Effects of Exogenous Androgens on Platelet Activity and Their Thrombogenic Potential in Supraphysiological Administration: A Literature Review

Abstract

Anabolic androgenic steroids (AAS), simply called "androgens", represent the most widespread drugs used to enhance performance and appearance in a sporting environment. High-dosage and/or long-term AAS administration has been associated frequently with significant alterations in the cardiovascular system, some of these with severe endpoints. The induction of a prothrombotic state is probably the most life-threatening consequence, suggested by numerous case reports in AAS-abusing athletes, and by a considerable number of human and animal studies assessing the influence of exogenous androgens on hemostasis. Despite over fifty years of research, data regarding the thrombogenic potential of exogenous androgens are still scarce. The main reason is the limited possibility of conducting human prospective studies. However, human observational studies conducted in athletes or patients, in vitro human studies, and animal experiments have pointed out that androgens in supraphysiological doses induce enhanced platelet activity and thrombopoiesis, leading to increased platelet aggregation. If this tendency overlaps previously existing coagulation and/or fibrinolysis dysfunctions, it may lead to a thrombotic diathesis, which could explain the multitude of thromboembolic events reported in the AAS-abusing population. The influence of androgen excess on the platelet activity and fluid-coagulant balance remains a subject of debate, urging for supplementary studies in order to clarify the effects on hemostasis, and to provide new compelling evidence for their claimed thrombogenic potential.

Keywords: AAS; anabolic androgenic steroids; androgens; hemostasis/haemostasis; platelet activity; platelet aggregation; platelet count; platelet reactivity; prothrombotic state; testosterone; thrombopoiesis; thrombosis; thrombotic diathesis.

Figure 1

Figure illustrating the influence of exogenous androgens A on various processes involved in platelet activation and subsequent aggregation. The proposed mechanisms of action (figured by red arrows) are as follows: 1. A increase gene expression of purinergic receptor 2Y₁₂ (P₂Y₁₂) of adenosine diphosphate (ADP). 2. A enhance cyclooxygenase-1 (COX-1) activity, increase thromboxane A₂ (TxA₂) synthesis, and enhance platelet TxA₂ receptor (TP) density. 3. By acting on androgen receptor (AR), A enhance platelet free calcium (Ca²⁺). The rise of cytosolic Ca²⁺ increases AR affinity. 4. A inhibit cytosolic nitric oxide synthase (NOS) activity and generate complementary processes on endothelium by reducing nitric oxide (NO) release and suppressing prostaglandin I₂ (PgI₂) production. 5. A increase vascular TxA₂ receptor density and endothelial TxA₂ synthesis. 6. A increase platelet activator factor (PAF) activity. PAF actions on platelets involves stimulation of phospholipase C (PLC) activity and inhibition of adenylyl cyclase (AC) activity, through which PAF stimulates platelet activation and aggregation. Other abbreviations used: FBG-fibrinogen; VWF-von Willebrand factor; GP-glycoprotein; PLA₂-phospholipase A₂; PAF-R platelet activation factor receptor; Ca, or Ca²⁺-intracellular calcium; P₂Y₁-purinergic receptor 2Y₁; PAR₁-protease-activated receptor-1; PAR₄-protease-activated receptor-4; IP₃-inositol 1,4,5-trisphosphate; DTS-dense tubular system; DAG -1,2-diacylglycerol; PKC-protein kinase C; DG-dense granule; AG-alfa-granule; IP-prostacyclin receptor; GC-guanylate cyclase; cAMP-cyclic adenosine monophosphate; cGMP-cyclic guanosine monophosphate; PKA-protein kinase A; PKG-protein kinase G; α2A-AR-alpha 2A adrenergic receptor; TGFβ-transforming growth factor beta; PDGF-platelet derived growth factor; PF4-platelet factor 4; HMWK-high-molecular-weight kininogen; Fa V-blood coagulation factor V; Fa XI-blood coagulation factor XI; PS–protein S; PAI-plasminogen activator inhibitor; PgG₂-prostaglandin G₂; PgH₂-prostaglandin H₂; rec.-receptors; other symbols: ↑-up regulation, ↓-down-regulation.