Testosterone therapy-induced erythrocytosis: can phlebotomy be justified?

Erythrocytosis, or elevated hematocrit, is a common side effect of testosterone therapy (TTh) in male hypogonadism. Testosterone stimulates erythropoiesis through an initial rise in erythropoietin (EPO), the establishment of a new EPO/hemoglobin 'set point', and a parallel decrease in the master iron regulator protein hepcidin, as well as several other potential mechanisms. Evidence shows an increased thrombotic risk associated with TTh-induced erythrocytosis. Several guidelines by endocrine organizations for the treatment of male hypogonadism recommend against starting TTh in patients presenting with elevated hematocrit at baseline or stopping TTh when its levels cannot be controlled. Besides dose adjustments, therapeutic phlebotomy or venesection is mentioned as a means of reducing hematocrit in these patients. However, evidence supporting the efficacy or safety of therapeutic phlebotomy in lowering hematocrit in TTh-induced erythrocytosis is lacking. In light of this dearth of evidence, the recommendation to lower hematocrit using therapeutic phlebotomy is notable, as phlebotomy lowers tissue oxygen partial pressure (pO2) and eventually depletes iron stores, thereby triggering various biological pathways which might increase thrombotic risk. The potential pros and cons should therefore be carefully weighed against each other, and shared decision-making is recommended for initiating therapeutic phlebotomy as a treatment in patients on TTh who present with increased hematocrit.

Coagulation profiles during and after anabolic androgenic steroid use: data from the HAARLEM study.

Background: Anabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk. Objectives: We investigated whether AAS influence coagulation parameters associated with VTE by assessing their changes during and after AAS use. Methods: The HAARLEM study enrolled 100 male amateur athletes voluntarily starting an AAS cycle between 2015 and 2018. We measured procoagulant and anticoagulant protein levels, D-dimer levels, endogenous thrombin potential (ETP), and clot lysis time (CLT) at baseline and during 2 years of follow-up. Changes in coagulation during AAS cycle, 3 months after its discontinuation, and 1 year after its inclusion compared with baseline were estimated using linear mixed models. The associations between AAS dose and duration of use with these outcomes were studied through adjusted multivariable linear regression. Results: Participants used AAS for a median of 13 weeks (IQR: 10-23) with a median weekly dose of 901 mg (IQR: 634-1345 mg). Mean levels of multiple coagulation factors (F) increased during use compared with baseline, whereas FVIII and von Willebrand factor levels remained unchanged. Protein S and D-dimer showed the biggest increase (22% [95% CI: 15-29] and 1.3-fold [95% CI: 1.2-1.5], respectively). CLT was 8 minutes longer (95% CI: 5-10) and ETP was 165 nM∗min (95% CI: -205 to -124) lower during the AAS cycle. A high weekly AAS dose and short cycle duration were associated with changes in protein S and ETP during use. All parameters returned to baseline values 3 months after discontinuation and remained similar after. Conclusion: During AAS use, procoagulant and anticoagulant protein levels increased in a reversible manner. The overall balance did not suggest a clear procoagulant state.

Predictors of Ongoing Androgen Abuse. A Prospective 2-year Follow up of 100 Male Androgen Abusers.

BACKGROUND: The abuse of androgens is common among visitors to fitness centers. Prospective data regarding patterns of androgen abuse and predictors of future use are not well studied. METHODS: This is a 2-year prospective observational cohort study among 100 male androgen abusers. The median age of the subjects was 31 years (range, 19-67 years). Participants were meticulously characterized and observed for 1 year before, during, and after the use of a cycle of androgens. They remained in follow-up for a second year to study subsequent androgen abuse. Using multivariable regression analysis we aimed to identify baseline sociodemographic factors and cycle characteristics that would predict future androgen abuse. RESULTS: Ninety-seven (97%) men completed the second year of follow-up. Sixty-three subjects (65%) abused androgens again and 16 (16%) for the entire duration of the second year. The variables that were positively associated with the cumulative time of androgen abuse during the 2 years of follow-up were historical cumulative androgen exposure and the intention to take part in bodybuilding competitions. Cycle duration in year 1 and training time at baseline were positively associated with repeated use in year 2. Cycle duration in the first year was also positively associated with the cumulative time of androgen abuse in the second year. For all the other investigated baseline variables and cycle characteristics, no associations with future use were found. CONCLUSION: The results of this study support the assumption that body building competitions are a driver for androgen abuse. Most androgen abusers use androgens repeatedly. The factors that predict future androgen abuse may assist in harm reduction strategies that aim to minimize long-term health problems in androgen abusers.

Clinical question: How to manage symptoms of hypogonadism in patients after androgen abuse?

Androgen abuse is relatively common amongst young (amateur) bodybuilders. After cessation, the hypothalamic-pituitary-gonadal (HPG) axis-which has been suppressed by the androgens-needs time to recover. The endogenous testosterone production often recovers within 3 months, however, prolonged or permanent post-androgen abuse hypogonadism (PPAAH) has been described. There is no widely accepted definition nor is its pathogenesis completely elucidated. To date it is a subject of debate whether PPAAH is a separate entity, reflecting irreversible damage to essential components of the HPG axis inflicted by long-term exposure to high doses of androgens. Alternately, it may be the result of longer than expected suppressive effects of androgen depots, undisclosed ongoing androgen abuse or undiagnosed unrelated disorders. Due to the lack of scientific evidence, the management of PPAAH is challenging. By combining clinical experience with evidence from the recent literature, a suggested outline of the management of androgen-abuse-induced hypogonadism are given.

Anabolic-androgenic steroid abuse and testicular function in men; recent insights.

The use of illegal androgens by young men is not uncommon. The majority of users take multiple courses of androgens during their lifetime, leading to a high cumulative exposure. An inseparable side effect is suppression of gonadal function. Although this usually recovers, recovery can take a long time and is not without symptoms. This review focusses on recent studies that have greatly increased our knowledge of the disruption and recovery of testicular function during and after androgen abuse. For the guidance and treatment of (potential) users, in-depth knowledge of this is indispensable.

Health effects of androgen abuse: a review of the HAARLEM study.

PURPOSE OF REVIEW: Data on the health effects of androgen abuse are mainly derived from lower level evidence, such as case series and cross-sectional studies. In the last few years a relatively large and prospective cohort initiative, the HAARLEM (health risks of anabolic androgenic steroid use by male amateur athletes) study, made an important contribution to current knowledge. RECENT FINDINGS: The HAARLEM study showed that all androgen abusers experience positive and negative effects, such as an increase in strength and acne and gynecomastia, respectively. Effects are generally reversible and acute life-threatening toxicity is rare. There is a distinct but limited impact on liver and kidney function. Gonadal function is disrupted but resumes normally after abuse is discontinued in the majority of athletes. The negative impact of androgens on cardiovascular parameters, such as blood pressure, hematocrit and lipid metabolism, as well as cardiac structure and function, seems to be the mechanism for premature atherosclerosis and cardiomyopathy, respectively, in long-term users. SUMMARY: It is beyond dispute that androgen abuse is harmful and much of the short-term toxicity is well documented. To prevent the long-term health hazards, there should be ample focus on preventive measures, both primary and secondary, and effective harm reduction strategies should be developed.

Prospective study on blood pressure, lipid metabolism and erythrocytosis during and after androgen abuse.

Androgen abuse is associated with unfavourable changes in blood pressure, lipid metabolism and erythrocytosis. Most knowledge is based on cross-sectional studies sensitive to bias. We assessed the magnitude of these effects and their recovery in a prospective cohort study which included 100 men (≥18 years) performing an androgen cycle. Clinic visits took place before the cycle, at the end, 3 months after and 1 year after start of the cycle and included measurement of blood pressure, lipid parameters and haematocrit. During androgen use, systolic and diastolic blood pressure increased 6.87 (95% CI 4.34-9.40) and 3.17 mmHg (1.29-5.04) compared to baseline respectively. LDL cholesterol and ApoB increased 0.45 mmol/L (0.29-0.61) and 18.2 mg/dl (13.5-22.8) respectively, whereas HDL cholesterol, ApoA and Lp(a) decreased with 0.40 mmol/L (-0.45 to 0.35), 36.6 mg/dl (30.2-42.9) and 37.6% (13.9-61.3). ANGPTL3 increased 20.3% (7.38-33.2). Mean haematocrit increased 0.03 L/L (0.02-0.03). Three months after the cycle, and 1 year after the start, these parameters returned to baseline. In conclusion, androgen abuse induces small but clinically relevant adverse changes in blood pressure, lipid metabolism and erythrocytosis which are rapidly reversible after cessation. As follow-up was limited to 1 year, the impact of androgen abuse on cardiovascular disease remains uncertain.

Anabolic-androgenic steroids: How do they work and what are the risks?

Anabolic-androgenic steroids (AAS) are a class of hormones that are widely abused for their muscle-building and strength-increasing properties in high, nontherapeutic, dosages. This review provides an up-to-date and comprehensive overview on how these hormones work and what side effects they might elicit. We discuss how AAS are absorbed into the circulation after intramuscular injection or oral ingestion and how they are subsequently transported to the tissues, where they will move into the extravascular compartment and diffuse into their target cells. Inside these cells, AAS can biotransform into different metabolites or bind to their cognate receptor: the androgen receptor. AAS and their metabolites can cause side effects such as acne vulgaris, hypertension, hepatotoxicity, dyslipidemia, testosterone deficiency, erectile dysfunction, gynecomastia, and cardiomyopathy. Where applicable, we mention treatment options and self-medication practices of AAS users to counteract these side effects. Clinicians may use this review as a guide for understanding how AAS use can impact health and to assist in patient education and, in some cases, the management of side effects.

A 29-year-old Bodybuilder with Liothyronine-induced Thyrotoxic Hypokalaemic Periodic Paralysis.

We describe a 29-year-old male bodybuilder with recurrent attacks of myalgia and muscle weakness associated with hypokalaemia and thyrotoxicosis due to abuse of liothyronine. The attacks quickly resolved after potassium supplementation and liothyronine cessation. We concluded that the patient had thyrotoxic hypokalaemic periodic paralysis (TPP). Although muscle weakness and hypokalaemia are prominent symptoms of TPP, underlying thyrotoxicosis may be overlooked. Up to 25% of androgen abusers also abuse thyroid hormone. Lack of recognition of thyroid hormone abuse as a cause of hypokalaemic periodic paralysis may result in unnecessary, potentially harmful medical investigations and improper treatment and advice. LEARNING POINTS: In patients with bouts of muscle weakness and hypokalaemia, thyrotoxic hypokalaemic periodic paralysis should be suspected and thyroid function should be evaluated.In bodybuilders and strength athletes, undisclosed abuse of performance and image-enhancing drugs, including thyroid hormone, should be suspected.

Anabolic Androgenic Steroids Induce Reversible Left Ventricular Hypertrophy and Cardiac Dysfunction. Echocardiography Results of the HAARLEM Study.

Background: The use of anabolic androgenic steroids (AAS) is not uncommon among strength athletes. Several cross-sectional studies have linked AAS use to heart disease, but a causal role for AAS is not certain and it is unknown whether cardiac changes are reversible. Methods: Men of at least 18 years old intending to start an AAS cycle on short notice were included for comprehensive 3D echocardiographic examination before (T0), at the end of the cycle (T1), and 1 year after inclusion (T2) after a recovery period. Details of the AAS cycle performed and the use of other performance and image-enhancing drugs (PIEDs) as well as illicit drug use were recorded. Trend analysis and multivariable regression analysis were performed with mixed effects linear models. Results: Thirty-one subjects were included. Between start (T0) and end of the cycle (T1), after a median AAS cycle duration of 16 weeks, 3D left ventricular ejection fraction declined with 4.9% (CI -7.2 to -2.5, P < 0.001), E/A-ratio declined with-0.45 (CI -0.69 to -0.21, P < 0.001), and 3D left atrial volume increased with 9.2 ml (CI 2.9-15.4, P = 0.004). Left ventricular mass increased with 28.3 g (CI 14.2-42.4, P < 0.001) and was positively correlated with AAS average weekly dose. After a median recovery time of 8 months (T2), all parameters returned to baseline. Conclusion: AAS induce left ventricular hypertrophy and impaired systolic and diastolic function in amateur strength athletes. The structural cardiac changes are positively associated with AAS dose and complete recovery occurred after AAS were discontinued.

Positive and negative side effects of androgen abuse. The HAARLEM study: A one-year prospective cohort study in 100 men.

An estimated 4-6% of fitness center visitors uses anabolic-androgenic steroids (AAS). Reliable data about adverse reactions of AAS are scarce. The HAARLEM study aimed to provide insight into the positive and negative effects of AAS use. One hundred men (≥18 years) who intended to start an AAS cycle on short notice were included for follow-up. Clinic visits took place before (T0 ), at the end (T1 ), and three months after the end of the AAS cycle (T2 ), and one year after the start of the cycle (T3 ), and comprised a medical history, physical examination, laboratory analysis, and psychological questionnaires. During the follow-up period, four subjects reported a serious adverse event, that is, congestive heart failure, acute pancreatitis, suicidal ideation, and exacerbation of ulcerative colitis. All subjects reported positive side effects during AAS use, mainly increased strength (100%), and every subject reported at least one negative health effect. Most common were fluid retention (56%) and agitation (36%) during the cycle, and decreased libido (58%) after the cycle. Acne and gynecomastia were observed in 28% and 19%. Mean alanine transaminase (ALT) and creatinine increased 18.7 U/l and 4.7 µmol/L, respectively. AAS dose and cycle duration were not associated with the type and severity of side effects. After one-year follow-up (T3 ), the prevalence of observed effects had returned to baseline. There was no significant change in total scores of questionnaires investigating wellbeing, quality of life, and depression. In conclusion, all subjects experienced positive effects during AAS use. Four subjects experienced a serious adverse event. Other side effects were mostly anticipated, mild, and transient.

Anabolic androgenic steroid abuse in young males.

This review summarizes 10 years experience with male abusers of anabolic androgenic steroids (AAS). The typical user of AAS is male, aged between 20 and 40 and lifting weights. Illegal AAS are cheap and easily obtained via internet or local suppliers. AAS are mostly used in cycles with a duration between 6 and 18 weeks. Most AAS cycles contain multiple agents, used simultaneously in a dose vastly exceeding a substitution dose. A variety of other performance and image-enhancing drugs are commonly used, including human growth hormone, thyroid hormone, tamoxifen, clomiphene citrate and human chorionic gonadotrophin. Short-term clinical and biochemical side effects are well established. Long-term side effects are uncertain, but may include heart failure, mood-and anxiety disorders, hypogonadism and subfertility. We share our views on the management of common health problems associated with AAS abuse.

Baseline characteristics of the HAARLEM study: 100 male amateur athletes using anabolic androgenic steroids.

BACKGROUND: The use of anabolic androgenic steroids (AAS) is common among visitors of fitness centers. Knowledge about health risks of AAS use is limited due to lack of clinical studies. METHODS: One hundred men, at least 18 years old, intending to start a cycle of AAS were recruited. Baseline demographical data and reasons for AAS use were recorded. Subjects provided samples of AAS for analysis with UPLC-QTOF-MS/MS. RESULTS: One hundred and eleven men were seen for a baseline visit. Nineteen percent had competed in bodybuilding competitions. Recent illicit drug use was reported by 56%. Seventy-seven percent of participants had used AAS in the past, and 97% of them had experienced side effects. After exclusion, 100 men comprised the cohort for follow-up. The AAS cycle performed had a median duration of 13 weeks (range 2-52), and the average dose of AAS equivalents was 901 mg per week (range 250-3.382). Subjects used other performance and image-enhancing drugs (PIEDs) such as growth hormone (21%). In total, 272 AAS samples were analyzed and 47% contained the AAS indicated on the label. The principal reason for AAS use was gain of muscle mass (44%). Forty-eight percent self-reported to being addicted to AAS. CONCLUSION: The HAARLEM study cohort shows that strength athletes use AAS in a wide variety of cycles and often also use illicit drugs and other potentially harmful PIEDs. The quality of the AAS used is strikingly low. Follow-up of the cohort will provide novel data regarding health risks of AAS use.

[Zoledronic acid; useful in osteopenia?] / Zoledroninezuur zinvol bij osteopenie?

A randomised, double-blind, placebo-controlled trial assessing the effect of zoledronic acid on osteopenia in 2000 women aged 65 years and older over a 6-year treatment period has revealed a statistically significant reduction of fracture incidence. Although the treatment effect seen in this study may have been somewhat overestimated due to selection, the implications for clinical practice could be considerable, as half of all women aged over 65 years are osteopenic and most fractures in the general population occur in this group. However, treatment with zoledronic acid is relatively expensive and the impact on health care costs of treating all older women with osteopenia would be dramatic. Additionally, the decision to treat should be based primarily on fracture risk, which is not only dependent on bone density, but also on other factors such as genetic susceptibility, risk of falling and previous fracture. Zoledronic acid should be reserved for osteopenic women who have an evidently high fracture risk due to these other factors.