The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

Rižner TL, Tea Lanišnik Rižner
Frontiers in pharmacology · 2016 · vol. 7 , pp. 30 · doi:10.3389/fphar.2016.00030 · PMID:26924986 · PMC4757672 · W2323264979
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This review examines the roles of sulfatase and sulfotransferases in local estrogen formation for gynecological diseases, noting altered enzyme activities in diseased tissues and potential for sulfatase as a drug target.

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This paper reviews how steroid sulfatase (STS) and steroid sulfotransferases (SULTs) regulate estrogen-dependent gynecological disease biology by controlling the interconversion of steroid sulfates (e.g., estrone sulfate to estrone, and dehydroepiandrosterone sulfate to dehydroepiandrosterone), alongside further conversion to estradiol. It synthesizes mechanistic and genetic information on STS/SULT regulation, including gene structure/transcripts, single nucleotide polymorphisms, enzyme kinetics, and summarized expression data across gynecological diseases, noting that mRNA/protein levels are often unchanged while STS activity is higher in cancerous endometrium, ovarian cancer cell lines, and adenomyosis. A key caveat emphasized is that clinical translation of sulfatase inhibition has so far not produced convincing clinical outcomes in endometrial cancer and endometriosis despite phase II trials. This paper is centrally about endometriosis and adenomyosis — it reviews the steroid sulfatase and sulfotransferase pathways, highlights increased sulfatase activity in adenomyosis, and discusses sulfatase inhibitor trial results and prior evidence in endometriosis.

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Abstract

Gynecological diseases such as endometriosis, adenomyosis and uterine fibroids, and gynecological cancers including endometrial cancer and ovarian cancer, affect a large proportion of women. These diseases are estrogen dependent, and their progression often depends on local estrogen formation. In peripheral tissues, estrogens can be formed from the inactive precursors dehydroepiandrosterone sulfate and estrone sulfate. Sulfatase and sulfotransferases have pivotal roles in these processes, where sulfatase hydrolyzes estrone sulfate to estrone, and dehydroepiandrosterone sulfate to dehydroepiandrosterone, and sulfotransferases catalyze the reverse reactions. Further activation of estrone to the most potent estrogen, estradiol, is catalyzed by 17-ketosteroid reductases, while estradiol can also be formed from dehydroepiandrosterone by the sequential actions of 3β-hydroxysteroid dehydrogenase-Δ(4)-isomerase, aromatase, and 17-ketosteroid reductase. This review introduces the sulfatase and sulfotransferase enzymes, in terms of their structures and reaction mechanisms, and the regulation and different transcripts of their genes, together with the importance of their currently known single nucleotide polymorphisms. Data on expression of sulfatase and sulfotransferases in gynecological diseases are also reviewed. There are often unchanged mRNA and protein levels in diseased tissue, with higher sulfatase activities in cancerous endometrium, ovarian cancer cell lines, and adenomyosis. This can be indicative of a disturbed balance between the sulfatase and sulfotransferases enzymes, defining the potential for sulfatase as a drug target for treatment of gynecological diseases. Finally, clinical trials with sulfatase inhibitors are discussed, where two inhibitors have already concluded phase II trials, although so far with no convincing clinical outcomes for patients with endometrial cancer and endometriosis.
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Local

STS and SULTs have pivotal roles in estrogen synthesis in peripheral tissues, and thus also in pre-receptor regulation of steroid hormone action. In premenopausal women, estrogens can be synthesized in the ovaries and in peripheral tissues (Labrie, 1991 ; Simpson, 2003 ). After menopause, when the ovaries cease to act, estrogens are formed only in the peripheral sites, which mainly include adipose tissue, but also bone, vascular endothelium, aortic smooth muscle cells, and brain (Simpson, 2003 ). Locally, estrogens can be formed from the inactive precursors of adrenal origin, DHEA-S, DHEA, and androstenedione, and of ovarian origin, DHEA and androstenedione, or from circulating E1-S (Figure 1 ). These steroid precursors are at relatively high concentrations in the blood of premenopausal and postmenopausal women, with DHEA-S at 3.4 ± 1.7 μM and 1.6 ± 1.0 μM, respectively (Labrie et al., 2006 ). DHEA and androstenedione are at 15.5 ± 7.6 nM and 3.4 ± 1.2 nM respectively, in premenopausal women, and 6.8 ± 4.1 nM and 1.4 ± 0.6 nM, respectively, in postmenopausal women (Labrie et al., 2006 ). Estrogens can thus be produced via the so-called aromatase pathway, from androstenedione and testosterone, by the actions of aromatase and 17-ketosteroid reductases (i.e., 17β-hydroxysteroid dehydrogenases; HSD17B), mainly HSD17B1. Estrogens can also be formed from DHEA-S by the actions of STS, 3β-hydroxysteroid dehydrogenases-Δ 4 -isomerase (HSD3B1, HSD3B2), aromatase (CYP19A1) and HSD17B or aldo-keto reductase 1C3 (AKR1C3) and CYP19A1, and from E1-S by the actions of STS and HSD17B (Rižner, 2013 ; Figure 1 ). The formation of E2 from E1-S is known as the STS pathway. E1-S is the most important estrogen in the peripheral blood, at 1.8 ± 1.1 nM and 0.6 ± 0.03 nM in premenopausal and postmenopausal women, respectively (Caron et al., 2009 ; Labrie et al., 2009 ). Studies in breast and endometrial cancers have shown that the STS pathway prevails over the aromatase pathway (Pasqualini et al., 1996 ; Chetrite et al., 2000 ; Purohit et al., 2011 ; Rižner, 2013 ). Higher E1-S, E1, and E2 plasma concentrations were observed for patients with breast cancer and endometrial cancer, compared to control women (Lépine et al., 2010 ; Tworoger et al., 2014 ) and high E1-S and E2 have been measured in breast cancer tissue (Chetrite et al., 2000 ), with high E2 and a high E2 to E1-S ratio reported in endometrial cancer tissue (Naitoh et al., 1989 ; Berstein et al., 2003 ). Most importantly, the levels of estrogens in breast and endometrial cancer tissue are 2- to 40-fold higher compared to plasma concentrations (Pasqualini et al., 1996 ; Berstein et al., 2003 ), further supporting intracrine formation and actions of estrogens. DHEA-S and E1-S can thus serve as precursors for E2 formation after their translocation into cells via the transporter proteins of the organic anion-transporting polypeptide and organic anion-transporter families (Mueller et al., 2015 ). STS can then hydrolyze DHEA-S and E1-S to DHEA and E1, respectively, while the SULTs can catalyze the reverse reactions. SULT1E1 inactivates E1 and E2 to form the corresponding sulfates, and SULT2A1 and SULT2B1 conjugate DHEA (Raftogianis et al., 2000 ; Meloche and Falany, 2001 ; Gamage et al., 2006 ; Pasqualini, 2009 ). The sulfated steroids can then be excreeted from the cells via the ABC transporters (Mueller et al., 2015 ). The resulting increased uptake together with the decreased excretion of DHEA-S and E1-S, and the disturbed delicate balance between the STS and SULT enzymes, might thus lead to increased levels of estrogens, which are associated with hormone-dependent diseases, including several gynecological diseases.

Author

The author confirms being the sole contributor of this work and approved it for publication. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Steroid

The SULTs catalyze the transfer of a sulfuryl group from 3′-phosphoadenosine-5′-phosphosulfate (PAPS) to the target molecule. This conjugation is typically involved in inactivation/detoxification reactions for a variety of substrates, such as xenobiotics, therapeutic drugs, toxic compounds, chemical carcinogens, bile acids, hormones and neurotransmitters, and it is also an important pathway for hormonal regulation (Geese and Raftogianis, 2001 ). The superfamily of cytosolic human SULTs comprises 13 SULT genes and spans four families: SULT1 includes three phenol SULT subfamilies (SULT1A, SULT1B, SULT1C) and an estrogen SULT (SULT1E1); SULT2s catalyze sulfonation of the hydroxyl groups of steroids (SULT2A1, SULT2B1); and there are two orphan SULT families, SULT4 and SULT6 (SULT4A1, SULT6B1) (reviewed in Geese and Raftogianis, 2001 ; Lindsay et al., 2008 ). SULT2A1 catalyzes the sulfonation of DHEA, androgens and estrogens, while SULT2B1 catalyzes sulfonation of only DHEA (Lindsay et al., 2008 ). Although SULTs in general have broad substrate specificity, SULT1E1 (E.C. 2.8.2.4.) has significantly greater affinity for the estrogens than other SULTs, and it inactivates E1 and estradiol (E2) with nM Km values (Falany et al., 1995 ; Table 1 ). SULT2A1 (E.C. 2.8.2.14) and SULT2B1 (E.C. 2.8.2.2) both catalyze sulfation of DHEA, although SULT2A1 shows much higher catalytic efficiency (Lu et al., 2008 ). The SULTs need PAPS as a coenzyme, and thus SULT expression has to be accompanied by expression of at least one of the two PAPS synthase genes (Mueller et al., 2015 ). The SULT1E1 gene has been localized to chromosome 4 (4q13.2), it has eight exons and a length of 20 kb, and it encodes a protein of 294 amino acids with a molecular mass of 35 kDa (Falany et al., 1995 ). Recombinant SULT1E1 has been crystalized, and the structure of the binary complex with PAPS (pdb code 1HY3; Pedersen et al., 2002 ) and several ternary complexes, including a complex with PAP and E2 (pdb code 4JVL; Gosavi et al., 2013 ), have been resolved. SULT1E1 is a dimer with an α/β motif that consists of five parallel β-strands surrounded by α-helices and a conserved α-helix across this structure (Pedersen et al., 2002 ) (Figure 3A ). The structure of the SULT1E1–PAP–E2 complex has revealed that E2 binds to a mostly buried hydrophobic pocket with the sulfuryl acceptor 3′ hydroxyl within H-bonding distance of the proposed catalytic His107, and Lys10. The Phe80 and Phe141 are involved in the positioning of the steroidal substrate and have been suggested to function as a steric gate, thus defining substrate specificity (Gosavi et al., 2013 ). SULT1E1 has three catalytic amino-acid residues: Lys47, His107, and Ser137 (Negishi et al., 2001 ). The proposed reaction mechanism is as follows: upon binding of PAPS, Ser137 forms an H-bond with Lys47, thus prevents its interaction with the bridging oxygen in PAPS and its further hydrolysis; His107 attracts a proton from the substrate hydroxyl (i.e., of E2, DHEA), and enables nucleophilic attack at the sulfur atom in PAPS. In the next step, Lys47 interacts with the 5′ phosphate of PAPS, which help in dissociation of the sulfuryl group and in its transfer to the substrate. Finally, the reaction products, PAP and E1-S are released, which completes the catalytic cycle (Gamage et al., 2006 ; Tibbs et al., 2015 ) (Figure 3B ). The crystallization and kinetics data have further suggested that the substrate inhibition that has been observed at high concentrations is a dead-end complex where both PAP and E2 are bound (Gosavi et al., 2013 ). Tertiary structure and reaction mechanism of the human SULT1E1 enzyme. (A) Structure of the human SULT1E1 enzyme in complex with PAP and E2 (pdb 4JVL). (B) Reaction mechanism and the roles of catalytical amino-acid residues His107, Lys47, and Ser137. The scheme was adopted from Thomas and Potter ( 2013 ). For the SULT1E1 gene, in addition to the primary transcript, there are two variant transcripts (i.e., variants X1, X2) that encode proteins of 294 amino acids and 181 amino acids. Currently more than 150 cSNPs are included in the SNP database for SULT1E1 , but none show MAF >0.01 (Table 2 ). Functional analysis has revealed decreased SULT1E1 activities for two nonsynonymous coding SNPs: Asp22Tyr and Ala32Val (Adjei et al., 2003 ). These cSNPs were found in African-American (Asp22Tyr) and Caucasian (Ala32Val) populations (Adjei et al., 2003 ). Additionally, the SNP rs6259 in the promoter region of SULT1E1 has been associated with increased risk of endometrial cancer (Rebbeck et al., 2006 ; Hirata et al., 2008 ), and SNPs * 959 G>A and IVS4-1653 T>C with increased recurrence of endometrial cancer (Choi et al., 2005 ). SULT1E1 is expressed in liver, secretory endometrium, fetal liver, lung, and kidney (Coughtrie, 2002 ). Expression of SULT1E1 is regulated by steroid hormones. In the normal endometrium, the highest expression of SULT1E1 was found for the secretory phase, which is consistent with regulation by progesterone (Falany and Falany, 1996 ; Rubin et al., 1999 ; Dassen et al., 2007 ), although Colette et al. recently reported that SULT1E1 expression is unchanged in the proliferative and secretory phases (Colette et al., 2013 ). In endometrial cancer cell line Ishikawa SULT1E1 is induced by steroid drug tibolone via progesterone receptor (Falany and Falany, 2006 ), while in liver it is repressed by xenobiotic activators of the pregnane X receptor and aryl hydrocarbon receptor peroxisome proliferator, and activated via peroxisome proliferator activated receptor α and the liver X receptor (Duanmu et al., 2007 ). Furthermore, studies have implied that SULT1E1 is also epigenetically regulated, as its expression is induced by the histone deacetylase inhibitor trichostatin A in MCF10A cells (Fu et al., 2010 ). SULT1E1 activity is also affected by ubiquitous pollutants, such as the polychlorinated biphenyls, which act as potent inhibitors with Ki values in the pM range, and thus they can exert their endocrine disrupting effects without binding to steroid hormone receptors (Kester et al., 2000 ). The SULT2A1 gene has been localized to chromosome 19 (19q13.3). It has six exons and a total length of 16 kb (Freimuth et al., 2004 ), with only one transcript known, which encodes a protein with 285 amino acids and a molecular mass of 34 kDa (Table 2 ). Several crystal structures of SULT2A1 binary complexes have been resolved (Tibbs et al., 2015 ), including complexes with DHEA (pdb code 1J99; Rehse et al., 2002 ) and PAPS (pdb code 4IFB). The complete kinetic mechanism of SULT2A1 has been defined, which revealed that the binding of DHEA and PAPS is random, while the rate-limiting step is nucleotide release. Here, the potent substrate inhibition with a Ki of 6.1 μM for DHEA can be explained by trapping PAP in a dead-end complex, which impedes the release of the nucleotide coenzyme (Wang et al., 2014 ). SULT2A1 is expressed in liver, adrenal gland, fetal adrenal, and fetal liver (Luu-The et al., 1995 ; Coughtrie, 2002 ). SULT2A1 has broad substrate specificity, as it can catalyze sulfonation of many hydroxysteroids, including DHEA, epiandrosterone, androsterone, testosterone, E2, cholesterol, various bile acids, pregnenolone, 17-ethinyl-E2 and cortisol (Lindsay et al., 2008 ). More than 160 cSNPs have been reported for SULT2A1 (Table 2 ). Functional analysis has revealed that the nonsynonymous SNPs Met57Thr, Glu186Val, Ala63Pro, and Lys227Glu result in decreased SULT2A1 activity when expressed in COS-1 cells (Nagata and Yamazoe, 2000 ). Interestingly, the SULT2A1 SNPs Ala63Pro, Lys227Glu and Ala261Thr have only been found in African-American populations, and these might explain the reported interethnic differences in SULT2A1 activity (Thomae et al., 2002 ; Hildebrandt et al., 2007 ). The SULT2A1 SNP Ala261Thr has an allele frequency of 13% in African-American populations (reported MAF, 0.0407) and is located within the dimerization motif, where it prevents formation of SULT2A1 dimers. Surprisingly Ala261Thr still has 93% of the wild-type enzyme activity. Also Ala63Pro is quite common, with an allele frequency of 5% in African-American populations, and a reported MAF of 0.024 (Table 2 ). The expression of SULT2A1 is regulated at the transcriptional level by the constitutive androstane receptor and pregnane X receptor (Echchgadda et al., 2007 ). As recently shown in human hepatocytes and the HepG2 cell line, the SULT2A1 gene is induced by E2 activation of estrogen receptor (ER)α via classical, direct binding to the estrogen response element, and via nonclassical, AP-1–mediated mechanisms (Li et al., 2014 ). SULT2A1 appears to be regulated also at the epigenetic level, as shown by induction of SULT2A1 expression after treatment of MCF7 cells with a histone deacetylase inhibitor (Fu et al., 2010 ). In the adrenal gland, the expression of SULT2A1 depends on two transcription factors: steroidogenic factor 1 and GATA-6 (Saner et al., 2005 ). The SULT2B1 isoforms SULT2B1a and SULT2B1b are products of alternative transcriptional initiation and mRNA splicing of the same gene, and are expressed in different tissues. SULT1B1a is expressed in colon, ovary, and fetal brain, and SULT2B1b in liver, colon, small intestine, placenta, ovary, uterus, and prostate (Geese and Raftogianis, 2001 ). SULT1B1a and SULT1B1b, which has an additional 23 N-terminal amino-acid residues, have been cloned and expressed in prokaryotic and eukaryotic systems, and purified and characterized (Geese and Raftogianis, 2001 ; Meloche and Falany, 2001 ). These enzymes catalyze sulfonation of 3β-hydroxysteroids, pregnenolone, 17α-hydroxypregnenolone and DHEA (Geese and Raftogianis, 2001 ). The structures of both SULT2B1a and SULT2B1b in binary complexes with PAP (pdb codes 1Q1Q, 1Q1Z, respectively Lee et al., 2003 ) have been resolved, as have two ternary complexes of SULT1Bb with PAP and pregnenolone (pdb code 1Q2O; Lee et al., 2003 ), and with PAP and DHEA (pdb code 1Q22, Lee et al., 2003 ; Tibbs et al., 2015 ). The SULT2B1 gene has been localized to chromosome 19 (19g13.3), and it comprises six exons with a total length of 48 kb (Geese and Raftogianis, 2001 ; Meloche and Falany, 2001 ; Freimuth et al., 2004 ). Three transcripts have been identified (variants 1, 2, X1) that encode proteins of 350, 365, and 221 amino acids (Table 2 ). Although more than 200 coding SNPs for SULT2B1 are currently included in the SNP database, there is only one nonsynonymous SNP: Arg33Gln, with MAF >0.01 (Table 2 ). So far, only a few of these SNPs have been studied in more detail. Recently, Lévesque et al. ( 2014 ) reported that SULT2B1 SNPs rs12460535, rs2665582, and rs10426628 are significantly associated with prostate cancer progression and hormone levels. The SULT enzymes are known to show profound substrate inhibition, and SULT2B1 is not an exception. DHEA inhibits SULT2B1a and SULT2B1b with Ki values of 48 μM and 22 μM, respectively (Geese and Raftogianis, 2001 ). Not much is known about the regulation of SULT2B1 . In normal endometrium, higher SULT2B1b mRNA levels have been seen in the mid-luteal phase, in agreement with progesterone regulation (Koizumi et al., 2010 ). In human endometrial stromal cells, the levels of SULT2B1b transcript were increased by cAMP or progesterone, while they were increased by cAMP or relaxin in endometrial epithelial cells, stimulating protein kinase A pathway (Koizumi et al., 2010 ). In prostate cancer cells, expression of SULT1B1b was shown to be regulated by vitamin D via heterodimer of vitamin D receptor and retinoid X receptor α (Seo et al., 2013 ).

Sulfatase

The development of STS inhibitors started in the 1990s, and to date, this has led to two compounds that have entered clinical trials (Poirier, 2015 ). STS inhibitors have been developed by several research groups and several pharmaceutical companies, and the current status of this field has been a topic of several educative reviews in the last few years (Mostafa and Taylor, 2013 ; Sadozai, 2013 ; Thomas and Potter, 2013 , 2015 ; Williams, 2013 ; Poirier, 2015 ). In general, the large number of STS inhibitors known to date can be divided into steroidal and nonsteroidal compounds, and further into sulfomoylated and nonsulfomoylated compounds (Maltais and Poirier, 2011 ). Among the steroidal compounds, estrogen O-sulfamates have been the most intensively studied in in-vitro and in-vivo models. These have included E1-3-O-sulfamate (EMATE) and E2-3-O-sulfamate (E2MATE), where EMATE was identified as the first irreversible STS inhibitor, although it was originally developed as a prodrug for estrogen replacement therapy (Sadozai, 2013 ; Thomas and Potter, 2015 ). Nonsteroidal inhibitors have also been developed, and an irreversible STS inhibitor, 667 Coumate (also known as STX64 and BN83495, and more recently referred to as irosustat), shows higher potency than EMATE (IC 50 , 8 nM vs. 25 nM, at 20 μM E1-S, against STS from placental microsomes) (Woo et al., 2000 ). This compound has high bioavailability, which was explained by its sequestration within erythrocytes, where it binds to carbonic anhydrase II (IC 50 , 25 nM) (Ho et al., 2003 ). A plethora of EMATE and 667 Coumate derivatives have been developed in the last few years as 2nd and 3rd generation STS inhibitors (Sadozai, 2013 ; Thomas and Potter, 2015 ). These have included the steroidal compound KW-2581 that showed no estrogenic activity (Ishida et al., 2007 ), and STX213 and STX1938, which have shown greater potency than 667 Coumate (Foster et al., 2008b ). In addition to classical STS inhibitors, dual inhibitors that target STS and aromatase have also been developed (Sadozai, 2013 ), as well as compounds with dual actions as STS inhibitors and prodrugs of selective estrogen modulators (Sadozai, 2013 ). Here, the nonsteroidal dual aromatase–STS inhibitor STX681 has shown great potential for treatment of hormone-dependent breast cancer (Foster et al., 2008a ), and the dual sulfamate STS inhibitor and antiestrogen SR16157 has also been studied (Rasmussen et al., 2007 ; Sadozai, 2013 ). The published data imply that inhibitors of STS have the potential for treatment of individual gynecological diseases. In the case of endometriosis, STS activity correlates with the severity of this disease, and Purohit et al. reported that the STS inhibitor STX64 almost completely blocked STS activity in vitro in eutopic and ectopic tissue from patients with peritoneal endometriosis (Purohit et al., 2008 ). Furthermore, E2MATE inhibited STS activity in endometrial tissue in vitro and in vivo in animal models, including in mouse uterus, liver, leukocytes and endometriotic lesions (Colette et al., 2011 ). Also, the inhibitor STX64 has been investigated in intact mouse endometrial cancer xenografts and ovariectomized mouse endometrial cancer xenograft models, and in the latter case, STX64 showed significant inhibition after daily 1–10 mg/kg oral doses (Foster et al., 2008c ), thus demonstrating the great potential of STS inhibitors as novel anticancer drugs. To the best of our knowledge, STS inhibitors have not yet been investigated in ovarian cancer, adenomyosis and myoma uteri, neither in vitro nor in vivo . Several clinical studies have already been performed with STS inhibitors (Thomas and Potter, 2015 ). Irosustat (i.e., 667 Coumate) was the first STS inhibitor to enter phase I clinical trials, in post-menopausal women with ER-positive breast cancer ( NCT01840488 ); (Stanway et al., 2006 ). Later, two phase II clinical studies were reported in breast cancer patients (ClinicalTrials.gov): the IPET trial was designed to look at the effects of irosustat using positron emission tomography scanning (Thomas and Potter, 2015 ), while the IRIS trial investigated the effects of combined treatment with irosustat and anastrozole (an aromatase inhibitor) ( NCT01785992 ). Unfortunately no study data are publicly available for these trials. Irosustat has also been investigated in ER-positive advanced/recurrent endometrial cancer in a phase II study ( NCT00910091 ). In this study, irosustat was evaluated vs. progestin megestrol acetate in 73 patients, with median age 68 years (range, 37–85 years). Here, 36 patients were randomized to irosustat (40 mg/day), and 37 to megestrol acetate (160 mg/day) (Pautier et al., 2012 ). After 6 months of treatment, 36.1 and 56.8% of the patients treated with irosustat and megestrol acetate, respectively, were alive and without disease progression. Progression free survival was 16 and 32 weeks for irosustat and megestrol acetate, respectively. Thus, in patients with advanced and recurrent disease, irosustat showed much lower clinical benefit compared to progestin megestrol acetate, which questioned the suitability of STS inhibitors for treatment of endometrial cancer. In a murine model, E2MATE reduced the weight of the endometriotic lesions, but had no effects on proliferation and apoptosis, or on STS expression (Colette et al., 2011 ), which led the Swiss-based biopharmaceutical company PregLem to investigate E2MATE in endometriosis patients. As described by Pohl et al. they first examined the effects of E2MATE in a phase I study (SAPHIR; EudraCT number: 2007-005662-12) in healthy women of reproductive age, through which they showed that E2MATE can inhibit STS in peripheral blood mononuclear cells, although it failed to inhibit STS in eutopic endometrium (Pohl et al., 2014 ). As a continuation, they investigated the effects of E2MATE (4 mg/week) and/or norethindrone acetate (NETA; 10 mg/day) in healthy nonpregnant women of reproductive age (i.e., 24–39 years). Twenty-four women were randomized to E2MATE, NETA or the combination E2MATE+NETA, for 4 weeks of treatment and 12 weeks of follow-up. In both the E2MATE and E2MATE+NETA groups, the STS activity in peripheral blood mononuclear cells and in the endometrium decreased by 90–91% and 89–96%, respectively, during treatment, and these inhibition levels remained high also 1 month after the treatments (Pohl et al., 2014 ). E2MATE and NETA have been further studied in endometriosis patients in a phase II study (EudraCT Number: 2011-005167-24), although at present, no results are publicly available.

Conclusions

The STS pathway is clearly implicated in local estrogen formation, and is thus also associated with enhanced estrogen actions. A vast amount of data supports an important role for STS in hormone-dependent diseases, including gynecological diseases like endometrial cancer, ovarian cancer, endometriosis, and adenomyosis, and indirectly also in uterine fibroids. However, the clinical studies that have evaluated STS inhibitors in gynecological diseases to date have not provided convincing data. Although the dual STS and aromatase inhibitors and dual action inhibitors/antiestrogens might provide better clinical performances compared to the classical STS inhibitors, these agents have not reached clinical studies to date. As the intricate local estrogen formation also depends on membrane transport of the sulfated steroids, this aspect needs to be investigated more in detail. This knowledge might contribute to a logical interpretation of the clinical studies to date, and might lead to the identification of novel drug targets and combined treatments that will target individual transporters and the STS enzyme.

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