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Long-acting testosterone undecanoate (TU) injection, but not oral TU, improves metabolic parameters in hypogonadal men

Image: medical pills and syringe

Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. Aversa A, Bruzziches R, Francomano D, et al. J Endocrinol Invest 2010;33(11):776-783.

This randomized, double-blind, double-dummy study was the first clinical trial to compare the efficacy and safety of long-term testosterone replacement therapy using two different preparations of testosterone undecanoate (TU), in hypogonadal men with metabolic syndrome (MetS) and/or type 2 diabetes mellitus (T2DM).1 Patients were randomized to one of three parallel treatment arms; oral TU (80 mg twice daily), intramuscular (IM) TU (1000 mg initially, then repeated every 12 weeks from week 6) or transdermal placebo gel (3–4 g/day). After 6 months, the oral testosterone group was crossed over to receive IM TU for 6 months; the other groups continued with their initial treatment for a further 6 months.

Fifty-two Caucasian men (mean age 57 years) with mean total T <320 ng/dl (11 nmol/L) met the selection criteria and were assigned to oral TU (n=10), IM TU (n=32) or placebo (control group; n=10). Twenty-five to 30% of men had both T2DM and MetS and 60 to 75% of men had mild-to-moderate erectile dysfunction (ED).

Key Points

After 6 months, IM testosterone undecanoate (TU):

  • Increased total and free T (TT and FT) (both p<0.0001)1

    • Serum TT levels were returned into the medium-high range of reference values (mean >500 ng/dL [17.35 nmol/L]) (Figure 1)1
  • Improved metabolic parameters by reducing homeostasis model assessment index of insulin resistance (HOMA-IR) (p<0.0001) (Table 1), decreasing waist circumference (p<0.0001), decreasing fat mass (p<0.001) and increasing fat-free mass (p<0.001)1
  • Improved International Index of Erectile Function (IIEF-5) and Aging Males’ Symptoms (AMS) scores (p<0.01)1
After 12 months, IM TU further:

  • Increased TT (Figure 1) and FT levels (p<0.0001)1
  • Improved metabolic parameters by additional reductions in HOMA-IR (p<0.001) (Table 1), waist circumference (p<0.001) and fat mass (p<0.001)1
  • Improved IIEF-5 and AMS scores (p<0.01), including AMS sexual function sub-domains (p<0.05)1
In contrast, after 6 months oral TU:

  • Did not increase TT (Figure 1) or FT levels from baseline1
  • Did not improve insulin sensitivity (Table 1), decrease waist circumference, decrease fat mass or increase fat-free mass1
  • Did not improve IIEF-5 and AMS scores1
In patients who crossed over from oral TU, 6 months of IM TU:

  • Increased TT (Figure 1) and FT from baseline and month 6 levels (p<0.0001)1
  • Improved metabolic parameters by reducing HOMA-IR (p<0.001) (Table 1), decreasing fat mass (p<0.001) and increasing fat free mass (p<0.001)1
  • Improved IIEF-5 and AMS scores (p<0.01)1
Other outcomes

  • There was no change in sex hormone binding globulin, estradiol, follicle-stimulating hormone, luteinizing hormone or prolactin levels at 12 months in any treatment group1
  • There were no significant changes from baseline in International Prostate Symptoms Score (IPSS) scores, body mass index (BMI), blood pressure (BP), lipid parameters, glycosylated haemoglobin (HbA1c) prostate-specific antigen (PSA) levels, prostate volume or liver enzymes in any treatment group1
  • Haemoglobin and haematocrit values increased with oral and IM TU, but remained stable and within the normal range during treatment1
  • The were no significant changes from baseline in the placebo group in any parameters studied.1

What is known

Male hypogonadism can be associated with MetS, T2DM, atherosclerosis, myocardial infarction and chronic heart failure, and it is increasingly recognized that low testosterone levels are an independent risk factor for these conditions.1-6 It is estimated that between 19% and 34% of men over the age of 60 years have serum testosterone levels below the lower limit of the normal range for healthy young men (approximately 300 ng/dL or 10.4 nmol/L).7,8 Men with MetS have an increased risk of developing T2DM and/or cardiovascular disease, and the presence of low testosterone levels can predict the development of insulin resistance and possible progression to overt T2DM.9 Therefore, restoring testosterone levels to the young healthy adult male reference range of approximately 300–1000 ng/dL (10–35 nmol/L) may improve metabolic parameters and reduce the burden of cardiovascular events.1 Although a number of different formulations of testosterone are available for long-term administration as testosterone replacement therapy, including oral and long-acting injectable formulations of testosterone undecanoate, comparative efficacy data have been lacking.

What this study adds

This study shows for the first time that oral TU is clinically ineffective in improving insulin sensitivity, body composition and ED in hypogonadal men with MetS and/or T2DM. In contrast, during the first 6 months of treatment the long-acting IM TU formulation returned serum T levels to the medium-high range of reference values (>500 ng/dL), increased FT levels and improved insulin sensitivity, body composition and sexual function. All of these parameters continued to improve during the second 6 months of treatment with IM TU. No major unwanted effects were observed with long-term IM TU, and there was no increase in prostate volume or obstructive symptoms.

Figure1: Change from baseline in total testosterone levels during treatment with oral or IM testosterone undecanoate (TU)

Table 1: Change from baseline in homeostasis model assessment index of insulin resistance (HOMA-IR) after treatment with oral or IM testosterone undecanoate (TU)
Oral TU (6 mo) then IM TU (6 mo) IM TU (12 mo)
Baseline 4.61 4.27
6 months 4.37 2.78*
12 months 3.01* 2.17*
* p<0.0001 vs baseline

References

1. Aversa A, Bruzziches R, Francomano D, et al. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest 2010;33(11):776-783.
2. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl 2009;30(1):23-32.
3. Malkin CJ, Pugh PJ, West JN, et al. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 2006;27(1):57-64.
4. Traish AM, Saad F, Feeley RJ, et al. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl 2009;30(5):477-494.
5. Fukui M, Kitagawa Y, Ose H, et al. Role of endogenous androgen against insulin resistance and atherosclerosis in men with type 2 diabetes. Curr Diabetes Rev 2007;3(1):25-31.
6. Traish AM, Guay A, Feeley R, et al. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009;30(1):10-22.
7. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95(6):2536-2559.
8. Kshirsagar A, Seftel A, Ross L, et al. Predicting hypogonadism in men based upon age, presence of erectile dysfunction, and depression. Int J Impot Res 2006;18(1):47-51.
9. Rodriguez A, Muller DC, Metter EJ, et al. Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. J Clin Endocrinol Metab 2007;92(9):3568-3572.

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