Baseline characteristics of normal weight, overweight and obese patients

Table 1 shows baseline characteristics, including the type of hypogonadism, comorbidities and concomitant medications in both treated and untreated groups.

Table 1 Baseline characteristics, comorbidities and concomitant medication at baseline in normal weight, overweight and obese men. Full size table

Effects of long-term TTh on anthropometric parameters in hypogonadal men with normal weight, overweight or obesity at baseline

At 11 years, in 26 men with normal weight receiving TTh, weight decreased by 3.4 ± 1.2 kg (p < 0.005) and increased by 6.1 ± 0.7 kg (p < 0.0001) in 37 men with normal weight who remained untreated (Fig. 1a, left panel). Similarly, in 113 overweight men on TTh, weight decreased by 8.5 ± 0.4 kg and increased by 6.0 ± 0.3 kg (p < 0.0001 for both) in 167 untreated overweight men (Fig. 1a, middle panel). In 281 obese men on TTh, weight decreased by 23.2 ± 0.3 kg and increased by 4.2 ± 0.5 kg (p < 0.0001 for both) in 193 untreated obese men (Fig. 1a, right panel).

Fig. 1 a Changes in weight (kg) in hypogonadal men with normal weight (left), overweight (middle) or obesity (right) treated with or without testosterone therapy. b Percent changes in weight in hypogonadal men with normal weight, overweight or obesity, at baseline, treated with or without testosterone therapy. c Changes in BMI (kg/m²) in hypogonadal men with normal weight, overweight or obesity at baseline treated with or without testosterone therapy. d Changes in waist circumference in hypogonadal men with normal weight, overweight or obese at baseline treated with or without testosterone therapy. Data are shown as least squares means ± standard errors. Shaded areas represent 95% confidence intervals. P values indicate statistical significance between groups for each year. Full size image

When % weight change was analyzed, men with normal weight on TTh lost 4.8 ± 1.5% (p < 0.005) while untreated men gained 8.0 ± 0.9% (p < 0.0001) (Fig. 1b, left panel). Men with overweight on TTh lost 9.6 ± 0.4% while untreated men gained 6.9 ± 0.3% (p < 0.0001 for both) (Fig. 1b, middle panel). Obese men on TTh lost 20.6 ± 0.3% while untreated obese men gained 5.1 ± 0.4% (p < 0.0001 for both) (Fig. 1b, right panel). The changes in weight with and without TTh in all three groups were reflected in corresponding changes in BMI (Fig. 1c).

In men with normal weight receiving TTh, WC decreased by 3.4 ± 0.8 cm and increased in untreated men by 5.5 ± 0.5 cm (p < 0.0001 for both) (Fig. 1d, left panel). In men with overweight on TTh, WC decreased by 4.7 ± 0.3 cm and increased by 5.5 ± 0.2 cm (p < 0.0001 for both) in untreated overweight men (Fig. 1d, middle panel). In obese men on TTh, WC decreased by 12.9 ± 0.2 cm and increased by 5.6 ± 0.4 cm (p < 0.0001 for both) in untreated obese men (Fig. 1d, right panel).

Effects of long-term TTh on blood pressure and pulse pressure in men with testosterone deficiency (TD) and normal weight, overweight or obesity at baseline

In men with normal weight receiving TTh, systolic blood pressure (SBP) decreased by 10.2 ± 3.1 mmHg (p < 0.005) and increased by 10.6 ± 1.8 mmHg (p < 0.0001) in untreated men with normal weight (Fig. 2a, left panel). In men with overweight on TTh, SBP decreased by 11.8 ± 1.1 mmHg and increased by 10.2 ± 0.9 mmHg (p < 0.0001 for both) in untreated overweight men (Fig. 2a, middle panel). In obese men on TTh, SBP decreased by 26.1 ± 0.8 mmHg and increased by 13.5 ± 1.3 mmHg (p < 0.0001 for both) in untreated obese men (Fig. 2a, right panel).

Fig. 2 a Changes in systolic blood pressure (mmHg) in hypogonadal men with normal weight, overweight or obesity at baseline treated with or without testosterone therapy. b Changes in diastolic blood pressure (mmHg) in hypogonadal men with normal weight, overweight or obesity at baseline treated with or without testosterone therapy. c Changes in pulse pressure in hypogonadal men with normal weight, overweight or obesity at baseline treated with or without testosterone therapy. Data are shown as least squares means ± standard errors. Shaded areas represent 95% confidence intervals. P values indicate statistical significance between groups for each year. Full size image

In men with normal weight on TTh, diastolic blood pressure (DBP) decreased by 2.9 ± 2.5 mmHg (NS) and increased by 7.0 ± 1.5 mmHg (p < 0.0001) in untreated normal-weight men (Fig. 2b, left panel). In overweight men on TTh, DBP decreased by 6.3 ± 0.9 mmHg and increased by 7.6 ± 0.7 mmHg (p < 0.0001 for both) in untreated overweight men (Fig. 2b, middle panel). In obese men on TTh, DBP decreased by 15.6 ± 0.6 mmHg and increased by 8.4 ± 0.9 mmHg (p < 0.0001 for both) in untreated obese men (Fig. 2b, right panel).

In men with normal weight on TTh, pulse pressure (PP) decreased by 7.4 ± 2.0 mmHg (p < 0.0005) and increased by 3.6 ± 1.1 mmHg (p < 0.005) in untreated men (Fig. 2c, left panel). In overweight men on TTh, PP decreased by 5.5 ± 0.8 mmHg and increased by 2.5 ± 0.6 mmHg (p < 0.0001 for both) in untreated men (Fig. 2c, middle panel). In obese men on TTh, PP decreased by 10.5 ± 0.5 mmHg and increased by 5.0 ± 0.8 mmHg (p < 0.0001 for both) in untreated obese men (Fig. 2c, right panel).

Effects of long-term TTh on lipid pattern in hypogonadal men with normal weight, overweight or obesity at baseline

In men with normal weight on TTh, total cholesterol (TC) decreased by 1.4 ± 0.2 mmol/L and increased by 1.3 ± 0.1 mmol/L (p < 0.0001 for both) in untreated men with normal weight (Fig. 3a, left panel). In overweight men on TTh, TC decreased by 1.8 ± 0.1 mmol/L and increased by 1.4 ± 0.1 mmol/L (p < 0.0001 for both) in untreated overweight men (Fig. 3a, middle panel). In obese men on TTh, TC decreased by 2.6 ± 0.0 mmol/L and it increased by 1.0 ± 0.1 mmol/L (p < 0.0001 for both) in untreated obese men (Fig. 3a, right panel).

Fig. 3 a Changes in total cholesterol (mmol/L) in hypogonadal men with normal weight (left), overweight (middle) or obesity (right) treated with or without testosterone therapy. b Changes in HDL (mmol/L) in hypogonadal men with normal weight (left), overweight (middle) or obesity (right) treated with or without testosterone therapy. c Changes in LDL (mmol/L) in hypogonadal men with normal weight (left), overweight (middle) or obesity (right) treated with or without testosterone therapy. d Changes in triglycerides (mmol/L) in hypogonadal men with normal weight (left), overweight (middle) or obesity (right) treated with or without testosterone therapy. e Changes in Non-HDL cholesterol (mmol/L) in hypogonadal men with normal weight (left), overweight (middle) or obesity (right) treated with or without testosterone therapy. f Changes in remnant cholesterol (mmol/L) in hypogonadal men with normal weight (left), overweight (middle) or obesity (right) treated with or without testosterone therapy. Data are shown as least squares means ± standard errors. Shaded areas represent 95% confidence intervals. P values indicate statistical significance between groups for each year. Full size image

In men with normal weight on TTh, HDL increased by 0.6 ± 0.1 mmol/L and decreased by 0.3 ± 0.1 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3b, left panel). In men with overweight on TTh, HDL increased by 0.4 ± 0.0 mmol/L and decreased by 0.3 ± 0.0 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3b, middle panel). In obese men on TTh, HDL increased by 0.4 ± 0.0 mmol/L and decreased by 0.2 ± 0.0 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3b, right panel).

In men with normal weight on TTh, LDL decreased by 0.8 ± 0.2 mmol/L and increased by 0.8 ± 0.1 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3c, left panel). In men with overweight on TTh, LDL decreased by 1.4 ± 0.1 mmol/L and increased by 0.9 ± 0.1 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3c, middle panel). In obese men on TTh, LDL decreased by 1.7 ± 0.0 mmol/L and increased by 0.9 ± 0.1 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3c, right panel).

In men with normal weight on TTh, triglyceride (TG) decreased by 0.2 ± 0.1 mmol/L (NS) and increased by 0.8 ± 0.1 mmol/L (p < 0.0001) in untreated men (Fig. 3d, left panel). In men with overweight on TTh, TG decreased by 0.6 ± 0.0 mmol/L and increased by 0.7 ± 0.0 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3d, middle panel). In obese men on TTh, TG decreased by 1.0 ± 0.0 mmol/L and increased by 0.5 ± 0.0 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3d, right panel).

In men with normal weight on TTh, Non-HDL decreased by 4.2 ± 0.8 mmol/L and increased by 2.7 ± 0.4 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3e, left panel). In men with overweight on TTh, Non-HDL decreased by 4.0 ± 0.3 mmol/L and increased by 3.1 ± 0.2 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3e, middle panel). In obese men on TTh, Non-HDL decreased by 4.3 ± 0.2 mmol/L and increased by 3.2 ± 0.3 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3e, right panel).

In men with normal weight on TTh, remnant cholesterol decreased by 1.2 ± 0.3 mmol/L and increased by 0.7 ± 0.2 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3f, left panel). In men with overweight on TTh, remnant cholesterol decreased by 0.8 ± 0.1 mmol/L and increased by 0.9 ± 0.1 mmol/L (p < 0.0001 for both) in untreated men (Fig. 3f, middle panel). In obese men on TTh, remnant cholesterol decreased by 1.3 ± 0.1 mmol/L (p < 0.0001) and increased by 0.3 ± 0.1 mmol/L (p < 0.001) in untreated men (Fig. 3f, right panel).

Effects of long-term TTh on serum T levels in hypogonadal men with normal weight, overweight or obesity at baseline

In men with normal weight on TTh, T increased by 8.9 ± 0.5 nmol/L (p < 0.0001) and decreased by 1.0 ± 0.3 nmol/L (p < 0.005) in untreated men (Supplementary Fig. 1, left panel). In men with overweight on TTh, T increased by 8.5 ± 0.2 nmol/L and decreased by 1.6 ± 0.2 nmol/L (p < 0.0001 for both) in untreated men (Supplementary Fig. 1, middle panel). In obese with obesity on TTh, T increased by 7.9 ± 0.1 nmol/L and decreased by 2.4 ± 0.3 nmol/L (p < 0.0001 for both) in untreated men (Supplementary Fig. 1, right panel).

Effects of long-term TTh on glycemic control in hypogonadal men with normal weight, overweight or obesity at baseline

In men with normal weight on TTh, fasting plasma glucose (FPG) decreased by 0.3 ± 0.2 mmol/L (NS) and increased by 0.8 ± 0.1 mmol/L (p < 0.0001) in untreated men (Supplementary Fig. 2A, left panel). In men with overweight on TTh, FPG decreased by 0.3 ± 0.2 mmol/L (NS) and increased by 0.8 ± 0.2 mmol/L (p < 0.0001) in untreated men (Supplementary Fig. 2A, middle panel). In obese men on TTh, FPG decreased by 1.0 ± 0.1 mmol/L and increased by 1.8 ± 0.1 mmol/L (p < 0.0001 for both) in untreated men (Supplementary Fig. 2A, right panel).

In men with normal weight on TTh, HbA 1c decreased by 0.2 ± 0.6% (NS) and increased by 1.7 ± 0.2% (p < 0.0001) in untreated men (Supplementary Fig. 2B, left panel). In men with overweight on TTh, HbA 1c decreased by 1.5 ± 0.2% and increased by 1.8 ± 0.1% (p < 0.0001 for both) in untreated men (Supplementary Fig. 2B, middle panel). In obese men on TTh, HbA 1c decreased by 2.2 ± 0.2% and increased by 2.8 ± 0.3% (p < 0.0001 for both) in untreated men (Supplementary Fig. 2B, right panel).

Major adverse events

As shown in Table 3, in men with normal weight receiving TTh, there was one death, and there was no occurrence of nonfatal MIs and strokes. In untreated men with normal weight, there were three deaths, four nonfatal MIs and six nonfatal strokes. In overweight men receiving TTh, there were four deaths, no nonfatal MIs and strokes. In untreated overweight men, there were 14 deaths, 21 nonfatal MIs and 11 nonfatal strokes. In obese men receiving TTh, there were 18 deaths, no nonfatal MIs and strokes. In untreated obese men, there were 60 deaths, 49 nonfatal MIs and 50 nonfatal strokes. In overweight men, incidence of MIs and strokes in untreated controls were statistically significantly higher compared with the T-treated men (p < 0.0001 and p < 0.005, respectively). In obese men, incidence of deaths, MIs and strokes were statistically significantly higher compared with T-treated men (p < 0.0001 for all three).

There was one prostate cancer in the untreated group (NS) with normal weight. Prostate cancer was diagnosed in 5 (4.1%) overweight men treated and 15 (9.1%) untreated men (NS). Prostate cancer was diagnosed in 7 (2.5%) obese men who were T-treated and 29 men (15.0%) who remained untreated (p < 0.0001). As expected, there were slight increases in PSA in both treated and untreated groups. Changes in PSA are shown in detail in Supplementary Table 2. As expected, there were slight increases in hemoglobin and hematocrit in the T-treated groups, but levels remained within the physiological reference ranges. We have not encountered a single case of deep vein thrombosis. It is worth noting that we have not encountered any patient with hematocrit greater than 54% in two consecutive measurements and therefore no actions were taken.