Improved beta-cell function after treatment with testosterone undecanoate

March 2018

STUDY: Dimitriadis GK, Randeva HS, Aftab S, et al. Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy. Endocrine. 2018. Feb 2. [Epub ahead of print]

It is well documented that excess body fat suppresses the hypothalamic-pituitary-gonadal (HPG) axis, which reduces endogenous testosterone production.1-3 One mechanism contributing to the HPG-axis suppression is elevated circulating estradiol, caused by aromatization of testosterone in adipocytes.2,3 In addition, insulin resistance - a hallmark of obesity 4 - is associated with a decreased Leydig cell testosterone secretion.5 Obesity in men is associated with a drop in testosterone levels comparable to that of 10 years of aging.

Here we present the results of a study that investigated the effect of treatment with testosterone undecanoate injections on glycemic control, beta cell function, and body composition.6


  • Treatment with testosterone undecanoate injections for up to 29 months (mean 15 months) resulted in a significant improvement in HbA1C (9 mmol/mol, P = 0.03) and a 52% improvement in beta cell function, as demonstrated by increased insulin secretion (evaluated by HOMA%B).
  • There was a significant 3.5 kg reduction in fat mass and 2.9 kg increase in lean body mass, and a trend for increased basal metabolic rate (BMR).
  • The insulinotropic effect of testosterone reported in the present study is especially interesting when considering that there is a progressive deterioration in beta-cell function in type 2 diabetes, and that early treatment can reverse beta-cell function impairment.

What is known about obesity-related secondary hypogonadism

The prevalence of testosterone deficiency in obese men can be as high as 79%.7,8 With the demographic trends of increased longevity and rising prevalence of obesity and type 2 diabetes, it is likely that obesity-related testosterone deficiency will become even more prevalent. Clinical features of obesity-related testosterone deficiency include sexual dysfunction (erectile dysfunction and poor libido), osteopenia and osteoporosis, reduced feelings of well-being, fatigue, impaired mood and concentration, sarcopenia, increased fat mass and dyslipidaemia.3 It is alarming that this adverse health condition is underrecognized and underdiagnosed.3

A growing body of evidence shows that testosterone therapy improves insulin sensitivity.9 A notable randomized placebo-controlled trial showed that testosterone therapy improves insulin sensitivity in men with type 2 diabetes, as measured by an improved glucose disposal rate during hyperinsulinemic euglycemic clamp (the gold standard method for evaluating insulin sensitivity).10 Increased insulin sensitivity has also been shown using the 2-stage glucose clamp method.11 Other controlled trials show that testosterone therapy reduces insulin resistance (as shown by reduced HOMA IR) and improves glycemic control (lowering of HbA1C and fasting glucose) in hypogonadal men with type 2 diabetes.12,13

These observations have been corroborated in animal studies that have shown beneficial effects of testosterone treatment on components of glucose uptake.14 In vitro data on the effects of testosterone in human subcutaneous adipocytes show increased expression of Glucose transporter type 4 (GLUT4) and Protein Kinase B (Akt), which in turn would be expected to increase glucose uptake and insulin sensitivity.10

However, the effects of testosterone on beta cell insulin release in hypogonadal men has not yet received much scientific investigation. In the TIMES 2 study, there were no changes in HOMA %B after testosterone therapy for 12 months.13 In normoglycaemic men ages 18-54 (mean 28) years old, endogenous testosterone levels correlated negatively with β-cell secretion (C-peptide).15

What this study adds

The primary outcome of this study was change in HbA1C in obese hypogonadal men following testosterone undecanoate intramuscular therapy. Secondary outcomes were changes in measures of insulin sensitivity and beta cell functioning (HOMA2 IR and HOMA %B, respectively), metabolic profile, body fat and lean mass, and fasting lipid profile.

13 obese hypogonadal men, 7 of whom had type 2 diabetes, were treated with testosterone undecanoate injection for 6 to 29 months. The dosing schedule of the testosterone undecanoate treatment was, as per prescribing information, as follows; after an initial intramuscular injection of 1000 mg testosterone undecanoate, the second injection was administered 6 weeks later, and all subsequent injections at intervals of 12 weeks.

As expected, there was a significant improvement in serum trough testosterone levels (the lowest level right before the next injection) between baseline and follow-up assessments (mean serum trough testosterone; from 6.7 nmol/L to 15.2 nmol/L.

Significant improvements in body composition were documented, with a reduction in fat mass of 3.5 kg and an increase in lean body mass of 2.9 kg, see figure 1. Body fat percentage was reduced by 2.8%.

HbA1C significantly improved from 7.3 to 6.5% (56 to 47 mmol/mol). Although there was a trend for reduction in insulin resistance (HOMA IR dropped from 5.5 to 4.5) this did not reach statistical significance. There was however, a significant improvement in beta-cell function (mean HOMA %B improved by 52%), despite only non-significant reductions in fasting glucose and insulin levels.

Although there was a numerical increase in basal metabolic rate (BMR), this also failed to reach significance. There were no changes in lipid parameters. There was a small increase in PSA from (0.8 to 1.1 ng/mL), which remained well within the normal range in all subjects.


Changes in body composition after testosterone undecanoate treatment for at least 6 months.

Figure 1. Changes in body composition after testosterone undecanoate treatment for at least 6 months.

Changes in beta-cell function after testosterone undecanoate treatment for at least 6 months.

Figure 2. Changes in beta-cell function after testosterone undecanoate treatment for at least 6 months.


HOMA (homeostatic model assessment) uses steady-state fasting glucose and fasting insulin levels to estimate the degrees of beta-cell deficiency and insulin sensitivity.

HOMA-B (also known as HOMA-%B) assesses beta-cell function by calculating the ratio of fasting insulin-to-fasting glucose concentrations (with empirically determined metabolic conversion factors included in the Equation, see below).

A similar calculation using the reverse equation is performed to determine the HOMA-IR, an index of fasting insulin resistance (opposite to the HOMA-S, which stands for insulin sensitivity).

Equations and Derived Values:

HOMA-B = (20 * fasting insulin concentration)/(fasting glucose concentration - 3.5)

HOMA-IR = (fasting insulin concentration * fasting glucose concentration)/22.5

HOMA-S = reciprocal of HOMA-IR = HOMA sensitivity index

*Calculations are based on mmol/L for glucose and mU/mL for insulin

By convention, a normal-weight, healthy person younger than 35 years old would have a HOMA-B (surrogate marker of beta-cell function) of 100% and a HOMA-IR (insulin resistance) of 1.0. These calibrations reflect the balance between endogenous glucose production and beta-cell insulin secretion, but only during the basal state.


This is the first study showing that testosterone treatment improved beta cell function (measured by HOMA %B).6 It is likely that the improvement in beta cell function is mediated, at least in part, through direct effects of testosterone on beta-cell insulin release.18,19 Experimental research shows that testosterone is important for insulin secretion in males.20 Testosterone seems to increase glucose-stimulated insulin secretion in a manner similar to glucagon like peptide-1 (GLP-1).19 Androgen receptor-deficient pancreatic islets exhibit altered expression of genes involved in inflammation and insulin secretion, demonstrating the importance of androgen action in β-cell health in the male, with implications for development of type 2 diabetes in men.21

The body composition improvements seen in this study - reduction in fat mass and increase in lean body mass – are some of the most well documented effects of testosterone treatment. A growing number of studies are also showing improvements in HbA1C,12,22-24 which was confirmed in this study.

An important limitation of this study is the small number of subjects. This limits the statistical power to detect effects that are caused by testosterone treatment, and likely explains the lack of change in lipid profiles that has been found in several other studies of testosterone therapy in obese men. Likewise, this also explains why the reduction in insulin resistance did not reach statistical significance (meaning that it could have been caused by chance).

Furthermore, given the well-established association between BMR and lean body mass [28], it is possible that significant changes in BMR would have been detected in a larger number of subjects. Another limitation is the relatively short duration of testosterone undecanoate therapy.

Nevertheless, the insulinotropic effect of testosterone reported in the present study is especially interesting when considering that there is a progressive deterioration in beta-cell function in type 2 diabetes.25 Pancreatic islet function is about 50% of normal at the time of type 2 diabetes diagnosis.25 Impaired beta-cell function (and possibly beta-cell mass) appears to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility has probably not been passed.25 Improved beta-cell function is likely a mechanism contributing to remission of type 2 diabetes that has been reported with long-term testosterone undecanoate treatment.26 This highlights the importance of starting testosterone treatment as early as possible in hypogonadal men, when the “window of reversibility” of impaired beta-cell function is still open.


  • Mah PM, Wittert GA. Obesity and testicular function. Mol Cell Endocrinol. 2010;316(2):180-186. Return to content
  • Cohen PG. The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone-estradiol shunt--a major factor in the genesis of morbid obesity. Med Hypotheses. 1999;52(1):49−51. Return to content
  • Saboor Aftab SA, Kumar S, Barber TM. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism. Clin Endocrinol (Oxf). 2013;78(3):330-337. Return to content
  • Barazzoni R, Gortan Cappellari G, Ragni M, Nisoli E. Insulin resistance in obesity: an overview of fundamental alterations. Eating and weight disorders: EWD. 2018. Return to content
  • Pitteloud N, Hardin M, Dwyer AA, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab. 2005;90(5):2636-2641. Return to content
  • Dimitriadis GK, Randeva HS, Aftab S, et al. Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy. Endocrine. 2018. Return to content
  • Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab. 2007;92(2):549-555. Return to content
  • Escobar-Morreale HF, Santacruz E, Luque-Ramirez M, Botella Carretero JI. Prevalence of 'obesity-associated gonadal dysfunction' in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update. 2017;23(4):390-408. Return to content
  • Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nature reviews Endocrinology. 2013;9(8):479-493. Return to content
  • Dhindsa S, Ghanim H, Batra M, et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care. 2016;39(1):82-91. Return to content
  • Sattler F, He J, Chukwuneke J, et al. Testosterone Supplementation Improves Carbohydrate and Lipid Metabolism in Some Older Men with Abdominal Obesity. Journal of gerontology & geriatric research. 2014;3(3):1000159. Return to content
  • Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006;154(6):899-906. Return to content
  • Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(4):828-837. Return to content
  • Kelly DM, Akhtar S, Sellers DJ, Muraleedharan V, Channer KS, Jones TH. Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse. Endocrine. 2016;54(2):504-515. Return to content
  • Praveen EP, Khurana ML, Kulshreshtha B, et al. Plasma testosterone in adult normoglycaemic men: impact of hyperinsulinaemia. Andrologia. 2012;44(5):293-298. Return to content
  • Cersosimo E, Solis-Herrera C, Trautmann ME, Malloy J, Triplitt CL. Assessment of pancreatic beta-cell function: review of methods and clinical applications. Current diabetes reviews. 2014;10(1):2-42. Return to content
  • Wallace TM, Levy JC, Matthews DR. Use and Abuse of HOMA Modeling. Diabetes Care. 2004;27(6):1487-1495. Return to content
  • Grillo ML, Jacobus AP, Scalco R, et al. Testosterone rapidly stimulates insulin release from isolated pancreatic islets through a non-genomic dependent mechanism. Horm Metab Res. 2005;37(11):662-665. Return to content
  • Navarro G, Xu W, Jacobson DA, et al. Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male. Cell metabolism. 2016;23(5):837-851. Return to content
  • Mauvais-Jarvis F. Role of Sex Steroids in beta Cell Function, Growth, and Survival. Trends in endocrinology and metabolism: TEM. 2016;27(12):844-855. Return to content
  • Xu W, Niu T, Xu B, Navarro G, Schipma MJ, Mauvais-Jarvis F. Androgen receptor-deficient islet beta-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse. J Diabetes Complications. 2017;31(5):787-795. Return to content
  • Saad F, Yassin A, Doros G, Haider A. Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies. Int J Obes (Lond). 2016;40(1):162-170. Return to content
  • Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. Andrologia. 2016:Jan 14. doi: 10.1111/and.12514. [Epub ahead of print]. Return to content
  • Saad F. Testosterone Therapy and Glucose Homeostasis in Men with Testosterone Deficiency (Hypogonadism). Adv Exp Med Biol. 2017;1043:527-558. Return to content
  • Wajchenberg BL. beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007;28(2):187-218. Return to content
  • Haider A, Haider KS, Saad F. Remission of type 2 diabetes in a hypogonadal man under long-term testosterone therapy. Endocrinology, diabetes & metabolism case reports. 2017;2017. Return to content