Abstract
Aims:
To study the effect of testosterone undecanoate on sexual functions, glycaemic parameters, and cardiovascular (CV) risk factors in hypogonadal men with type 2 diabetes mellitus (T2DM).
Methods:
It was an open label, single-arm interventional study where testosterone undecanoate (TU) was used in 105 T2DM males aged 30–60 years with hypogonadism. The effect of TU on sexual functions was assessed using the Aging Male Symptoms (AMS) Scale and the International Index of Erectile Function-5 (IIEF-5) Questionnaire. The effect on glycaemic parameters, cardiovascular risk factors (lipids, high-sensitivity C-reactive protein [hsCRP] and carotid intima media thickness [CIMT]) were assessed over a period of 54 weeks of TU therapy.
Results:
Prevalence of hypogonadism in T2DM patients was 19.1%, of which 74.1% had functional hypogonadism. AMS and IIEF-5 scores showed negative and positive correlation, respectively, with baseline serum testosterone levels. The AMS score showed a significant reduction of 5.8% and IIEF-5 score improved by 31.5% at 54 weeks of TU therapy. Glycosylated hemoglobin (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), and lipids such as total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) were significantly reduced by 0.6%, 10.9%, 6.28%, 9.04%, and 6.77%, respectively, at 54 weeks. CIMT was significantly reduced by 2.57% at 54 weeks, whereas no significant change observed with hsCRP.
Conclusions:
TU is an effective treatment modality for hypogonadal men with T2DM, and it has beneficial effects on sexual functions, glycaemic parameters, and CV risk factors.
Keywords: AMS, HOMA-IR, hypogonadism, IIEF-5, T2DM, testosterone replacement therapy, testosterone undecanoate
INTRODUCTION
Hypogonadism in type 2 diabetes mellitus (T2DM) is defined as low testosterone levels with signs and symptoms of hypogonadism. Nearly 35%–40% of men with T2DM have decreased testosterone levels, which is three-times higher than that of the general population.[1–4] Men with T2DM have reduced sexual functions due to associated microvascular and macrovascular complications, autonomic neuropathy, hypogonadism, depression, and use of multiple drugs.[5] Testosterone deficiency, a frequent association in patients with T2DM, may present with diminished libido, loss of vigour, poor cognitive function, irritability, and depression.[6]
There appears to be no consensus on accepted lower limits of normal total testosterone levels. The European Male Aging Study (EMAS) and International Society for the Study of the Aging Male (ISSAM)’s hypogonadism panel proposed 316.8 ng/dL (11 nmol/L) and 348.7 ng/dL (12.1 nmol/L) as the lower limit of normal testosterone levels, respectively.[7,8] In Caucasians, the normal testosterone range for total testosterone among healthy, non-obese men aged 19–39 years was 264–916 ng/dL (2.5th and 97.5th percentile).[9] Similarly, there are no definitive treatment guidelines for management of T2DM patients with hypogonadism. A broad consensus exists that symptomatic men having total testosterone below 231 ng/dL (8 nmol/L) may benefit from replacement therapy and those with 231–346 ng/dL (8–12 nmol/L) may be considered for a 3- to 6-month trial of replacement therapy.[10,11] T2DM is associated with 2- to 3-times increased cardiovascular disease (CV) risk and mortality. Reducing CV risk factors is the standard of care in T2DM to decrease the risk of cardiovascular disease (CVD) risk. Testosterone replacement therapy (TRT) has been found to have variable results on reduction of CV risk factors.
The objective of the present study was to assess the association of low serum testosterone levels with signs and symptoms of hypogonadism in T2DM and to assess the effect of TU therapy on sexual functions, glycaemic parameters (glycosylated hemoglobin [HbA1c], fasting plasma glucose [FPG], homeostasis model assessment of insulin resistance [HOMA-IR]), lipid parameters (total cholesterol, triglycerides, high-density lipoprotein [HDL], and low-density lipoprotein [LDL]), high-sensitivity C-reactive protein (hsCRP) and CIMT over a period of one year. For the present study, a serum total testosterone level of 264 ng/dL was chosen as the lower limit of normal level which is the 2.5th percentile of normal serum total testosterone range. Testosterone undecanoate (1000 mg/4 mL) was chosen in the present study because it ensures better compliance with minimal side effects. It was given intramuscularly at 0, 6, 18, 30, and 42 weeks.
MATERIAL AND METHODS
It was a one-year, prospective study of 120 patients of T2DM with hypogonadism. The study period was from October 2019 to February 2021. It was conducted in the Department of Endocrinology of MKCG Medical College and Hospital. After obtaining clearance from the Institutional Ethics Committee and informed consent from patients, participants were selected according to inclusion and exclusion criteria. This study was registered in Clinical Trials Registry of India with registration number as CTRI/2019/09/021175.
Inclusion Criteria: Patients with T2DM aged 30–60 years, experiencing symptoms of hypogonadism using the Aging Male Symptoms (AMS) score ≥27 and the presence of any one of the following three sexual symptoms, that is, decreased sexual interest, absent or rare morning erections, and erectile dysfunction (ED) underwent biochemical evaluation. The patients who had morning (7–9 am) serum total testosterone level of <264 ng/dL (2.5th percentile of harmonized reference range for total testosterone in healthy, non-obese young men)[9] after re-confirmation at one week were included in the study.
The AMS scale is a self-administered scale of health-related quality of life (HRQoL).[12] The AMS scale was previously validated and often used for assessment of severity in hypogonadism. It contains 17 questions with responses ranging from a score of 0–5 with maximum score of 85. While a symptom score of ≤26 is non-significant, scores of 27–36, 37–49, and >50 are taken to be consistent with mild, moderate, and severe hypogonadism, respectively.[12] The International Index of Erectile Function (IIEF-5) Questionnaire is used for assessment of erectile function and it is a validated tool for the evaluation of ED.[13] It contains five items that focus on erectile function and intercourse satisfaction. Each question has a response ranging from 1 to 5. Thus, the total score ranges from 5 to 25. ED is classified into five severity levels based on the IIEF-5 scores: severe (5–7), moderate (8–11), mild to moderate (12–16), mild (17–21), and no ED (22–25).
Exclusion Criteria: The following patients were excluded from the study: patients suffering from severe debilitating disease, history of prostate or breast cancer, elevated haematocrit (>48%), elevated prostate-specific antigen (PSA, >4.0 μg/L), PSA increase >1.4 μg/L within any 12-month period, palpable prostate nodule and induration on digital rectal examination (DRE), severe obstructive sleep apnoea (OSA), severe lower urinary tract symptoms (LUTS) (International Prostate Symptom Score [IPSS] >19), previously treated hypogonadism, acute coronary event in the last 6 months, chronic obstructive lung disease, and recent use of phosphodiesterase-5 inhibitors (within the last 6 months).
After selecting subjects as per the pre-defined inclusion and exclusion criteria, anthropometric parameters like height, weight, and waist circumference were measured. Body mass index (BMI) was calculated using the following formula: BMI = Weight (kg)/[Height (m) 2]. AMS and IIEF-5 scores were recorded. Fasting blood samples were taken from 7 am to 9 a.m. to measure serum total testosterone (TT), luteinizing hormone (LH), follicle stimulating hormone (FSH), FPG, HbA1c, fasting lipids (TC, TG, HDL, LDL), hsCRP, haematocrit, serum fasting insulin (patients not receiving insulin), and serum PSA. Serum TT was done on Abbott Architect, using competitive chemiluminescent immunoassay (CLIA). Intra- and inter-assay coefficient of variability was 2.49% and 6.5%, respectively, with a range of 181–772 ng/dL. HOMA-IR was calculated as follows: HOMA-IR = Fasting serum Insulin × FPG/405 (fasting serum insulin in μIU/mL and FPG in mg/dL). Carotid intima media thickness (CIMT) of carotid arteries was done by a single experienced radiologist using General Electric Logiq S7 Expert/Pro ultrasonic device, with 9 L-D probe, frequency band 3.1–10 MHz in B mode. Intima–media thickness (IMT) was measured on three sections of both carotid arteries: communis, internal, and bulbus. At each investigated section, IMT measurements were taken three times and the average value for each section was subsequently calculated. Patients with baseline serum TT less than 231 ng/dL were classified as having severe hypogonadism (sHG) and those who had ≥231 ng/dL to <264 ng/dL were classified as having mild hypogonadism (mHG).
Selected patients were then administered intramuscular (IM) injection of 1000 mg of testosterone undecanoate (TU) in the upper outer quadrant of the gluteal region at 0, 6, 18, 30, and 42 weeks. TT was measured at the end of each dosing interval, just prior to the next injection to maintain levels the mid-normal range (350–600 ng/dL). FPG and postprandial plasma glucose were measured at each monthly visit for maintenance of glycaemic control. Patients were re-evaluated at 6, 18, 30, 42, and 54 weeks. At each visit anthropometric parameters, AMS, and IIEF-5 scores were recorded. Fasting lipids were measured at 0, 18, 30, and 54 weeks. Serum insulin and hsCRP were measured at baseline and again at 54 weeks. PSA, haematocrit, and CIMT were measured at 0, 30, and 54 weeks. Response to TU therapy was defined for the present study as the following: those who had decrease in AMS score and/or had an increase in IIEF-5 score at 54 weeks were considered as responders, whereas those who had increase or no change of AMS score or decrease or no change in IIEF-5 scores were considered as non-responders. At any point of time, the patient was to be withdrawn from the study if any of the following parameters were reached: haematocrit >54%, PSA >4 μg/L, and palpable abnormality on DRE or IPSS score >19. Each patient was followed for 54 weeks or till he was withdrawn from the study. Patients withdrawn were not included in the final analysis.
Statistical Analysis: Data were entered into a Microsoft Excel datasheet and analysed using the Statistical Package for the Social Sciences (SPSS) 24 (IBM Corp.). Descriptive statistical methods such as mean and standard deviation were applied to summarize continuous variables. Categorical data was summarized as percentages or proportion. Paired t-test was used to compare in-between the groups, and unpaired t-tests were used to compare between groups. A P value of 0.05 was considered as significant. Graphs and charts were generated using SPSS 24 and Windows Microsoft Excel.
RESULTS
A total of 850 consecutive male patients with T2DM were screened for hypogonadism. One hundred sixty-two patients (19.1%) were found to have hypogonadism, of which 42 were excluded as 29 had primary hypogonadism and 13 had secondary hypogonadism due to other causes. Fifteen out of 120 patients were not included in the final analysis as nine were lost to follow-up and six were withdrawn from the study (four had increased levels of haematocrit >54% during the study; and two had IPSS of >19). Thus, the data obtained from 105 patients with T2DM and hypogonadism formed the basis of our study [Figure 1].
Figure 1.
Flowchart depicting patient selection
Baseline characteristics of the cohort: The mean age and duration of diabetes were 46.5 ± 8.3 years and 7.2 ± 3.5 years, respectively. The majority of patients were in the age group of 51–55 years (24.8%, n = 26) followed by 17.1% each in the 41–45 and 46–50 age groups. Thirty-nine percent of patients (n = 41) had diabetes mellitus for ≤5 years and 24.8% (n = 26) had for more than 10 years. The mean BMI of the study population was 23.31 ± 2.48 kg/m2. BMI was normal in 49.5% of patients (n = 52), and 21.9% (n = 23) and 28.6% (n = 30) were overweight and obese, respectively, according to the Asian criteria of BMI.[14] Serum total testosterone and BMI were negatively correlated at the baseline (r = −0.45, P < 0.01). Moderate symptoms of hypogonadism (AMS score of 37–49) were present in 69.5% of patients (n = 73) and severe symptoms (AMS score >50) in 26.7% of patients (n = 28). There were only 3.8% of patients (n = 4) who had mild symptoms of hypogonadism. Based on serum TT, mild hypogonadism (serum TT of 231 to <264 ng/dL) and severe hypogonadism (serum TT <231 ng/dL) were found in 62.9% (n = 66) and 37.1% (n = 39) of patients with T2DM, respectively. Adequate glycaemic control (HbA1c ≤7.0% [53 mmol/mol]) was present in 26.7% of patients (n = 28), and 73.3% of patients (n = 77) had poor glycaemic control (HbA1c >7% [53 mmol/mol]) at baseline [Table 1].
Table 1.
Baseline characteristics of the whole cohort (n=105)
| Number of Patients (n) | 105 |
|---|---|
| Mean age (years) | 46.5±8.3 |
| 30-35; n (%) | 15 (14.3%) |
| 36-40; n (%) | 12 (11.4%) |
| 41-45; n (%) | 18 (17.1%) |
| 46-50; n (%) | 18 (17.1%) |
| 51-55; n (%) | 26 (24.8%) |
| 56-60; n (%) | 16 (15.2%) |
| Mean duration of Diabetes Mellitus (years) | 7.2±3.5 |
| ≤5; n (%) | 41 (39%) |
| 6-10; n (%) | 38 (36.2%) |
| >10; n (%) | 26 (24.8%) |
| Mean Weight (kg) | 63.31±7.66 |
| Mean BMI (kg/m2) | 23.31±2.48 |
| <23.0; n (%) | 52 (49.5%) |
| 23.0-27.4; n (%) | 23 (21.9%) |
| ≥27.5; n (%) | 30 (28.6%) |
| Mean Waist Circumference (cm) | 88.54±4.93 |
| <90.0; n (%) | 54 (51.4%) |
| ≥90.0; n (%) | 51 (48.6%) |
| Mean AMS Score | 46.1±6.2 |
| 27-36 (mild); n (%) | 4 (3.8%) |
| 37-49 (moderate); n (%) | 73 (69.5%) |
| ≥50 (severe); n (%) | 28 (26.7%) |
| Mean IIEF-5 Score | 12.6±2.2 |
| Mean Serum Total Testosterone (ng/dL) | 235.1±21.1 |
| Mild hypogonadism (231-<264 ng/dL); n (%) | 66 (62.9%) |
| Severe hypogonadism (<231 ng/dL); n (%) | 39 (37.1%) |
| Fasting Plasma Glucose (mg/dL) | 167.6±33.0 |
| Mean HbA1c % (mmol/mol) | 7.9±1.0 |
| ≤7.0% (≤53 mmol/mol); n (%) | 28 (26.7%) |
| >7.0% (>53 mmol/mol); n (%) | 77 (73.3%) |
| Mean HOMA-IR | 5.5±1.0 |
| Mean Serum Total Cholesterol (mg/dL) | 187.8±25.3 |
| Mean Serum Triglycerides (mg/dL) | 168.2±35.1 |
| Mean Serum HDL (mg/dL) | 38.8±4.7 |
| Mean Serum LDL (mg/dL) | 115.4±25.4 |
| Mean Serum hsCRP (mg/L) | 2.21±0.67 |
| Mean Haematocrit (%) | 43.5±2.0 |
| Mean Serum PSA (µg/L) | 1.3±0.3 |
| Mean CIMT (mm) | 0.700±0.057 |
Values are mean±SD. BMI, Body mass index; AMS, Aging Male Symptoms; IIEF-5, International Index of Erectile Function; HbA1c, Glycosylated haemoglobin; HDL, High-density lipoprotein; LDL, Low-density lipoprotein; hsCRP: High-sensitivity C-reactive protein; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; PSA, Prostate-specific antigen; CIMT, Carotid intima media thickness
Effect of TRT on anthropometric parameters: The mean body weight reduced non-significantly by 0.09 kg at 30 weeks and significantly by 0.30 kg at 54 weeks from the baseline mean body weight of 63.31 ± 7.66 kg. Similarly, the BMI also decreased significantly by 0.11 kg/m2 at 54 weeks, from 23.31 ± 2.48 kg/m2 to 23.20 ± 2.45 kg/m2. However, the decrease in waist circumference was not significant [Table 2].
Table 2.
Effect of testosterone undecanoate on anthropometric and glycaemic parameters
| Weeks of Follow-Up | Mean±SD (kg) | Difference from Baseline (kg) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|---|---|---|---|---|
| Weight | ||||
| Baseline | 63.31±7.66 | |||
| 18 weeks | 63.28±7.62 | 0.04 | 0.06 | 0.309 |
| 30 weeks | 63.22±7.60 | 0.09 | 0.15 | 0.062 |
| 54 weeks | 63.02±7.61 | 0.30 | 0.47 | <0.001 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (kg/m2) | Difference from Baseline (kg/m2) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| BMI | ||||
| Baseline | 23.31±2.48 | |||
| 18 weeks | 23.29±2.46 | 0.01 | 0.06 | 0.316 |
| 30 weeks | 23.27±2.46 | 0.03 | 0.14 | 0.064 |
| 54 weeks | 23.20±2.45 | 0.11 | 0.47 | <0.001 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (cm) | Difference from Baseline (cm) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| Waist Circumference | ||||
| Baseline | 88.54±4.93 | |||
| 18 weeks | 88.53±4.69 | 0.01 | 0.01 | 0.991 |
| 30 weeks | 88.46±4.75 | 0.09 | 0.10 | 0.415 |
| 54 weeks | 88.43±4.74 | 0.12 | 0.13 | 0.240 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (%) [mmol/mol] | Difference from Baseline (%) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| HbA1c % | ||||
| Baseline | 7.9±1.0 [63] | |||
| 18 weeks | 7.8±0.8 [62] | 0.1 | 1.0 | 0.055 |
| 30 weeks | 7.7±0.7 [61] | 0.2 | 2.3 | 0.002 |
| 54 weeks | 7.3±0.4 [56] | 0.6 | 7.4 | <0.001 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (mg/dL) | Difference from Baseline (mg/dL) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| FPG | ||||
| Baseline | 167.6±33 | |||
| 54 weeks | 136±14.3 | 31.6 | 18.8 | <0.001 |
|
| ||||
| Weeks of Follow-Up | Mean±SD | Difference from Baseline | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| HOMA-IR | ||||
| Baseline | 5.5±1.0 | |||
| 54 weeks | 4.9±0.9 | 0.6 | 10.9 | 0.002 |
Values are mean±SD. BMI, Body mass index; FPG, Fasting plasma glucose; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance
Effect of TRT on glycaemic parameters: Mean HbA1c at baseline was 7.9% ±1.0% and reduced significantly to 7.7% ±0.7% and to 7.3% ±0.4% with absolute decrease of 0.2% and 0.6% at 30 weeks and 54 weeks, respectively. FPG at baseline was 167.6 ± 33 mg/dL and reduced significantly to 136.0 ± 14.3 mg/dL at 54 weeks with an absolute decrease of 31.6 mg/dL. HOMA-IR was assessed at baseline and 54 weeks of TRT in 71 patients who were not on insulin treatment. At baseline mean, HOMA-IR was 5.5 ± 1.0 and decreased to 4.9 ± 0.9 at 54 weeks with decrease of 0.6 (10.9%) which was statistically significant [Table 2].
Effect of TRT on sexual functions: The mean AMS score was 46.1 ± 6.2 at baseline, and it showed a significant negative correlation (r = −0.533; P < 0.001) with the baseline serum TT [Figure 2]. TU therapy reduced AMS score by 1.5 (3.2%) and 2.7 (5.8%) at 30 weeks and 54 weeks, respectively, which were statistically significant. The mean baseline IIEF-5 score (12.6 ± 2.2) showed a significant positive correlation (r = +0.477; P < 0.001) with baseline serum TT [Figure 2]. IIEF-5 score showed a significant increase of 0.9 (6.9%) at 18 weeks and 4.0 (31.5%) at 54 weeks [Table 3].
Figure 2.
Scatter plot showing correlation of baseline serum TT with baseline AMS score and baseline IIEF-5 scores
Table 3.
Effect of testosterone replacement therapy (TRT) on sexual functions and cardiovascular risk factors
| Weeks of Follow-Up | Mean±SD | Difference from Baseline | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|---|---|---|---|---|
| AMS Score | ||||
| Baseline | 46.1±6.2 | |||
| 18 weeks | 45.9±5.7 | 0.2 | 0.5 | 0.524 |
| 30 weeks | 44.6±6.1 | 1.5 | 3.2 | 0.001 |
| 54 weeks | 43.4±6.5 | 2.7 | 5.8 | <0.001 |
|
| ||||
| Weeks of follow-Up | Mean±SD | Difference from Baseline | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| IIEF-5 Score | ||||
| Baseline | 12.6±2.2 | |||
| 18 weeks | 13.5±2.4 | 0.9 | 6.9 | 0.007 |
| 30 weeks | 14.4±2.5 | 1.7 | 13.8 | <0.001 |
| 54 weeks | 16.6±2.2 | 4 | 31.5 | <0.001 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (mg/dL) | Difference from Baseline (mg/dL) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| Serum Total Cholesterol | ||||
| Baseline | 187.79±25.30 | |||
| 18 weeks | 184.74±23.43 | 3.05 | 1.62 | 0.375 |
| 30 weeks | 181.43±19.09 | 6.36 | 3.39 | 0.050 |
| 54 weeks | 176.00±17.26 | 11.79 | 6.28 | <0.001 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (mg/dL) | Difference from Baseline (mg/dL) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| Serum Triglycerides | ||||
| Baseline | 168.16±35.07 | |||
| 18 weeks | 165.09±25.60 | 3.06 | 1.82 | 0.497 |
| 30 weeks | 159.98±23.30 | 8.17 | 4.86 | 0.047 |
| 54 weeks | 156.77±27.73 | 11.38 | 6.77 | 0.010 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (mg/dL) | Difference from Baseline (mg/dL) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| Serum LDL Cholesterol | ||||
| Baseline | 115.36±25.38 | |||
| 18 weeks | 112.57±24.28 | 2.79 | 2.42 | 0.433 |
| 30 weeks | 109.85±19.48 | 5.51 | 4.78 | 0.095 |
| 54 weeks | 104.93±18.78 | 10.63 | 9.04 | <0.001 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (mg/dL) | Difference from Baseline (mg/dL) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| Serum HDL Cholesterol | ||||
| Baseline | 38.80±4.71 | |||
| 18 weeks | 39.16±4.20 | 0.36 | 0.93 | 0.529 |
| 30 weeks | 39.58±4.27 | 0.78 | 2.02 | 0.207 |
| 54 weeks | 39.71±4.04 | 0.92 | 2.37 | 0.102 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (mg/L) | Difference from Baseline (mg/L) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| hsCRP | ||||
| Baseline | 2.21±0.67 | |||
| 54 weeks | 2.08±0.57 | 0.13 | 5.98 | 0.072 |
|
| ||||
| Weeks of Follow-Up | Mean±SD (mm) | Difference from Baseline (mm) | Percentage Change from Baseline (%) | P (Compared with Baseline) |
|
| ||||
| CIMT | ||||
| Baseline | 0.700±0.057 | |||
| 30 weeks | 0.695±0.046 | 0.005 | 0.71 | 0.454 |
| 54 weeks | 0.682±0.042 | 0.018 | 2.57 | 0.007 |
Values are mean±SD. AMS, Aging Male Symptoms; IIEF-5, International Index of Erectile Function-5; LDL, Low-density lipoprotein; HDL, High-density lipoprotein; hsCRP, High-sensitivity C-reactive protein; CIMT, Carotid intima media thickness
Effect of TRT on cardiovascular risk factors: Mean serum TC, LDL, and TG showed significant reduction of 6.28%, 9.04%, and 6.77%, respectively, at 54 weeks. Mean HDL level showed no significant change from baseline either at 30 weeks or 54 weeks of TU therapy. The TG levels showed significant reduction from 30 weeks of TU therapy. Serum hsCRP was assessed at baseline and 54 weeks of TRT. It was 2.21 ± 0.67 mg/L at baseline and was found to have a reduction of 0.13 mg/L (5.98%) at 54 weeks, but it was not statistically significant. CIMT was assessed at baseline, 30 weeks, and 54 weeks of TRT. It was 0.700 ± 0.057 mm at baseline and decreased non-significantly to 0.695 ± 0.046 mm at 30 weeks and significantly to 0.682 ± 0.042 mm at 54 weeks (2.57%) [Table 3].
Response to Testosterone Undecanoate Therapy: In the present study, 91.4% of patients (n = 96/105) responded to TU therapy and 8.5% (n = 9/105) were non-responders. Various baseline parameters in responders and non-responders were compared and were not significantly different except in terms of the baseline serum testosterone. Responders had higher AMS score and lower IIEF-5 scores at baseline compared to that of non-responders. The mean baseline testosterone levels in the responders group was significantly lower compared to non-responders (234 vs 245 ng/dl, P = 0.05). TU therapy decreased AMS and/or increased IIEF-5 in both severe hypogonadism (sHG) and mild hypogonadism (mHG) groups. There were 97.4% of responders (n = 38/39) in the sHG group and 87.8% of responders (n = 58/66) in the mHG group [Table 4].
Table 4.
Baseline characteristics of non-responders and responders to testosterone undecanoate therapy
| Parameters | Non-responder (Mean±SD) | Responder (Mean±SD) | P |
|---|---|---|---|
| No. of patients; n/total (%) | 9/105 (8.5%) | 96/105 (91.4%) | - |
| Age (years) | 50.3±7.2 | 46.2±8.3 | 0.13 |
| Duration of DM (years) | 6.8±3.4 | 7.2±3.6 | 0.7 |
| Weight (kg) | 64.8±8.1 | 63.2±7.6 | 0.58 |
| BMI (kg/m2) | 23.6±2.7 | 23.3±2.5 | 0.71 |
| Waist circumference (cm) | 88.5±6.7 | 88.6±4.8 | 0.96 |
| Baseline AMS score | 42.4±4.2 | 46.4±6.3 | 0.02 |
| Change in AMS score | +3.3±2.4 | −3.3±6.1 | - |
| Baseline IIEF-5 score | 15.0±1.9 | 12.4±2.1 | 0.003 |
| Change in IIEF-5 score | −0.8±0.8 | 4.4±2.7 | - |
| Baseline serum total testosterone (ng/dL) | 245.5±16.6 | 234.2±21.3 | 0.05 |
| No. of patients with mild hypogonadism (≥231-<264 ng/dl) n/total (%) | 8/66 (12.1%) | 58 (87.8%) | 0.14 |
| No. of patients with severe hypogonadism (<231 ng/dl) (n, %) n/total (%) | 1 (2.5%) | 38 (97.4%) | |
| Fasting plasma glucose (mg/dL) | 156.6±25.6 | 168.6±33.5 | 0.21 |
| Mean HbA1c % | 7.9±0.9 | 7.9±1.1 | 0.88 |
Values are mean±SD. AMS, Aging Male Symptoms; IIEF-5, International Index of Erectile Funtion-5; BMI, Body mass index; FPG, Fasting plasma glucose; HbA1c, Glycosylated haemoglobin
Sexual functions improved significantly in both mHG and sHG groups. There was differential effect of TU therapy on AMS and IIEF-5 scores. IIEF-5 scores improved more in severe hypogonadism compared to mild hypogonadism (40.8% vs 26.7%), whereas AMS scores showed improvement of 4.9% vs 6.3% in severe and mild hypogonadism, respectively. This could be due to the non-specific nature of AMS scores [Table 5].
Table 5.
Effect of testosterone undecanoate therapy on sexual functions among patients with mild hypogonadism and severe hypogonadism
| Parameter | Weeks of Follow-up | Severe Hypogonadism (TT <231.0 ng/dL) | Mild Hypogonadism (TT ≥231.0-<264.0 ng/dL) | ||||
|---|---|---|---|---|---|---|---|
|
|
|
||||||
| Mean±SD | Change (%)# | P* | Mean±SD | Change (%)# | P* | ||
| AMS Score | 0 weeks | 48.95±6.63 | 44.36±5.32 | ||||
| 18 weeks | 48.56±5.94 | 0.79 | 0.505 | 44.26±5.01 | 0.24 | 0.792 | |
| 30 weeks | 47.95±5.78 | 2.04 | 0.194 | 42.64±5.34 | 3.89 | 0.001 | |
| 54 weeks | 46.51±6.07 | 4.98 | 0.029 | 41.53±6.02 | 6.39 | <0.001 | |
| IIEF-5 Score | 0 weeks | 11.49±1.62 | 13.32±2.21 | ||||
| 18 weeks | 13.26±2.49 | 15.40 | 0.001 | 13.67±2.34 | 2.62 | 0.389 | |
| 30 weeks | 14.15±2.75 | 23.21 | <0.001 | 14.52±2.28 | 8.99 | 0.003 | |
| 54 weeks | 16.18±2.28 | 40.85 | <0.001 | 16.88±2.09 | 26.73 | <0.001 | |
Values are mean±SD. #Percentage change from baseline within the group. *P for within group comparison from baseline. AMS, Aging Male Symptoms; IIEF-5, International Index of Erectile Function-5
DISCUSSION
There is a frequent association of hypogonadism in patients with T2DM; this was confirmed in the present study. In the present study, the prevalence of hypogonadism among 850 T2DM patients who were screened was 19.1%. Functional hypogonadism was the most common form of hypogonadism observed in 74.1% of patients. TU therapy in patients with hypogonadism and T2DM improved sexual functions significantly starting from 18 weeks. There was also reduction in weight and improvement in glycaemic parameters and CV risk factors at 54 weeks of TU therapy.
The prevalence of hypogonadism in the present study was similar to previous studies that showed a prevalence of 15%–20% in T2DM patients.[15–17] However, Dhindsa et al.[18] found a prevalence of 33% in the age group of 28–80 years in T2DM patients, which could be due to older population, higher BMI, and criteria of hypogonadism used.
Anthropometric parameters showed significant improvements with TU therapy with mean decrease in body weight and BMI of 0.30 kg and 0.11 kg/m2, respectively, at 54 weeks. However, waist circumference showed no significant change with TU therapy. Body weight and BMI showed decreasing trend from 18 weeks onward and reached significance at 54 weeks. The decrease in BMI in the present study was lower compared to studies by Antonič et al.[19] and Khripun et al.,[20] where they observed a decrease of 0.7 kg/m2 and 2 kg/m2, respectively. However, all studies are not concordant in reduction of BMI. Some studies showed no significant decrease in BMI on TU therapy.[21,22] Waist circumference in the present study showed no significant decrease at 54 weeks. Studies on waist circumference have found variable results, with some showing decrease,[19,20] some no change,[23] and some even an increase in waist circumference (WC) after TRT.[24] This decrease in body weight and BMI could be attributed to decrease in visceral adipose tissue, induction of hormone-sensitive lipase, decreased uptake of triglycerides by adipocytes,[25,26] and differentiation of pluripotent mesenchymal stem cells to myogenic lineage rather than to adipogenic lineage.[27]
In our study, we clinically evaluated sexual functions in patients with T2DM and hypogonadism by using two psychometric scales. AMS and IIEF -5 scores showed significant negative and positive correlation with baseline serum testosterone levels, respectively. Similar negative correlation of AMS score with serum testosterone was seen in a study by Kang et al.[28] However, it was not statistically significant. Significant improvement in AMS score started at 30 weeks and it persisted till 54 weeks. Almehmadi et al.[29] and Hackett et al.[30] showed decrease in AMS using TU at 12 weeks and 30 weeks, respectively. However, a few studies have shown no significant reduction in AMS score.[19,22,23] ED is a major concern in patients with T2DM and hypogonadism. In the present study, ED as assessed by IIEF-5 score, also showed improvement with TRT from 18 weeks onwards. Similar improvement in IIEF-5 score had been observed in studies by Almehmadi et al.[29] (using TU) and Shigehara et al.[31] (using testosterone enanthate 250 mg monthly) at 3 months and 6 months of TRT, respectively.
There was significant improvement in AMS and IIEF-5 scores after TU therapy. As IIEF-5 is more specific in nature, it showed more improvement following TU therapy compared to non-specific nature of AMS. The response to TU therapy was observed in both severe and mild hypogonadism (97% vs 87%, respectively), although it was more in severe hypogonadism compared to mild hypogonadism but could not reach statistical significance. The present study showed that men with type 2 diabetes who had lower baseline serum testosterone levels may show a better response than others. Improvement in sexual functions is due to improvement of androgen deficiency associated with aging,[21,22] increase in sexual desire, erectile function, sexual frequency, ejaculation, and sexual satisfaction.[22,32-34]
There was a significant reduction in HbA1c from baseline to 54 weeks (0.6%). FPG also showed significant reduction of 31.6 mg/dL over a period of 54 weeks. The decrease in HbA1c in the present study may be attributed to multiple factors like the effect of treatment with drugs, TRT, and lifestyle measures. Since there is no control group, it is difficult to attribute the reduction in HbA1c to TRT. The significant improvement in HbA1c and FPG in the present study was concordant to the study by Hackett et al.,[30] showing reduction of 0.24% and 18 mg/dL using TU in severe hypogonadal men with T2DM. Other studies also have shown significant reduction in HbA1c ranging from 0.20% to 0.96% and in FPG ranging from 7.2 to 32.4 mg/dL.[19-21] However, studies were not concordant with regard to improvement in FPG and HbA1c on TU therapy.[23,31,35,36] Improved glycaemic profile in patients receiving TRT can be due to decreased weight, BMI, improved HOMA-IR, and increase in muscle mass. HOMA-IR was assessed at baseline and at 54 weeks in 71 patients who were not on insulin therapy and it showed a significant reduction of 0.6. Significant decrease in HOMA-IR ranging from 1.7 to 4.6 was also noted in various studies.[20,21,37] Reduction of HOMA-IR by testosterone can be explained by a variety of mechanisms including large number of androgen receptors on visceral adipocytes,[38] testosterone-induced increase in the insulin receptor, and suppression of the inflammatory state by decreasing pro-inflammatory cytokines (IL-1b, IL-6, and TNF-α) and increasing anti-inflammatory cytokine (IL-10).[39-41]
There was improvement in TC, TG, and LDL levels at 54 weeks, and a similar observation was found in studies by TT trials[37] and Antonič et al.[19] at one year of TU therapy. However, a few studies have found no significant change in lipid levels after TRT,[31,36] probably because most of the patients were already on long-term statin therapy. hsCRP serves as an alternative predictor of CVD, endothelial dysfunction, and as a biomarker of systemic low-grade inflammation.[42] It was reduced by 0.13 mg/L (5.98%) at 54 weeks of TU therapy but did not reach statistical significance (P = 0.072). Similar observations were made by Gianatti et al.[43] and Kapoor et al.[21] in their studies. Beneficial effects of decreasing CRP may be related to observations that CRP increases apoptosis of endothelial cells and blocks differentiation of endothelial progenitor cells, eventually blocking angiogenesis.[44] CIMT was evaluated at baseline, at 30 weeks, and 54 weeks. It showed a significant decrease of 0.018 mm (2.57%) at 54 weeks. Similar to the present study, other studies have found reduction in CIMT at 54 weeks.[45] Improvement in hsCRP and CIMT with TRT can be due to multiple mechanisms. Testosterone has a direct effect on androgen receptors present on endothelium and vascular smooth muscle cells.[46] It stimulates activity of endothelial progenitor cells and modulates vascular tone by regulating vasodilation.[47,48] It reduces ET-1 and resistin, which play a role in activation of endothelium and triggering the proliferation of vascular smooth muscle, leading to progression of atherosclerosis.[20,49,50]
Mild adverse event of injection site pain occurred in 90% of patients but they recovered within 1–2 days. Other mild adverse effects like nausea and vomiting were not reported in the study. Haematocrit and PSA were monitored in patients during TU therapy. Significant increase was seen in both PSA and haematocrit levels. Increase in haematocrit (>54%) leading to discontinuation was seen in four patients and they were excluded from the final analysis. None of the patients showed increase of PSA >4 ng/ml which should lead to discontinuation of therapy. However, two patients had IPSS score of >19, leading to discontinuation of treatment and exclusion of therapy. Severe adverse events like fat embolism or OSA were not reported in the present study. Only five patients missed single dose and three patients missed two doses of TU.
The main limitation of our study was that it was an open-label, single-arm intervention study. Inclusion of placebo arm could have further strengthened the results. Insulin resistance was assessed by HOMA-IR rather than by gold standard hyperinsulinemic-euglycemic clamp. In the present study, serum TT was used rather than free testosterone because of unavailability of accurate assays for the same (equilibrium dialysis). Serum testosterone was measured using CLIA; to reduce variability and confirm low levels of serum testosterone, repeat measurements were performed one week apart. However, the main strength of the study was that, only T2DM patients with clinical and biochemical criteria for hypogonadism were included. TU was used in the present study unlike previous trials where testosterone enanthate and other esters were used.
Thus, institution of TRT in the form of TU in hypogonadal men with T2DM having serum TT <264 ng/dL produces beneficial effects like reduction in weight, BMI, HOMA-IR, FPG, HbA1c, and CV risk factors. These effects are over and above the improvements in sexual functions brought by TRT.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Endocrine Society of India (ESI), Research Grant.
Conflicts of interest
There are no conflicts of interest.
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