Effects of tadalafil treatment combined with physical activity in patients with low onset hypogonadism: results from a not-randomized single arm phase 2 study

Abstract

Purpose: To investigate a possible relation between penile Doppler ultrasound examination (PDUE) parameters and efficacy of chronic therapy with tadalafil (TAD) combined with a protocol of aerobic physical activity (PA) in patients with late onset hypogonadism (LOH). Methods: The study evaluated 30 patients consecutively enrolled with LOH and erectile dysfunction which present contraindication to hormonal replacement therapy for concomitant prostate disease. These patients were subjected to a combined protocol with phosphodiesterase V selective inhibitors (TAD 5 mg daily) and aerobic PA.

Results: After three months, we observed significant improvements in erectile function [IIEF-5, median (IQR) = 13.0 (7.0–18.0) versus 6.0 (5.0–6.75); p < 0.01] and of the main metabolic [homeostatic model assessment index, median (IQR) = 2.5 (1.62–3.37) versus 3.0 (2.0–3.75); p < 0.01; body mass index, median (IQR) = 27.0 (24.0–28.75) versus 27.5 (24.0–29.5)] and vascular parameters [peak systolic velocity, median (IQR) = 29.5 (24.25–31.0) versus 28.0 (23.0–24.25); acceleration time, median (IQR) = 114 (105.25–134.0) versus 115.0 (106.5–134.0)], assessed by PDUE.

Conclusion: PA in association with phosphodiesterase V inhibitors could compensate the effects of hypogonadism on erectile function and facilitate the clinical response to these drugs even in the absence of adequate serum concentrations of total testosterone.

• Erectile dysfunction
• penile Doppler
• PDE5i
• LOH
• physical activity

Introduction

Low concentrations of total testosterone (TT) represent an important cause for erectile dysfunction (ED) [1] and are also associated with lower clinical response to treatment with phosphodiesterase V selective inhibitors (PDE5i) considered the first choice for the treatment of these patients [2]. Testosterone (T) plays a regulating action on the adequate bioavailability of nitric oxide, essential for the mechanism of these drugs [2,3]. Moreover the severity of endothelial dysfunction is associated with the presence of hypogonadism and it represents an independent mechanism responsible for ED [4]. Several evidences have documented these associations, in particular the high frequency of hypogonadism among the poor responders to PDE5i and therefore the evaluation of serum TT is suggested in the diagnostic algorithm of ED before starting therapy [2,4–6]. The assumption of PDE5i [7] and the sexual activity [8] may determine increase in serum concentrations of TT, this aspect should be considered in the clinical management of hypogonadal patients with ED. In particular, the recent study of Spitzer and colleagues [7] suggests a possible direct action of Sildenafil on testicular function.

Earlier we documented that regular aerobic physical activity (PA) in patients with ED is associated with improvements of endothelial and hormonal function and therefore this should be recommended in the therapeutic approach of these patients [9].

Among the first level clinical examinations in the management of patients with ED, penile Doppler ultrasound evaluation (PDUE) represents an essential step [10,11] in particular for the possible differential diagnosis of vascular causes. Generally hypogonadal patients have severe vascular arterial insufficiency that can anticipate vascular systemic alterations [12].

A peak systolic velocity (PSV) > 30 cm/s, an end-diastolic velocity (EDV) of <3 cm/s and a resistance index (IR) > 0.8 are generally considered normal [10,11]. Further vascular investigation is unnecessary when a duplex examination is normal. Another useful parameter for the diagnosis of arterial insufficiency is represented by the acceleration time (AT) > 100 mm/s that has more power than PSV to diagnose atherosclerotic ED [13]. Recently it has been suggested the use of flaccid penile acceleration associated with a threshold effect in predicting major adverse cardiovascular events at a value <1.17 m/sin apparently lower-risk individuals [14].

In the clinical practice, the hypogonadal patients, despite the high frequency of penile arterial insufficiency, have vascular parameters characterized by high variability [12]. There are not in the literature evidences regarding a possible threshold value of these parameters with predictive value about the clinical response to PDE5i in these patients.

Based on these premises, the aim of this study was to investigate the impact of combined therapy with tadalafil (TAD) and aerobic PA on PDUE parameters in patients with late onset hypogonadism (LOH).

Materials and methods

Thirty patients consecutively enrolled, with a diagnosis of LOH formulated in accordance with international guidelines [15] and severe grade of ED according to scores of the questionnaire five-item version of the International Index of Erectile Function 5 (IIEF-5) [16] were subjected to pharmacological treatment with TAD 5 mg daily for a total duration of 90 days.

Before and after the treatment, all patients were subjected to the following diagnostic algorithm:

1. IIEF-5 questionnaire;

2. Physical examination for evaluation of the Body Mass Index (BMI);

3. Hormonal evaluation: TT, luteinizing hormone (LH);

4. Blood sample for blood glucose and fasting insulin levels for calculating homeostatic model assessment (HOMA);

5. PDUE

All patients underwent an aerobic PA protocol (Table 1) given by a specialist and observation of the Mediterranean diet’s principles (Table 1) explained by the specialist at the enrollment and were supported by a nutritionist [17,18].

Table 1. Protocol of aerobic physical activity and Mediterranean diet’s principles observed by patients during the study.

Detection of target heart rate according to Karvonen’s formula:

Frequency of cardiac reserve (FCR)=Maximum heart rate – Basal cardiac frequencyMore generally: THR = (maximum heart rate* – basal cardiac frequency) × % Intensity)+basal cardiac frequency, where: intensity = 70%–80% for aerobic workDoses of activity: 150 min of moderate intensity aerobic activity per weekDuration of bouts: 30 minPractical advice: All patients practiced physical activity with heart rate training between 40 and 60% of maximum heart rate.*Maximum heart rate: 220 – age of patient

Principles of the traditional Mediterranean diet observed during the study:

(1) High ratio of monounsaturated to saturated dietary lipids (mainly olive oil);

(2) Moderate ethanol consumption;

(3) High consumption of legumes;

(4) High consumption of non-refined cereals, including bread;

(5) High consumption of fruits;

(6) High consumption of vegetables;

(7) Low consumption of meat and meat products;

(8) Moderate consumption of milk and dairy products.

Hormonal measurements

Blood sampling was performed at 8.00 am, after at least 8 h of sleep. LH, TT evaluation was performed by electrochemiluminescence immunoassay (ECLIA) with Cobas equipment. Normal values were LH = 1.7–8.6 mIU/mL, TT = 2.49–8.36 ng/mL.

Ultrasound evaluation

All the patients underwent dynamic echo-color Doppler of the penile arteries with pulsed Doppler analysis, following intracavernous injection of 15–20 mcg of alprostadil to determine changes in the cavernous artery diameters and in PSV. Following injection, PSV, AT and EDT were evaluated after 10, 20 and 30 min. A PSV <30 cm/s and non-temporal peak systolic progression with EDT <5 cm/s suggested arterial disease. Acceleration time is a dimension that reflects all the previously mentioned PDUE parameters, because it reflects both PSV and the time elapsed to reach it. It is calculated as [(PSV − EDT)/systolic rise time, m/s²]. Systolic rise time is the time measured from the start of systolic peak velocity to the maximum value.

Exclusion criteria

Patients with contraindications to the use of TAD according to the data sheet.

Patient characteristics

According to the guidelines of European Association of Urology [19], none of the examined patients underwent pharmacological treatment with T for the presence of at least one of the following conditions:

• Family history of prostate cancer;

• Prostate Specific Antigen (PSA) level between 2.1 and 4.0 ng/mL;

• Suspicious PSA density, PSA velocity, PSA doubling time;

• Free/total PSA ratio <0.25;

The study was approved by the Internal Institutional Board and all examined patients signed informed consent to the processing of personal data.

Statistical analysis

Continuous variables are presented as median (interquartile range) and differences between groups were tested by Student’s independent t-test or Mann–Whitney U test according to their normal or not-normal distribution, respectively (normality of variables’ distribution was tested by Kolmogorov–Smirnov test). Pearson’s or Spearman’s correlation analysis was performed to identify statistical associations between variables. Age-adjusted linear regression models were performed to verify factors correlated with IIEF-5 after treatment and expressed as beta-coefficient. The beta-coefficient showed the entity of the variation of the independent variable by each increase of the dependent value. All tests were completed using SPSS v. 19 software (SPSS Inc, IBM Corp, Somers, NY). For all statistical comparisons significance was considered as p < 0.05.

Results

After therapy we observed a significant reduction of the main anthropometric and metabolic parameters (HOMA and BMI), moreover we observed a significant increase of the main vascular parameters that evaluate the arterial phase (PSV and AT) and finally a significant increase of IIEF-5 score (Table 2). The value of PSV obtained after therapy had a negative correlation with BMI and HOMA and a positive correlation with the IIEF-5 score (Table 3). The value of AT obtained after therapy correlates positively with BMI and HOMA and negatively with the IIEF-5 score (Table 3). The value of EDV obtained after therapy had a negative correlation with the IIEF-5 score (Table 3). Multivariate analysis showed a positive relation between PSV and IIEF-5 score and a negative relation between AT, EDV and IIEF-5 score (Table 4). Multiple linear regression analysis showed significant association between PSV (beta = 1.13; p < 0.01), AT (beta= −1.08; p < 0.01), EDV (−0.97; p < 0.01) and IIEF-5 score after treatment (Figure 1).

Table 2. Baseline and after therapy characteristics of patients.

	Baseline (n = 30)	After therapy (n = 30)	p values
Age, median (IQR)	59.0 (55.2–62.2)	–	–
BMI, median (IQR)	27.5 (24.0–29.5)	27.0 (24.0–28.7)	<0.01
HOMA, median (IQR)	3.0 (2.0–3.7)	2.5 (1.6–3.4)	<0.01
TT, median (IQR)	2.0 (1.9–2.2)	2.1 (1.92–2.2)	0.40
LH, median (IQR)	2.1 (1.6–2.3)	2.0 (1.6–2.3)	0.04
PSV, median (IQR)	28.0 (23.0–24.2)	29.5 (24.2–31.0)	<0.01
AT, median (IQR)	115.0 (106.5–134.0)	114.0 (105.2–134.0)	<0.01
EDV, median (IQR)	0.0 (0.0–2.0)	0.0 (0.0–2.0)	0.08
IR, median (IQR)	1.0 (0.90–1.0)	0.8 (0.91–1.0)	0.02
IIEF-5, median (IQR)	6.0 (5.0–6.7)	13.0 (7.0–18.0)	<0.01

Table 3. Correlation between penile Doppler ultrasound and clinical parameters after therapy.

	PSV	AT	EDV
BMI	−0.51*	0.55*	0.29
HOMA	−0.45*	0.45*	0.13
TT	−0.01	0.14	0.40
LH	0.19	−0.262	0.32
IR	0.46*	−0.41	−0.98*
IIEF-5	0.91^**	−0.97^**	−0.47*

*p < 0.05.

**p < 0.01.

Table 4. Multivariate adjusted linear regression between penile Doppler ultrasound parameters and IIEF-5 after therapy.

	Beta	p values
PSV	1.13 (1.48; 1.86)	<0.01
AT	−1.08 (−2.10; −0.36)	<0.01
EDV	−0.97 (−7.44; −1.44)	<0.01

Figure 1. Linear regression analysis between PSV at baseline (a), AT at baseline (b) and IIEF-5 after treatment.

Discussion

The results of this study showed that a combined therapeutic approach (pharmacological with PDE5i, associated with change in lifestyle) in patients with LOH results in a significant improvement of the metabolic, vascular and sexual parameters, without hormonal replacement therapy (HRT) and without significant increase in serum concentrations of TT. We believe that these results deserve further discussion for several reasons:

1. The improvement in sexual, metabolic and vascular function, occurs even in the absence of adequate serum TT;

2. It is strengthened the evidence of a positive association between PDE5i and aerobic PA about the therapeutic efficacy for these patients;

3. It confirms the importance of PDUE as a diagnostic tool to assess the vascular improvements obtained after therapy, moreover it showed relationship with the quality of the erectile function;

The importance of TT replacement therapy has been also previously documented. In particular, Yassin et al. found that TT therapy significantly improved obesity parameters (body weight, waist circumference and BMI) and lowered total cholesterol, LDL cholesterol, triglycerides, fasting blood glucose, HbA1c, and blood pressure over the 5-year study. TT treatment resulted in a sustained improvement in erectile function and muscle and joint pain, which contributed to an improvement in long-term health-related quality of life [20].

In contrast to other evidences that showed an increase of TT serum levels after administration of TAD [8,21] in the present study we did not observe this result. This apparent discrepancy could be explained for the use of low daily doses, with a different scheme of therapy compared with these studies. However considering the role of the PA capable of modifying the main metabolic parameters and consequently reducing the severity of insulin resistance, a reduction in T would be desirable [9]. Further studies will need to evaluate this aspect after a longer period of treatment.

The scientific literature has clearly shown that in the clinical practice adequate serum concentrations of TT are essential for adequate clinical response to PDEi [22], in fact T positively modulate the bioavailability of nitric oxide and the expression of the phosphodiesterase V in the corpora cavernosa [23]. However we must consider that LOH (model chosen for this study) could be influenced by two factors: time of onset of the disease (difficult to evaluate in the clinical practice) and relative accuracy of the methodology used for the determination serum concentrations of TT (chemiluminescence) [24]. However the recent study of Goldfischer and colleagues reported that in patients with partial clinical response to “on demand” treatment with PDE5i, TAD 5 mg daily improved ED and sexual functions placebo irrespective of T levels [25]. Previously in a randomized, double-blind, parallel, placebo-controlled trial Spitzer et al. showed that Sildenafil plus T was not superior to sildenafil plus placebo in improving erectile function in men with ED and low TT levels [7]. Zhang and colleagues, in another therapeutic protocol showed that TAD combined with L-carnitine is safe and effective for the treatment of LOH with ED with no significant differences compared to patients treated with TAD and T [26].

However, it should point out that the relationship between TT and ED could be multifactorial and not necessarily linear. In fact, some patients with lower TT could have good erectile response [27]. Moreover, also a polymorphism, the CAG repeat polymorphism in exon 1 of the androgen receptor gene (CAG)n, modulates androgen effects. Clinically, the (CAG)n polymorphism causes marked modulations of androgenicity in eugonadal men in various tissues and psychological traits and may cause the clinical picture of hypogonadism in the presence of normal T concentrations [28]. Finally, TT effects on erections may also depend on microanatomical penile structures, comorbidities and the duration of TT deficiency.

The association between multiple cardiovascular disease-risk factors and ED has been extensively demonstrated [29–32]. In this context, the main underlying common factor is represented by endothelial dysfunction. This latter is explained by an abnormal response of endothelium that leads to a lower bioavailability of nitric oxide and impairs vasodilation, with consequences like atherosclerosis, acute coronary syndromes and ED likewise [33]. On the basis of these premises, the role of PA may play a consistent contribute to the improvement of erectile function, as demonstrated by previous experimental and clinical studies [33]. Data from the Massachusetts Male Aging Study, carried out with a sample of 1156 men aged 40–70 years followed for 8.8 years, showed that the lowest risk for ED was among the physically active men, as compared with sedentary men (5200 kcal/day of PA). In an Italian randomized, single-blind trial of 110 obese men, detailed guidance on how to lose 10% or more of body weight by reducing caloric intake and increasing PA levels, 2 years after the initial intervention, led to BMI reduction and erectile function improvement, as assessed by the IIEF. It is in fact plausible, that PA lifestyle improves endothelial function, not only preventing but also mitigating the onset of ED and associated cardiovascular disease-risk factors [33].

On the other side, PDE5i still remain the first-line medication for ED and are known for their pharmacological properties that activate signaling molecule involved in smooth muscle relaxation, activating soluble guanylylcyclase and increasing tissue concentration of cyclic guanosine monophosphate [34]. In terms of overall efficacy and adverse events, a recent meta-analysis by Chen et al. demonstrated that PDE5i are effective in treating ED and are generally safe and well tolerated [35]. Nevertheless, pharmacological characteristics of the PDE5i may differ, such as time to onset of action, duration of effect, interaction with fatty meals and adverse events, but no randomized controlled trial has never directly compared all currently available PDE5i [35,36].

A previous study, performed by Maio et al., aiming to determine the effects of PA in the treatment of ED, founded that the use of PDE5i combined with PA practice (3 h/week) was more effective in treating ED than PDE5i alone [37].

Based on all these considerations, it should be plausible that both PA and PDE5i may in synergy act to restore nitric oxide levels in patients with ED. This dual treatment may have significant benefits also by ameliorating the response to PDE5i and reducing dosage.

The main limitation of this study is the lack of a control group that did not practice PA, this aspect must be evaluated in subsequent trials.

After treatment the vascular parameters assessed by PDUE improved significantly, this aspect is of great importance for the potential systemic consequences. PDUE is a diagnostic tool capable of evaluating the initial alterations of endothelial and cardiac function in these patients, as previously demonstrated by our and other groups [12,38,39]. An original aspect associated to the results of the present study is represented by the positive relationship between PSV and metabolic and sexual parameters and negative association between AT and the same parameters. PSV and AT evaluate the arterial phase of the corpora cavernosa. Further studies on a larger number of patients will need to evaluate a possible threshold with predictive value on the clinical response to PDE5i in patients with low or normal serum TT. Certain thresholds of PSV and AT may be associated with a degree of endothelial function able to compensate the relative lack of TT.

In the clinical practice, LOH patients with contraindication to the pharmacological treatment with T due to concomitant prostatic diseases are very common [19,27], however they have a high frequency of sexual dysfunction [40]. There are few studies in the literature that evaluated the effectiveness of a combined protocol (PDE5i and aerobic PA) on the quality of erectile function. Previously we reported that aerobic PA in middle-aged patients with ED improved PDUE parameters and reduced the severity of endothelial apoptosis [40]. In our opinion the clinical management of these patients should be reevaluated, with the adequate evaluation of a role for the PA among the main objectives [41]. Finally, it is important to consider the particular characteristics of the muscular exercise in LOH patients for the consequences on serum TT concentrations [9,42] that are different according to different types of PA (conditioned by several parameters; duration, intensity, frequency) and for the possible contraindications according to the muscle strength of the patient that should be adequate to support it.

Before concluding we would point out some limitations of the current study. First of all the phase 2 design of the study and the lack of a placebo group could represent a possible limitation of this research. In addition, we did not include control patients who did not receive PA prescription. In this latter case, the specific impact of PA on our clinical outcomes should be better investigated in a randomized, placebo/control clinical trial.

On the other side, the strength of this paper is represented by the evaluation of the combined treatment between TAD and PA in men with LOH, supporting the hypothesis of a broad-spectrum treatment of this disease.

Conclusions

Patients with LOH and ED associated may have advantages through a therapeutic protocol (PDE5i daily and aerobic PA) with improvement in sexual, metabolic and vascular parameters, without TRT and no significant changes in serum TT. PDUE represents an important diagnostic tool to assess these changes and the correlation of vascular parameters with IIEF-5 score could be an element of further evaluation aimed to find a threshold at the beginning of therapy to identify patients who will have a favorable pharmacological response to PDE5i.

Declaration of interest

The authors declare no conflict of interest.