The combination of a progestin such as norethindrone acetate (NETA) reducing the ovarian estrogen production with a steroid sulfatase (STS) inhibitor (STS-I) decreasing the local estrogen production could result in a new treatment option for endometriosis. The study reported was a randomized, double-blind, and placebo-controlled study to investigate the pharmacodynamics, pharmacokinetics, and safety of the STS-I PGL2001 (E2MATE) and NETA. A total of 24 healthy women of reproductive age were treated with weekly doses of PGL2001 or daily doses of NETA or a combination of both compounds for 4 weeks. Four weeks of treatment with PGL2001 or PGL2001 + NETA reduced the STS activity in the endometrium by 91% (±3%) and 96% (±4%), respectively, and comparable values were observed 1 month after the treatment was stopped. The combined treatment of PGL2001 + NETA led to significantly higher STS inhibition at both times (P < .01 and P < .05, respectively). This study showed that administration of PGL2001 alone at 4 mg/week or combined with NETA to healthy women of reproductive age led to STS inhibition and changes in functional STS biomarkers in the endometrium, resulting in synergistic effects of PGL2001 and NETA on STS activity.
RogersPAD'HoogheTMFazleabasA. Priorities for endometriosis research: recommendations from an international consensus workshop. Reprod Sci. 2009;16(4):335–346.
StreuliIdeZDBorgheseBSantulliPBatteuxFChapronC. New treatment strategies and emerging drugs in endometriosis. Expert Opin Emerg Drugs. 2012;17(1):83–104.
5.
RochaALReisFMPetragliaF. New trends for the medical treatment of endometriosis. Expert Opin Investig Drugs. 2012;21(7):905–919.
6.
KitawakiJKadoNIshiharaHKoshibaHKitaokaYHonjoH. Endometriosis: the pathophysiology as an estrogen-dependent disease. J Steroid Biochem Mol Biol. 2002;83(1-5):149–155.
7.
PurohitAFosterPA. Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers. J Endocrinol. 2012;212(2):99–110.
8.
PurohitAWooLWPotterBV. Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism. Mol Cell Endocrinol. 2011;340(2):154–160.
9.
WooLWPurohitAPotterBV. Development of steroid sulfatase inhibitors. Mol Cell Endocrinol. 2011;340(2):175–185.
10.
MaltaisRPoirierD. Steroid sulfatase inhibitors: a review covering the promising 2000-2010 decade. Steroids. 2011;76(10-11):929–948.
11.
ZeitounKTakayamaKSasanoH. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J Clin Endocrinol Metab. 1998;83(12):4474–4480.
12.
SmucTPuceljMRSinkovecJHusenBTholeHLanisnikRT. Expression analysis of the genes involved in estradiol and progesterone action in human ovarian endometriosis. Gynecol Endocrinol. 2007;23(2):105–111.
13.
SmucTHevirNRibic-PuceljMHusenBTholeHRiznerTL. Disturbed estrogen and progesterone action in ovarian endometriosis. Mol Cell Endocrinol. 2009;301(1-2):59–64.
14.
DelvouxBGroothuisPD'HoogheTKyamaCDunselmanGRomanoA. Increased production of 17beta-estradiol in endometriosis lesions is the result of impaired metabolism. J Clin Endocrinol Metab. 2009;94(3):876–883.
15.
BulunSEImirGUtsunomiyaH. Aromatase in endometriosis and uterine leiomyomata. J Steroid Biochem Mol Biol. 2005;95(1-5):57–62.
16.
PasqualiniJR. The selective estrogen enzyme modulators in breast cancer: a review. Biochim Biophys Acta. 2004;1654(2):123–143.
17.
CarlstromKBergqvistALjungbergO. Metabolism of estrone sulfate in endometriotic tissue and in uterine endometrium in proliferative and secretory cycle phase. Fertil Steril. 1988;49(2):229–233.
18.
YamamotoTNoguchiTTamuraTKitawakiJOkadaH. Evidence for estrogen synthesis in adenomyotic tissues. Am J Obstet Gynecol. 1993;169(3):734–738.
19.
EzakiKMotoyamaHSasakiH. Immunohistologic localization of estrone sulfatase in uterine endometrium and adenomyosis. Obstet Gynecol. 2001;98(5 pt 1):815–819.
20.
UtsunomiyaHItoKSuzukiT. Steroid sulfatase and estrogen sulfotransferase in human endometrial carcinoma. Clin Cancer Res. 2004;10(17):5850–5856.
21.
DassenHPunyadeeraCKampsR. Estrogen metabolizing enzymes in endometrium and endometriosis. Hum Reprod. 2007;22(12):3148–3158.
22.
PurohitAFusiLBrosensJWooLWPotterBVReedMJ. Inhibition of steroid sulphatase activity in endometriotic implants by 667 COUMATE: a potential new therapy. Hum Reprod. 2008;23(2):290–297.
23.
HowarthNMPurohitAReedMJPotterBV. Estrone sulfamates: potent inhibitors of estrone sulfatase with therapeutic potential. J Med Chem. 1994;37(2):219–221.
24.
ElgerWPalmeHJSchwarzS. Novel oestrogen sulfamates: a new approach to oral hormone therapy. Expert Opin Investig Drugs. 1998;7(4):575–589.
25.
SahlinLElgerWHeddenA. Effects of estradiol and estradiol sulfamate on the liver of ovariectomized or ovariectomized and hypophysectomized rats. J Steroid Biochem Mol Biol. 2002;80(4-5):457–467.
26.
HoYTPurohitAVickerN. Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates. Biochem Biophys Res Commun. 2003;305(4):909–914.
27.
MacCarthy-MorroghLTownsendPAPurohitA. Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest, apoptosis, and microtubule assembly in human breast cancer cells. Cancer Res. 2000;60(19):5441–5450.
28.
ChanderSKPurohitAWooLWPotterBVReedMJ. The role of steroid sulphatase in regulating the oestrogenicity of oestrogen sulphamates. Biochem Biophys Res Commun. 2004;322(1):217–222.
29.
ColetteSDefrereSLousseJC. Inhibition of steroid sulfatase decreases endometriosis in an in vivo murine model. Hum Reprod. 2011;26(6):1362–1370.
30.
VercelliniPPietropaoloGDeGOPasinRChiodiniACrosignaniPG. Treatment of symptomatic rectovaginal endometriosis with an estrogen–progestogen combination versus low-dose norethindrone acetate. Fertil Steril. 2005;84(5):1375–1387.
31.
VercelliniPSomiglianaEViganoPAbbiatiADaguatiRCrosignaniPG. Endometriosis: current and future medical therapies. Best Pract Res Clin Obstet Gynaecol. 2008;22(2):275–306.
32.
LoeblECBaxterCRCurreriPW. The mechanism of erythrocyte destruction in the early post-burn period. Ann Surg. 1973;178(6):681–686.
33.
SimpsonER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol. 2003;86(3-5):225–230.
34.
MaitokoKSasakiH. Gonadotropin-releasing hormone agonist inhibits estrone sulfatase expression of cystic endometriosis in the ovary. Fertil Steril. 2004;82(2):322–326.
35.
FalanyCN. Enzymology of human cytosolic sulfotransferases. FASEB J. 1997;11(4):206–216.
36.
Muneyyirci-DelaleOKaracanM. Effect of norethindrone acetate in the treatment of symptomatic endometriosis. Int J Fertil Womens Med. 1998;43(1):24–27.
