Effect of treatment with testosterone undecanoate injection on insulin resistance, glycemic control, endothelial function and atherosclerosis

June 2021

Atherosclerosis is the underlying cause of cardiovascular disease.1 It is well-documented that low testosterone is associated with a large number of risk factors for atherosclerosis, and a growing number of studies show that testosterone has several beneficial effects on the cardiovascular system in men.2-6

We previously summarized the results of a 1-year double-blind, placebo-controlled randomized clinical trial (RCT) that investigated the effect of treatment with testosterone undecanoate injection on markers of insulin resistance, glycemic control, endothelial function and atherosclerosis.7 Here we present 2-year data from this study, showing that longer-term testosterone therapy results in further improvements compared to 1- year treatment.8,9

KEY POINTS

  • Low testosterone is associated with risk factors for atherosclerosis, such as insulin resistance, endothelial dysfunction and atherosclerosis.
  • Study shows that treatment with testosterone undecanoate injection in men with hypogonadism improves insulin resistance, endothelial function and atherosclerosis.
  • Improvements were greater after 2 years, suggesting that shorter-term treatment (6-12 months) is not enough for achievement of health benefits with testosterone therapy.

What is known about

Carotid intima-media thickness (CIMT) is a validated noninvasive technique for measuring the atherosclerotic burden, and represents a surrogate measure of atherosclerosis.10,11 Multiple studies have shown that low testosterone is associated with increased CIMT in both middle-aged and older men.12-22 Importantly, low free testosterone has been found to be associated with progression of CIMT independent of age, and after adjustment for several cardiovascular risk factors (body mass index, waist- to-hip ratio, hypertension, diabetes, smoking and cholesterol levels).17

Unlike CIMT, which measures the extent of established carotid atherosclerosis, endothelial dysfunction is an early marker for atherosclerosis that can be detected before structural changes to the vessel wall appear.23 The most common non-invasive assessment of endothelial dysfunction is forearm flow mediated dilatation (FMD).24 Like CIMT, low testosterone has been found to be associated with endothelial dysfunction independent of age and other risk factors.25 The harmful effect of endothelial dysfunction on cardiovascular risk is elevated in the presence of hypogonadism,26 suggesting a protective effect of testosterone on the endothelium and blood vessels.

Both CIMT 27,28 and FMD 29,30 predict cardiovascular events and mortality, in some studies even after adjustment for age, sex, and vascular risk factors.31 Among previous studies that investigated the effect of testosterone therapy on markers of atherosclerosis (CIMT and coronary artery calcium score), most found a beneficial effect, especially on CIMT.32-35 Even young men (age 24-39 years) with idiopathic hypogonadotropic hypogonadism have higher CIMT and lower FMD compared to age-matched peers, and both CIMT and FMD is improved in this patient population with testosterone therapy.36

Long-term real-life evidence studies have shown that the health benefits of testosterone therapy occur progressively over time with continuous uninterrupted testosterone therapy, as explained in “Practical advice for effective testosterone therapy”. What follows is a summary of results achieved after 2 years of treatment with testosterone undecanoate injection on markers of insulin resistance, glycemic control, endothelial function and atherosclerosis, and a comparison with results achieved after 1 year.

What this study adds

Men (n=28) in the testosterone group continued to receive treatment with testosterone undecanoate injection (1000 mg i.m. every 10 weeks, after an initial interval of 6 weeks) for another year, and 2-year results were analysed and compared to 1-year results. All men had hypogonadism, obesity and type 2 diabetes. Results for year 1 and year 2 are given in table 1, and changes in CIMT, FMD and HOMA-IR are illustrated in figure 1.

Table 1: Results achieved year 1 and year 2 after treatment with testosterone undecanoate injection in men with hypogonadism, obesity and type 2 diabetes.8

Parameter Baseline Year 1 Year 2 Change after 1 year Change after 2 years
BMI (kg/m2) 34.03 33.25 32.45 -0.80 -1.59
Waist size (cm) 116.48 114.9 112.96 -1.58 -3.51
FPG (mmol/L) 10.06 8.83 8.23 -1.23 -1.83
HbA1c (%) 8.12 7.18 6.60 -0.94 -1.51
HOMA-IR 11.45 6.81 5.51 -4.64 -5.94
Total cholesterol (mmol/L) 5.31 4.62 4.34 -0.7 -0.97
LDL (mmol/L) 2.79 2.70 2.39 -0.09 -0.40
HDL (mmol/L) 1.01 1.04 * 1.15 0.03 * 0.15
Triglycerides (nmol/L) 2.86 2.32 * 1.86 -0.54 * -0.99
FMD (%) 4.68 7.07 7.14 2.40 2.46
CIMT (mm) 0.89 0.79 0.73 -0.10 -0.14

* Not statistically significantly compared to baseline. All other changes are statistically significant.


Data from Groti Antonič K, Antonič B, Žuran I, Pfeifer M. Testosterone treatment longer than 1 year shows more effects on functional hypogonadism and related metabolic, vascular, diabetic and obesity parameters (results of the 2-year clinical trial). The aging male : the official journal of the International Society for the Study of the Aging Male. Dec 2020;23(5):1442-1454.

 

Figure 1: Effect on carotid intima-media thickness (CIMT) after year 1 and year 2 of treatment with testosterone undecanoate injection in men with hypogonadism, obesity and type 2 diabetes.8

Effect on carotid intima-media thickness (CIMT) after year 1 and year 2 of treatment with testosterone undecanoate injection in men with hypogonadism, obesity and type 2 diabetes.

CIMT = carotid intima-media thickness, FMD = flow mediated dilatation, HOMA-IR = Homeostatic Model Assessment for Insulin Resistance
Data from Groti Antonič K, Antonič B, Žuran I, Pfeifer M. Testosterone treatment longer than 1 year shows more effects on functional hypogonadism and related metabolic, vascular, diabetic and obesity parameters (results of the 2-year clinical trial). The aging male : the official journal of the International Society for the Study of the Aging Male. Dec 2020;23(5):1442-1454.

The 2-year report of this study also analysed changes in safety parameters. No cardiovascular adverse events occurred, and no patient was diagnosed with prostate cancer. As expected, hematocrit increased gradually during testosterone therapy (table 2). The rise in hematocrit did not exceed the upper limit of 0.52 at any time point for any subject. There was also a small elevation in PSA levels (table 2). Of 28 men in the testosterone group, 27 patients never had PSA >4 μg/L or a year-over-year increase of >1.4 μg/L. The single remaining study participant had been enrolled with pre-existing diagnosed BPH, confirmed by prostate biopsy, and was under regular supervision by a urologist, who deemed the BPH was not severe enough to warrant exclusion from the study. The patient’s baseline serum PSA was 4.0 μg/L, and did not change during the first year, but increased to 5.00 μg/L after the second year, resulting in termination of testosterone therapy.

Men in the placebo group (year 1) were switched to receive testosterone therapy in year 2. Of 27 men, 2 were diagnosed with BPH.

In one patient, PSA increased from 1.17 μg/L to 2.67 μg/L after 3 months, and again from 2.70 μg/L after 6 months to 5.20 μg/L after 12 months.

In the other patient, baseline PSA was 3.03 μg/L and remained steady until the 6-month mark, when it first rose >4.00 μg/L (to 4.04 lg/L), and then to 5.40 μg/L at 12 months.

Both patients discontinued testosterone therapy and underwent prostate biopsy; prostate cancer was excluded and BPH was diagnosed in both men.

Table 2: Change in hematocrit in men with obesity and hypogonadism and Type 2 Diabetes receiving treatment with testosterone undecanoate injection for 2 years.8,9

Time point Hematocrit PSA (μg/L)
Baseline 0.427 0.645
3 months 0.438 * 0.700 *
6 months 0.449 0.735
12 months 0.453 0.825
15 months 0.456 0.970
18 months 0.458 1.050
24 months 0.460 1.175

* Not statistically significantly compared to baseline. All other changes are statistically significant.
 

Data from:
 

Groti Antonič K, Antonič B, Žuran I, Pfeifer M. Testosterone treatment longer than 1 year shows more effects on functional hypogonadism and related metabolic, vascular, diabetic and obesity parameters (results of the 2-year clinical trial). The aging male : the official journal of the International Society for the Study of the Aging Male. Dec 2020;23(5):1442-1454.
Groti Antonič K, Antonič B, Pfeifer M. Effects of Testosterone Therapy on Erythrocytosis and Prostate Adverse Events in Obese Males with Functional Hypogonadism and Type 2 Diabetes in a 2-Year Clinical Trial. Androgens: Clinical Research and Therapeutics. 2020/10/01 2020;1(1):85-93.

 

The study concluded that treatment with testosterone undecanoate injection for 2 years, compared to 1 year, resulted in further improvements in CIMT, FMD, BMI, waist size, HbA1c, triglycerides, LDL and HDL cholesterol. Additional longer-term studies on effects of testosterone therapy on atherosclerosis, endothelial function and insulin resistance are warranted.

Commentary

The 2-year data summarized above show that uninterrupted treatment with testosterone undecanoate injection results in further improvements in markers of insulin resistance, glycemic control, endothelial function and atherosclerosis. It is noteworthy that the increase in HDL and reduction in triglycerides did not become statistically significant until after 2 years of testosterone therapy. This confirms the importance of longer-term treatment when evaluating the benefits of testosterone therapy in men with hypogonadism.

Furthermore, the present study confirmed the safety of treatment with testosterone undecanoate injection, showing that there were no cases of adverse cardiovascular events nor prostate cancer. Hematocrit stayed below 52% in all men, and PSA remained below PSA >4 μg/L and never exceeded a year-over-year increase of >1.4 μg/L in the majority of men.

In contrast to most previous studies investigating the effect of testosterone therapy on atherosclerosis,32-36 in the TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) trial, testosterone therapy did not affect markers of atherosclerosis (intima-media thickness and coronary artery calcium score).35 However, in men not taking statins, one marker of atherosclerosis (coronary artery calcium) was significantly lower in the testosterone group than in the placebo group. For more information about this study, see “Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men

In the present study, most subjects were taking statins and hypertension medications, which may explain the reduction in CIMT in the placebo group. Nevertheless, the reduction in CIMT was twice as large among men treated with testosterone (from 0.89 to 0.79, -0.10) compared to those treated with placebo (from 0.83 to 0.78, -0.05). In another 2-year study, treatment with testosterone undecanoate for 1 year reduced CIMT by -0.22 mm (from a baseline value of 1.03).33 The greater baseline CIMT suggests that the reduction in CIMT with testosterone therapy is greater in men with more severe atherosclerosis.

To put this in perspective, one can compare the reductions in CIMT after testosterone therapy with that seen in statin trials. In the ARBITER trial, atorvastatin reduced CIMT by only -0.034 after 1 year.37 Hence, testosterone therapy is a promising treatment in men with hypogonadism, who are at increased risk of heart disease.4 Indeed, long-term treatment with testosterone undecanoate for 8 years has been shown to reduce mortality by 66% and 92%, as well as non-fatal heart attacks and strokes, compared to men not receiving testosterone therapy.38-41

A previous study showed that treatment with testosterone undecanoate injection for 5 years in men with hypogonadism, obesity and type 2 diabetes reduced incidence of recurrent stroke and mortality.42 For more information, see “Hypogonadism and testosterone treatment following stroke in men with type 2 diabetes” It is presumable that reduction in atherosclerosis, endothelial dysfunction and insulin resistance, as shown in the present study, contributed to the reduced incidence of recurrent stroke and mortality.

References

  • Toth PP. Subclinical atherosclerosis: what it is, what it means and what we can do about it. Int J Clin Pract. Aug 2008;62(8):1246-54. Return to content
  • Pastuszak AW, Kohn TP, Estis J, Lipshultz LI. Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. The journal of sexual medicine. Sep 2017;14(9):1095-1103. Return to content
  • Gencer B, Bonomi M, Adorni MP, Sirtori CR, Mach F, Ruscica M. Cardiovascular risk and testosterone - from subclinical atherosclerosis to lipoprotein function to heart failure. Reviews in endocrine & metabolic disorders. Jun 2021;22(2):257-274. Return to content
  • Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc. Feb 2015;90(2):224-51. Return to content
  • Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process. Atherosclerosis. Dec 2009;207(2):318-27. Return to content
  • Lorigo M, Mariana M, Oliveira N, Lemos MC, Cairrao E. Vascular Pathways of Testosterone: Clinical Implications. Journal of cardiovascular translational research. Feb 2020;13(1):55-72. Return to content
  • Groti K, Zuran I, Antonic B, Forsnaric L, Pfeifer M. The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. The aging male : the official journal of the International Society for the Study of the Aging Male. Sep 2018;21(3):158-169. Return to content
  • Groti Antonič K, Antonič B, Žuran I, Pfeifer M. Testosterone treatment longer than 1 year shows more effects on functional hypogonadism and related metabolic, vascular, diabetic and obesity parameters (results of the 2-year clinical trial). The aging male : the official journal of the International Society for the Study of the Aging Male. Dec 2020;23(5):1442-1454. Return to content
  • Groti Antonič K, Antonič B, Pfeifer M. Effects of Testosterone Therapy on Erythrocytosis and Prostate Adverse Events in Obese Males with Functional Hypogonadism and Type 2 Diabetes in a 2-Year Clinical Trial. Androgens: Clinical Research and Therapeutics. 2020/10/01 2020;1(1):85-93. Return to content
  • Centurion OA. Carotid Intima-Media Thickness as a Cardiovascular Risk Factor and Imaging Pathway of Atherosclerosis. Critical pathways in cardiology. Dec 2016;15(4):152-160. Return to content
  • Doneen AL, Bale BF. Carotid intima-media thickness testing as an asymptomatic cardiovascular disease identifier and method for making therapeutic decisions. Postgrad Med. Mar 2013;125(2):108-23. Return to content
  • De Pergola G, Pannacciulli N, Ciccone M, Tartagni M, Rizzon P, Giorgino R. Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men. Int J Obes Relat Metab Disord. Jul 2003;27(7):803-7. Return to content
  • Dorr M, Wallaschofski H, Friedrich N. Association of low total testosterone levels and prevalent carotid plaques: result of the study of health in Pomerania. Eur J Epidemiol. 2009;24(7):389-91. Return to content
  • Fu L, Gao QP, Shen JX. Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients. Asian journal of andrology. Mar 2008;10(2):214-8. Return to content
  • Fukui M, Kitagawa Y, Nakamura N, et al. Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes. Diabetes Care. Jun 2003;26(6):1869-73. Return to content
  • Makinen J, Jarvisalo MJ, Pollanen P, et al. Increased carotid atherosclerosis in andropausal middle-aged men. J Am Coll Cardiol. May 17 2005;45(10):1603-8. Return to content
  • Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SW, van der Schouw YT. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation. May 4 2004;109(17):2074-9. Return to content
  • Soisson V, Brailly-Tabard S, Empana JP, et al. Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis. Jul 2012;223(1):244-9. Return to content
  • Svartberg J, von Muhlen D, Mathiesen E, Joakimsen O, Bonaa KH, Stensland-Bugge E. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med. Jun 2006;259(6):576-82. Return to content
  • Tsujimura A, Yamamoto R, Okuda H, et al. Low serum free testosterone level is associated with carotid intima-media thickness in middle-aged Japanese men. Endocr J. Sep 30 2012;59(9):809-15. Return to content
  • van den Beld AW, Bots ML, Janssen JA, Pols HA, Lamberts SW, Grobbee DE. Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol. Jan 1 2003;157(1):25-31. Return to content
  • Vikan T, Johnsen SH, Schirmer H, Njolstad I, Svartberg J. Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromso study. Eur J Epidemiol. 2009;24(6):289-95. Return to content
  • Sitia S, Tomasoni L, Atzeni F, et al. From endothelial dysfunction to atherosclerosis. Autoimmunity reviews. Oct 2010;9(12):830-4. Return to content
  • Matsuzawa Y, Lerman A. Endothelial dysfunction and coronary artery disease: assessment, prognosis, and treatment. Coron Artery Dis. Dec 2014;25(8):713-24. Return to content
  • Akishita M, Hashimoto M, Ohike Y, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res. Nov 2007;30(11):1029-34. Return to content
  • Novo S, Iacona R, Bonomo V, Sansone A, Di Piazza M, Pavone C. Lower plasma testosterone levels enhance the predictive value of endothelial dysfunction for future cardiovascular events: A 5-year prospective study. Int J Cardiol. Dec 15 2016;225:197-199. Return to content
  • Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. Jan 30 2007;115(4):459-67. Return to content
  • Cao JJ, Arnold AM, Manolio TA, et al. Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. Circulation. Jul 3 2007;116(1):32-8. Return to content
  • Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A. Prognostic Value of Flow-Mediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta-Analysis. Journal of the American Heart Association. Nov 13 2015;4(11) Return to content
  • Xu Y, Arora RC, Hiebert BM, et al. Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis. European heart journal cardiovascular Imaging. Jul 2014;15(7):736-46. Return to content
  • Lorenz MW, von Kegler S, Steinmetz H, Markus HS, Sitzer M. Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke. Jan 2006;37(1):87-92. Return to content
  • Zitzmann M, Vorona E, Wenk M, Saad F, Nieschlag E. Testosterone administration decreases carotid artery intima media thickness as a marker of impaired vascular integrity in middle-aged overweight men. Journal of Men's Health. 2009;6(3):243. Return to content
  • 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. The journal of sexual medicine. Oct 2010;7(10):3495-503. Return to content
  • Francomano D, Bruzziches R, Barbaro G, Lenzi A, Aversa A. Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. J Endocrinol Invest. Apr 2014;37(4):401-11. Return to content
  • Basaria S, Harman SM, Travison TG, et al. Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA. Aug 11 2015;314(6):570-81. Return to content
  • Dogan BA, Karakilic E, Tuna MM, Arduc A, Berker D, Guler S. Effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with idiopathic hypogonadotropic hypogonadism. Clin Endocrinol (Oxf). Mar 2015;82(3):422-8. Return to content
  • Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. Oct 15 2002;106(16):2055-60. Return to content
  • Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. J Cardiovasc Pharmacol Ther. Sep 2017;22(5):414-433. Return to content
  • Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes (Lond). Jun 2020;44(6):1264-1278. Return to content
  • Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. The aging male : the official journal of the International Society for the Study of the Aging Male. Feb 20 2020;23(1):81-92. Return to content
  • Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes, obesity & metabolism. Nov 2020;22(11):2055-2068. Return to content
  • Morgunov LY, Denisova IA, Rozhkova TI, Stakhovskaya LV, Skvortsova VI. Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus. The aging male : the official journal of the International Society for the Study of the Aging Male. Mar 2020;23(1):71-80. Return to content