Dr. Ron’s Research Review – May 22, 2013

© 2013

This week’s research review is part 2 of the adverse effects of testosterone use.

The Testosterone in Older Men with Mobility Limitations Trial found an increased incidence of cardiovascular events in men randomized to testosterone, resulting in enrollment cessation by trial's Data and Safety Monitoring Board. Within the testosterone group, the 6-month increase in free testosterone was significantly greater in men who experienced cardiovascular events than in those who did not (mean 10.6 (4.6-16.7) vs. 5.2 (3.0-7.5) ng/dL, p = .05). (Basaria, Davda et al. 2013)

A recent article described thrombosis, deep venous thrombosis (DVT) pulmonary embolism (PE; n = 9) and hip-knee osteonecrosis (n = 5) that developed after testosterone therapy (median 11 months) in 14 previously healthy patients (13 men and 1 woman; 13 Caucasian and 1 African American), with no antecedent thrombosis and previously undiagnosed thrombophilia-hypofibrinolysis. (Glueck, Richardson-Royer et al. 2013)

One study of 8 men found reversible infertility associated with testosterone therapy for symptomatic hypogonadism. All patients had received multiple testosterone undecanoate (Nebido) injections at local clinic due to androgen deficiency symptoms combined with lower serum testosterone level. When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia-hypofibrinolysis, thrombosis occurs.  (Bang, Lim et al. 2013)

Dr. Ron


Articles

Reversible infertility associated with testosterone therapy for symptomatic hypogonadism in infertile couple

         (Bang, Lim et al. 2013) Download

Purpose: Androgen replacement therapy has been shown to be safe and effective for most patients with testosterone deficiency. Male partners of infertile couples often report significantly poorer sexual activity and complain androgen deficiency symptoms. We report herein an adverse effect on fertility caused by misusage of androgen replacement therapy in infertile men with hypogonadal symptoms. Materials and Methods: The study population consisted of 8 male patients referred from a local clinic for azoospermia or severe oligozoospermia between January 2008 and July 2011. After detailed evaluation at our andrology clinic, all patients were diagnosed with iatrogenic hypogonadism associated with external androgen replacement. We evaluated changes in semen parameters and serum hormone level, and fertility status. Results: All patients had received multiple testosterone undecanoate (Nebido(R)) injections at local clinic due to androgen deficiency symptoms combined with lower serum testosterone level. The median duration of androgen replacement therapy prior to the development of azoospermia was 8 months (range: 4-12 months). After withdrawal of androgen therapy, sperm concentration and serum follicle-stimulating hormone level returned to normal range at a median 8.5 months (range: 7-10 months). Conclusion: Misusage of external androgen replacement therapy in infertile men with poor sexual function can cause temporary spermatogenic dysfunction, thus aggravating infertility.

Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation

         (Basaria, Davda et al. 2013) Download

BACKGROUND: Testosterone in Older Men with Mobility Limitations Trial found an increased incidence of cardiovascular events in men randomized to testosterone, resulting in enrollment cessation by trial's Data and Safety Monitoring Board. We evaluated changes in gonadal hormones and markers of inflammation and coagulation to elucidate risk factors associated with cardiovascular events. METHODS: Men aged 65 years or more, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Changes in total and free testosterone, estradiol and estrone, C-reactive protein, interleukin 6, fibrinogen, plasminogen activator inhibitor-1, and pro-brain naturetic peptide were compared between groups and within the testosterone group between subjects who experienced cardiovascular events and those who did not. RESULTS: Of 209 men randomized (mean age 74 years), gonadal hormones and biomarkers were available in 179 men. Baseline body mass index, gonadal hormones, lipids, Framingham risk scores, and other biomarkers were similar in the two treatment groups. Within the testosterone group, the 6-month increase in free testosterone was significantly greater in men who experienced cardiovascular events than in those who did not [mean (95% confidence interval), 10.6 (4.6-16.7) vs 5.2 (3.0-7.5) ng/dL, p = .05]. In multivariable logistic regression analysis, the change in the serum levels of free testosterone was associated with cardiovascular events. CONCLUSION: Mobility-limited older men who experienced cardiovascular events had greater increases in serum free testosterone levels than those who did not.

Testosterone, Thrombophilia, and Thrombosis

         (Glueck, Richardson-Royer et al. 2013) Download

We describe thrombosis, deep venous thrombosis (DVT) pulmonary embolism (PE; n = 9) and hip-knee osteonecrosis (n = 5) that developed after testosterone therapy (median 11 months) in 14 previously healthy patients (13 men and 1 woman; 13 Caucasian and 1 African American), with no antecedent thrombosis and previously undiagnosed thrombophilia-hypofibrinolysis. Of the 14 patients, 3 were found to be factor V Leiden heterozygotes, 3 had high factor VIII, 3 had plasminogen activator inhibitor 1 4G4G homozygosity, 2 had high factor XI, 2 had high homocysteine, 1 had low antithrombin III, 1 had the lupus anticoagulant, 1 had high anticardiolipin antibody Immunoglobulin G, and 1 had no clotting abnormalities. In 4 men with thrombophilia, DVT-PE recurred when testosterone was continued despite therapeutic international normalized ratio on warfarin. In 60 men on testosterone, 20 (33%) had high estradiol (E2 >42.6 pg/mL). When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia-hypofibrinolysis, thrombosis occurs. The DVT-PE and osteonecrosis after starting testosterone are associated with previously undiagnosed thrombophilia-hypofibrinolysis. Thrombophilia should be ruled out before administration of exogenous testosterone.


Risks and benefits of testosterone therapy in older men

         (Spitzer, Huang et al. 2013) Download

In young men (defined as age <50 years) with classic hypogonadism caused by known diseases of the hypothalamus, pituitary or testes, testosterone replacement therapy induces a number of beneficial effects, for example, the development of secondary sex characteristics, improvement and maintenance of sexual function, and increases in skeletal muscle mass and BMD. Moreover, testosterone treatment in this patient population is associated with a low frequency of adverse events. Circulating testosterone levels decline progressively with age, starting in the second and third decade of life, owing to defects at all levels of the hypothalamic-pituitary-testicular axis. In cohort studies, testosterone levels are associated weakly but consistently with muscle mass, strength, physical function, anaemia, BMD and bone quality, visceral adiposity, and with the risk of diabetes mellitus, coronary artery disease, falls, fractures and mortality. However, the clinical benefits and long-term risks of testosterone therapy-especially prostate-related and cardiovascular-related adverse events-have not been adequately assessed in large, randomized clinical trials involving older men (defined as age >65 years) with androgen deficiency. Therefore, a general policy of testosterone replacement in all older men with age-related decline in testosterone levels is not justified.


References

Bang, J. K., J. J. Lim, et al. (2013). "Reversible infertility associated with testosterone therapy for symptomatic hypogonadism in infertile couple." Yonsei Med J 54(3): 702-6. [PMID: 23549818]

Basaria, S., M. N. Davda, et al. (2013). "Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation." J Gerontol A Biol Sci Med Sci 68(2): 153-60. [PMID: 22562960]

Glueck, C. J., C. Richardson-Royer, et al. (2013). "Testosterone, Thrombophilia, and Thrombosis." Clin Appl Thromb Hemost. [PMID: 23615294]

Spitzer, M., G. Huang, et al. (2013). "Risks and benefits of testosterone therapy in older men." Nat Rev Endocrinol. [PMID: 23591366]