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, Finland b Department of Obstetrics & Gynecology, Turku University Hospital, 20520 Turku, Finland c Turku Center for Disease Modeling, University of Turku, 20014 Turku, Finland article info Article history: Available online 22 August 2011 Keywords: Steroidogenesis Pre-receptor regulation Estrogen receptor Coregulator Hydroxysteroid (17beta) dehydrogenase Aromatase abstract Endometriosis is an estrogen-dependent gynecological disease where endometrium-like tissue grows outside uterine cavity. Endometriotic cell proliferation is stimulated by estrogens acting predominantly via their nuclear receptors. Estrogen receptors (ESR1, ESR2) are ligand activated transcription factors whose activation is dependent on the cell-specific dynamic expression of the receptors, on the interacting proteins and on the ligand availability. The different types of endometriotic lesions, peritoneal, deep, and ovarian endometriosis, may respond to estrogens differentially due to differences in the expression of the receptors and interacting proteins, and due to potential differences in the ligand availability regulated by the local estrogen synthesis. This review summarizes the current knowledge of estrogen synthesizing enzymes and estrogen receptors in different types of endometriosis lesions. Further studies are still needed to define the possible differences in steroid metabolism in different types of endometriotic lesions. Ó 2011 Elsevier Ireland Ltd. All rights reserved. Contents 1. Endometriosis as an estrogen-dependent disease ........................................................................... 146 2. Source of estrogens in endometriosis ..................................................................................... 147 3. Local estradiol synthesis in endometriosis lesions ........................................................................... 147 3.1. Production of estrone in endometriosis .............................................................................. 147 3.2. Activation of estrone to estradiol in endometriosis .................................................................... 150 3.3. Release of estrone and estradiol from their sulfate conjugates ........................................................... 150 4. Inactivation of estrogens ............................................................................................... 150 5. Estrogen receptors in endometriosis ...................................................................................... 151 5.1. ESR1 and ESR2, endometriotic cell proliferation and inflammation ....................................................... 151 5.2. GPER.......................................................................................................... 151 5.3. Estrogen receptor coregulators in endometriosis ...................................................................... 152 6. Ovarian endometriosis ................................................................................................. 152 References .......................................................................................................... 152 1. Endometriosis as an estrogen-dependent disease Endometriosis is an estrogen-dependent gynecological disease characterized by endometrial-like tissue growing outside the uterine cavity, typically on the pelvic peritoneum, in the ovaries and in the rectovaginal septum (Giudice, 2010). A severe disease typically results in extensive pelvic adhesions and deformation of pelvic anatomy, often leading to pain and infertility. The incidence of endometriosis is estimated to be 10% in women of reproductive age, while the frequency rises to 50–60% within women with pain with or without infertility (Giudice, 2010). Several factors have been suggested to be involved in the pathogenesis of the disease. These include hormonal regulation, inflammation, as well as genetic and environmental factors. 0303-7207/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2011.08.022 ⇑ Corresponding author at: Department of Physiology, Institute of Biomedicine, University of Turku, 20014 Turku, Finland. Tel.: +358 23337571; fax: +358 2 2502610. E-mail addresses: kaisa.huhtinen@utu.fi (K. Huhtinen), mrstah@utu.fi (M. Ståhle), antti.perheentupa@utu.fi (A. Perheentupa), matti.poutanen@utu.fi (M. Poutanen). 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