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Long-term testosterone therapy is associated with a reduction in obesity parameters, improved metabolic syndrome and health-related quality of life in men with hypogonadism

Long-term tt is associated with a reduction in obesity parameters, improved mets and health-related quality of life in men with hypogonadism

Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Yassin AA, Doros G. Clinical Obesity 2013;3:73–83.

Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. Yassin DJ, Doros G, Hammerer PG, et al. J Sex Med 2014;11:1567–76.

This editorial summarises two papers based on the same observational study of 261 hypogonadal men: the first focused specifically on obesity and assessed the long-term effects of normalising testosterone (T) levels on obesity parameters.1 The second paper focused on parameters associated with the metabolic syndrome (MetS) as well as obesity measures.2

Hypogonadism is associated with several clinical symptoms, including increased adiposity, reduced muscle mass, reduced bone density, obesity, diabetes, and erectile dysfunction (ED).3 Diabetes and obesity are of particular concern as they are well known risk factors for cardiovascular disorders.4 Although, several studies have found that treatment with T can ameliorate these symptoms,5,6 it is not known if these improvements can be sustained in the long-term. The studies summarised in this editorial investigated the long-term effects of testosterone undecanoate (TU) on a number of these symptoms.

Both papers analysed the same registry of 261 hypogonadal men (aged 59.5 ± 8.4 years), all of whom had sought treatment for ED at a single urologist’s office. Patients received parenteral TU 1000 mg at baseline, week 6 and every 12 weeks thereafter for up to 5 years. All 261 patients were followed for ≥1 year, 260 patients for 2 years, 237 for 3 years, 195 for 4 years and 163 for 5 years. Adherence to treatment was excellent and the decline in patient numbers each year represented duration of treatment rather than drop-out rates.1,2

The first paper measured anthropometric parameters. Patient height, body weight, body mass index (BMI) and waist circumference (WC) were measured at baseline, and weight, BMI and WC were measured at least once a year. Blood samples were taken prior to the next TU injection, consequently this meant that T levels measured were trough levels.1

The second paper also measured (at baseline and at every visit) body weight, WC and BMI as well as parameters associated with the MetS; total cholesterol, LDL, HDL, triglycerides, glucose, HbA1c (glycated hemoglobin), blood pressure (BP) and total T concentrations.2

Key Points

  • In an unselected cohort of hypogonadal men presenting with ED to a single urologist’s office, only 4% were of normal weight, 34% were overweight, and 62% were obese

    • In the obese subgroup, 94% of men were obese (BMI 30.0–39.9 kg/m2) and 6% were excessively obese (BMI ≥40.0 kg/m2)
    • Only 3% had a normal WC (≤94 cm), 28% had an increased waist size (94–101.9 cm), and 69% had a substantially increased waist size (≥102 cm)
  • At the end of the observation period (maximum 5 years) 96% of men had lost weight (mean loss 11.1 kg)

    • Weight loss was gradual and was sustained across the 5-year study period (Table 1)
    • At baseline, weight ranged from 68 kg to 141 kg (mean 100.1 ± 14.0 kg)

      • At the end of the observational period this decreased to a range of 67 kg to 124 kg (mean 92.2 ± 11.2 kg) (7.9% reduction, p<0.0001 over 5 years)
    • 98% of men showed a reduction in WC with a mean decrease of 9.4 cm
    • Mean WC decreased from 107.7 ± 10.0 cm (range 88–148 cm) to 99.0 ± 9.0 cm (range 85–137 cm) (p>0.0001 over 5 years)
  • In the obese subgroup (n=162), mean weight loss was 12.8 kg and mean reduction in WC was 10.5 cm

    • Approximately 95% of the obese men lost weight, 98% had a reduction in WC
    • Both weight loss and reduction in WC were significant across the treatment period
  • MetS parameters were measured in the same overall cohort:

    • Lipid pattern improved with substantial and sustained reductions in total cholesterol, LDL and triglycerides, and an increase in HDL (Table 2)

      • Between baseline and the end of the 5-year study period, total cholesterol was reduced by 17.2% (p<0.0001), LDL cholesterol was reduced by 19.5% (p<0.0001), triglycerides decreased by 21.0% (p<0.0001), and HDL cholesterol increased by 34.5% (p<0.05)
    • The total cholesterol to HDL ratio, a cardiovascular risk marker, declined from 6.84 to 4.09 over the course of the study
    • Fasting glucose and HbA1c decreased, suggesting improved glycemic control

      • Fasting blood glucose levels significantly decreased from 111.92 ± 36.69 mg/dL to 99.02 ± 18.10 mg/dL (11.5% reduction, p<0.0001)
      • HbA1c¬ decreased over the course of the study from 6.55 ± 1.2% to 5.63 ± 0.64%
    • Both systolic and diastolic BP decreased significantly

      • Mean SBP significantly decreased from 137.39 ± 13.05 mmHg to 122.35 ± 5.96 mmHg (p<0.0001)
      • From baseline to the end of the 5-year study period there was also a significant decrease in DBP from 82.11 ± 9 mmHg to 77.68 ± 4.07 mmHg (p<0.0001)
  • Long-term health-related quality of life was improved by TU treatment resulting from contributions of sustained improvements in erectile function (p<0.0001) and muscle and joint pain
  • No increased risk of prostate cancer was observed; prostate cancer was seen in only 2.3% of TU-treated hypogonadal men

What is known

Between 29.3% and 52.6% of obese men have T levels below the recommended levels.7,8 Treatment with T is associated with an increase in muscle mass and an overall decrease in weight due to loss of fat mass, this weight loss contributes to a positive feedback loop by increasing T levels.9 In addition to a reduction of fat mass in hypogonadal men, treatment with TU is associated with an increase in mood and motivation which may contribute to a more active lifestyle facilitating further weight loss.10

Low T levels also contribute to an increased risk of MetS by increasing insulin resistance, LDL, total cholesterol, triglycerides and reducing HDL levels. Treatment with TU in patients with symptoms of the MetS is associated with a reversal of these changes as T levels reach normal concentrations.5,6

However, as there have been few studies with TU over a long treatment period (>2 years),10-12 it is unknown if the improvements in parameters associated with obesity and the MetS can be sustained in the long term.

What these studies add

Long-term treatment with TU in hypogonadal men resulted in improvements in obesity parameters.1 A significant (p<0.0001), sustained and gradual weight loss of approximately 11 kg occurred in 96% of hypogonadal men treated with TU. This weight reduction was also associated with a decrease in BMI and WC, both of which were sustained over the 5-year treatment period. In the obese subgroup, this reduction was more prominent in patients with baseline BMI ≥30 kg/m2.

Parameters affected by the MetS also improved, including lipid and glucose parameters and BP, that were sustained across the 5-year treatment period.2 Patient’s health-related quality of life also improved in the long-term, as demonstrated by a sustained improvement in erectile function (p<0.0001) and muscle and joint pain with long-term TU treatment.

The length of these studies allowed for the optimal effects of TU treatment to be seen, thus providing a timescale for symptom improvements in hypogonadal men treated with T. Indeed, lipid parameters and quality of life improved after only 4 weeks. Nevertheless, it should be noted that it can take more than 12 months for the maximum benefits of T therapy to be observed.

Neither analysis found evidence that long-term treatment with TU increases the risk of prostate carcinoma. They reported that only 2.3% of men observed developed prostate cancer. This equates to an incidence of 55.4 per 10,000 patient-years, whereas other trials examining prostate cancer found an incidence of 116 per 10,000 patient-years13 and 96.6 per 10,000 patient-years.14

These findings suggest that long-term treatment with TU in hypogonadal men is well tolerated and effective in reducing both anthropometric parameters of obesity and individual parameters affected by the MetS, and is associated with an increase in patients’ health-related quality of life.

 

Table 1. Mean % weight change from baseline to study end in hypogonadal men treated with testosterone undecanoate.1

  Year 1
(n=261)
Year 2
(n=241)
Year 3
(n=257)
Year 4
(n=194)
Year 5
(n=162)
Weight change from baseline, % (mean ± SD) –3.2 ± 0.3* –5.6 ± 0.3*† –7.5 ± 0.3*† –9.1 ± 0.3*† –10.5 ± 0.4*†

SD, standard deviation.*p<0.0001 vs. baseline, †p<0.0001 vs. previous year

 

Table 2. Change in lipid parameters from baseline to study end in hypogonadal men treated with testosterone undecanoate.2

  Baseline
(n=260)
End of 5-year study period
(n=162)
Total cholesterol 256.24 ± 51.06 212.2 ± 40.88*
Triglycerides 252.05 ± 95.23 199.04 ± 52.34*
LDL 157.09 ± 28.43 126.41 ± 33.7*
HDL 41.34 ± 12.15 55.62 ± 14.66†

All data are given as mg/dL, mean ± SD.

HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation. *p<.0001 vs. baseline, †p<0.05 vs. baseline

References

1. Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes 2013;3(3-4):73-83.
2. Yassin DJ, Doros G, Hammerer PG, et al. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. J Sex Med 2014;11(6):1567-1576.
3. Saad F, Aversa A, Isidori AM, et al. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev 2012;8(2):131-143.
4. Wang C, Jackson G, Jones TH, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care 2011;34(7):1669-1675.
5. Saad F, Gooren L, Haider A, et al. An exploratory study of the effects of 12 month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Arch Androl 2007;53(6):353-357.
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. Corona G, Rastrelli G, Monami M, et al. Body mass index regulates hypogonadism-associated CV risk: results from a cohort of subjects with erectile dysfunction. J Sex Med 2011;8(7):2098-2105.
8. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006;60(7):762-769.
9. Corona G, Rastrelli G, Monami M, et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol 2013;168(6):829-843.
10. Saad F, Haider A, Doros G, et al. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring) 2013;21(10):1975-1981.
11. Aversa A, Bruzziches R, Francomano D, et al. Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aging Male 2012;15(2):96-102.
12. Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010;7(10):3495-3503.
13. Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360(13):1310-1319.
14. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360(13):1320-1328.

Last updated: 2018
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