Anabolic steroid use and ischaemic stroke in a young fitness enthusiast

Abstract

We report a case of ischaemic stroke in a 34-year-old male recreational bodybuilder following a 3-month period of anabolic androgenic steroid (AAS) use and 1-month period of ‘post-cycle therapy’ (tamoxifen and clomiphene citrate), the latter treatments aimed at restoring normal endogenous testosterone production after initial AAS use. We hypothesise a transient drug-related prothrombotic state with paradoxical embolisation via an atrial septal defect which was later found on bubble echocardiogram. We highlight a rare but important cause of stroke in younger patients which is relevant given the increasing use of AAS misuse among casual fitness enthusiasts. We explore the various possible mechanisms by which AAS use can increase ischaemic stroke risk in such patients.

Background

Anabolic androgenic steroids (AAS) are compounds that are structurally related to testosterone and which bind to androgen receptors exerting masculinising and anabolic effects, increasing both skeletal muscle mass and maximal voluntary strength.¹ The World Anti-Doping Agency therefore prohibits AAS use in elite athletes.²

The non-medical use of AAS is a growing public health problem.³ The global lifetime prevalence rate of AAS use has been estimated to be as high as 6.4% for men and 1.6% in women.³ The estimated number of people aged 16–59 years reporting lifetime use of anabolic steroids increased in England and Wales from 194 000 in 2005/2006 to 271 000 in 2015/2016.⁴ Abusers typically use 5–15 times the recommended medical doses of AAS and may be at risk of adverse cardiovascular and cerebrovascular outcomes.⁵ Use is not only confined to bodybuilders and professional sportsmen but is increasing among casual fitness enthusiasts, non-competitive bodybuilders and amateur athletes (both male and female) who may wish to improve their physical appearance, body image or performance.⁶

The authors report a case of ischaemic stroke in a recreational bodybuilder following a 3-month period of AAS use and a 1-month period of ‘post-cycle therapy’. We hypothesise a transient prothrombotic state with paradoxical embolisation and emphasise the importance of considering AAS use as a risk factor for ischaemic stroke in a younger person.

Case presentation

A 34-year-old non-professional bodybuilder presented to the emergency department with a 1-day history of headache and right-sided visual loss. He had been unable to drive following the onset of symptoms, and his wife reported that he seemed confused.

He had no significant medical history and denied taking regular medications. He reported infrequent alcohol intake and was an ex-smoker having smoked 10 cigarettes per day for a period of 8 years. There was no relevant family history of stroke. On closer questioning, the patient reported having recently injected AAS intramuscularly for the first time (testosterone propionate and trenbolone acetate, 25 and 50 mg, respectively, per day) over 12 weeks prior to the stroke. This was followed by 4 weeks of ‘post-cycle therapy’ which consisted of daily tamoxifen 20–40 mg and clomiphene citrate 25–50 mg with the aim of restoring normal endogenous testosterone production and avoiding oestrogenic side effects.

On examination, the patient was alert and orientated. Heart rate was 77 beats/min with a regular pulse, and blood pressure 120/76 mm Hg. Oxygen saturations were 95% on air, afebrile. Cardiovascular, respiratory and abdominal examinations were unremarkable. Cranial nerve examination revealed a right homonymous superior quadrantanopia, and this was later confirmed with formal orthoptic visual field analysis. Pupils were equal and reactive to light, nystagmus was absent. Central and peripheral nervous system examination was otherwise normal. In particular, there was no clinical evidence of lower limb deep vein thrombosis.

Investigations

Admission blood tests including full blood count, plasma viscosity, C reactive protein, liver function tests, urea, creatinine and other electrolytes were unremarkable. Random glucose, cholesterol profile and thyroid-stimulating hormone levels were all within normal range. ECG showed sinus rhythm with evidence of left ventricular hypertrophy. Chest X-ray demonstrated clear lungs and normal mediastinum.

A ‘young stroke’ blood profile was sent (autoimmune profile, antineutrophil cytoplasmic antibodies, complement, rheumatoid factor, lupus anticoagulant, anticardiolipin antibodies and HIV screen); results were all within normal limits.

MRI of the head demonstrated an acute left occipital infarct in the distribution of the left posterior cerebral artery (figure 1).

Figure 1.

(A, B) Axial DWI/ADC demonstrating high signal on B1000 diffusion sequence and low signal on ADC MAP consistent with acute infarct in the left PCA vascular territory. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; MAP, mean apparent propagator; PCA, posterior cerebral artery.

CT angiogram showed patent carotid and vertebral arteries bilaterally with no evidence of stenosis or dissection and normal intracranial vessels. A formal digital subtraction angiography was not undertaken due to the low clinical suspicion of arterial dissection.

No arrhythmia was detected on telemetry or prolonged (7-day) holter monitoring. Echocardiogram demonstrated no valve abnormalities and no dilatation of the ventricles with good ventricular systolic function bilaterally. Bubble echo demonstrated a large left-to-right shunt at rest across the atrial septum, consistent with either an atrial septal defect or patent foramen ovale.

Differential diagnosis

After ruling out common causes of ischaemic stroke and considering the temporal association with symptoms, we hypothesised a transient prothrombotic state due to anabolic steroid use with paradoxical embolisation via the visualised cardiac defect.

Treatment

The patient was admitted to the stroke ward for initial management, which consisted of high-dose aspirin (300 mg) and statin therapy (atorvastatin 40 mg). He was reviewed by the physiotherapy, occupational therapy and orthoptic departments during his admission. In light of the bubble echo findings, transoesophageal echocardiography was performed which demonstrated a large secundum atrial septal defect.

Outcome and follow-up

The patient remained stable and normotensive on the ward. Modified Rankin score was 1, Montreal Cognitive Assessment score 30/30. He was discharged home after 2 days and advised not to drive pending further orthoptic review.

The patient subsequently underwent successful percutaneous closure of the defect and was initially managed post-procedure with dual antiplatelet therapy (figures 2 and 3).

Figure 2.

ASD closure device (11 mm waist diameter, left disc=25 mm, right disc=21 mm). ASD, atrial septal defect.

Figure 3.

ASD closure device sized against a ruler. ASD, atrial septal defect.

Fortunately, the patient’s vision improved sufficiently to enable him to resume driving and full-time working with no restrictions.

Discussion

We report a 34-year-old man who developed embolic stroke following supraphysiological use of AAS over a period of 12 weeks.

The adverse effects exerted by supraphysiological use of AAS are numerous. Although some harms are more superficial, for example, acne and balding, AAS misuse can be linked to more serious physical (eg, cardiovascular) and psychological (eg, psychosis) problems.⁴ There may also be complications related to the injection process including localised pain, cellulitis and abscesses, and the risk of blood-borne viral infection.

There are several case reports of cardiovascular and cerebrovascular disease associated with supraphysiological use of AAS, but only a few relating to ischaemic stroke. AAS have the potential to cause cardiovascular harm via a number of different mechanisms. These include atherogenic, thrombotic/haemostatic and vasospastic effects and also via direct myocardial injury.⁷

The atherogenic effects of AAS are in part due to their effects on cholesterol metabolism. AAS abuse may cause an increase in low-density lipoprotein cholesterol and decrease in high-density lipoprotein cholesterol by up to 20%.⁵ This is mainly due to the ability of AAS to increase the activity of an enzyme, hepatic triglyceride lipase, which regulates serum lipids and lipoproteins, and the resulting lipid changes decrease the regression of atherosclerotic plaques.⁸ AAS have also been linked to reduced apolipoprotein A1 levels which is linked to the development of atherosclerosis of the arterial wall.⁹ AAS are also capable of increasing vascular tone and arterial tension thereby promoting atherothrombotic phenomena.¹⁰ The overall risk of arterial disease is increased by threefold to sixfold and can occur within 9 weeks of AAS administration.⁵

Of particular relevance to this case are the effects of AAS on haematopoiesis and coagulation. AAS may induce a hypercoagulable state by means of increasing platelet production of thromboxane A2, decreasing production of prostacyclin and increasing fibrinogen levels, which results in enhanced platelet aggregation and thrombus formation.¹⁰ AAS also act both directly and indirectly via stimulation of erythropoietin, to increase haematopoiesis.¹¹ When used in supraphysiological doses, levels of haemoglobin and haematocrit are also significantly increased.¹² This consequence is exploited when using AAS to enhance performance in competitive sport by increasing oxygen transport to cells.¹³ Elevated haematocrit has been shown to be an independent risk factor for stroke which interacts synergistically with elevated blood pressure.¹⁴ Hypercoagulability is also induced by increased levels of clotting factors and plasminogen after AAS administration.¹⁵ If used long term, AAS can also elevate serum homocysteine levels leading to increased risk of ischaemic stroke.¹⁶

Third, AAS may also induce vasospasm of blood vessels by inhibiting synthesis of nitric oxide, an endothelial-derived smooth muscle relaxing factor.⁸

Finally AAS have been hypothesised to induce direct myocardial cell injury which can lead to cell death and scar formation thus predisposing to arrhythmias.⁸ This is felt to be mediated by increased fibrosis of the myocardium due to aldosterone-like effects.⁶ AAS may also lead to growth-promoting effects on cardiac tissue as in hypertrophic cardiomyopathy, and there have been case reports of ischaemic stroke in association with AAS-induced cardiomyopathy.^{5 6}

There are other indirect factors that may heighten the risk profile and therefore the potential adverse consequences of AAS including the possibility they may be used alongside other illicit psychoactive substances and alcohol, and also the potential for adulteration of non-prescription drugs and supplements.⁴

The use of oestrogen-modulating medications following the period of AAS therapy in this case is also noteworthy in terms of increasing overall risk of thromboembolism. In a 2016 UK survey of AAS abuse, 51% and 34% of people reported using tamoxifen and clomiphene as post-cycle therapy, respectively.⁴ Post-cycle therapy is a process used by bodybuilders and steroid users to help return their bodies to a normal pre-AAS use physiological state. Our patient took a combination of clomiphene and tamoxifen to achieve this. Clomiphene citrate is a selective oestrogen receptor modulator (SERM) used for the treatment of subfertility in women which can stimulate endogenous androgen production and improve the testosterone to oestradiol ratio—this underpins its role after a period of AAS use. Clomiphene citrate administration causes an increase in pituitary gonadotropins release, followed by increased oestradiol levels, which has a thrombogenic effect. Hence, use of clomiphene may be associated with increased risk of venous thrombosis, particularly if patients have known risk factors.¹⁷ Likewise tamoxifen, another SERM has been shown to increase venous thrombosis and increase the risk of stroke by 82% in patients treated for breast cancer.¹⁸ Paradoxical embolism via a patent foramen ovale or atrial septal defect in the setting of venous thrombosis could explain the increased risk of stroke with both of these medications, which, according to a local expert haematological opinion, is equal to the risk from the period of AAS use itself.

Our case contributes to the growing body of literature concerning the use of AAS and risk of ischaemic stroke. We suggest a number of putative mechanisms whereby both periods of AAS misuse and ensuing post-cycle therapy regimes may heighten risk of ischaemic stroke in patients otherwise at low risk of cerebrovascular disease.

Learning points.

• The non-medical use of anabolic androgenic steroids (AAS) is increasing among casual fitness enthusiasts and amateur athletes, both male and female.

• AAS have the potential to cause cardiovascular harm and can therefore increase risk of ischaemic stroke.

• Stroke physicians should recognise AAS use (along with ‘post-cycle therapy’) as a risk factor for cerebrovascular disease and to consider the possibility of anabolic steroid misuse in younger adults presenting with cryptogenic stroke.