Halotestin (fluoxymesterone) particular cardiovascular disease risks arise out of its 11β-HSD2 inhibition
Cormac Mannion
Suppresses cortisol oxidation by competitive 11β-HSD2 inhibition while increasing serum & free cortisol. [1]:
Whereas oxymetholone, oxymesterone, danazol, and testosterone showed medium inhibitory potential, fluoxymesterone was a potent inhibitor of human 11β-HSD2 (half-maximal inhibitory concentration [IC(50)] of 60-100nM in cell lysates; IC(50) of 160nM in intact SW-620, and 530nM in MCF-7 cells). Measurements with rat kidney microsomes and lysates of cells expressing recombinant mouse 11β-HSD2 revealed much weaker inhibition by the AAS tested, indicating that the adverse effects of AAS-dependent 11β-HSD2 inhibition cannot be investigated in rats and mice. Furthermore, we provide evidence that fluoxymesterone is metabolized to 11-oxofluoxymesterone by human 11β-HSD2. Structural modeling revealed similar binding modes for fluoxymesterone and cortisol, supporting a competitive mode of inhibition of 11β-HSD2-dependent cortisol oxidation by this AAS. No direct modulation of mineralocorticoid receptor (MR) function was observed. Thus, 11β-HSD2 inhibition by fluoxymesterone may cause cortisol-induced MR activation, thereby leading to electrolyte disturbances and contributing to the development of hypertension and cardiovascular disease.
11β-HSD2
11β-HSD2 is an enzyme that controls the oxidation of cortisol. Its inhibition leads to glucocorticoid-mediated MR activation, potassium excretion, sodium and water retention, and increased blood pressure (Ferrari, 2010; Ferrari et al., 2001; Serra et al., 2002). [1]. Halotestin competitively inhibits 11β-HSD2, thereby leading to glucocorticoid-mediated MR activation. [1]. AAS that inhibit this enzyme may aggravate atherosclerosis via MR activation and inflammatory processes in the vascular endothelium (Glazer, 1991; Thompson et al., 1989). [1].
11β-HSD2 confers specificity (for aldosterone) to the MR: because the MR has a similar affinity for cortisol as for aldosterone (but cortisol & corticosterone circulate at levels orders of magnitude > aldosterone), 11β-HSD2 converts cortisol ⇒ (inactive) cortisone in cells expressing MR (including epithelial cells & the [vascular endothelium]), ensuring that aldosterone occupies the MR. [2].
Note: GH/IGF-I does not affect 11β-HSD2, but rather [via IGF-I] ⇒ ↓11β-HSD1 activity [↓conversion of inactive cortisone ⇒ active cortisol] ⇒ ↓C [active cortisol] ⇒ ↓gluconeogenesis & hepatic glucose output ⇒ ↑insulin sensitivity, but also, where ACTH is low [e.g., hypopituitarism], potential adrenal insufficiency.
References
[1] Barbosa, J., Seal, U. S., & Doe, R. P. (1971). Effects of Anabolic Steroids on Hormone-Binding Proteins, Serum Cortisol and Serum Nonprotein-Bound Cortisol. The Journal of Clinical Endocrinology & Metabolism, 32(2), 232–240. doi:10.1210/jcem-32-2-232
[2] Ferrari P. The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochim Biophys Acta. 2010 Dec;1802(12):1178-87. doi:10.1016/j.bbadis.2009.10.017
About the Author
Type-IIx is an expert on drugs used in enhanced bodybuilding, author of Bolus: A Practical and Reference Guide for the Use of human Growth Hormone and GH Secretagogues whose articles can be found on Meso-Rx <https://thinksteroids.com/author/type-iix> and his Team Ampouletude website <https://ampouletude.com/articles> with various other projects, including symposiums accessible at https://ampouletude.com/~type-iix and the Gear, Growth, and Gains Podcast and its Discord Server <https://discord.gg/gear-growth-gains>