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Effects of testosterone therapy in adult males with hypogonadism and T2DM: A meta-analysis and systematic review (2022)
Satesh Kumar, Mahima Khatri, Rahat Ahmed Memon, Jordan Llerena Velastegui, Kristina Zumbana Podaneva, Daniela Benitez Gutierrez, Bilawal Nadeem, Akhil Raj Anumolu, Masood Azhar, Ahmad Zain
abstract
Background and aims: Testosterone supplementation therapy (TST) is a longstanding treatment for
hypogonadal men with type 2 diabetes mellitus (T2DM), even though the benefits of TST are variable
among trials. This meta-analysis was done to determine the specific role of TST in hypogonadal men with
T2DM.
Methods: PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled
trials (RCTs) and observational studies. To quantify the specific effects of TST, we estimated pooled mean
differences (MDs) and relative risks with 95% confidence intervals (CIs).
Results: Our meta-analysis included 1596 hypogonadal T2DM subjects from 12 randomized controlled
trials and one observational study. TST can significantly enhance glycemic control compared to placebo
by decreasing homeostatic model assessment of insulin resistance (WMD ¼ 1.55 [-2.65, 0.45];
p ¼ 0.26; I2 ¼ 20.2%), fasting glucose (WMD ¼ 0.35 [-0.79, 0.10]; p ¼ 0.07; I2 ¼ 69.7%), fasting insulin
(WMD ¼ 2.88 [-6.12, 0.36]; p ¼ In addition, TST can decrease cholesterol (WMD ¼ 0.28 [-0.47, 0.09]
p ¼ 0.0008; I2 ¼ 91%) and triglyceride (WMD ¼ 0.23 [-0.43, 0.03] p ¼ 0.03; I2 ¼ 79.2%). Furthermore,
Testosterone therapy is related to a significant rise in total testosterone levels (WMD ¼ 5.08 [2.90, 7.26]
p ¼ 0.0002; I2 ¼ 92.9%). Pooling of free testosterone levels indicated a larger increase in the patients who
got TST than placebo (WMD ¼ 81.21 [23.87, 138.54] p ¼ 0.07; I2 ¼ 70%).
Conclusion: Our findings suggested that TST can enhance glycemic control and hormone levels and
reduce total cholesterol, triglyceride, and LDL cholesterol whereas increasing HDL cholesterol in hypogonadal
T2DM patients. Therefore, in these patients, we propose TST alongside anti-diabetic treatment.
1. Introduction
According to the 2018 Endocrine Society Clinical Practice Guidelines, hypogonadism is a clinical syndrome caused by the testis's inability to produce physiological testosterone levels or a normal percentage of spermatozoa due to pathology in one or more hormonal concentrations of the hypothalamic-pituitary-testicular axis [1]. The prevalence of hypogonadism in the general population ranges from 5 to 12.3% in men aged 30 to 79, with an incidence of 12.3 per 1000 inhabitants/year.2 Male hypogonadism is diagnosed when patients exhibit symptoms and signs of testosterone deficiency and consistently low serum total testosterone and free testosterone concentrations [1]. Free testosterone concentrations less than 225 pmol/l (65 pg/ml) are considered diagnostic and support the use of replacement therapy [2]. Hypogonadism can significantly impact patients' multiple organ functions and quality of life and has developed into a global medical issue. Numerous studies have recently established a link between type 2 diabetes mellitus (T2DM) and hypogonadism. This is because obesity is a strong risk factor for testosterone deficiency (TD), which further increases fat accumulation, insulin resistance (IR), and glycemic control deterioration, constructing a negative spiral [3]. Around 25%-33% of men with T2DM have hypogonadotropic hypogonadism, which has been implicated as a risk factor for developing T2DM. There is a growing and sometimes contradictory body of research examining whether testosterone should be used in the standard clinical management of T2DM [4].
Numerous studies have demonstrated that testosterone therapy improves metabolic syndrome (MetS) components, and lipid profile decreases fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels, improves insulin sensitivity, reduces inflammation, and decreases systolic as well as diastolic blood pressures in males with T2DM [5]. Additionally, long-term testosterone therapy has been proposed to prevent prediabetes progression to T2DM in men with hypogonadism and improve the quality of life as measured by the Aging Males' Symptoms (AMS) questionnaire [5]. Nevertheless, some studies produced contradictory findings. For example, several studies have shown that testosterone replacement therapy (TRT) can significantly reduce the homeostatic model assessment of insulin resistance (HOMA-IR) levels, fasting serum glucose (FSG), and fasting serum insulin (FSI), and HBA1C percentage in hypogonadal patients with T2DM [6]. Moreover, other data indicated that these indicators did not decrease significantly in TRT groups. TRT has been associated with improvements in lipid panel variables such as total cholesterol (TC), triglycerides (TG), and serum low-density lipoprotein (LDL) cholesterol, as well as an increase in serum high-density lipoprotein (HDL) cholesterol in some studies [7,8]. Other studies failed to demonstrate a statistically significant improvement in lipid metabolism.
Meta-analysis is a research method used to systematically synthesize or merge the findings of single, independent studies, using statistical methods to calculate an overall or absolute effect and test how sensitive their results are to their own systematic review protocol (study selection and statistical analysis). Only a few randomized control trials and observational studies have been conducted to investigate the role of TRT in male hypogonadism associated with TDM, and the majority of them have produced inconsistent findings. As a result, we conducted a systematic review and meta-analysis to ascertain the exact role of TRT in hypogonadal men with T2DM. To the best of our knowledge, this is the first recently updated meta-analysis that compares the various effects of testosterone therapy versus the control arm having placebo or no treatment.
3.4. The effects on glucometabolism (Fig. 2)
3.5. The effect on lipid parameters (Fig. 3)
3.6. The effect on blood pressure, body fat percentages, and BMI indexes (Fig. 4)
3.7. The effects on AMS and IIEF scores (Fig. 5)
3.8. Mortality (Fig. 6)
3.9. The effects on hormonal levels (Fig. 7)
5. Conclusion
According to our meta-analysis, testosterone therapy can improve glycemic control, reduce total cholesterol, HDL levels, and triglycerides, as well as decrease BMI and waist circumference in hypogonadal T2DM patients. In these patients, we recommend this therapy in addition to anti-diabetic therapy. In addition, additional standard quality RCTs are required to investigate the additional effects of Testosterone therapy in hypogonadal men with T2DM.
Satesh Kumar, Mahima Khatri, Rahat Ahmed Memon, Jordan Llerena Velastegui, Kristina Zumbana Podaneva, Daniela Benitez Gutierrez, Bilawal Nadeem, Akhil Raj Anumolu, Masood Azhar, Ahmad Zain
abstract
Background and aims: Testosterone supplementation therapy (TST) is a longstanding treatment for
hypogonadal men with type 2 diabetes mellitus (T2DM), even though the benefits of TST are variable
among trials. This meta-analysis was done to determine the specific role of TST in hypogonadal men with
T2DM.
Methods: PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled
trials (RCTs) and observational studies. To quantify the specific effects of TST, we estimated pooled mean
differences (MDs) and relative risks with 95% confidence intervals (CIs).
Results: Our meta-analysis included 1596 hypogonadal T2DM subjects from 12 randomized controlled
trials and one observational study. TST can significantly enhance glycemic control compared to placebo
by decreasing homeostatic model assessment of insulin resistance (WMD ¼ 1.55 [-2.65, 0.45];
p ¼ 0.26; I2 ¼ 20.2%), fasting glucose (WMD ¼ 0.35 [-0.79, 0.10]; p ¼ 0.07; I2 ¼ 69.7%), fasting insulin
(WMD ¼ 2.88 [-6.12, 0.36]; p ¼ In addition, TST can decrease cholesterol (WMD ¼ 0.28 [-0.47, 0.09]
p ¼ 0.0008; I2 ¼ 91%) and triglyceride (WMD ¼ 0.23 [-0.43, 0.03] p ¼ 0.03; I2 ¼ 79.2%). Furthermore,
Testosterone therapy is related to a significant rise in total testosterone levels (WMD ¼ 5.08 [2.90, 7.26]
p ¼ 0.0002; I2 ¼ 92.9%). Pooling of free testosterone levels indicated a larger increase in the patients who
got TST than placebo (WMD ¼ 81.21 [23.87, 138.54] p ¼ 0.07; I2 ¼ 70%).
Conclusion: Our findings suggested that TST can enhance glycemic control and hormone levels and
reduce total cholesterol, triglyceride, and LDL cholesterol whereas increasing HDL cholesterol in hypogonadal
T2DM patients. Therefore, in these patients, we propose TST alongside anti-diabetic treatment.
1. Introduction
According to the 2018 Endocrine Society Clinical Practice Guidelines, hypogonadism is a clinical syndrome caused by the testis's inability to produce physiological testosterone levels or a normal percentage of spermatozoa due to pathology in one or more hormonal concentrations of the hypothalamic-pituitary-testicular axis [1]. The prevalence of hypogonadism in the general population ranges from 5 to 12.3% in men aged 30 to 79, with an incidence of 12.3 per 1000 inhabitants/year.2 Male hypogonadism is diagnosed when patients exhibit symptoms and signs of testosterone deficiency and consistently low serum total testosterone and free testosterone concentrations [1]. Free testosterone concentrations less than 225 pmol/l (65 pg/ml) are considered diagnostic and support the use of replacement therapy [2]. Hypogonadism can significantly impact patients' multiple organ functions and quality of life and has developed into a global medical issue. Numerous studies have recently established a link between type 2 diabetes mellitus (T2DM) and hypogonadism. This is because obesity is a strong risk factor for testosterone deficiency (TD), which further increases fat accumulation, insulin resistance (IR), and glycemic control deterioration, constructing a negative spiral [3]. Around 25%-33% of men with T2DM have hypogonadotropic hypogonadism, which has been implicated as a risk factor for developing T2DM. There is a growing and sometimes contradictory body of research examining whether testosterone should be used in the standard clinical management of T2DM [4].
Numerous studies have demonstrated that testosterone therapy improves metabolic syndrome (MetS) components, and lipid profile decreases fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels, improves insulin sensitivity, reduces inflammation, and decreases systolic as well as diastolic blood pressures in males with T2DM [5]. Additionally, long-term testosterone therapy has been proposed to prevent prediabetes progression to T2DM in men with hypogonadism and improve the quality of life as measured by the Aging Males' Symptoms (AMS) questionnaire [5]. Nevertheless, some studies produced contradictory findings. For example, several studies have shown that testosterone replacement therapy (TRT) can significantly reduce the homeostatic model assessment of insulin resistance (HOMA-IR) levels, fasting serum glucose (FSG), and fasting serum insulin (FSI), and HBA1C percentage in hypogonadal patients with T2DM [6]. Moreover, other data indicated that these indicators did not decrease significantly in TRT groups. TRT has been associated with improvements in lipid panel variables such as total cholesterol (TC), triglycerides (TG), and serum low-density lipoprotein (LDL) cholesterol, as well as an increase in serum high-density lipoprotein (HDL) cholesterol in some studies [7,8]. Other studies failed to demonstrate a statistically significant improvement in lipid metabolism.
Meta-analysis is a research method used to systematically synthesize or merge the findings of single, independent studies, using statistical methods to calculate an overall or absolute effect and test how sensitive their results are to their own systematic review protocol (study selection and statistical analysis). Only a few randomized control trials and observational studies have been conducted to investigate the role of TRT in male hypogonadism associated with TDM, and the majority of them have produced inconsistent findings. As a result, we conducted a systematic review and meta-analysis to ascertain the exact role of TRT in hypogonadal men with T2DM. To the best of our knowledge, this is the first recently updated meta-analysis that compares the various effects of testosterone therapy versus the control arm having placebo or no treatment.
3.4. The effects on glucometabolism (Fig. 2)
3.5. The effect on lipid parameters (Fig. 3)
3.6. The effect on blood pressure, body fat percentages, and BMI indexes (Fig. 4)
3.7. The effects on AMS and IIEF scores (Fig. 5)
3.8. Mortality (Fig. 6)
3.9. The effects on hormonal levels (Fig. 7)
5. Conclusion
According to our meta-analysis, testosterone therapy can improve glycemic control, reduce total cholesterol, HDL levels, and triglycerides, as well as decrease BMI and waist circumference in hypogonadal T2DM patients. In these patients, we recommend this therapy in addition to anti-diabetic therapy. In addition, additional standard quality RCTs are required to investigate the additional effects of Testosterone therapy in hypogonadal men with T2DM.
