Anadrol

Oxymetholone, marketed as Anadrol-50 (Syntex, later Unimed Pharmaceuticals, now Alaven Pharmaceutical) and Anapolon (Imperial Chemical Industries and generics), is a synthetic 17-alpha-alkylated derivative of dihydrotestosterone first described by Ringold et al. at Syntex in 1959 and introduced into clinical medicine in the early 1960s for the treatment of anemias, osteoporosis, and catabolic wasting states. The compound is the 2-hydroxymethylene analog of 17-alpha-methyl-dihydrotestosterone (mestanolone), bearing an unusual hydroxymethylene substituent at the C2 position that confers oral bioavailability through resistance to first-pass hepatic inactivation and that can be metabolically cleaved to yield mestanolone as an active metabolite. Oxymetholone is one of the most potent oral anabolic-androgenic steroids in clinical use, exhibiting a high ratio of anabolic to androgenic activity in classical levator ani and ventral prostate bioassays while paradoxically demonstrating low direct binding affinity for the androgen receptor in competitive displacement studies. The principal pharmacodynamic effects are stimulation of erythropoiesis through increased renal erythropoietin production (with urinary erythropoietin levels elevated up to fivefold at therapeutic doses), promotion of positive nitrogen balance and skeletal muscle protein synthesis, and a poorly characterized but clinically significant estrogenic activity that occurs despite the compound's structural inability to undergo aromatization, possibly through direct activation of estrogen receptor alpha. The compound received approval from the United States Food and Drug Administration for the treatment of anemias caused by deficient red blood cell production, including acquired aplastic anemia, congenital aplastic anemia, myelofibrosis, and hypoplastic anemias due to the administration of myelotoxic drugs. In the mid-1970s, the FDA restricted the approved indication exclusively to anemias characterized by deficient erythropoiesis, withdrawing prior approvals for osteoporosis and general catabolic states. Clinical investigation has subsequently extended to HIV/AIDS-associated wasting (Hengge et al. 2003 Phase III trial demonstrating 3.0 to 3.5 kg weight gain over 16 weeks at 100 to 150 mg daily), antithrombin III deficiency, and pediatric growth failure, with varying degrees of success. The hepatotoxic liability of the 17-alpha-alkylated structure is the principal safety concern: cholestatic jaundice occurs in approximately 1 percent of treated patients, typically within 1 to 4 months of initiation; peliosis hepatis (blood-filled sinusoidal cysts) develops with prolonged administration and has resulted in fatal hepatic rupture and hemorrhage in case reports; and hepatocellular carcinoma and hepatic adenoma have been reported after 2 to 15 years of continuous use, predominantly in patients with Fanconi anemia and aplastic anemia receiving chronic androgen therapy. The compound is classified as a Schedule III controlled substance in the United States under the Controlled Substances Act and is subject to equivalent regulatory controls in most jurisdictions. This monograph reviews the chemistry, synthesis, and structure-activity relationships of oxymetholone; the androgen receptor, erythropoietic, and estrogenic pharmacology; the limited but clinically relevant pharmacokinetic record; the preclinical pharmacology in animal models of anemia and wasting; the clinical evidence base across anemia, HIV wasting, and ancillary indications; sourcing and quality verification for research applications; reconstitution and handling; stack interactions and combinations with other anabolic and therapeutic agents; the adverse-event and safety signal including detailed hepatotoxicity characterization; and a comparative assessment of five alternative anabolic-androgenic agents (oxandrolone, nandrolone decanoate, stanozolol, testosterone enanthate, danazol) against oxymetholone on five competency standards.