Stanozolol

Stanozolol (abbrev. Stz), sold under many brand names, is a synthetic androgen and anabolic steroid (AAS) medication derived from dihydrotestosterone (DHT). It is used to treat hereditary angioedema.<ref name="IndexNominum2000">Template:Cite book</ref><ref name="Drugs.com">Template:Cite web</ref><ref name="Llewellyn_2011">Template:Cite book</ref> It was developed by American pharmaceutical company Sterling-Winthrop in 1962, and has been approved by the U.S. Food and Drug Administration for human use, though it is no longer marketed in the United States.<ref name="Llewellyn_2011" /><ref name="Drugs@FDA">Template:Cite web</ref> It is also used in veterinary medicine.<ref name="Drugs.com" /><ref name="Llewellyn_2011" /> Stanozolol has mostly been discontinued, and remains available in only a few countries.<ref name="Drugs.com" /><ref name="Llewellyn_2011" /> It is given by mouth in humans or by injection into muscle in animals.<ref name="Llewellyn_2011" />

Unlike most AAS, stanozolol is not esterified and is sold as an aqueous suspension, or in oral tablet form.<ref name="Llewellyn_2011" /> The drug has a high oral bioavailability, due to a C17α alkylation which allows the hormone to survive first-pass liver metabolism when ingested.<ref>Template:Cite web</ref><ref name="Llewellyn_2011" /> It is because of this that stanozolol is also sold in tablet form.<ref name="Llewellyn_2011" />

Stanozolol is one of the AAS commonly used as performance-enhancing drugs and is banned from use in sports competition under the auspices of the World Anti-Doping Agency (WADA). It is an anabolic steroid that is known to have a diuretic effect. Additionally, stanozolol has been highly restricted in US horse racing.<ref>Template:Cite web</ref><ref>Template:Cite web</ref><ref>Template:Cite web</ref>

Medical uses

Stanozolol has been used with some success to treat venous insufficiency. It stimulates blood fibrinolysis and has been evaluated for the treatment of the more advanced skin changes in venous disease such as lipodermatosclerosis. Several randomized trials noted improvement in the area of lipodermatosclerosis, reduced skin thickness, and possibly faster ulcer healing rates with stanozolol.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> It is also being studied to treat hereditary angioedema, osteoporosis, and skeletal muscle injury.<ref>Template:Cite journal</ref><ref name="Tingus_1993">Template:Cite journal</ref>

Non-medical uses

Stanozolol is used for physique- and performance-enhancing purposes by competitive athletes, bodybuilders, and powerlifters.<ref name="Llewellyn_2011" />

Side effects

Side effects of stanozolol include virilization (masculinization), hepatotoxicity,<ref name="Llewellyn_2011" /> cardiovascular disease, and hypertension.

Pharmacology

Pharmacodynamics

As an AAS, stanozolol is an agonist of the androgen receptor (AR), similarly to androgens like testosterone and DHT.<ref name="Llewellyn_2011" /><ref name="Kicman_2008">Template:Cite journal</ref> Its affinity for the androgen receptor is about 22% of that of dihydrotestosterone.<ref name="Doods_1991">Template:Cite book</ref> Stanozolol is not a substrate for 5α-reductase as it is already 5α-reduced, and so is not potentiated in so-called "androgenic" tissues like the skin, hair follicles, and prostate gland.<ref name="Llewellyn_2011" /><ref name="Kicman_2008" /> This results in a greater ratio of anabolic to androgenic activity compared to testosterone.<ref name="Llewellyn_2011" /><ref name="Kicman_2008" /> In addition, due to its 5α-reduced nature, stanozolol is non-aromatizable, and hence has no propensity for producing estrogenic effects such as gynecomastia or fluid retention.<ref name="Llewellyn_2011" /><ref name="Kicman_2008" /> Stanozolol also does not possess any progestogenic activity of significance.<ref name="Llewellyn_2011" /><ref name="Kicman_2008" /> Because of the presence of its 17α-methyl group, the metabolism of stanozolol is sterically hindered, resulting in it being orally active, although also hepatotoxic.<ref name="Llewellyn_2011" /><ref name="Kicman_2008" />

Multi-receptor activity and stem-cell differentiation

In addition to classical AR signaling, in-vitro work with mesenchymal stem-cell micromass cultures shows that stanozolol:

• Binds to the progesterone receptor (PR) and to an unidentified membrane receptor that drives Prostaglandin E2 (PGE₂) synthesis via COX-2 induction.<ref name="Mori_2020">Template:Cite thesis</ref>
• Induces a feed-forward loop in which PGE₂ amplifies BMP2 expression, accelerating osteogenic and chondrogenic differentiation.<ref name="Mori_2020" />
• Causes sustained phosphorylation of PKCε, an isoform linked to suppression of the hypertrophic cartilage marker MATN1 and to formation of articular-cartilage (interzone) phenotypes.<ref name="Mori_2020" />

Pharmacological blockade of either PR (mifepristone) or COX-2 (indomethacin) abolishes these effects, confirming that stanozolol’s osteochondral activity requires simultaneous PR signaling and PGE₂-driven crosstalk with the BMP2 pathway.<ref name="Mori_2020" />

Additionally, stanozolol has been shown to exert activity via estrogen receptor alpha (ERα) in vivo. In a rat model of GnRH agonist-induced growth plate suppression, stanozolol restored chondrocyte proliferation via ERα activation, indicating selective estrogen receptor-mediated effects in growth plate cartilage.<ref name="Zhu_2011">Template:Cite journal</ref>

Pharmacokinetics

Stanozolol has high oral bioavailability, due to the presence of its C17α alkyl group and the resistance to gastrointestinal and liver metabolism that it results in.<ref name="Maini_2014" /><ref name="Bilezikian_2002">Template:Cite book</ref><ref name="Herron_2015">Template:Cite book</ref> The medication has very low affinity for human serum sex hormone-binding globulin (SHBG), about 5% of that of testosterone and 1% of that of DHT.<ref name="Saartok_1984">Template:Cite journal</ref> Stanozolol is metabolized in the liver, ultimately becoming glucuronide and sulfate conjugates.<ref name="Hsu_2013" /> Its biological half-life is reported to be 9 hours when taken by mouth and 24 hours when given by intramuscular injection in the form of an aqueous suspension.<ref name="Ruiz_2011" /><ref name="Thieme_2009">Template:Cite book</ref> It is said to have a duration of action of one week or more via intramuscular injection.<ref name="Hsu_2013" />

Chemistry

Stanozolol, also known as 17α-methyl-2'H-androst-2-eno[3,2-c]pyrazol-17β-ol, is a synthetic 17α-alkylated androstane steroid and a derivative of 5α-dihydrotestosterone (DHT) with a methyl group at the C17α position and a pyrazole ring attached to the A ring of the steroid nucleus.<ref name="IndexNominum2000" />

Synthesis

Various chemical syntheses of stanozolol have been published.<ref name="Publishing2013">Template:Cite book</ref>

Detection in body fluids

Stanozolol is subject to extensive hepatic biotransformation by a variety of enzymatic pathways. The primary metabolites are unique to stanozolol and are detectable in the urine for up to 10 days after a single 5–10 mg oral dose. Methods for detection in urine specimens usually involve gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite book</ref>

History

In 1962, Stanozolol was brought to market in the US by Winthrop under the tradename "Winstrol" and in Europe by Winthrop's partner, Bayer, under the name "Stromba".<ref name="Levin_1962">Template:Cite journal</ref>

Also in 1962, the Kefauver Harris Amendment was passed, amending the Federal Food, Drug, and Cosmetic Act to require drug manufacturers to provide proof of the effectiveness of their drugs before approval.<ref>Template:Cite web</ref> The FDA implemented its Drug Efficacy Study Implementation (DESI) program to study and regulate drugs, including stanozolol, that had been introduced prior to the amendment. The DESI program was intended to classify all pre-1962 drugs that were already on the market as effective, ineffective, or needing further study.<ref>Template:Cite web</ref> The FDA enlisted the National Research Council of the National Academy of Sciences to evaluate publications on relevant drugs under the DESI program.<ref>Template:Cite web</ref>

In June 1970 the FDA announced its conclusions on the effectiveness of certain AAS, including stanozolol, based on the NAS/NRC reports made under DESI. The drugs were classified as probably effective as adjunctive therapy in the treatment of senile and postmenopausal osteoporosis but only as an adjunct, and in pituitary dwarfism (with a specific caveat for dwarfism, "until growth hormone is more available"), and as lacking substantial evidence of effectiveness for several other indications. Specifically, the FDA found a lack of efficacy for stanozolol as "an adjunct to promote body tissue-building processes and to reverse tissue-depleting processes in such conditions as malignant diseases and chronic nonmalignant diseases; debility in elderly patients, and other emaciating diseases; gastrointestinal disorders resulting in alterations of normal metabolism; use during pre-operative and postoperative periods in undernourished patients and poor-risk surgical cases due to traumatism; use in infants, children, and adolescents who do not reach an adequate weight; supportive treatment to help restore or maintain a favorable metabolic balance, as in postsurgical, postinfectious, and convalescent patients; of value in pre- operative patients who have lost tissue from a disease process or who have associated symptoms, such as anorexia; retention and utilization of calcium; surgical applications; gastrointestinal disease, malnourished adults, and chronic illness; pediatric nutritional problems; prostatic carcinoma; and endocrine deficiencies."<ref name="FedReg1970">Template:Cite journal</ref> The FDA gave Sterling six months to stop marketing stanozolol for the indications for which there was no evidence for efficacy, and one year to submit further data for the two indications for which it found probable efficacy.<ref name="FedReg1970" />

In August and September 1970, Sterling submitted more data; the data was not sufficient but the FDA allowed the drug to continue to be marketed, since there was an unmet need for drugs for osteoporosis and pituitary dwarfism, but Sterling was required to submit more data.<ref name=FedReg1984>Food and Drug Administration Notice. Docket No 80N-0276; DESI 7630. Winstrol Tablets; Drugs for Human Use; Drug Efficacy Study Implementation, Revocation of Exemption; Followup Notice and Opportunity for Hearing on Proposal to Withdraw Approval of New Drug Federal Register, April 23, 1984. page 17094-99</ref>

In 1980 the FDA removed the dwarfism indication from the label for stanozolol since human growth hormone drugs had come on the market, and mandated that the label for stanozolol and other steroids say: "As adjunctive therapy in senile and postmenopausal osteoporosis. AAS are without value as primary therapy but may be of value as adjunctive therapy. Equal or greater consideration should be given to diet, calcium balance, physiotherapy, and good general health promoting measures." and gave Sterling a timeline to submit further data for other indications it wanted for the drug.<ref name="FedReg1980">Food and Drug Administration Notice. Docket No 80N-0276; Drugs for Human Use; Drug Efficacy Study Implementation; Conditions for Continued Marketing of Anabolic Steroids for Treatment Federal Register Vol 45 No. 213. October 31 1980. pages 72291-93</ref> Sterling submitted data to the FDA intended to support the effectiveness of Winstrol for postmenopausal osteoporosis and aplastic anemia in December, 1980 and August 1983 respectively. The FDA's Endocrinologic and Metabolic Drugs Advisory Committee considered the data submitted for osteoporosis in two meetings held 1981 and the data for aplastic anemia in 1983.<ref name="FedReg1984" />

In April 1984, the FDA announced that the data was not sufficient, and withdrew the marketing authority for stanozolol for senile and postmenopausal osteoporosis and for raising hemoglobin levels in aplastic anemia.<ref name="FedReg1984" /><ref>The Pink Sheet 30 April 1984 Sterling Winstrol (Stanozolol) NDA Withdrawal Process Beginning, FDA</ref>

In 1988, Sterling was acquired by Eastman Kodak for $5.1 billion and in 1994 Kodak sold the drug business of Sterling to Sanofi for $1.675 billion.<ref name="Collins_2000">Template:Cite journal</ref><ref name="LAT62494">Template:Cite news</ref>

Sanofi had stanozolol manufactured in the US by Searle, which stopped making the drug in October 2002.<ref>Template:Cite web</ref> Even with no drug in production, Sanofi sold the stanozolol business to Ovation Pharmaceuticals in 2003, along with the two other drugs.<ref name="Ovationsale">Template:Cite web</ref> At that time, the drug had not been discontinued and was considered a treatment for hereditary angioedema.<ref name="Ovationsale" /> In March 2009, Lundbeck purchased Ovation<ref>Template:Cite web</ref>

In 2010, Lundbeck withdrew stanozolol from the market in the US; as of 2014 no other company is marketing stanozolol as a pharmaceutical drug in the US but it can be obtained via a compounding pharmacy.<ref>Template:Cite web</ref><ref name="OrangeBook">FDA Drugs@FDA: Stanozolol</ref><ref name="HAEA" /><ref name="Craig_2012" />

Pfizer had marketed stanozolol as a veterinary drug; in 2013 Pfizer spun off its veterinary business to Zoetis<ref>Zoetis. 24 June 2013 Zoetis Press Release: Zoetis Becomes Fully Independent With Acceptance of Pfizer Shares Tendered in Exchange Offer Template:Webarchive</ref> and in 2014 Pfizer transferred the authorizations to market injectable and tablet forms of stanozolol as a veterinary drug to Zoetis.<ref>Template:Cite web</ref><ref>Template:Cite web</ref>

It is used in veterinary medicine as an adjunct in the management of wasting diseases, to stimulate the formation of red blood cells, arouse appetite, and promote weight gain, but the evidence for these uses is weak. It is used as a performance-enhancing drug in race horses. Its side effects include weight gain, water retention, and difficulty eliminating nitrogen-based waste products and it is toxic to the liver, especially in cats. Because it may promote the growth of tumors, it is contraindicated in dogs with enlarged prostates.<ref>Template:Cite book</ref>Template:Rp

Stanozolol and other AAS were commonly used to treat hereditary angioedema attacks, until several drugs were brought to market specifically for treatment of that disease, the first in 2009: Cinryze, Berinert, ecallantide (Kalbitor), icatibant (Firazyr) and Ruconest.<ref name="HAEA">The US Hereditary Angioedema Association Treatments</ref><ref name="Craig_2012">Template:Cite web</ref> Stanozolol is still used long-term to reduce the frequency of severity of attacks.<ref>Template:Cite book</ref>

Society and culture

File:Winstrol tablets.JPG

Stanozolol 50 mg tablets

Generic names

Stanozolol is the generic name of stanozolol in English, German, French, and Japanese and its Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, and Template:Abbrlink, while stanozololum is its name in Latin, stanozololo is its name in Italian and its Template:Abbrlink, and estanozolol is its name in Spanish.<ref name="IndexNominum2000" /><ref name="Morton_2012">Template:Cite book</ref><ref name="Drugs.com" /> Androstanazole, androstanazol, stanazol, stanazolol, and estanazolol are unofficial synonyms of stanozolol.<ref name="IndexNominum2000" /><ref name="Drugs.com" /> It is also known by its former developmental code name WIN-14833.<ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name="Morton_2012" />

Brand names

Brand names under which stanozolol is or has been marketed include Anaysynth, Menabol, Neurabol Caps., Stanabolic (veterinary), Stanazol (veterinary), Stanol, Stanozolol, Stanztab, Stargate (veterinary), Stromba, Strombaject, Sungate (veterinary), Tevabolin, Winstrol, Winstrol Depot, and Winstrol-V (veterinary).<ref name="IndexNominum2000" /><ref name="Drugs.com" />

Legal status in the United States

In the United States, like other AAS, stanozolol is classified as a controlled substance under federal regulation; they were included as Schedule III controlled substances under the Anabolic Steroids Control Act of 1990 which was passed as part of the Crime Control Act of 1990.<ref>Template:Cite book</ref>Template:Rp

Doping in sports

Stanozolol and other synthetic steroids were first banned by the International Olympic Committee and the International Association of Athletics Federations in 1974, after methods to detect them had been developed.<ref>Template:Cite book</ref>Template:Rp There are many known cases of doping in sports with stanozolol by professional athletes. Stanozolol is especially widely used by the athletes from post-Soviet countries.Template:Citation needed As of 2015, it is banned by World Anti-Doping Agency<ref>Template:Cite journal</ref> and United States Anti-Doping Agency.<ref>Template:Cite web</ref>

Research

Stanozolol has been investigated in the treatment of a number of dermatological conditions including urticaria, hereditary angioedema, Raynaud's phenomenon, cryofibrinogenemia, and lipodermatosclerosis.<ref name="Helfman_1995">Template:Cite journal</ref>