J Endocrinol Invest (2014) 37:401–411 DOI 10.1007/s40618-014-0066-9

ORIGINAL ARTICLE

Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study D. Francomano • R. Bruzziches • G. Barbaro A. Lenzi • A. Aversa



Received: 6 February 2014 / Accepted: 2 March 2014 / Published online: 18 March 2014 Ó Italian Society of Endocrinology (SIE) 2014

Abstract Purpose Modifications of cardiovascular and metabolic parameters during testosterone (T) replacement and withdrawal have never been investigated in severely obese hypogonadal men. Methods Twenty-four severely obese (mean BMI 42; mean age 54.5) hypogonadal men (mean T = 245 ± 52 ng/dL) were enrolled in an observational, parallel-arm, open-label, 54-week study of hypocaloric diet plus physical activity (DPE; n = 12) or DPE plus T injections (DPE ? T; n = 12), followed by 24 weeks of DPE alone. Primary endpoints were variations from baseline of cardiovascular (cardiac performance, blood pressure, endothelial function, carotid intima-media thickness, CIMT; epicardial fat thickness, EF) and body composition (fat/ lean mass) parameters. Secondary endpoints were variations from baseline of hormonal (T and GH) and metabolic (oral glucose tolerance test, lipids, fibrinogen) parameters. Results At 54 weeks, DPE ? T showed improvements in EF, ejection fraction, diastolic function, CIMT and endothelial function (p \ 0.01 vs. controls). Also, hormonal (T, p \ 0.0001; GH, p \ 0.01), metabolic (HOMA, p \ 0.01; microalbuminuria, p \ 0.01), lipid (total cholesterol, p \ 0.05) and inflammatory (fibrinogen, p \ 0.05) parameters improved. After 24 weeks from T withdrawal, all cardiac and hormonal parameters returned to baseline, while fat but not lean mass and blood pressure ameliorations were maintained. An inverse relationship either

D. Francomano  R. Bruzziches  G. Barbaro  A. Lenzi  A. Aversa (&) Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University, Rome, Italy e-mail: [email protected]

between EF vs. endothelial function and EF vs. T levels was found (r2 = -0.46, p \ 0.001 and r2 = -0.56, p \ 0.0005, respectively) while direct relationship between T vs. endothelial function occurred (r2 = 0.43, p \ 0.005) in DPE ? T. A 33 % dropout rate was reported in DPE without serious adverse events. Conclusions In middle-aged hypogonadal obese men, 1-year T treatment was safe and improved cardio-metabolic and hormonal parameters. We firstly demonstrated that T withdrawal determines a return back to hypogonadism within 6 months, with loss of cardiovascular and some body composition improvements attained. Keywords Male hypogonadism  Testosterone replacement therapy  Endothelial function  Carotid artery intima-media thickness  Epicardial adipose tissue  Left ventricular mass and function

Introduction Obesity is reaching epidemic proportions worldwide and in the United States, 63 % of men and 55 % of women are classified as overweight. Of these, 22 % are deemed severely overweight, with a body mass index above 30 kg/m2, and the consequences of this rapid increase are serious [1]. Approximately 80 % of obese adults suffer from at least one, and 40 % from two or more of the diseases associated with obesity, such as diabetes mellitus type 2, hypertension, cardiovascular disease (CVD), gallbladder disease, cancers, and diseases of the locomotor system, such as arthrosis [2]. Obesity contributes to pathologies, such as the metabolic syndrome (MS), CVD, diabetes, hypertension, endothelial dysfunction (EDys) and testosterone (T) deficiency [3].

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Numerous studies have found a direct association between male obesity with lower plasma T levels [4] and other studies have shown that low T levels are predictive for the development of visceral obesity [5] with an increase of fat mass and a decrease in lean body mass compared to eugonadal men [6]. There is also an independent association between plasma T concentration and insulin sensitivity [7, 8], and obese men with diabetes appear to be at high risk of developing secondary hypogonadism [9]. Therefore, it can be assumed that often hypogonadism, visceral adiposity, insulin resistance and MS may coexist in the same subjects. This cluster of abnormalities is associated with an increased risk of diabetes and CVD, affecting not only quality of life but also life expectancy. In addition, low levels of androgens have been associated with CVD progression, especially coronary artery disease (CAD) and increased mortality [10, 11]. Hence, the pathogenetic mechanisms linking hypogonadism with obesity, insulin resistance, diabetes and cardio-metabolic features appear to be complex and often multidirectional [12]. Visceral obesity can probably be considered a relevant cause of hypogonadism, but at the same time hypogonadism could be a cause of obesity and insulin resistance, consequently establishing a vicious cycle [13]. The aim of the present study was to evaluate the effects of T replacement therapy (TRT) on cardiovascular and metabolic parameters in hypogonadal obese men and whether T-withdrawal results in maintenance of improvements obtained when compared with lifestyle changes only.

Materials and methods Study population In this observational, open-label, parallel-arm study, we investigated the effects of diet and physical exercise (DPE) alone or in combination with intramuscular T undecanoate (NebidÒ) for 54-week duration on cardiac function and metabolic parameters in hypogonadal men with severe obesity (mean BMI 42). Afterwards, a 24-week extension period of T withdrawal was observed. Twenty-four male patients (mean 54 ± 8 years) who met the study inclusion/ exclusion criteria entered the study. Each subject received DPE alone (n = 12) or DPE plus T (1,000 mg/12 weeks from week 6; n = 12), depending on their willing to receive or not TRT or depending from the presence of absolute contraindications to TRT administration. During the outpatient clinic admission, each patient was assigned to a personalized nutritional program (hypocaloric diet), with the recommendation to develop at least 150 min/week of aerobic exercise of moderate intensity (50–70 % of

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maximum heart rate) and/or at least 90 min/week of vigorous exercise ([70 % of maximum heart rate). Physical activity should have been distributed in at least 3 days/ week, with no more than two consecutive days without activity [14]. Each patient prescription was made by a psychologist along with a nutritionist in our multidisciplinary Unit of evaluation of the obese patients. At baseline and every 3 months the following were assessed: general physical examination and anthropometric parameters, i.e. weight, height, BMI, waist circumference, systolic and diastolic blood pressure, heart rate, blood samples and, thereafter, digital rectal examination (DRE). At baseline and every 6 months, DEXA for the evaluation of body composition was performed. At baseline and after 54 weeks, DEXA for BMD, echocardiography, endothelial function by Endopat2000 and Carotid Intima-Media Thickness (CIMT) by Duplex Ultrasonography were investigated. At 78 weeks, after 24 weeks of withdrawal T treatment, each patient repeated all measurements. Inclusion/exclusion criteria Patients were included in the study if they were aging between 40 and 65 years, had severe obesity and total T (TT) serum level below 3.45 ng/mL (12 nmol/L) or calculated free T (FT) levels\250 pmol/L (72 pg/mL) on two early morning separate days (between 8:00 and 11:00 a.m.) at least 1 week apart, and at least two symptoms of hypogonadism as stated by International Guidelines and clinical questionnaires [15]. The following patients were excluded from the study: use of androgen therapy or anabolic steroids within 12 months of entry into the study; suspicion or known history of prostate or breast cancer; history of drug or alcohol abuse; suspicion or known history of tumors; blood coagulation irregularities; diagnosed symptomatic obstructive sleep apnea syndrome (OSAS); polycythemia with an hematocrit level C52 % at entry to the study; ageadjusted elevated prostate-specific antigen (PSA) level or abnormal DRE of prostate suggestive of cancer and severe symptomatic benign prostatic hyperplasia; patients using 5-a-reductase inhibitors; hyperprolactinemia or organic hypothalamicpituitary pathology; uncontrolled thyroid disorders; uncontrolled diabetes (HbA1c C 11 %) and/or in treatment with insulin; severe cardiac (NHYA class III or above), hepatic or renal insufficiency; severe neurological and psychiatric disease; patients requiring or undergoing fertility treatment; any other reason which the investigator feels precludes safe inclusion of the patient. All concomitant oral hypoglycemic, antihypertensive and lipid-lowering medications were permitted and continued throughout the study without dose adjustments. Written informed consent was obtained before commencement of

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the study, according to Protocol and Good Clinical Practice (GCP) on the conducting and monitoring of clinical studies, and approved by our Internal Review Board. Main outcomes measures The primary outcomes were variations from baseline of cardiac systolic/diastolic performance and epicardial fat (EF) by echocardiography [16], blood pressure, the CIMT, [17] and endothelial dysfunction by Endopat2000 [18], as previously published. CV risk score was evaluated using the risk engine derived from the ‘‘Progetto Cuore study’’ (see also http://www.cuore.iss.it) [19]. Secondary outcomes were variations from baseline of hormonal (total and free T, GH), lipid (total and HDL cholesterol, triglycerides) and inflammatory plasma levels (fibrinogen and high-sensitivity c-reactive protein, hsCRP), of the homeostasis model assessment index of insulin resistance (HOMA-IR), anthropometric measurements (body mass index—BMI, weight, waist circumference) and body composition by dual-energy X-ray absorptiometry (overall lean and fat mass, subtotal and trunk fat). Biochemical and instrumental evaluations Hormonal assessment included TT measured by electrochemiluminescence (method Immulite 2000 Siemens, Milan, Italy; within and between-assay coefficients of variation were 5.1 and 7.2 %), luteinizing hormone (LH), plasma T and calculated FT, sex hormone-binding globulin (SHBG), Estradiol (E2). The following metabolic and safety parameters included plasma total cholesterol, highdensity lipoprotein (HDL) and triglycerides, prostate-specific antigen (PSA), blood glucose, insulin, glycosylated hemoglobin (HbA1c), hemoglobin and hematocrit, liver and kidney functions serum bilirubin, gamma glutamyl transferase (c-GT), serum glutamate oxalacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT), albumin and creatinine according to previously published procedures [17]. To assess insulin sensitivity, we calculated the HOMA-IR. HOMA-IR was calculated using the formula [fasting insulin in mU/L 9 fasting glucose in mmol/L]/22.5. Lean, total fat and total body mass were calculated using a whole-body dual-energy X-ray absorptiometry (DEXAHOLOGIC QDR-1000) according to the instructions of the manufacturer and to the previous standardized procedures [20]. Trans-rectal ultrasound (TRUS) of the prostate using a 7-Mhz multiplanar rectal probe (PHILIPS HDI 5000, Germany) and the assessments of carotid atheroma by a 7.5–13 MHz broadband linear array transducer with the standard software according to our standardized procedure

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(Sonocalc IMT) were implemented by the same operator according to standardized procedures [17]. EDys was investigated by peripheral arterial tonometry (PAT; EndoPAT2000, Itamar Medical, Caesarea, Israel) according to previously published procedure [18]. Instead of the natural logarithm of PAT ratio, we evaluated the average amplitude of PAT signal in the post-occlusion period (test signal, T) compared to that in the baseline (B) signal before occlusion, utilizing the same time intervals as for RHI calculation, but not indexed to contralateral arm (referred to as T/B ratio), which was also manually obtained [21]. Each subject had a transthoracic 2D-guided M-mode echocardiogram using commercially available equipment (Hewlett-Packard Sonor 500) performed by the same trained operator (GB). Standard parasternal and apical views were obtained in the left lateral decubitus position. All echocardiograms were recorded and analyzed offline for EF quantification, according to the method previously described and validated by Iacobellis and Willens [22]. EF was identified as the echo-free space between the outer wall of the myocardium and the visceral layer of pericardium. EF thickness was measured perpendicularly on the free wall of the right ventricle at end-systole in three cardiac cycles. Maximum EF thickness was measured at the point on the free wall of the right ventricle along the midline of the ultrasound beam, perpendicular to the aortic annulus, used as an anatomic landmark for this view. The average value of three cardiac cycles from each echocardiographic view was considered. Left ventricular (LV) mass and adjusted LV mass by height 2.7 were calculated as previously described [23]. Safety Patients with the following clinical laboratory parameters were withdrawn during the course of study: if hematocrit level C52 %, PSA level increased [1.0 ng/mL above the baseline PSA; if baseline PSA was \2.0 ng/mL, PSA level increased [50 % of the baseline PSA; if baseline PSA was [2.0 ng/mL. Statistical analyses Data was analyzed using t tests (for single between-group comparisons), analysis of covariance (for between-group comparisons at specific time points, using baseline scores as a covariate), and a mixed linear regression model on repeated measures data (for between-group comparisons across all time points) to analyze data for an Intent-to-Treat Group [including all subjects enrolled and treated in this trial with values imputed for their Last Observation Carried Forward (LOCF) for any subjects who did not complete the trial] and a Completer’s Group (including only data from

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subjects who completed the trial per protocol). Data were expressed as mean ± standard deviation only when normally distributed, and as median (quartiles) when nonparametric. With a two-sided alpha value of 5 % and power of 90 %, a sample size of 7 subjects per arm would be able to detect a difference of 7 % reduction in the subtotal fat mass between groups from baseline. Also, we tested for the differences between treatment groups, using analysis of variance for repeated measures. Multiple regression analysis was carried out for EF versus T/B in TU group of patients. A p value of 0.05 ± SD was considered statistically significant. Statistical analysis was carried out using the computer statistical package SPSS/4.0 (SPSS, Chicago, IL, USA) and SAS/6.4 (SAS Institute, Cary, NC, USA).

J Endocrinol Invest (2014) 37:401–411 Table 1 Demographic characteristics of the study population Demographic characteristics

DPE

DPE ? T

Patients (n)

12

12

Mean age ± SD (years)

53 ± 8

56 ± 9

Caucasian (%)

100 %

100 %

Weight ± SD (kg)

129 ± 16

123 ± 23

BMI ± SD (kg/m2)

42.6 ± 5.2

40.3 ± 6.5

Waist circumference (cm)

134 ± 12

132 ± 13

Only MS: n (%)

9 (75 %)

8 (66 %)

Only T2DM: n (%)

0 (0 %)

0 (0 %)

T2DM ? MS: n (%)

3 (25 %)

4 (33 %)

Erectile dysfunction: n (%)

4 (33 %)

5 (40 %)

No sexual intercourse PDE5-I use

2 (15 %) 2 (15 %)

3 (25 %) 2 (15 %)

0 (0 %)

0 (0 %)

Therapy*

Results Baseline characteristics of the study population are shown in Table 1. No statistically significant difference was detected between the two groups and all men suffered of late-onset hypogonadism. In DPE ? T, a significant improvement in total and free T was found after 54 weeks (p \ 0.0001) that was not maintained after 24-week withdrawal (Table 2). No variations on T levels were obtained in DPE group throughout the study observation period. Interestingly, only DPE ? T group showed a significant improvement of GH (p \ 0.01), that was not maintained at 78-week follow-up. No significant improvement in either serum T levels or in other hormonal parameters was found after DPE. BMI, waist circumference and subtotal fat mass improved only after 54 weeks in DPE group (p \ 0.01), and the effect was lost at 78 weeks; a strong and persistent improvement on anthropometric and body composition variations were obtained after DPE ? T treatment (Table 2). Also, improvements of lean mass (p \ 0.0001) and fat mass (p \ 0.01) were obtained only for DPE ? T group after 54 weeks, but were lost at withdrawal for lean mass only (Table 2). Systolic and diastolic blood pressure showed a significant reduction for both treatment groups that was maintained also after withdrawal (p \ 0.01, Table 3). Glycemia, basal and peak insulin serum levels after 60 min OGTT, total and LDL cholesterol improved only after DPE ? T treatment group, and maintained the significance after withdrawal (p \ 0.01, Table 3). Insulin sensitivity (HOMA-i) improved after both treatments, but with a stronger significance in DPE ? T group (p \ 0.05 and p \ 0.01, respectively, Table 3). Microalbuminuria levels improved after both treatments (p \ 0.01, Table 3). No variation during the treatment on PSA and hematocrit serum levels was found (Table 3).

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None Oral hypoglycemic

6 (50 %)

4 (33 %)

Antihypertensive

6 (50 %)

6 (50 %)

Statins

2 (15 %)

3 (25 %)

Fibrates

1 (8 %)

0 (0 %)

Others

2 (15 %)

2 (15 %)

MS metabolic syndrome, T2DM type 2 diabetes mellitus, DPE diet and physical activity, DPE ? T: diet and physical activity plus testosterone * Stable for comorbidities for at least 6 months

After 54 weeks, only DPE ? T group showed a significant improvement on cardiovascular parameters and performance as demonstrated by a reduction of EF (p \ 0.01), and the improvement of circumferential myocardial shortening (p \ 0.01), ejection fraction (p \ 0.01) and E/A ratio (p \ 0.01). Each improvement was lost after the 24-week follow-up period (Fig. 1a–d, respectively). The different percentages of the trunk and EF lost after 54 weeks for both groups is shown in Fig. 2a, b. A significant improvement of CIMT was obtained only for DPE ? T group after 54 weeks (p \ 0.01), but a return to baseline levels has been showed after withdrawal (Fig. 2c). Accordingly, a significant improvement of endothelial function as expressed by T/B ratio was reached only for DPE ? T group (p \ 0.01) after 54 weeks, but was lost after withdrawal (Fig. 2d). Interestingly, we observed for the first time either an inverse relationship between EF vs. endothelial function (r2 = -0.46; p \ 0.001, Fig. 3a) or T levels (r2 = -0.56, p \ 0.0005, Fig. 3b). Also, a direct relationship between T and endothelial function was found (r2 = 0.43, p \ 0.005, Fig. 3c) in DPE ? T only. Therefore, only after DPE ? T treatment, patients showed a significant reduction of the overall cardiovascular risk (p \ 0.01, Fig. 3d).

n.s.

\0.05 1,578 ± 3,936

70,144 ± 6,377

\0.01

\0.0001 72,758 ± 4,872 69,185 ± 5,504

20,879 ± 6,356 n.s.

n.s. 74,481 ± 5,394

21,807 ± 11,412 n.s. 21,085 ± 9,759

74,506 ± 4,352

24,544 ± 11,101

75,917 ± 4,925

Trunk-fat mass (g)

Total lean mass (g)

n.s.

15,632 ± 3,523

28.2 ± 3.7 \0.0001 33.4 ± 3.6 30.5 ± 11.1 30.7 ± 7.0 32.7 ± 7.1 Sub total fat (%)

\0.05

n.s.

\0.001

\0.0005

36.01 ± 5.8 \0.0001

27.7 ± 3.5

122.4 ± 11.8 \0.0001

35.75 ± 5.3

120.11 ± 11.3 132.9 ± 13.8

40.32 ± 6.5 \0.05

n.s. 129.5 ± 11.1 \0.05

40.46 ± 5.7 40.83 ± 5.2 43.17 ± 5.5

127.9 ± 11.5 133.4 ± 11.7 Waist circumference (cm)

BMI (kg/m2)

\0.05

\0.001

n.s

163 ± 35 121.0 ± 18 n.s \0.0001 157 ± 30 107.5 ± 18

n.s n.s.

0.66 ± 0.5 \0.01 0.34 ± 0.35

156 ± 13 122.8 ± 23 n.s n.s.

n.s 0.06 ± 0.05 n.s

171 ± 41 122.5 ± 17 187 ± 63 120.8 ± 15 180 ± 43 128.8 ± 16 IGF-1 (ng/mL) Weight (kg)

0.07 ± 0.04 0.17 ± 0.07 GH (ng/mL)

n.s. \0.05

1.07 ± 0.09

n.s.

n.s.

30 ± 6 n.s. 27 ± 4

0.55 ± 0.4 2 ± 0.7

31 ± 13 n.s.

n.s. 3.5 ± 1.7

33 ± 13 n.s.

n.s. 2.85 ± 1.5

35 ± 17 35 ± 16

1.65 ± 0.4

17-b estradiol (pg/mL)

\0.01

1.07 ± 0.8

405

LH (mIU/mL)

n.s. 34 ± 23 SHBG (nmol/L)

37 ± 24

n.s.

34 ± 14

n.s.

31 ± 13

30 ± 9

n.s.

35 ± 12

n.s.

n.s.

312 ± 52

5.82 ± 2.0

\0.0001

\0.0001 11.47 ± 2.9

490 ± 52 245 ± 52

4.63 ± 0.9 n.s.

n.s. 309 ± 124

5.8 ± 1.2 n.s.

n.s. 301 ± 123

5.36 ± 2.1

237 ± 53

4.53 ± 1.4

Total testosterone (ng/mL)

?54 weeks p ?78 weeks p ?54 weeks

Table 2 Variation of anthropometrics, hormonal parameters, body and bone composition

Free testosterone (ng/mL)

Baseline Baseline

p

Diet and physical exercise ? testosterone (n = 12) Diet and physical exercise (n = 12)

?78 weeks

p

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Four patients in the DPE group did not complete the study with an overall dropout rate of 33 % and were not included in the statistical analysis because of poor compliance to the study protocol, as suggested by our multidisciplinary team of evaluation. All men in DPE ? T group were completers. No serious emergent adverse events were recorded for both treatments during the study.

Discussion In this study, we have demonstrated that TU treatment is more effective than DPE alone, in achieving improvements in cardio-metabolic and hormonal changes in severely obese hypogonadal men. To our knowledge, this is the first controlled study that demonstrates that TU treatment improves obesity-induced diastolic function, cardiac parameters as well as surrogate markers of EDys, i.e. CIMT and Endopat2000; this prompted us to conclude that TU treatment should be maintained throughout the period, in those men with increased cardiovascular risk (CVR), such as severely obese hypogonadal male subjects. In a previous study, similar results on surrogate markers of endothelial function and cardiovascular risk were obtained without DPE program, after 2 years of treatment with TU when compared with placebo [17]. The new finding of the present study is that in severely obese hypogonadal men, T withdrawal led to maintenance of metabolic, fat but not lean mass, and blood pressure parameters, whereas hormonal (testosterone) and cardiovascular parameters returned to baseline. It is well known that in hypogonadal state a reduction of lean mass and an increase in visceral fat mass occur. Visceral obesity in turn, may determine by itself, decreased insulin sensitivity and a reduction of T levels [24]. Thus, central obesity as measured by waist circumference may represent an important determinant for the occurrence of hypogonadal–metabolic syndrome [25]. Obesity leads to increased central and total blood volumes along with decreased systemic arterial resistance, resulting in high cardiac output state-related adaptations in the cardiac structure. Persistence of these hemodynamic changes ultimately results in diastolic dysfunction; however, whether these changes progress to significant systolic dysfunction or not is controversial. Also, obesity may be in turn associated with structural myocardial changes that are independent of its effects on risk factors, i.e. OSAS or CAD. Extensive review of the available literature regarding assessment of systolic function in the obese suggests that isolated obesity does not appear to be associated with significant LV systolic dysfunction or dilated cardiomyopathy [26]. Subclinical changes of LV structure and function including abnormal relaxation and strain have

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123 399 ± 50 3,425 ± 2,327

202 ± 24 41 ± 9 151 ± 58 110 ± 35 6.3 ± 0.7 10.9 ± 1.5 435 ± 39 3,701 ± 1,304

Total cholesterol (mg/dL)

HDL cholesterol (mg/dL) Triglycerides (mg/dL)

LDL cholesterol (mg/dL)

HBA1C (%)

Homocysteine (lmol/L)

Fibrinogen (mg/dL) 21 ± 14 0.4 ± 0.22 43 ± 4.1

Microalbuminuria (mg/g/24/h)

Total PSA (ng/mL)

Hematocrit (%)

43.1 ± 3.8

0.56 ± 0.4

13 ± 9

10.3 ± 2.7

5.9 ± 0.5

119 ± 29

45 ± 8 155 ± 52

200 ± 34

6.4 ± 4.2

9.5 ± 5.5

HOMA-i

138 ± 65

22 ± 14

115 ± 18

170 ± 79

30 ± 14

84 ± 7

133 ± 17

Insulin 60 min. (lU/mL)

123 ± 40

Glycemia (mg/dL)

87 ± 3

Insulin (lU/mL)

148 ± 13

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Hs-PCR (lg/L)

?78 weeks

p

n.s.

44.2 ± 3.2

0.45 ± 0.35

15 ± 12

n.s.

3,266 ± 2,806

n.s. \0.01

10 ± 2.5 404 ± 51

n.s.

6.1 ± 0.6

121 ± 35

40 ± 6 143 ± 63

\0.05

n.s.

n.s.

n.s. n.s.

202 ± 38

6.5 ± 4.5

\0.05 n.s.

133 ± 83

22 ± 15

n.s

n.s.

118 ± 15

82 ± 7

n.s.

130 ± 13

\0.01 \0.01

\0.01

n.s.

n.s.

n.s.

n.s.

\0.05

n.s.

n.s.

n.s.

n.s. n.s.

n.s.

n.s.

n.s

n.s.

n.s.

\0.01

43.6 ± 3.3

0.85 ± 0.6

23 ± 11

3,187 ± 895

397 ± 43

11 ± 1.7

6.1 ± 0.8

140 ± 17

41 ± 7 144 ± 27

208 ± 21

8.4 ± 5.7

116.9 ± 57

29 ± 16

120 ± 34

85 ± 7

135 ± 14

47.4 ± 3.6

1.07 ± 0.9

12 ± 8

2,750 ± 1,040

374 ± 39

11 ± 1.4

5.7 ± 0.6

106 ± 24

46 ± 6 143 ± 23

180 ± 20

3.3 ± 1.7

68 ± 35

13 ± 6

102 ± 14

81 ± 8

130 ± 10

?54 weeks

1.01 ± 0.8 45.7 ± 2.9

n.s. \0.01

10 ± 4

3,250 ± 1,372

\0.05 \0.01

361 ± 77

11.7 ± 1.3 \0.05

n.s.

5.8 ± 0.7

108 ± 34

\0.05 n.s.

44 ± 9 151 ± 58

n.s. n.s.

185 ± 18

78 ± 48

\0.01 \0.05

14 ± 15 3.7 ± 1.3

103 ± 11

\001 \0.01 \0.01

79 ± 7

128 ± 12

?78 weeks

\0.01

\0.01

p

Baseline

p

Baseline

?54 weeks

Diet and physical exercise ? testosterone (n = 12)

Diet and physical exercise (n = 12)

Table 3 Variations of blood pressure levels, metabolic and safety parameters

n.s.

n.s.

\0.01

n.s.

\0.05

n.s.

n.s.

\0.05

n.s. n.s.

\0.05

\0.01

n.s.

\0.05

\001

\0.01

\0.01

p

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407

Fig. 1 Variations from baseline of a epicardial fat, b circumferential myocardial shortening, c ejection fraction, d E/A ratio, evaluated by echocardiography. (DPE ? T diet and physical activity plus testosterone. *p \ 0.01 vs. control group and baseline)

been reported in overweight subjects, even after adjustment for mean arterial pressure, age, gender, and LV mass [27, 28]. In this context, it is extremely important to understand the mechanisms by which obesity may cause LV dysfunction with a preserved ejection fraction. Epidemiologic studies have shown that EF, a metabolically active fat depot, is strongly associated with obesity, MS, diabetes and CAD [29, 30]. The relationship of EF thickness to diastolic function is unknown. The proximity of EF to the coronary arteries has been used to explain the association of EF with increased coronary artery calcium, atherosclerotic plaque and myocardial ischemia [31, 32]. Although these factors may be responsible for diastolic dysfunction, EF may also have a direct paracrine effect on the myocardium and thus alter the structural properties of the LV. Recent studies have found that EF is an independent predictor of impaired diastolic function in apparently healthy overweight patients even after accounting for associated comorbidities such as MS, hypertension, and subclinical CAD [33]. In a study conducted in a group of patients with hypogonadotropic

hypogonadism (Klinefelter’s syndrome), it has been demonstrated a clear reduction in cardiac performance resulting from an alteration of subclinical LV diastolic function. The authors attributed this condition to chronic androgen deficiency and to the resulting impaired metabolic state of these patients who often do not receive adequate replacement therapy [34]. A recent study has confirmed the presence of this subclinical dysfunction in the cardiovascular system of these patients, which is not improved as a result of TRT [35]. Considerable evidence exists with regard to the role of TRT in increasing and maintaining muscle mass and reducing fat mass; and therefore, on its indirect regulatory capacity on body composition and cardio-metabolic risk factors [36]. This suggests that hypogonadism may be an important contributor in developing visceral obesity and that TRT may turn out to be beneficial in managing obesity, also in combination with exercise and diet [37– 39]. In the present study, we provide for the first time, consistent evidence that TRT improves both cardiac performance and EF thickness, and that T withdrawal is not

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(a)

DPE+T

DPE

(b)

-2 -4 -6 -8 -10

(c)

DPE+T

DPE

0

% Trunk Fat Lost

% EP Fat Lost

0

-5 -10 -15 -20 -25 -30

(d)

Fig. 2 Different reductions in the percentage of fat loss at a epicardial fat and b trunk-fat levels are shown. Variations from baseline of c carotid intima-media thickness and d endothelial function are

shown. (DPE ? T diet and physical activity plus testosterone. * p \ 0.01 vs. control group and baseline)

able to maintain such outcomes. The effects of TRT on cardiac function appear to be directly mediated by androgen receptor activation, as demonstrated by different percentages of total vs. epicardial body fat percentage decrease obtained. Accordingly, some studies conducted in patients with chronic heart failure undergoing TRT showed a significant improvement of cardiac symptoms and exercise tolerance [40, 41]. The mechanisms underlying these observations remain unknown, although it has been suggested that T may result in an increase in cardiac index and a decrease in peripheral vascular resistance [42]. Despite TRT in older frail men has been sometimes reported to be an hazard [43], several small studies have demonstrated that TRT may improve intermediate outcomes, myocardial ischemia and exercise capacity in patients at risk and in those with proven CVD [44, 45]. Furthermore, previous studies have also reported a 39 % reduction in mortality among patients receiving TRT [46], and in a recent metanalysis, patients with moderate to severe heart failure have been shown to benefit from TRT on exercise capacity and metabolic indices [47]. In the present study, we have observed that significant improvement of endothelial function was obtained in the T group,

which was lost after withdrawal. Also, we demonstrate for the first time either an inverse relationship between EF vs. endothelial function or EF vs. T levels, and a direct relationship between T and endothelial function. This clearly suggests that T level improvements may be correlated to a significant reduction of CVR markers such as CIMT and EF in severely obese hypogonadal men, as well as to amelioration in overall CVR as evaluated by specific cardiac risk engines. In agreement with excellent safety outcomes reported by our patients, we recommend to consider TRT as an adjunctive therapy for the treatment of those men affected by severe obesity-associated hypogonadism, in whom the correction of lifestyle factors alone, i.e. diet and physical exercise, may not be such effective in decreasing cardiovascular risk factors and the progression of atherosclerosis [16]. We are aware that the study has several limitations. Despite our correct preliminary evaluation of sample size, the study enrolled a limited number of cases that were nevertheless sufficient for appropriate statistic elaboration. We want to reinforce the concept that no randomization to treatment occurred, since subjects were allocated to each treatment arm simply on the basis of their willing or not to

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Fig. 3 Multivariate analysis shows a an inverse relationship between epicardial fat and endothelial function (r2 = -0.46; p \ 0.001); b an inverse relationship between epicardial fat and Total T (r2 = -0.56; p \ 0.0005); c a direct relationship between endothelial function and

Total T (r2 = 0.43; p \ 0.005); d the variation of cardiovascular (CV) risk (%) as evaluated by Progetto Cuore (p \ 0.01 vs. control group and baseline)

receive and/or to the presence of absolute contraindications to TRT; as expected, the control group were slightly more obese than the treatment group. Another study limitation is represented by the impossibility to ascertain patients’ adherence to hypocaloric diet and physical activity throughout the study period. We prescribed lifestyle changes by our psychologists’ and nutritionists’ single intervention, and checked results obtained by interviewing each patient at different time points of the study. In conclusion, we demonstrated for the first time that TRT is beneficial on cardiac function in severely obese patients and that withdrawal is not a good prevention strategy for reducing CV risk. If male hypogonadism remains clinically unrecognized, this can subsequently lead to significant morbidity and mortality. Therefore, it is important that this condition is managed appropriately with TRT and weight reduction. In the current literature, there are no reported studies comparing TRT versus weight reduction and subsequent T withdrawal in hypogonadal obese men. Weight reduction in patients with secondary hypogonadism is recommended, as is the case of obese patients. However, encouragement of weight reduction

alone (without TRT) cannot be endorsed and recommended as an effective treatment for male hypogonadism and its associated sequelae, unless clear evidence is produced to demonstrate this. Acknowledgments The authors wish to thank Dr. Andrea D’Amselmo for revising English language. Conflict of interest Dr. Aversa and Dr. Davide Francomano received speakers’ honoraria from Bayer Healthcare. The other authors have nothing to declare.

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Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study.

Modifications of cardiovascular and metabolic parameters during testosterone (T) replacement and withdrawal have never been investigated in severely o...
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