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

01 July 2019

STUDY: 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. 2019:1-12.

Erectile dysfunction is one of the three main sexual symptoms (the other being poor morning erection and low sexual desire) that are indicative of low testosterone levels.1 Not surprisingly, hypogonadism (also known as testosterone deficiency or low testosterone) is the most common hormonal cause of erectile dysfunction.2

Erectile dysfunction is the most common type of sexual dysfunction reported in urology practice, and reason for prescribing testosterone therapy when accompanied with lab tests showing low testosterone levels.

Here we summarise the results of a study that evaluated the effects of long-term treatment with undecanoate injections for up to 12 years in hypogonadal men with varying degrees of erectile dysfunction.3 

KEY POINTS

Erectile dysfunction is a primary sexual symptom indicative of low testosterone levels, and hypogonadism is the most common hormonal cause of erectile dysfunction.
Erectile dysfunction commonly precedes development of cardiovascular disease; both conditions improve with testosterone therapy.
Long-term treatment with testosterone undecanoate injections progressively improves erectile function for up to 9 years, while reducing incidence of MI, stroke and death, compared to untreated men.

What is known about testosterone, erectile dysfunction and cardiovascular disease

Although the prevalence of erectile dysfunction increases with age - it affects 10% of young men 20-30 years old, but as many as 70% of men aged ≥70 years 4-6 - loss of erectile function does not seem to be caused by aging per se. For example, type 2 diabetes is a stronger risk factor for erectile dysfunction than age.7Obesity, hypertension, cardiovascular disease, depression and lower urinary tract symptoms (LUTS) are common conditions that are also associated with erectile dysfunction.5,8-10 Erectile dysfunction frequently coexists with cardiovascular disease; both conditions share risk factors – such as obesity, hypertension, metabolic syndrome, diabetes, and smoking –  with endothelial dysfunction as the pathophysiologic link.11 Notably, erectile dysfunction may be the earliest sign of subclinical cardiovascular disease 12 and often precedes the manifestations of cardiovascular disease.11,13 Therefore, aggressive cardiovascular risk assessment should be conducted in men with erectile dysfunction.14

Men with type 2 diabetes have a 3.6-fold higher risk of developing erectile dysfunction compared to men without diabetes, and also tend to develop erectile dysfunction 10 to 15 years earlier than men without type 2 diabetes.8 The prevalence of erectile dysfunction in men with type 2 diabetes is as high as 86%.8,15 Considering that testosterone is involved in central as well as peripheral neural mechanisms of penile erection,16 it is not surprising that the prevalence of hypogonadism mirrors that of erectile dysfunction; up to 81% of men with type 2 diabetes are hypogonadal.17-20 Accordingly, in 2018 the American Diabetes Association amended the Standards of Medical Care in Diabetes with the recommendation to routinely measure total testosterone levels in men with diabetes and symptoms of hypogonadism, such as erectile dysfunction.21

Numerous studies have shown that testosterone therapy improves erectile dysfunction.22-25 However, there is a paucity of long-term studies. Therefore, the aim of the present study was to fill this knowledge gap by evaluating hypogonadal men with erectile dysfunction of varying degrees, who had been treated with testosterone undecanoate injections for up to 12 years. 

What this study adds

This was an observational, prospective ongoing registry study including 805 symptomatic hypogonadal men with a baseline total testosterone level of ≤12.1 nmol/L (350 ng/dL). Patients who were started on testosterone therapy were treated with injections of testosterone undecanoate at 3-month intervals after an initial 6-week interval. Patients not receiving testosterone therapy served as controls.

Erectile dysfunction severity was assessed with the International Index of Erectile Function – Erectile Function Domain (IIEF-EF) questionnaire. A cut-off score of 22 (range 0-30) was set to differentiate patients with no or mild erectile dysfunction (“no/mild ED”) and mild-to-moderate-to-severe-to-very severe erectile dysfunction (“moderate/severe ED”). 

At baseline, no/mild ED (IIEF-EF score ≥22) was recorded in 298 patients (prevalence 37%), of which 154 patients were started on testosterone therapy and 144 served as a control group. Moderate/severe ED (IIEF-EF score <22) was recorded in 507 patients (prevalence 63%), of which 258 were started on testosterone therapy and 249 served as a control group. 

IIEF-EF and AMS

At baseline, the mean testosterone level in all groups was approximately 10 nmol/L. Treatment with testosterone undecanoate normalized total testosterone levels after the first injection and kept total testosterone within the normal range for the entire duration of the study. In untreated groups, total testosterone levels progressively declined during the entire observation period. In the final analysis, testosterone levels in the testosterone groups had increased to approximately 18.5 nmol/L, while in the untreated groups testosterone levels dropped to approximately 8 nmol/L.

Changes in erectile dysfunction were consistent with changes in testosterone levels. Throughout the observation period, IIEF-EF scores steadily improved (increased) in both testosterone groups, with a clear improvement in the no/mild group (+4 points) and an even greater improvement in the moderate/severe (+11 points). Conversely, the untreated moderate/severe groups showed progressive worsening of erectile dysfunction over time, in parallel with their declining testosterone levels (Figure 1).

Changes in IIEF-EF in patients with no/mild and moderate/server

Figure 1: Changes in IIEF-EF in patients with no/mild and moderate/severe erectile dysfunction during treatment with testosterone undecanoate injections, compared to untreated (control) patients. P-values in the graph indicate statistical significance compared to the previous year.

AMS scores decreased by approximately 30 points in the testosterone groups during the first 2 years of treatment and then remained constant (Figure 2). In both control groups, AMS scores slightly decreased in the first year of observation but then steadily increased during the remaining years.

Changes in AMS

Figure 2: Changes in AMS scores in patients with no/mild and moderate/severe erectile dysfunction during treatment with testosterone undecanoate injections, compared to untreated (control) patients.

Anthropometric parameters

Both testosterone groups experienced a marked weight loss throughout the entire treatment period. Body weight was reduced by approximately 18 kg, waist circumference by 10 cm, and BMI by 6 kg/m2(Figures 3a-4c). In stark contrast, both untreated groups experienced increased body weight by +3.2 kg, waist circumference by +4.1 cm and BMI by +1.0 kg/m2 .

Changes in body weight (kg) in patients

Figure 3a: Changes in body weight (kg) in patients with no/mild and moderate/severe erectile dysfunction during treatment with testosterone undecanoate injections, compared to untreated (control) patients.

Changes in waist circumference (cm) in patients

Figure 3b: Changes in waist circumference (cm) in patients with no/mild and moderate/severe erectile dysfunction during treatment with testosterone undecanoate injections, compared to untreated (control) patients.

Changes in BMI (kg/m2 ) in patients with no/mild

Figure 3c: Changes in BMI (kg/m2 ) in patients with no/mild and moderate/severe erectile dysfunction during treatment with testosterone undecanoate injections, compared to untreated (control) patients.

Metabolic parameters

In both testosterone-treated groups there was an improvement in the lipid profile; total cholesterol, LDL and non-HDL cholesterol, and triglycerides decreased, while HDL increased. In both untreated groups, all lipid parameters progressively deteriorated further over time.

A similar pattern was seen in glycemic control. In both testosterone groups there was a considerable reduction in HbA1c and fasting glucose. In both untreated groups, a further deterioration of glycemic control was observed.

Blood pressure

In both testosterone-treated groups, systolic and diastolic blood pressure were reduced by -19/-23 mmHg and -12/-11 mmHg, respectively. In both untreated groups, blood pressure increased by +6/+11 mmHg (systolic) and +2/+7 mmHg (diastolic). Pulse pressure was reduced by -8/-11 mmHg in the TTh groups, whereas in both control groups an increase by 3 mmHg was noted.

Urinary function and prostate parameters 

In both testosterone-treated groups, IPSS total score was reduced by 4.6 points, whereas in the untreated groups the score increased by 2.4 and 2.8 points, respectively. Prostate volume increased in all groups, but this increase was more pronounced in the untreated groups. 

In both testosterone-treated groups, there was a small (0.2 ng/mL) non-significant (meaning it could be caused by chance rather than a true treatment effect) increase in PSA levels from baseline. In contrast, in the untreated groups, PSA significantly increased by 0.4 and 1.0 ng/ml in the no/mild erectile dysfunction group and moderate/severe erectile dysfunction group, respectively. The incidence of prostate cancer was 3.2 vs. 6.9% in in the testosterone-treated groups combined and placebo groups, respectively.

Mortality and major adverse cardiovascular events

Adverse events are illustrated in figure 4. In the testosterone treated groups, no myocardial infarction (MI) nor stroke occurred during the entire observation period. 

In the untreated groups, MI and stroke occurred in 18.9% and 14.9% of patients with moderate/severe erectile dysfunction, respectively, and 16% and 15.3% in patients with no/mild erectile dysfunction. 

In the testosterone treated groups, death from all causes occurred in 6.5% and 2.3% of men with no/mild erectile dysfunction and moderate/severe erectile dysfunction, respectively.

In the untreated groups, death occurred in 14.6% and 21.3% of men with no/mild erectile dysfunction and moderate/severe erectile dysfunction, respectively.

In the testosterone treated groups, prostate cancer occurred in 0% and 2.3% of men with no/mild erectile dysfunction and moderate/severe erectile dysfunction, respectively.

In the untreated groups, prostate cancer occurred in 6.9% and 6.8% of men with no/mild erectile dysfunction and moderate/severe erectile dysfunction, respectively. 

Adverse events (%) in patients with no/mild

Figure 4: Adverse events (%) in patients with no/mild and moderate/severe erectile dysfunction during treatment with testosterone undecanoate injections, compared to untreated (control) patients.

ED = erectile dysfunction, MI = myocardial infarction, T = testosterone

Commentary

The main findings of this study are that long-term testosterone therapy with testosterone undecanoate injections for up to 12 years substantially improves erectile function, obesity measures, cardiometabolic risk factors, prostate cancer incidence and urinary function.3 It is notable that the improvement in erectile function was even stronger in patients with moderate/severe erectile dysfunction at baseline (increased IIEF-EF scores by 12 points) than in patients with no/mild erectile dysfunction at baseline (increased IIEF-EF scores by 5 points). These results meet the requirement of minimal clinically important increase in IIEF-EF score from baseline of 4.26 In contrast, in the untreated groups, IIEF-EF scores decreased by 10 and 15 points in the no/mild erectile dysfunction and moderate/severe erectile dysfunction groups, respectively. 

The present study analyzing the effect of testosterone therapy with testosterone undecanoate injections on erectile function for 12 years is the longest reported observation to date. It is highly remarkable that erectile function continued to significantly improve for each successive year for 9 years.3 This study confirms and extends findings from a previous study which showed that treatment with testosterone undecanoate injections resulted in a similar significant and continuous improvement in IIEF-EF for 4 years.22 These two studies underscore the importance of long-term testosterone therapy for achievement of maximal therapeutic effect.

It was previously believed that maximal improvements in erectile function are achieved after 3-6 months of testosterone therapy.27 Based on this belief, several clinical guidelines recommend that men who present with symptoms such as erectile dysfunction but have borderline low testosterone levels should be given a therapeutic trial of testosterone therapy for 3 months 28, 6 months 29 or 12 months 30, to see if it works. The 4-year 22 and 12-year 3 data clearly show that a therapeutic trial of testosterone therapy for even 1 year is not enough to achieve maximal improvement in erectile function.  

It is also notable that AMS scores continued to improve for 2 years. Symptoms which are evaluated with the AMS scale, especially erectile dysfunction, are primary symptoms associated with hypogonadism 31 and symptomatic improvement is a major indicator of the effectiveness of testosterone therapy. Therefore, it is critical for healthcare professionals to be informed that patients with hypogonadism who have been on testosterone therapy for 3-12 months but not experienced the expected improvement in erectile function (or other symptoms) yet will likely do so if they stay on testosterone therapy without interruption for a longer time period.

The beneficial effect of long-term testosterone therapy on major adverse cardiovascular events was clearly confirmed in the present study.3 In the testosterone treated groups, there was no MI and no stroke. The lack of major adverse cardiovascular events in patients with moderate/severe erectile dysfunction is particularly remarkable considering their worse baseline health status and higher mortality risk. In contrast, in the untreated groups, MI and stroke occurred in 16% and 15% of patients with no/mild erectile dysfunction, and in 19% and 15% of patients with moderate/severe erectile dysfunction. This notable difference between testosterone treated and untreated groups is likely explained by the improvement of cardiovascular risk factors – obesity, hypertension, glycemic control, lipid profile – in men who had been treated with testosterone undecanoate. Another study also reported a reduction in major adverse cardiovascular event and mortality after long-term treatment with testosterone undecanoate.32  It has also previously been shown that testosterone therapy in stroke patients with hypogonadism and type 2 diabetes significantly reduced the incidence of recurrent stroke,  as well as mortality during a 5-year follow-up.33 This is consistent with observational data showing that testosterone deficiency may increase risk for ischemic events,33 and that normalization of testosterone levels may protect vascular function by reducing vasoconstriction and increasing coronary blood flow.34 

Another highly remarkable finding in the present study is that there were no signs of negative impact on the prostate after long-term testosterone therapy with testosterone undecanoate injections for 12 years. In fact, the incidence of prostate cancer was more than twice as high in the untreated groups combined compared to the testosterone-treated groups combined (6.9% vs. 3.1%). In accordance with these results, several other studies have found that testosterone therapy may have a protective effect against prostate cancer, especially high-grade prostate cancer.35-37

In summary, the novel finding in the present study is that during long-term treatment with testosterone undecanoate injections, erectile function continued to significantly improve for each successive year for 9 years.3 This was accompanied by a marked reduction in mortality and prostate cancer, and not a single patient had an MI or stroke. In contrast, in untreated men erectile dysfunction worsened over time while the incidence of MI, stroke and mortality markedly increased. 

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