11-Ketotestosterone

Structural Image:
11-ketotestosterone

Nomenclature:
17β-hydroxy-4-androstene-3,11-dione or
17b-hydroxy-4-androstene-3,11-dione

Synonyms:
11-ketotestosterone
ketotestosterone
11-KT

History:
The commercial production of 11-oxygenated steroids like cortisone, cortisol, 11-ketotestosterone, and adrenosterone was made possible by the discovery of microbial fermentation techniques by the Kalamazoo-based pharmaceutical company Upjohn. The compound they chose to bring to market was the far stronger – though also far more androgenic – 9a-fluoro steroid fluoxymesterone. For a detailed article on both the history and structure of fluoxymesterone, see here.
Apart from fluoxymesterone, 11-oxygenated anabolic products would not be seen commercially until Patrick Arnold’s 11-oxo (adrenosterone) was released in 2008. He later followed this up with the ‘active’ form 11-ketotestosterone, as a topical spray, in 2010.

Anabolic and Androgenic Activity:
The anabolic and androgenic activities of 11-ketotestosterone do not appear to have been assayed in mammals, either parenterally or orally.
Researchers at Upjohn found the 17a-methylated analogue 11-keto-17a-methyltestosterone to be more anabolic and less androgenic than methyltestosterone in the rat assay. [1] In fact, they found 11-oxygenation consistently increased anabolic potency across a range of steroids. [2]
The transcriptional activity of 11-KT in the murine androgen receptor was investigated and it was found to activate AR-mediated transcription effectively as strongly as testosterone (though weaker than DHT). [3]

Biosynthesis
In humans 11-ketotestosterone is produced by the conversion of adrenally secreted 11b-hydroxyandrostenedione via 11b-HSD2 and 17b-HSD. [4] 11-KT is also believed to be produced from androgens in the testes and ovaries via steroid 11β-hydroxylase (CYP11B1). It may also be formed endogenously from the side-chain cleavage of corticosteroids, though the contribution of this route to the pool of 11-oxygenated androgens is small. [5][6]

11-ketotestosterone biosynthesis

Structure and Function:
Testosterone is the primary androgen in mammals, including humans. In fish, 11-ketotestosterone is the primary and most potent androgen. 11-ketotestosterone differs from testosterone by the addition of a ketone function at carbon 11. 11-oxygenation is normally associated in humans with corticosteroids such as cortisone.

In the Leydig cells of the testes and ovaries 11-KT is believed to function to reduce local levels of glucocorticoids, to reduce their suppression of steroidogenesis. It may also play a role in stimulating folliculogenesis. [3]

11-ketotestosterone is a moderately potent inhibitor of 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1). The 4,5-dihydro metabolite 5α-androstan-3β,17β-diol-11-one is an even stronger 11bHSD1 inhibitor. [7]

11b-HSD1 is an oxidation of nicotinamide adenine dinucleotide phosphate-dependent oxidoreductase in key glucocorticoid target tissues such as liver, gonads, and adipose tissue, converting cortisone to cortisol, thereby regulating the level of active glucocorticoid available for intracellular glucocorticoid receptors. [3]

11b-HSD1 inhibition reduces cortisol levels in glucocorticoid-sensitive tissues like adipose (fat) tissue and in the liver by limiting the conversion of (inactive) cortisone to (active) cortisol. High levels of glucocorticoids in those tissues can cause adipocyte differentiation (leading to increased fat deposits), increased hepatic glucose production (leading to insulin resistance), and other complications, so 11b-HSD1 inhibitors are an emerging therapeutic target for pharmaceutical companies. [8]
For a brief overview of the subject, the reader is invited to read this article: An introduction to 11β-HSD1 inhibition.

Metabolism
While the metabolism of 11-ketotestosterone has not been examined in humans, it’s expected to follow a similar pattern to that of adrenosterone (11-oxo).
11-keto compounds like adrenosterone and 11-ketotestosterone are incapable of aromatization (they aren’t transformed in vivo to estrogen or estrogenic metabolites). [3][9]
Metabolism will involve reduction of the 11-keto group (to an 11b-OH), reduction of the 3-keto, oxidation of the 17b-OH, and reduction of the C-4,5 double bond (to both 5a- and 5b-H metabolites).

11-spray XI-KT icon

References:
[1] Lyster SC, Lund GH, Stafford RO. Androgenic and myotrophic properties of orally administered 9-fluoro-11-oxymethyltestosterones. Endocrinology. 1956 Jun;58(6):781–5.
[2] Hormonal Steroids, Proc. 1st Int. Congr., 2, L. Martini, A. Pecile, Eds. (Academic Press, New York, 1965) pp 59-67.
[3] Yazawa T, Uesaka M, Inaoka Y, Mizutani T, Sekiguchi T, Kajitani T, et al. Cyp11b1 Is Induced in the Murine Gonad by Luteinizing Hormone/Human Chorionic Gonadotropin and Involved in the Production of 11-Ketotestosterone, a Major Fish Androgen: Conservation and Evolution of the Androgen Metabolic Pathway. Endocrinology. 2008 Apr 1;149(4):1786–92.
[4] Rege J, Nakamura Y, Satoh F, Morimoto R, Kennedy MR, Layman LC, et al. Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab. 2013 Mar;98(3):1182–8.
[5] Dorfman RI. In Vivo Metabolism of Neutral Steroid Hormones. JCEM. 1954 Mar 1;14(3):318–25.
[6] Bloem L, Storbeck K-H, Schloms L, Swart A. 11β-Hydroxyandrostenedione Returns to the Steroid Arena: Biosynthesis, Metabolism and Function. Molecules. 2013 Oct 25;18(11):13228–44.
[7] Latif SA, Pardo HA, Hardy MP, Morris DJ. Endogenous selective inhibitors of 11β-hydroxysteroid dehydrogenase isoforms 1 and 2 of adrenal origin. Molecular and Cellular Endocrinology. 2005 Nov 24;243(1–2):43–50.
[8] Wamil M, Seckl JR. Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target. Drug Discovery Today. 2007 Jul;12(13–14):504–20.
[9] Gual C, Morato T, Hayano M, Gut M, Dorfman RI. Biosynthesis of Estrogens. Endocrinology. 1962 Dec 1;71(6):920–5.

© Total Flex Blog 2013