title: Tetrahydrogestrinone is a potent but unselective binding steroid and affects glucocorticoid signalling in the liver.
abstract: Tetrahydrogestrinone (THG) is a steroid recently identified to be misused as doping agent. However, the knowledge on functions of this substance in humans or animal models is rather limited. Therefore, it was our aim to further characterize the pharmacological profile of THG and identify potential adverse side effects. THG was synthesized, the purity was confirmed and its biological activity was tested. The potency of THG to transactivate AR dependent reporter gene expression was two orders of magnitude lower compared to dihydrotestosterone. THG binds with high affinity but unselective to the androgen (AR), progesterone (PR), glucocorticoid (GR) and mineralocorticoid (MR) receptor. Treatment of orchiectomised rats with THG resulted in a stimulation of prostate, seminal vesicle and levator ani muscle, indicating androgenic and anabolic properties. In the liver THG, in contrast to testosteronepropionate (TP), down regulates the expression of the GR dependent tyrosine aminotransferase gene (TAT). In summary, our results demonstrate that THG is not a specific AR agonist. THG exhibits a high binding affinity to all tested steroid hormone receptors and binds with highest affinity to the GR. Our in vivo data are indicative of an anabolic and androgenic potency of THG, but the repression of TAT demonstrates that THG also interferes with the glucocorticoid hormone system. Therefore, it is conceivable that an intake will result in adverse side effects.
authors.affiliation: Center for Preventive Doping Research, Institute of Cardiovascular Research and Sports Medicine, Department of Molecular and Cellular Sports Medicine, German Sport University Cologne, Cologne, 50927 Colonge, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Friedel
authors.forename: H
authors.initials: H
authors.lastname: Geyer
authors.forename: M
authors.initials: M
authors.lastname: Kamber
authors.forename: U
authors.initials: U
authors.lastname: Laudenbach-Leschowsky
authors.forename: W
authors.initials: W
authors.lastname: Schänzer
authors.forename: M
authors.initials: M
authors.lastname: Thevis
authors.forename: G
authors.initials: G
authors.lastname: Vollmer
authors.forename: O
authors.initials: O
authors.lastname: Zierau
authors.forename: P
authors.initials: P
authors.lastname: Diel
mesh_terms: D045930:Anabolic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005867:Gestrinone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012669:Seminal Vesicles / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D015003:Yeasts / Q000235:genetics
chemical_list: D045930:Anabolic Agents; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D005867:Gestrinone; C479553:tetrahydrogestrinone