Haemostatic Effects of Supraphysiological Levels of Testosterone in Normal Men

Abstract

SummaryThe effects of exogenous testosterone on the haemostatic system were studied in a group of 32 healthy men undergoing a clinical trial of hormonal male contraception. The men received 200 mg testosterone oenanthate (TE) weekly i.m., and plasma samples were taken pretreatment, at defined time points up to 52 weeks of treatment, and 4 and 8 weeks after discontinuing TE. This dose of TE caused a 2-fold increase in trough plasma testosterone levels.TE caused a fall in plasma fibrinogen concentration after 16 weeks of treatment. This was sustained for the duration of TE treatment and recovered to pretreatment levels during the recovery phase. There was also a sustained fall in the level of C4b binding protein which showed a rebound to levels above pretreatment during recovery. Levels of antithrombin III and prothrombin fragment F1.2 rose initially during TE treatment, and levels of protein C, protein S (free) and plasminogen activator inhibitor fell, but the concentrations of these factors all returned to pretreatment levels during continued treatment. There was no change in the plasma concentrations of β-thromboglobulin, tissue plasminogen activator, protein S (total), or D-dimer. There was a sustained increase in haemoglobin concentration and haematocrit, without any change in platelet count.The observed changes were consistent with mild activation of the haemostatic system during initial treatment with testosterone. After several months the raised activation markers had returned to pretreatment levels indicating that a new equilibrium had been established which did not appear to be prothrombotic. The increase in prothrombin fragment F1.2 for the first 32 weeks, and at four weeks after discontinuation of treatment, is consistent with prolonged mildly increased prothrombinase activity. The observed substantial fall in fibrinogen is likely to have reduced, whereas the small rise in haemoglobin will have increased, the tendency to arterial thrombosis. We conclude that supraphysiological doses of testosterone do not result in a sustained marked prothrombotic state, but these results do not exclude a small change in thrombotic risk.

Oral, but Not Transdermal, Administration of Estrogens Lowers Tissue-Type Plasminogen Activator Levels in Humans Without Affecting Endothelial Synthesis

“…Interestingly, oral administration of the androgenic steroid stanozolol has been shown to decrease tPA and PAI-1 antigen levels. 46 This contrasts with the lack of effect of parenteral administration of testosterone esters in males 47 and in females in our present and previous studies. 1,2 This raises the possibility that distinct androgenic compounds have different effects on tPA and PAI-1 levels; alternatively, the route of administration of androgens may be relevant.…”

Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina

“…Apart from fibrinogen, the observed alterations in haemostatic factors returned to pretreatment levels during continued treatment. An increase in both haemoglobin and haematocrit was noticed which was sustained throughout the study period (31). It was concluded that supraphysiological doses of testosterone do not result in a pro-thrombotic state, which is supported by our current study.…”

“…In a study of 32 healthy men who received 200 mg testosterone oethanthate by weekly intramuscular injection for 52 weeks in a trial of hormonal male contraception (31), testosterone therapy resulted in a reduction in fibrinogen and PAI-1activity, together with decreases in serum concentrations of the prothrombotic factors protein C and protein S (31). There was no change in the level of tPA, although an increase in antithrombin III activity was observed (31). Apart from fibrinogen, the observed alterations in haemostatic factors returned to pretreatment levels during continued treatment.…”

Association Between Serum Testosterone Concentration and Carotid Atherosclerosis in Men With Type 2 Diabetes

“…In keeping with our previous finding that decreased concentrations of testosterone as a result of castration might play an important role in insulin resistance (8,9), an inverse correlation was found, although it did not reach statistical significance, between serum testosterone and fasting serum C-peptide concentrations in men with type 2 diabetes treated without insulin. Testosterone concentration is inversely correlated with procoagulable factors, plasminogen activator inhibitor, and fibrinogen (26). Testosterone has also been shown to act as a vasodilator in both the coronary and systemic circulations in in vitro animal models (27), and short-term intracoronary administration of testosterone, at physiologic concentrations, induces coronary artery dilation and increases coronary blood flow in men with established coronary artery disease (28).…”