title: Steroidogenic pathways involved in androgen biosynthesis in eumenorrheic women and patients with polycystic ovary syndrome.
abstract: The conventional Δ5 and Δ4 steroidogenic pathways mediate androgen production in females. While multiple non-conventional pathways to dihydrotestosterone (DHT) have recently been postulated in humans, the functional significance of these pathways remains to be elucidated. The aim of this study was to clarify the origin of androgens in healthy women and in patients with polycystic ovary syndrome (PCOS), a multifactorial disorder characterized by androgen overproduction. We measured 13 steroids in blood samples of 31 eumenorrheic females and 28 PCOS patients using liquid chromatography-tandem mass spectrometry and chemiluminescent enzyme immunoassay. We found that 17-hydroxy (17-OH) progesterone (17-OHP), androstenedione (Δ4A), testosterone, androstanedione, androsterone, and androstanediol levels were higher in the patient group than in the eumenorrheic group, while levels of other steroids were comparable between the two groups. In the eumenorrheic group, DHT levels were correlated with testosterone, androstanedione, and androstanediol. Quantitative correlations were also observed among 17-OH allopregnanolone, androsterone, androstanediol, and DHT, and among Δ4A, androstanedione, androsterone, and androstanediol. In the patient group, DHT levels were correlated with testosterone levels, but not with androstanedione or androstanediol levels. Δ4A and testosterone paralleled 17-OHP. Androstanedione, androsterone, androstanediol, and 17-OH allopregnanolone were quantitatively correlated. In both groups, multivariable linear regression analyses suggested relationships between androsterone and androstanedione, as well as between androsterone and 17-OH allopregnanolone. These results indicate that multiple androgen biosynthesis pathways are operating in eumenorrheic females and PCOS patients. In PCOS patients, excessive androgens are produced primarily via the conventional pathways, while two alternative pathways; i.e., an androstanedione-mediated pathway and a so-called backdoor pathway, likely serve as sources of a weak androgen and potential precursors of DHT.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic address: saito-kz@ncchd.go.jp.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokushima Graduate School, Institute of Health Biosciences, Tokushima 770-8503, Japan. Electronic address: matsuzaki.toshiya@tokushima-u.ac.jp.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Matsuzaki
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokushima Graduate School, Institute of Health Biosciences, Tokushima 770-8503, Japan. Electronic address: iwasa.takeshi@tokushima-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwasa
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. Electronic address: miyado-m@ncchd.go.jp.
authors.forename: Mami
authors.initials: M
authors.lastname: Miyado
authors.affiliation: Division of Reproductive Medicine, Center for Maternal-Fetal-Neonatal and Reproductive Medicine, National Medical Center for Children and Mothers, Tokyo 157-8535, Japan. Electronic address: saitou-hi@ncchd.go.jp.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: thaseg@a6.keio.jp.
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Laboratory Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: keiko.homma@adst.keio.ac.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Homma
authors.affiliation: Division of Statistical Analysis, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo 157-8535, Japan. Electronic address: inoue-ei@ncchd.go.jp.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Inoue
authors.affiliation: ASKA Pharmaceutical Medical Corporation, Kanagawa 213-8522, Japan. Electronic address: miyashiro@ap-med.co.jp.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Miyashiro
authors.affiliation: Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic address: t.kubota.gyne@tmd.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Obstetrics and Gynecology, The University of Tokushima Graduate School, Institute of Health Biosciences, Tokushima 770-8503, Japan. Electronic address: irahara@tokushima-u.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Irahara
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan. Electronic address: tomogata@hama-med.ac.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. Electronic address: fukami-m@ncchd.go.jp.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
mesh_terms: D000328:Adult; D000728:Androgens / Q000097:blood*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006728:Hormones / Q000097:blood*; D006801:Humans; D011085:Polycystic Ovary Syndrome / Q000097:blood*; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D000728:Androgens; D006728:Hormones
keywords: Androgen; Backdoor pathway; Ovary; Polycystic ovary syndrome