differentially due to differences in the expression of thereceptors and interacting proteins, and due to potential differences in the ligand availability regulated bythe local estrogen synthesis. This review summarizes the current knowledge of estrogen synthesizingenzymes and estrogen receptors in different types of endometriosis lesions. Further studies are stillneeded to define the possible differences in steroid metabolism in different types of endometrioticlesions.

� 2011 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Endometriosis as an estrogen-dependent disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1462. Source of estrogens in endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473. Local estradiol synthesis in endometriosis lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

3.1. Production of estrone in endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473.2. Activation of estrone to estradiol in endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1503.3. Release of estrone and estradiol from their sulfate conjugates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

4. Inactivation of estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505. Estrogen receptors in endometriosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

5.1. ESR1 and ESR2, endometriotic cell proliferation and inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515.2. GPER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515.3. Estrogen receptor coregulators in endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

6. Ovarian endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

1. Endometriosis as an estrogen-dependent disease

Endometriosis is an estrogen-dependent gynecological diseasecharacterized by endometrial-like tissue growing outside the

d Ltd. All rights reserved.

gy, Institute of Biomedicine,358 23337571; fax: +358 2

n), [email protected] (M. Ståhle),[email protected] (M. Poutanen).

uterine cavity, typically on the pelvic peritoneum, in the ovariesand in the rectovaginal septum (Giudice, 2010). A severe diseasetypically results in extensive pelvic adhesions and deformation ofpelvic anatomy, often leading to pain and infertility. The incidenceof endometriosis is estimated to be 10% in women of reproductiveage, while the frequency rises to 50–60% within women with painwith or without infertility (Giudice, 2010).

Several factors have been suggested to be involved in thepathogenesis of the disease. These include hormonal regulation,inflammation, as well as genetic and environmental factors.

http://dx.doi.org/10.1016/j.mce.2011.08.022

mailto:[email protected]




http://dx.doi.org/10.1016/j.mce.2011.08.022

http://www.sciencedirect.com/science/journal/03037207

http://www.elsevier.com/locate/mce

K. Huhtinen et al. / Molecular and Cellular Endocrinology 358 (2012) 146–154 147

Endometriotic tissue proliferates in response to systemic estrogens.The appearance of lesions is related to menstrual cycle and estrogenaction, and the reduction of estrogen effects e.g. following meno-pause typically diminishes the disease. Accordingly, the currentmedical therapies for endometriosis is based on the inhibition ofsystemic estrogen action resulting in restricted proliferation.Endometriotic cells also have their own estrogen production, whichis expected to enhance the growth of the diseased tissue. Also otherhormones e.g. progesterone (P4), retinoic acid (RA), and androgensaffect the endometrial and endometriotic cell proliferation andcounteract the estrogen action.

2. Source of estrogens in endometriosis

In premenopausal women, the main source of circulating estro-gens is the ovary where it is synthesized by granulosa cells of thegrowing follicle during the mid- and late-proliferative phase of themenstrual cycle. In the secretory phase, P4 and estradiol (E2) areproduced by corpus luteum. They promote the decidual differentia-tion of the estrogen-primed endometrial stromal cells. The ovariesalso release estrone (E1), estrone sulfate (E1-S), and the androgenicprecursors of estrogen production, such as 4-androstenedione (A4),and dehydroepiandrosterone (DHEA). A4, DHEA and its sulfate(DHEA-S) are also released to circulation by the adrenal. They areconverted to E1 by 3 beta-hydroxysteroid dehydrogenase/Delta5 ? 4-isomerase type 2 (HSD3B2) and cytochrome P450 19A1(CYP19A1, aromatase). Finally, E1 is converted to the more potentE2 by hydroxysteroid (17beta) dehydrogenase (HSD17B) activity.

Estrogens are also released into circulation by peripheral tissuesas estrogen sulfates of which E1-S is the predominant circulatingestrogen sulfate whereas estradiol sulfate (E2-S) levels are consid-erably lower (Bulun and Simpson, 1994; Harada, 1992). Active E1and E2 are formed from circulating or locally synthesized E1-Sand E2-S by the activity of steroid sulfatase (STS; Labrie, 1991;Simpson, 2003). It has also been demonstrated that estrogen targettissues may synthesize E2 de novo from cholesterol by the classicalsteroidogenic pathway (Attar et al., 2009).

3. Local estradiol synthesis in endometriosis lesions

Among the peripheral tissues, also endometriosis lesions havebeen suggested to express all the enzymes required to synthesize

A

HSD1, 7,

Adrenal gland

Ovary

A4

E1

E2

Fig. 1. Source of estradiol in endometriosis. A4, androstenedione; CYP11A1, cholesterolCYP19A1, cytochrome P450 19A1 (aromatase); DHEA, dehydroepiandrosterone; DHEA-S,S, estradiol sulfate; STS, steroid sulfatase; StAR, steroidogenic acute regulatory protein;

estrogens de novo from cholesterol without the need for andro-genic precursors (Attar and Bulun, 2006; Fig 1).

3.1. Production of estrone in endometriosis

Cholesterol is transferred from cytoplasm to mitochondrion bysteroidogenic acute regulatory protein (StAR). The protein andmRNA expression of StAR have been shown to be increased in per-itoneal endometriosis and ovarian endometriotic stromal cells ascompared with healthy endometrium (Attar et al., 2009; Tsaiet al., 2001; Table 1). Disease stage (Tsai et al., 2001) or the phaseof the menstrual cycle (Attar et al., 2009) were shown not to affectthe expression. Data indicate that especially prostaglandin E2(PGE-2) stimulates StAR expression in human endometriotic stro-mal cells (Attar et al., 2009; Tsai et al., 2001) via CCAAT/enhancerbinding protein (C/EBP), beta binding to the cyclic AMP-responsiveelement-binding protein 1 (CREB) and cis-element (Hsu et al.,2008). Elevated StAR activity, thus, would provide an increasedsource of cholesterol for steroid synthesis in endometriotic cells.

Cholesterol is converted to pregnenolone by the mitochondrialcholesterol side-chain cleavage enzyme (CYP11A1), while itsexpression in endometriosis is poorly understood. The mRNAexpression has been analyzed only in two studies (Table 1). In com-parison with healthy endometrium, one study provided evidencefor an increased expression in peritoneal endometriosis and cul-tured stromal cells derived from ovarian endometriosis (Attaret al., 2009), while in the another study no differences in CYP11A1mRNA between ectopic and healthy endometrium was observed(Tsai et al., 2001). Neither of the studies evaluated the amount ofCYP11A1 protein or its enzymatic activity.

There are two alternative pathways for A4 synthesis after theproduction of pregnenolone (Fig. 1). Both pathways utilize theenzymes steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)and HSD3B2, and the intermediate products depend on thesequence by which the enzymes are applied. Similarly to thatreported for CYP11A1, the data on the expression CYP17A1 andHSD3B2 in endometriosis is puzzling (Table 1). In some studiesthe mRNA of these two enzymes has been reported to be signifi-cantly higher in peritoneal and ovarian endometriosis as comparedwith healthy endometrium (Attar et al., 2009; Borghese et al.,2008), while some studies have shown detectable mRNA expres-sion, but no differences in the mRNA levels between the two

CYP19A1

Estrone

Estradiol

Cholesterol

ndrostenedione

Endometriosis

DHEA

HSD3B

StAR, CYP11A1, CYP17A1

17B 12

HSD17B2(4, 8, 10)

STS

STS

Peripheral tissues

E1-S

E2-S

side-chain cleavage enzyme; CYP17A1, steroid 17-alpha-hydroxylase/17,20 lyase;dehydroepiandrosterone sulfate; E1, estrone; E1-S, estrone sulfate; E2, estradiol; E2-HSD17B, hydroxysteroid (17beta) dehydrogenase.

Table 1Expression of steroid metabolizing enzymes and estrogen receptors in different types of endometriosis as compared with healthy or eutopic endometrium.

Gene Tissue or celltype studied

mRNA Protein References

Expression Method used Expression Method used

Star OvEndo Up-regulated qRT-PCR Attar et al., 2009; Tsai et al., 2001Up-regulated Western blot Tsai et al., 2001

PeEndo Up-regulated qRT-PCR Attar et al., 2009; Tsai et al., 2001Up-regulated Western blot Tsai et al., 2001

DEEP Up-regulated qRT-PCR Up-regulated Western blot Tsai et al., 2001CYP11A1

(P450scc)OvEndo No change qRT-PCR Tsai et al., 2001

Up-regulated qRT-PCR Attar et al., 2009PeEndo No change qRT-PCR Tsai et al., 2001

Up-regulated qRT-PCR Attar et al., 2009DEEP No change qRT-PCR Tsai et al., 2001

CYP17A1(P450c17)

OvEndo No change qRT-PCR Tsai et al., 2001Up-regulated microarray Borghese et al., 2008

PeEndo No change qRT-PCR Tsai et al., 2001Up-regulated qRT-PCR Attar et al., 2009

DEEP No change qRT-PCR Tsai et al., 2001

HSD3B2 OvEndo No change qRT-PCR Tsai et al., 2001Up-regulated Microarray Borghese et al., 2008

PeEndo No change qRT-PCR Tsai et al., 2001Up-regulated qRT-PCR Attar et al., 2009

DEEP No change qRT-PCR Tsai et al., 2001

CYP19A1(P450arom)

OvEndo Up-regulated qRT-PCR,array

Attar et al., 2009; Bukulmezet al., 2008; Noble et al., 1997;Smuc et al., 2007, 2009; Vouket al., 2011;

No change qRT-PCR Colette et al., 2009Up-regulated/positive

Immunohistochemistry Hudelist et al., 2007; Kitawakiet al., 1997; Velasco et al., 2006;

No change Immunohistochemistry Vouk et al., 2011Not detected Western blot,

immunohistochemistryColette et al., 2009

PeEndo Up-regulated qRT-PCR Attar et al., 2009; Bukulmezet al., 2008; Noble et al., 1996

Up-regulated Western blot Bukulmez et al., 2008No change qRT-PCR Colette et al., 2009

Not detected Western blot,immunohistochemistry

Colette et al., 2009

Up-regulated Immunohistochemistry Hudelist et al., 2007DEEP No change qRT-PCR Colette et al., 2009

Up-regulated qRT-PCR Dassen et al., 2007; Matsuzakiet al.,2006b

Not detected Western blot,immunohistochemistry

Colette et al., 2009

Up-regulated Immunohistochemistry Hudelist et al., 2007

SF-1 OvEndo qRT-PCR Attar et al., 2009; Utsunomiyaet al., 2008

Western blot,immunohistochemistry

Attar et al., 2009; Utsunomiyaet al., 2008

Ovarian Immunohistochemistry Noël et al., 2011Mesenchymatouscells

PeEndo qRT-PCR Attar et al., 2009Western blot,immunohistochemistry

Attar et al., 2009

Immunohistochemistry Noël et al., 2011DEEP Immunohistochemistry Noël et al., 2011

HSD17B1 OvEndo Up-regulated qRT-PCR Smuc et al., 2007, 2009DEEP Up-regulated qRT-PCR Down-regulated Immunohistochemistry Dassen et al., 2007

HSD17B7 OvEndo Up-regulated qRT-PCR Smuc et al., 2007, 2009

HSD17B12 OvEndo Up-regulated qRT-PCR Smuc et al., 2007, 2009

HSD17B2 OvEndo Down-regulated

qRT-PCR Cheng et al., 2008

No change qRT-PCR Smuc et al., 2007, 2009Up-regulated qRT-PCR Matsuzaki et al., 2006a

Extra-ovarianendo

Down-regulated

qRT-PCR Zeitoun et al., 1998;

PeEndo Up-regulated RT-PCR Carneiro et al., 2007DEEP Down-

regulatedqRT-PCR Dassen et al., 2007; Matsuzaki

et al., 2006bNo change Immunohistochemistry Dassen et al., 2007

148 K. Huhtinen et al. / Molecular and Cellular Endocrinology 358 (2012) 146–154

Table 1 (continued)

Gene Tissue or celltype studied

mRNA Protein References

Expression Method used Expression Method used

HSD17B4 OvEndo No change RT-PCR Smuc et al., 2009DEEP Down-

regulatedRT-PCR Dassen et al., 2007

HSD17B8 OvEndo No change RT-PCR Smuc et al., 2009

HSD17B10

HSD17B14

STS OvEndo Up-regulated RT-PCR Smuc et al., 2007, 2009No change Enzyme activity Delvoux et al., 2009

PeEndo No change Enzyme activity Delvoux et al., 2009DEEP No change RT-PCR No change Immunohistochemistry Dassen et al., 2007

No change Enzyme activity Delvoux et al., 2009

SULT1E1 OvEndo No change Immunohistochemistry Hudelist et al., 2007No change RT-PCR Smuc et al., 2007, 2009

PeEndo No change Immunohistochemistry Hudelist et al., 2007DEEP No change Immunohistochemistry Hudelist et al., 2007

Up-regulated RT-PCR Dassen et al., 2007

ESR1 OvEndo Down-regulated

RT-PCR,Southern blot

Brandenberger et al., 1999

Down-regulated

qRT-PCR Matsuzaki et al., 2001; Smucet al., 2007; Xue et al., 2007

No change qRT-PCR Fujimoto et al., 1999Extra-ovarianendo

No change Western blot Attia et al., 2000

PeEndo Down-regulated

qRT-PCR Matsuzaki et al., 2001

DEEP RT-PCR

ESR2 OvEndo Up-regulated RT-PCR Bukulmez et al., 2008; Fujimotoet al., 1999; Smuc et al., 2007;Xue et al., 2007

Increased Immunohistochemistry Bukulmez et al., 2008Not altered RT-PCR,

Southern blotBrandenberger et al., 1999

Not altered qRT-PCR Matsuzaki et al., 2001PeEndo Down-

regulatedqRT-PCR Matsuzaki et al., 2001

DEEP RT-PCR

ESR1/ESR2 OvEndo Down-regulated

RT-PCR,Southern blot

Brandenberger et al., 1999

Down-regulated

qRT-PCR Bukulmez et al., 2008; Fujimotoet al., 1999; Matsuzaki et al.,2001; Smuc et al., 2007; Xueet al., 2007

PeEndo (red) Not altered qRT-PCRPeEndo (black) Down-

regulatedqRT-PCR Bukulmez et al., 2008; Matsuzaki

et al., 2001

OvEndo, ovarian endometriosis; PeEndo, peritoneal endometriosis; DEEP, deep endometriosis.


tissues (Tsai et al., 2001). However, cultured endometriotic stromalcells were able to produce P4 from cholesterol (Tsai et al., 2001)further confirming the presence of at least the CYP11A1 andHSD3B2 enzymes in endometriotic tissue. Furthermore, both theP4 synthesis (Tsai et al., 2001) and expression of CYP11A1,CYP17A1 and HSD3B2 (Attar et al., 2009) have been shown to beenhanced by PGE-2, suggesting that inflammation may stimulatede novo steroid synthesis in endometriosis. However, the expres-sion of these steroidogenic enzymes or their role in deeply infiltrat-ing endometriosis, in other words in endometriotic lesionspenetrating into the retroperitoneal space or the wall of the pelvicorgans to a depth of at least 5 mm, have not been reported.

CYP19A1 catalyzes the conversion of A4 to E1 as well as testos-terone (T) to E2. The enzyme has been shown to be expressed inendometriosis by measuring the mRNA, protein, and enzymaticactivity (Table 1; for review, see Attar and Bulun, 2006). IncreasedCYP19A1 expression as compared with eutopic endometrium hasbeen detected in ovarian (Attar et al., 2009; Bukulmez et al.,

2008; Hudelist et al., 2007; Kitawaki et al., 1997; Noble et al.,1997; Smuc et al., 2007; Vouk et al., 2011), peritoneal (Attaret al., 2009; Bukulmez et al., 2008; Noble et al., 1996), and deep(Dassen et al., 2007; Hudelist et al., 2007; Matsuzaki et al.,2006b) endometriosis without cyclical changes (Bukulmez et al.,2008).

There are data indicating that a positive feedback loop enhancesthe CYP19A1 expression in endometriosis (Bulun, 2009). In thismodel, peritoneal fluid cytokines, TNF-a and IL-6, stimulateCYP19A1 expression in endometriotic stromal cells (Velasco et al.,2006). Locally expressed CYP19A1 and HSD17B1 activities increasethe local tissue E2 level, and the locally produced E2 induces cyclo-oxygenase 2 (COX-2) enzyme expression (Tamura et al., 2004),thereby increasing the synthesis of PGE-2. PGE-2, in turn, is a potentstimulator of StAR and CYP19A1 in endometriotic stromal cells, andthis further promotes E2 synthesis. The effect of PGE-2 is possiblymediated by stimulating the expression of SF-1, a transcription fac-tor, which has been shown to be highly expressed in endometriosis


but not in healthy endometrium (Attar et al., 2009). In addition, SF-1 is also likely to induce the expression of other steroidogenic en-zymes (CYP11A1, HSD3B2, and CYP17A1; Attar et al., 2009). Activa-tion of this regulatory cycle is expected to result in a continuousformation of estrogens and prostaglandin formation in endometri-osis. Furthermore, prostaglandins and cytokines mediate pain,inflammation and infertility (for review, see Bulun, 2009). Thus,inflammation and the induced estrogen-induced cell proliferationseem to be closely connected in endometriosis.

3.2. Activation of estrone to estradiol in endometriosis

The reductive activity of HSD17Bs catalyses the conversion of E1to E2 or A4 to T. This is one of the essential steps in E2 synthesis as itutilizes E1 produced from both androgens and E1-S for E2 activation.It is important to note that the affinity of the 17-hydroxysteroidssuch as E2 and T to the corresponding nuclear receptors is up to20-fold higher than the corresponding 17-keto forms, E1 and A4,respectively. In addition to activating and inactivating sex steroids,several of the HSD17B enzymes are involved in other metabolicpathways as well, metabolizing e.g. retinoids, fatty acids and sterols(reviewed by Marchais-Oberwinkler et al., 2011; Moeller and Adam-ski, 2006, 2009). Thus, HSD17Bs regulate the ligand availability forseveral nuclear receptors. While many of the HSD17Bs have a widevariety of substrates, one substrate and catalytic activity is typicallyshared by several HSD17B enzymes. Thus, the total cellular HSD17Bactivity is the sum of the expression of several HSD17Bs. Currently,13 different human HSD17B enzymes with individual cell-specificexpression profiles, substrate specificities, and unique regulatorymechanisms have been identified (Moeller and Adamski, 2006,2009). Of these enzymes HSD17B1, 3, 5, 7, and 12 have been shownto present predominantly reductive activity.

Several studies have demonstrated either the presence(Zeitoun et al., 1998) or increased expression (Borghese et al.,2008; Dassen et al., 2007; Smuc et al., 2007) of HSD17B1 in ovarian(Borghese et al., 2008; Smuc et al., 2007) or deep infiltrating (Dassenet al., 2007) endometriosis at mRNA level (Table 1). Similarly, a his-tological analysis of established endometriotic foci showed strongHSD17B1 protein expression in a marmoset monkey model (Einspa-nier et al., 2006). HSD17B1 is the HSD17B enzyme which possessesthe highest specificity for steroids as substrate, and displays thehighest catalytic activity for activation of E1 to E2 among allHSD17Bs (Rizner, 2009). In line with the expression of HSD17B1 inendometriosis the conversion of E1 to E2 has been shown to be in-creased in various types of endometriosis (Delvoux et al., 2009).The expression of other HSD17B enzymes in endometriosis is lesswell known. However, the mRNA for HSD17B7 and HSD17B12 hasbeen shown to be up-regulated in ovarian endometriosis as com-pared with healthy endometrium (Smuc et al., 2009; Smuc et al.,2007), and both of these enzymes might, thus, be involved in activa-tion of E1 to E2. While most of the studies have been carried out inovarian endometriosis, only limited data are available for theexpression of various HSD17Bs in peritoneal or deep endometriosis.

3.3. Release of estrone and estradiol from their sulfate conjugates

Endometriosis is able to locally produce estrogens from E1-S andE2-S, which are circulating at high concentrations. This is due to thepresence of steroid sulfatase activity (STS; Pasqualini et al., 1989), sofar detected in ovarian and peritoneal endometriosis (Carlströmet al., 1988; Purohit et al., 2008; Table 1). A relatively high STS activ-ity has been measured in some endometriotic implants, and theactivity was shown to correlate with the severity of the disease(Purohit et al., 2008). On the other hand, no alterations in STS mRNAor protein expression between endometriosis lesions and healthyendometrium were detected in another study reported (Dassen

et al., 2007). However, the sulfatase pathway of E2 synthesis is con-sidered to be important in the pathogenesis of endometriosis, andSTS inhibitors have been suggested for the treatment of endometri-osis (Colette et al., 2011; Purohit et al., 2008). Supporting thishypothesis, a STS inhibitor was recently shown to decrease endome-triosis lesion size in a mouse model (Colette et al., 2011).

4. Inactivation of estrogens

E2 can be inactivated through conversion to E1 by oxidativeHSD17B-activity, and via the formation of sulfate- or glucorineconjugates by the activities of estrogen sulfotransferases andUDP-glucuronosyltransferases, respectively. Currently, HSD17B2is thought to be the major HSD17B enzyme inactivating E2 to E1in endometriosis. Other HSD17Bs catalyze this reaction as well,but their catalytic efficacies are weaker as compared withHSD17B2 (Rizner, 2009).

In the healthy endometrium, the expression of HSD17B2 ishighly increased in the secretory phase, due to its regulation byP4 (Casey et al., 1994; Zeitoun et al., 1998). Its aberrant expression,i.e. the lack of increase at the secretory phase, has been confirmedin deep endometriosis (Dassen et al., 2007; Matsuzaki et al.,2006b), ovarian endometriotic cysts (Cheng et al., 2008), and in ex-tra-ovarian endometriosis (Zeitoun et al., 1998), mainly at themRNA level (Table 1). However, conflicting results have also beenreported (Carneiro et al., 2007; Matsuzaki et al., 2006a; Smucet al., 2009; Smuc et al., 2007). Decreased HSD17B2 expression isexpected to result in a persistently high E2 levels in the endometri-osis lesions throughout the menstrual cycle. Accordingly, de-creased inactivation of E2 to E1 has recently been demonstratedin endometriosis lesions (Delvoux et al., 2009) as compared withthe normal endometrium.

The aberrant expression of HSD17B2 in endometriosis isassumed to be caused by an impaired action of P4 in the endome-triotic epithelial cells (Attia et al., 2000; Zeitoun et al., 1998).However, the deficient HSD17B2 expression may also be a resultof stromal defect (Yang et al., 2001). In this scenario P4 stimulatesepithelial HSD17B2 mRNA expression via stromal PR-B thatinduces the secretion of paracrine factors (e.g. retinoid acid) thatregulate HSD17B2 expression in the epithelial cells (Cheng et al.,2008).

The absence of HSD17B2 appears not to be compensated by otherHSD17Bs. The data available indicate that the expression ofHSD17B4 or 8 is not altered in ovarian endometriotic cysts as com-pared with the endometrium of women with uterine leiomyomas(Smuc et al., 2009), and a down-regulation of HSD17B4 has beenreported in deep infiltrating endometriosis (Dassen et al., 2007).Currently, no data are available for HSD17B10 or HSD17B14 inendometriosis.

In addition to converting E2 to E1, HSD17B2 acts as a 20a-hydroxysteroid dehydrogenase, thereby activating 20a-hydroxy-progesterone to P4 (Puranen et al., 1999). Furthermore, studies intransgenic mice have suggested that the enzyme is involved inthe metabolism of retinoids (Rantakari et al., 2008; Zhongyiet al., 2007). It is, thus, interesting to note that retinoic acids (RA)have been shown to mediate the stroma-dependent P4 action inendometrial epithelial cells, and also to mediate the P4-dependentregulation of HSD17B2. P4 stimulates the stroma to secrete RA,which increases the HSD17B2 mRNA expression in human endo-metrium (Cheng et al., 2008), while in endometriosis RA uptakeand its antiproliferative effects are decreased because of dysregu-lated progesterone receptor action (Pavone et al., 2010, 2011;Fig. 2). Furthermore, the expression of P4-regulated RA inactivatingCYP26A1 is diminished in endometriosis lesions in the secretoryphase of the menstrual cycle (Cheng et al., 2008; Deng et al.,

Normal endometrium

RA intake

RA catabolism

Endometriosis

RA intake

RA catabolism

Fig. 2. Impaired progesterone signaling in endometriosis may alter retinoic acidand estradiol actions. E2, estradiol; HSD17B2, hydroxysteroid (17beta) dehydroge-nase type 2; P4, progesterone; RA, retinoic acid.


2003). It has been suggested, that the net effect of imbalanced RAaction contribute to decreased apoptosis and increased survival ofendometriotic tissue (Pavone et al., 2010). In conclusion, the al-tered P4 action in endometriosis may impair both RA and E2 ac-tions, and down-regulated HSD17B2 activity may further affecton both P4 and RA metabolism.

E2 can be inactivated also by sulfate conjugation catalyzed byestrogen sulfotransferase (SULT1E1; Pasqualini, 2009). Its expres-sion is increased in the secretory phase endometrium most proba-bly via P4 regulation (Rubin et al., 1999). In contrast to HSD17B2,SULT1E1 is expressed in ovarian, peritoneal and deep infiltratingendometriosis similarly to normal and eutopic endometrium (Das-sen et al., 2007; Hudelist et al., 2007; Smuc et al., 2007). Therefore,due to the diminished HSD17B2 activity, SULT1E1 might becomeas the major pathway inactivating E2 in endometriosis.

5. Estrogen receptors in endometriosis

The major effects of estrogens are mediated by their classical nu-clear receptors (ESR) 1 and 2 (also called as a and b, respectively), theactions of which are regulated by ligand availability and by the pres-ence of various coregulators (Musgrove and Sutherland, 2009). Inaddition, the estrogen signaling can be mediated through non-geno-mic mechanisms via cytoplasmic or membrane bound ESRs, and bythe action of G-protein coupled estrogen receptor 1 (GPER; Hammesand Levin, 2007; Musgrove and Sutherland, 2009). Ligand binding tothese ESRs induce the assembly of functional protein complexes thatactivate signaling cascades such as PI3K and Src pathways, and re-sult in activation of transcription factors, such as Akt and Erk (Mus-grove and Sutherland, 2009). In addition to their steroidal ligands,ESRs can be activated by mechanisms activated by receptor tyrosinekinases, including epidermal growth factor receptor, ERBB2 (HER2)and the insulin-like growth factor receptor. Activated receptor tyro-sine kinases phosphorylate Erk or Akt serine/threonine kinaseswhich lead to ligand-independent activation of the ESR (Musgroveand Sutherland, 2009).

5.1. ESR1 and ESR2, endometriotic cell proliferation and inflammation

In the healthy endometrium, both ESR1 and ESR2 are expressed,although ESR1 predominates over ESR2, and their expression dif-fers during the menstrual cycle (Matsuzaki et al., 2001). Estro-gen-mediated proliferation in endometrium is promoted mainlythrough the activation of ESR1 (Shang, 2006). However, several

studies have shown down-regulation of ESR1 in different types ofendometriosis lesions (Table 1; Brandenberger et al., 1999; Matsu-zaki et al., 2001; Smuc et al., 2007; Xue et al., 2007). In contrast,ESR2 expression is increased in ovarian endometriosis (Table 1;Bukulmez et al., 2008; Fujimoto et al., 1999; Smuc et al., 2007;Xue et al., 2007), probably due to hypomethylation of the promoter(Xue et al., 2007). ESR2 has been shown to down-regulate ESR1expression in ovarian endometriosis (Trukhacheva et al., 2009).Accordingly, a greatest decrease in ESR1/ESR2 ratio has been ob-served in ovarian endometriosis, in comparison to the healthy oreutopic endometrium (Brandenberger et al., 1999; Bukulmezet al., 2008; Fujimoto et al., 1999; Matsuzaki et al., 2001; Smucet al., 2007; Xue et al., 2007), while the ratio was not altered inred peritoneal lesions (Brandenberger et al., 1999; Matsuzakiet al., 2001). Interestingly, ESR2 knockdown via siRNA was shownto decrease endometriotic stromal cell proliferation (Trukhachevaet al., 2009), suggesting that in addition to ESR1, also ESR2 stimu-lates the cell cycle and contributes to the proliferation of endome-triotic stromal cells (Trukhacheva et al., 2009). Furthermore, ESR2specific agonist has been shown to reduce lesion size in a nudemouse model (Harris et al., 2005).

Estrogens also show anti-inflammatory actions by repressingthe expression of several inflammatory genes through the NF-j Bpathway, including IL-6, IL-8, or TNF-a (Cvoro et al., 2008; Rayet al., 1997). These events may be mediated by both ESR1 andESR2, but the data indicate a major role for ESR2 in mediatingthe anti-inflammatory E2 actions (Cvoro et al., 2008). Accordingly,a selective ESR2 agonists has been shown to repress pro-inflamma-tory genes, and presented with beneficial effects in a preclinicalinflammation model, without promoting growth of the uterus(Cvoro et al., 2008; Xiu-li et al., 2009).

5.2. GPER

The trans-membrane G protein-coupled estrogen receptor 1(GPER, GPR30) has been implicated in rapid non-genomic effectsof estrogens. GPER mRNA was recently shown to be predominantlyexpressed in the glandular and luminal epithelial cells in the nor-mal endometrium, being highest at mid- and late-proliferativephase (Kolkova et al., 2010). The cyclic regulation was found tobe similar to that of ESR1 mRNA, suggesting regulation by ovariansteroids. However, in contrast to the mRNA, GPER protein waspresent in endometrial tissue without cyclic variation (Kolkovaet al., 2010).

Primary human endometriotic (H-38) cells possess highermRNA expression of GPER as compared with healthy endometrium(Lin et al., 2009). These cells also possess high CYP19A1 and SF-1expression with no detectable ESR1 or ESR2 mRNA. However, thevalidity of the cell culture model for endometriosis is not fully de-fined. GPER appears to be highly expressed also in endometrialcancer tissues and cancer cell lines (He et al., 2009; Lin et al.,2009). The high expression of GPER in endometrial cancer wasshown to induce cell proliferation and invasion, and expressioncorrelated with high-grade endometrial carcinoma (He et al.,2009). The results suggest that GPER activation in the endometriot-ic cell line (Lin et al., 2009) as well as in endometrial cancer cells(He et al., 2009; Lin et al., 2009) stimulates the phosphatidylinosi-tol 3-kinase (PI3K) and MEK/ERK mitogen-activated protein kinase(MAPK) pathways. Furthermore, cell proliferation, SF-1 andCYP19A1 (a target for SF-1) expression (Lin et al., 2009) were stim-ulated by GPER-mediated signaling in endometrial cancer cells.The GPER-mediated non-genomic estrogen signaling may, thus,play a role in endometrial diseases (He et al., 2009). However,the expression and role of GPER in different types of endometriosislesions is not known. In contrast to the studies with human endo-metrial cancer cells, a recent study (Gao et al., 2011) showed that


in the mouse uterus GPER acts as a negative regulator of the ESR1-dependent E2 growth response. Similarly to humans, GPER wasprimarily localized in the mouse uterine epithelial cells, while itsactivation alters gene expression and mediates inhibition ofERK1/2 and ESR1 phosphorylation in the stromal compartment,suggesting the involvement of paracrine signaling (Gao et al.,2011).

5.3. Estrogen receptor coregulators in endometriosis

Coregulators are essential for the nuclear receptors to mediatetheir target gene responses. However, only few reports are pres-ently available on the presence of ESR co-activators or co-repres-sors in endometriosis. Proline, Glutamic acid, Leucine rich Protein1 (PELP1) is an ESR-coregulator and also a potential proto-onco-gene. It has been shown to promote CYP19A1 expression in humanendometrial stromal cells, possibly by interacting with the orphanreceptor estrogen-related receptor alpha (ESRRA; Vadlamudi et al.,2010). The PELP1 staining intensity was shown to be higher in ec-topic endometrium as compared with eutopic endometrium. Thus,up-regulated PELP1 may stimulate CYP19A1 expression inendometriotic cells, which may lead to increased E2 synthesis,and a positive E2-ESR signaling loop (Vadlamudi et al., 2010). How-ever, a recent study showed reduced ESRRA expression in ovarianendometriosis (Cavallini et al., 2011).

The nuclear receptor co-activator 1 (NCOA1) has been sug-gested to affect the transcriptional activity of ESR1 in ovarianendometriosis (Kumagami et al., 2011). Its expression co-localizeswith ESR1, and it was the most highly expressed co-activator of theNCOA-family members studied (Kumagami et al., 2011). There isalso evidence for a cyclic expression of NCOA1 in eutopic endome-trial epithelium, the expression being highest in the proliferativephase (Suzuki et al., 2010). Thus, the down-regulation of NCOA1was supposed to be related to reduced proliferative activity inendometriotic epithelia (Suzuki et al., 2010). However, in endome-triosis, the expression of NCOA1 in the proliferative phase was sig-nificantly lower than that in eutopic endometrium, and waswithout cyclic changes during the menstrual cycle.

Nuclear receptor interacting protein 1 (NRIP1) specifically inter-acts with the hormone-dependent activation domain AF2 of nucle-ar receptors and modulates transcriptional activity of severalnuclear receptors including ESR1, estrogen-related receptors andretinoic receptors (for review, see Fritah et al., 2010; Wei, 2004).Interestingly, NRIP1 gene variants were associated with endome-triosis in a case-control study (Caballero et al., 2005). In line withthis, NRIP1, inhibits the StAR promoter activity by binding to SF-1 and DAX-1 (Sugawara et al., 2001). In addition, NRIP1 has a rolein the regulation of inflammatory response by regulating the NF-jB/RelA-dependent cytokine gene expression, and accordingly,NRIP1 deficiency was show to inhibit of pro-inflammatory path-ways in macrophages (Zschiedrich et al., 2008). However, no datais currently available for NRIP1 expression in endometriosis or hu-man endometrium. A piece of information has also been shownthat the expression of steroid receptor co-activator EP300 (p300)and the co-repressors NCOR1 and NCOR2 are constitutively ex-pressed in human eutopic endometrium (Suzuki et al., 2010). Pres-ently, there is insufficient information about the expression ofnuclear receptor interacting proteins in endometriosis lesions,and thus their role in steroid hormone dependent growth of the ec-topic endometrium is poorly understood.

6. Ovarian endometriosis

Among different types of endometriosis the highest level ofCYP19A1 expression has been observed in ovarian endometriosis

(Colette et al., 2009). This was suggested to support the theory ofdistinct entities of different types of endometriosis lesions (Heilieret al., 2006). However, there is also a study demonstrating thehighest CYP19A1 mRNA levels in peritoneal implants, and in thosespecimens the expression correlated well with the inflammatorystage of endometriosis (Bukulmez et al., 2008). It is notable thatCYP19A1 is highly expressed in ovarian granulosa cells, and is pres-ent also in adipose tissue and intact peritoneum (Bulun et al.,1993; Kyama et al., 2008). This might explain the contradictory re-sults (Colette et al., 2009), and highlights the need of a careful his-to-pathological characterization of the tissue specimens studied.

Similarly, contradictory results have been presented for SF-1. Itwas reported to be up-regulated both in ovarian endometriosis(Borghese et al., 2008; Bulun et al., 2009; Utsunomiya et al.,2008) and peritoneal endometriosis (Attar et al., 2009), while ina recent study no significant increase in SF-1 expression was iden-tified in any types of endometriosis (Noël et al., 2011). Over-expression of ESR2 and decreased ESR1/ESR2 ratio have similarlybeen shown in ovarian endometriosis but not e.g. in red peritoneallesions (Table 1; (Matsuzaki et al., 2001). Also HSD17B1 is highlyexpressed in ovarian steroid synthesizing granulosa cells adjacentto endometrioma cyst (Ghersevich et al., 1994). Interestingly,mRNA levels of StAR have recently been shown to be similarly ex-pressed in ovarian endometriosis and benign ovaries, and was sig-nificantly lower in endometriosis associated ovarian cancer andovarian cancer not associate with endometriosis (Banz et al., 2010).

Histological sections of ovarian endometriotic specimens ofteninclude ovarian tissue with follicles and steroidogenic granulosaand theca cells. Thus, it has been suggested that ovarian tissue inclose proximity of endometriotic cysts would influence the resultsperformed with whole tissue specimens (e.g. microarray analysis,qRT-PCR and Western blot; Delvoux et al., 2009). Expression ofboth CYP19A1 (Delvoux et al., 2009) and SF-1 (Noël et al., 2011)in ovarian endometriotic cysts have been suggested to originatefrom ovarian cells rather than endometriotic stromal or epithelialcells. Similarly, ESR2, HSD17B1 and StAR are all highly expressedin the ovary, which raises the question of the origin of these pro-teins in ovarian endometriosis specimens. Therefore, it would beof importance to study the observed alterations in the steroido-genic enzymes in different cell types within ovarian endometrioticspecimens. For example, CYP19A1 expression in endometriotic epi-thelial and stromal cells has been evidenced using laser capturemicrodisection (Matsuzaki et al., 2006b). A proper comparativestudy is still needed to evaluate the possible differences in steroidmetabolism in different lesion types.

References

Attar, E., Bulun, S., 2006. Aromatase and other steroidogenic genes inendometriosis: translational aspects. Human Reproduction Update 12, 49–56.

Attar, E., Tokunaga, H., Imir, G., Yilmaz, M., Redwine, D., Putman, M., Gurates, B.,Attar, R., Yaegashi, N., Hales, D., Bulun, S., 2009. Prostaglandin E2 viasteroidogenic factor-1 coordinately regulates transcription of steroidogenicgenes necessary for estrogen synthesis in endometriosis. Journal of ClinicalEndocrinology and Metabolism 94, 623–631.

Attia, G., Zeitoun, K., Edwards, D., Johns, A., Carr, B., Bulun, S., 2000. Progesteronereceptor isoform A but not B is expressed in endometriosis. Journal of ClinicalEndocrinology and Metabolism 85, 2897–2902.

Banz, C., Ungethuem, U., Kuban, R.J., Diedrich, K., Lengyel, E., Hornung, D., 2010. Themolecular signature of endometriosis-associated endometrioid ovarian cancerdiffers significantly from endometriosis-independent endometrioid ovariancancer. Fertility and Sterility 94, 1212–1217.

Borghese, B., Mondon, F., Noël, J., Fayt, I., Mignot, T., Vaiman, D., Chapron, C., 2008.Gene expression profile for ectopic versus eutopic endometrium provides newinsights into endometriosis oncogenic potential. Molecular Endocrinology 22,2557–2562.

Brandenberger, A., Lebovic, D., Tee, M., Ryan, I., Tseng, J., Jaffe, R., Taylor, R., 1999.Oestrogen receptor (ER)-alpha and ER-beta isoforms in normal endometrial andendometriosis-derived stromal cells. Molecular Human Reproduction 5, 651–655.


Bukulmez, O., Hardy, D., Carr, B., Word, R., Mendelson, C., 2008. Inflammatory statusinfluences aromatase and steroid receptor expression in endometriosis.Endocrinology 149, 1190–1204.

Bulun, S., 2009. Endometriosis. The New England Journal of Medicine 360,268–279.

Bulun, S., Rosenthal, I., Brodie, A., Inkster, S., Zeller, W., DiGeorge, A., Frasier, S.,Kilgore, M., Simpson, E., 1993. Use of tissue-specific promoters in the regulationof aromatase cytochrome P450 gene expression in human testicular andovarian sex cord tumors, as well as in normal fetal and adult gonads. Journal ofClinical Endocrinology and Metabolism 77, 1616–1621.

Bulun, S., Simpson, E., 1994. Competitive reverse transcription-polymerase chainreaction analysis indicates that levels of aromatase cytochrome P450transcripts in adipose tissue of buttocks, thighs, and abdomen of womenincrease with advancing age. Journal of Clinical Endocrinology and Metabolism78, 428–432.

Bulun, S., Utsunomiya, H., Lin, Z., Yin, P., Cheng, Y., Pavone, M., Tokunaga, H.,Trukhacheva, E., Attar, E., Gurates, B., Milad, M., Confino, E., Su, E., Reierstad, S.,Xue, Q., 2009. Steroidogenic factor-1 and endometriosis. Molecular and CellularEndocrinology 300, 104–108.

Caballero, V., Ruiz, R., Sainz, J.A., Cruz, M., López-Nevot, M.A., Galán, J.J., Real, L.M., deCastro, F., López-Villaverde, V., Ruiz, A., 2005. Preliminary molecular geneticanalysis of the Receptor Interacting Protein 140 (RIP140) in women affected byendometriosis. Journal of Experimental and Clinical Assisted Reproduction 2,11.

Carlström, K., Bergqvist, A., Ljungberg, O., 1988. Metabolism of estrone sulfate inendometriotic tissue and in uterine endometrium. Fertility and Sterility 49,229–233.

Carneiro, M., Morsch, D., Camargos, A., Spritzer, P., Reis, F., 2007. Expression of17beta-hydroxysteroid dehydrogenase type 2 in pelvic endometriosis.Gynecological Endocrinology 23, 188–192.

Casey, M.L., MacDonald, P.C., Andersson, S., 1994. 17 beta-Hydroxysteroiddehydrogenase type 2: chromosomal assignment and progestin regulation ofgene expression in human endometrium. Journal of Clinical Investigation 94,2135–2141.

Cavallini, A., Resta, L., Caringella, A.M., Dinaro, E., Lippolis, C., Loverro, G., 2011.Involvement of estrogen receptor-related receptors in human ovarianendometriosis. Fertil Steril 96, 102-6.Cheng, Y., Imir, A., Fenkci, V., Yilmaz, M.,Bulun, S., 2007. Stromal cells of endometriosis fail to produce paracrine factorsthat induce epithelial 17beta-hydroxysteroid dehydrogenase type 2 gene andits transcriptional regulator Sp1: a mechanism for defective estradiolmetabolism. Am J Obstet Gynecol 196, 391.e391-397; discussion 391.e397–398.

Cheng, Y., Yin, P., Xue, Q., Yilmaz, B., Dawson, M., Bulun, S., 2008. Retinoic acid (RA)regulates 17beta-hydroxysteroid dehydrogenase type 2 expression inendometrium: interaction of RA receptors with specificity protein (SP) 1/SP3for estradiol metabolism. Journal of Clinical Endocrinology and Metabolism 93,1915–1923.

Colette, S., Defrère, S., Lousse, J.C., Van Langendonckt, A., Gotteland, J.P., Loumaye, E.,Donnez, J., 2011. Inhibition of steroid sulfatase decreases endometriosis in anin vivo murine model. Human Reproduction 26, 1362–1370.

Colette, S., Lousse, J., Defrère, S., Curaba, M., Heilier, J., Van Langendonckt, A.,Mestdagt, M., Foidart, J., Loumaye, E., Donnez, J., 2009. Absence of aromataseprotein and mRNA expression in endometriosis. Human Reproduction 24,2133–2141.

Cvoro, A., Tatomer, D., Tee, M., Zogovic, T., Harris, H., Leitman, D., 2008. Selectiveestrogen receptor-beta agonists repress transcription of proinflammatorygenes. Journal of Immunology 180, 630–636.

Dassen, H., Punyadeera, C., Kamps, R., Delvoux, B., Van Langendonckt, A., Donnez, J.,Husen, B., Thole, H., Dunselman, G., Groothuis, P., 2007. Estrogen metabolizingenzymes in endometrium and endometriosis. Human Reproduction 22, 3148–3158.

Delvoux, B., Groothuis, P., D’Hooghe, T., Kyama, C., Dunselman, G., Romano, A., 2009.Increased production of 17beta-estradiol in endometriosis lesions is the resultof impaired metabolism. Journal of Clinical Endocrinology and Metabolism 94,876–883.

Deng, L., Shipley, G., Loose-Mitchell, D., Stancel, G., Broaddus, R., Pickar, J., Davies, P.,2003. Coordinate regulation of the production and signaling of retinoic acid byestrogen in the human endometrium. Journal of Clinical Endocrinology andMetabolism 88, 2157–2163.

Einspanier, A., Lieder, K., Brüns, A., Husen, B., Thole, H., Simon, C., 2006. Induction ofendometriosis in the marmoset monkey (Callithrix jacchus). Molecular HumanReproduction 12, 291–299.

Fritah, A., Christian, M., Parker, M.G., 2010. The metabolic coregulator RIP140: anupdate. American Journal of Physiology, Endocrinology and Metabolism 299,E335–E340.

Fujimoto, J., Hirose, R., Sakaguchi, H., Tamaya, T., 1999. Expression of oestrogenreceptor-alpha and -beta in ovarian endometriomata. Molecular HumanReproduction 5, 742–747.

Gao, F., Ma, X., Ostmann, A.B., Das, S.K., 2011. GPR30 Activation Opposes Estrogen-Dependent Uterine Growth via Inhibition of Stromal ERK1/2 and EstrogenReceptor Alpha (ER{alpha}) Phosphorylation Signals. Endocrinology 152, 1434–1447.

Ghersevich, S., Poutanen, M., Martikainen, H., Vihko, R., 1994. Expression of 17 beta-hydroxysteroid dehydrogenase in human granulosa cells: correlation withfollicular size, cytochrome P450 aromatase activity and oestradiol production.Journal of Endocrinology 143, 139–150.

Giudice, L., 2010. Clinical practice Endometriosis. The New England Journal ofMedicine 362, 2389–2398.

Hammes, S.R., Levin, E.R., 2007. Extranuclear steroid receptors: nature and actions.Endocrine Reviews 28, 726–741.

Harada, N., 1992. A unique aromatase (P-450AROM) mRNA formed by alternativeuse of tissue-specific exons 1 in human skin fibroblasts. Biochemical andBiophysical Research Communications 189, 1001–1007.

Harris, H.A., Bruner-Tran, K.L., Zhang, X., Osteen, K.G., Lyttle, C.R., 2005. A selectiveestrogen receptor-beta agonist causes lesion regression in an experimentallyinduced model of endometriosis. Human Reproduction 20, 936–941.

He, Y.Y., Cai, B., Yang, Y.X., Liu, X.L., Wan, X.P., 2009. Estrogenic G protein-coupledreceptor 30 signaling is involved in regulation of endometrial carcinoma bypromoting proliferation, invasion potential, and interleukin-6 secretion via theMEK/ERK mitogen-activated protein kinase pathway. Cancer Science 100,1051–1061.

Heilier, J., Donnez, O., Van Kerckhove, V., Lison, D., Donnez, J., 2006. Expression ofaromatase (P450 aromatase/CYP19) in peritoneal and ovarian endometriotictissues and deep endometriotic (adenomyotic) nodules of the rectovaginalseptum. Fertility and Sterility 85, 1516–1518.

Hsu, C.C., Lu, C.W., Huang, B.M., Wu, M.H., Tsai, S.J., 2008. Cyclic adenosine 3’,5’-monophosphate response element-binding protein and CCAAT/enhancer-binding protein mediate prostaglandin E2-induced steroidogenic acuteregulatory protein expression in endometriotic stromal cells. AmericanJournal of Pathology 173, 433–441.

Hudelist, G., Czerwenka, K., Keckstein, J., Haas, C., Fink-Retter, A., Gschwantler-Kaulich, D., Kubista, E., Singer, C., 2007. Expression of aromatase and estrogensulfotransferase in eutopic and ectopic endometrium: evidence for unbalancedestradiol production in endometriosis. Reproduction Science 14, 798–805.

Kitawaki, J., Noguchi, T., Amatsu, T., Maeda, K., Tsukamoto, K., Yamamoto, T.,Fushiki, S., Osawa, Y., Honjo, H., 1997. Expression of aromatase cytochromeP450 protein and messenger ribonucleic acid in human endometriotic andadenomyotic tissues but not in normal endometrium. Biology of Reproduction57, 514–519.

Kolkova, Z., Noskova, V., Ehinger, A., Hansson, S., Casslén, B., 2010. G protein-coupled estrogen receptor 1 (GPER, GPR 30) in normal human endometriumand early pregnancy decidua. Molecular Human Reproduction 16, 743–751.

Kumagami, A., Ito, A., Yoshida-Komiya, H., Fujimori, K., Sato, A., 2011. Expressionpatterns of the steroid receptor co-activator family in human ovarianendometriosis. Journal of obstetrics & gynaecology Research, in press.doi:10.1111/j.1447-0756.2010.01509.x.

Kyama, C., Overbergh, L., Mihalyi, A., Meuleman, C., Mwenda, J., Mathieu, C.,D’Hooghe, T., 2008. Endometrial and peritoneal expression of aromatase,cytokines, and adhesion factors in women with endometriosis. Fertility andSterility 89, 301–310.

Labrie, F., 1991. Intracrinology. Molecular and Cellular Endocrinology 78, C113–C118.

Lin, B., Suzawa, M., Blind, R., Tobias, S., Bulun, S., Scanlan, T., Ingraham, H., 2009.Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogueactivates SF-1 and promotes endometrial cell proliferation. Cancer Research 69,5415–5423.

Marchais-Oberwinkler, S., Henn, C., Möller, G., Klein, T., Negri, M., Oster, A., Spadaro,A., Werth, R., Wetzel, M., Xu, K., Frotscher, M., Hartmann, R.W., Adamski, J.,2011. 17b-Hydroxysteroid dehydrogenases (17b-HSDs) as therapeutic targets:protein structures, functions, and recent progress in inhibitor development.Journal of Steroid Biochemistry and Molecular Biology 125, 66–82.

Matsuzaki, S., Canis, M., Pouly, J., Botchorishvili, R., Déchelotte, P., Mage, G., 2006a.Differential expression of genes in eutopic and ectopic endometrium frompatients with ovarian endometriosis. Fertility and Sterility 86, 548–553.

Matsuzaki, S., Canis, M., Pouly, J., Déchelotte, P., Mage, G., 2006b. Analysis ofaromatase and 17beta-hydroxysteroid dehydrogenase type 2 messengerribonucleic acid expression in deep endometriosis and eutopic endometriumusing laser capture microdissection. Fertility and Sterility 85, 308–313.

Matsuzaki, S., Murakami, T., Uehara, S., Canis, M., Sasano, H., Okamura, K., 2001.Expression of estrogen receptor alpha and beta in peritoneal and ovarianendometriosis. Fertility and Sterility 75, 1198–1205.

Moeller, G., Adamski, J., 2006. Multifunctionality of human 17beta-hydroxysteroiddehydrogenases. Molecular and Cellular Endocrinology 248, 47–55.

Moeller, G., Adamski, J., 2009. Integrated view on 17beta-hydroxysteroiddehydrogenases. Molecular and Cellular Endocrinology 301, 7–19.

Musgrove, E.A., Sutherland, R.L., 2009. Biological determinants of endocrineresistance in breast cancer. Nature Reviews Cancer 9, 631–643.

Noble, L., Simpson, E., Johns, A., Bulun, S., 1996. Aromatase expression inendometriosis. Journal of Clinical Endocrinology and Metabolism 81, 174–179.

Noble, L., Takayama, K., Zeitoun, K., Putman, J., Johns, D., Hinshelwood, M., Agarwal,V., Zhao, Y., Carr, B., Bulun, S., 1997. Prostaglandin E2 stimulates aromataseexpression in endometriosis-derived stromal cells. Journal of ClinicalEndocrinology and Metabolism 82, 600–606.

Noël, J.C., Anaf, V., Borghese, B., Vaiman, D., Fayt, I., Chapron, C., 2011. Thesteroidogenic factor-1 protein is not expressed in various forms ofendometriosis but is strongly present in ovarian cortical or medullarymesenchymatous cells adjacent to endometriotic foci. Fertility and Sterility95, 2655–2657.

Pasqualini, J., 2009. Estrogen sulfotransferases in breast and endometrial cancers.Annals of the New York Academy of Sciences 1155, 88–98.

Pasqualini, J., Gelly, C., Nguyen, B., Vella, C., 1989. Importance of estrogen sulfates inbreast cancer. Journal of Steroid Biochemistry 34, 155–163.

http://dx.doi.org/10.1111/j.1447-0756.2010.01509.x


Pavone, M.E., Reierstad, S., Sun, H., Milad, M., Bulun, S.E., Cheng, Y.H., 2010. Alteredretinoid uptake and action contributes to cell survival in endometriosis. Journalof Clinical Endocrinology and Metabolism 95, E300–E309.

Pavone, M.E., Dyson, M., Reierstad, S., Pearson, E., Ishikawa, Cheng, Y.H.H.,Bulun, S.E., 2011. Endometriosis express a molecular pattern cosistent withdecreased retinoid uptake, metabolism and action. Human Reproduction 26,2157–2164.

Puranen, T., Kurkela, R., Lakkakorpi, J., Poutanen, M., Itäranta, P., Melis, J., Ghosh, D.,Vihko, R., Vihko, P., 1999. Characterization of molecular and catalytic propertiesof intact and truncated human 17beta-hydroxysteroid dehydrogenase type 2enzymes: intracellular localization of the wild-type enzyme in the endoplasmicreticulum. Endocrinology 140, 3334–3341.

Purohit, A., Fusi, L., Brosens, J., Woo, L., Potter, B., Reed, M., 2008. Inhibition ofsteroid sulphatase activity in endometriotic implants by 667 COUMATE: apotential new therapy. Human Reproduction 23, 290–297.

Rantakari, P., Strauss, L., Kiviranta, R., Lagerbohm, H., Paviala, J., Holopainen, I.,Vainio, S., Pakarinen, P., Poutanen, M., 2008. Placenta defects and embryoniclethality resulting from disruption of mouse hydroxysteroid (17-beta)dehydrogenase 2 gene. Molecular Endocrinology 22, 665–675.

Ray, P., Ghosh, S., Zhang, D., Ray, A., 1997. Repression of interleukin-6 geneexpression by 17 beta-estradiol: inhibition of the DNA-binding activity of thetranscription factors NF-IL6 and NF-kappa B by the estrogen receptor. FEBSLetters 409, 79–85.

Rizner, T., 2009. Estrogen metabolism and action in endometriosis. Molecular andCellular Endocrinology 307, 8–18.

Rubin, G., Harrold, A., Mills, J., Falany, C., Coughtrie, M., 1999. Regulation ofsulphotransferase expression in the endometrium during the menstrual cycle,by oral contraceptives and during early pregnancy. Molecular HumanReproduction 5, 995–1002.

Shang, Y., 2006. Molecular mechanisms of oestrogen and SERMs in endometrialcarcinogenesis. Nature Reviews Cancer 6, 360–368.

Simpson, E., 2003. Sources of estrogen and their importance. Journal of SteroidBiochemistry and Molecular Biology 86, 225–230.

Smuc, T., Hevir, N., Ribic-Pucelj, M., Husen, B., Thole, H., Rizner, T., 2009. Disturbedestrogen and progesterone action in ovarian endometriosis. Molecular andCellular Endocrinology 301, 59–64.

Smuc, T., Pucelj, M., Sinkovec, J., Husen, B., Thole, H., Lanisnik Rizner, T., 2007.Expression analysis of the genes involved in estradiol and progesterone actionin human ovarian endometriosis. Gynecological Endocrinology 23, 105–111.

Sugawara, T., Abe, S., Sakuragi, N., Fujimoto, Y., Nomura, E., Fujieda, K., Saito, M.,Fujimoto, S., 2001. RIP 140 modulates transcription of the steroidogenic acuteregulatory protein gene through interactions with both SF-1 and DAX-1.Endocrinology 142, 3570–3577.

Suzuki, A., Horiuchi, A., Oka, K., Miyamoto, T., Kashima, H., Shiozawa, T., 2010.Immunohistochemical detection of steroid receptor cofactors in ovarianendometriosis: involvement of down-regulated SRC-1 expression in thelimited growth activity of the endometriotic epithelium. Virchows Archiv456, 433–441.

Tamura, M., Deb, S., Sebastian, S., Okamura, K., Bulun, S.E., 2004. Estrogen up-regulates cyclooxygenase-2 via estrogen receptor in human uterinemicrovascular endothelial cells. Fertility and Sterility 81, 1351–1356.

Trukhacheva, E., Lin, Z., Reierstad, S., Cheng, Y., Milad, M., Bulun, S., 2009. Estrogenreceptor (ER) beta regulates ERalpha expression in stromal cells derived fromovarian endometriosis. Journal of Clinical Endocrinology and Metabolism 94,615–622.

Tsai, S., Wu, M., Lin, C., Sun, H., Chen, H., 2001. Regulation of steroidogenic acuteregulatory protein expression and progesterone production in endometrioticstromal cells. Journal of Clinical Endocrinology and Metabolism 86, 5765–5773.

Utsunomiya, H., Cheng, Y., Lin, Z., Reierstad, S., Yin, P., Attar, E., Xue, Q., Imir, G.,Thung, S., Trukhacheva, E., Suzuki, T., Sasano, H., Kim, J., Yaegashi, N., Bulun, S.,2008. Upstream stimulatory factor-2 regulates steroidogenic factor-1expression in endometriosis. Molecular Endocrinology 22, 904–914.

Vadlamudi, R.K., Rajhans, R., Chakravarty, D., Nair, B.C., Nair, S.S., Evans, D.B., Chen,S., Tekmal, R.R., 2010. Regulation of aromatase induction by nuclear receptorcoregulator PELP1. Journal of Steroid Biochemistry and Molecular Biology 118,211–218.

Velasco, I., Rueda, J., Acién, P., 2006. Aromatase expression in endometriotic tissuesand cell cultures of patients with endometriosis. Molecular HumanReproduction 12, 377–381.

Vouk, K., Smuc, T., Guggenberger, C., Ribic-Pucelj, M., Sinkovec, J., Husen, B., Thole,H., Houba, P., Thaete, C., Adamski, J., Rizner, T.L., 2011. Novel estrogen-relatedgenes and potential biomarkers of ovarian endometriosis identified bydifferential expression analysis. Journal of Steroid Biochemistry andMolecular Biology 125, 231–242.

Wei, L.N., 2004. Retinoids and receptor interacting protein 140 (RIP140) in generegulation. Current Medicinal Chemistry 11, 1527–1532.

Xiu-li, W., Wen-jun, C., Hui-hua, D., Su-ping, H., Shi-long, F., 2009. ERB-041, aselective ER beta agonist, inhibits iNOS production in LPS-activated peritonealmacrophages of endometriosis via suppression of NF-kappaB activation.Molecular Immunology 46, 2413–2418.

Xue, Q., Lin, Z., Cheng, Y., Huang, C., Marsh, E., Yin, P., Milad, M., Confino, E.,Reierstad, S., Innes, J., Bulun, S., 2007. Promoter methylation regulates estrogenreceptor 2 in human endometrium and endometriosis. Biology of Reproduction77, 681–687.

Yang, S., Fang, Z., Gurates, B., Tamura, M., Miller, J., Ferrer, K., Bulun, S.E., 2001.Stromal PRs mediate induction of 17beta-hydroxysteroid dehydrogenase type 2expression in human endometrial epithelium: a paracrine mechanism forinactivation of E2. Molecular Endocrinology 15, 2093–2105.

Zeitoun, K., Takayama, K., Sasano, H., Suzuki, T., Moghrabi, N., Andersson, S., Johns,A., Meng, L., Putman, M., Carr, B., Bulun, S., 1998. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure tometabolize 17beta-estradiol. Journal of Clinical Endocrinology and Metabolism83, 4474–4480.

Zhongyi, S., Rantakari, P., Lamminen, T., Toppari, J., Poutanen, M., 2007. Transgenicmale mice expressing human hydroxysteroid dehydrogenase 2 indicate a rolefor the enzyme independent of its action on sex steroids. Endocrinology 148,3827–3836.

Zschiedrich, I., Hardeland, U., Krones-Herzig, A., Berriel Diaz, M., Vegiopoulos, A.,Müggenburg, J., Sombroek, D., Hofmann, T.G., Zawatzky, R., Yu, X., Gretz, N.,Christian, M., White, R., Parker, M.G., Herzig, S., 2008. Co-activator function ofRIP140 for NFkappaB/RelA-dependent cytokine gene expression. Blood 112,264–276.

estrogen biosynthesis and signaling in endometriosis

Documents