title: Inhibition of type 1 17β-hydroxysteroid dehydrogenase impairs the synthesis of 17β-estradiol in endometriosis lesions.
abstract: BACKGROUND
  Endometriosis affects 10% of the women before menopause and has important personal, professional, and societal economic burdens. Because current medical treatments are aimed at reducing the symptoms only, novel therapeutic targets should be identified. Endometriosis is estrogen dependent and in some patients the endometriosis tissue is able to produce estrogens in an autocrine/paracrine manner. In a number of patients, this is the consequence of the high local activity of the 17β-hydroxysteroid-dehydrogenases (17β-HSDs), enzymes able to generate active estrogens from precursors with low activity.
  
  
  OBJECTIVE
  The objective of the study was to identify the 17β-HSD(s) responsible for the high local generation of estrogens in endometriosis and test the possibility to inhibit these enzymes for therapeutic purposes.
  
  
  METHODS
  The expression of different 17β-HSDs involved in the estrogen metabolism was assessed by real-time PCR in eutopic and ectopic tissue from endometriosis patients (n=14). These biopsies had previously confirmed unbalanced local 17β-HSD activity, which caused high estrogen generation. The possibility to block the synthesis of estrogens by one inhibitor specific for type 1 17β-HSD was assessed by HPLC in tissue lysates from endometriosis tissues (n=27).
  
  
  RESULTS
  In all but one of the patients, a high type 1 17β-HSD level is associated with the unbalanced metabolism of estrogens, leading to higher estrogen synthesis in endometriosis than in the endometrium inside the uterus. Inhibition of type 1 17β-HSD restores to various extents, depending on the patient, the correct metabolism. In 19 of 27 patients analyzed (70%), the 17β-HSD type 1 inhibitor decreased the generation of 17β-estradiol by greater than 85%.
  
  
  CONCLUSIONS
  Inhibition of 17β-HSD type 1 can be a potential future treatment option aimed at restoring the correct metabolic balance of estrogens in endometriosis patients with increased local 17β-HSD type 1 enzyme activity.
authors.affiliation: GROW School for Oncology and Developmental Biology, Department of Obstetrics and Gynaecology (B.D., G.A.D., A.R.), and CAIM, Cardiovascular Research institute Maastricht, Department of Pharmacology (R.J.J.H.), Maastricht University Medical Centre, 6202 AZ Maastricht, The Netherlands; Department of Obstetrics and Gynaecology (T.D., C.K.), University Hospital Gasthuisberg, 3000 Leuven, Belgium; and Forendo Pharma Ltd (P.K.), FI-20520 Turku, Finland.
authors.forename: Bert
authors.initials: B
authors.lastname: Delvoux
authors.forename: Thomas
authors.initials: T
authors.lastname: D'Hooghe
authors.forename: Cleophas
authors.initials: C
authors.lastname: Kyama
authors.forename: Pasi
authors.initials: P
authors.lastname: Koskimies
authors.forename: Rob J J
authors.initials: RJ
authors.lastname: Hermans
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Dunselman
authors.forename: Andrea
authors.initials: A
authors.lastname: Romano
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004715:Endometriosis / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007410:Intestinal Diseases / Q000378:metabolism / Q000473:pathology; D010049:Ovarian Diseases / Q000378:metabolism / Q000473:pathology; D010532:Peritoneal Diseases / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase