Long-term Effects: Testosterone

Effects of Intermission and Resumption of Long-term Testosterone Replacement Therapy on Body Weight and Metabolic Parameters in Hypogonadal in Middle-aged and Elderly Men

Aksam Yassin; Yousef Almehmadi; Farid Saad; Gheorghe Doros; Louis Gooren

Clin Endocrinol. 2016;84(1):107-114.

Abstract and Introduction

Abstract

Objective: In addition to primary and secondary (‘classical’) hypogonadism, hypogonadism occurring in middle-aged and elderly men has been recognized. There is evidence that restoring T levels to normal improves body weight, serum lipids and glucose levels.

Design: Observational registry study.

Patients: Two hundred and sixty-two hypogonadal, middle-aged and elderly, men received testosterone replacement treatment (TRT). After having been on TRT for a mean duration of 65·5 months, TRT was temporarily intermitted in 147 patients for a mean of 16·9 months (Group I) due to cost reimbursement issues and in seven men due to prostate cancer. All these men resumed TRT for a mean period of 14·5 months. Of the cohort, 115 men were treated continuously (designated as Group C). To compare on-treatment to off-treatment periods, three periods of equal duration were defined: pre-intermission (on TRT), during intermission (off TRT) and post-intermission (on TRT after resumption of TRT). For proper comparison, the same periods were analyzed for those patients who continued TRT throughout (Group C).

Measurements: Variables of body weight, glucose metabolism, lipids, blood pressure and C-reactive protein (CRP).

Results: in Group C there was a continuous improvement of body weight, serum lipids, glucose, HbA1c, blood pressure and CRP. In Group I there was a similar initial improvement which was reversed upon intermission of T administration but which appeared again when T treatment was reinstated.

Conclusions: Our observation indicates that T administration improves body weight and metabolic factors in men with hypogonadism but withdrawal of T reverses these beneficial effects to appear again when TRT is resumed.

Back to Top

Introduction

In addition to primary and secondary hypogonadism, hypogonadism based on the decline of serum testosterone (T) levels in some ageing men has received extensive attention over the last decades.[1] The term late-onset hypogonadism (LOH), distinguishing it from primary and secondary hypogonadism, has been proposed to describe this form of hypogonadism.[1] While it was initially thought that chronological age per se was an important determinant of LOH, this did not hold up in later research.[1] A far more important determinant of the decline of T in ageing men is obesity, but also impaired general health.[2] The role of obesity is supported in a study from Russia on serum T levels in obese men <40 years. Their hormonal profiles were not different from obese men labelled as men with LOH.[3] The role of obesity is supported by the reversibility of low T levels by weight loss.[1,2] Over time, there have been increasingly indications that the decline of serum T with ageing to subnormal levels has important consequences for the health of elderly men.[4]

In view of the findings that ageing in itself is not a key factor in the decline of T levels in some ageing men, the term LOH may be abandoned.[5] Below-normal levels of serum T appeared to be associated with significantly higher risks of all-cause and cardiovascular mortality.[6] In further analysis, the level of serum T and the presence of sexual symptoms were significant and independent factors.[7] In a recent review, advanced age, obesity, a diagnosis of metabolic syndrome and a poor general health status were the predictors of LOH and its co-morbidities.[8] Diabetes mellitus was correlated with hypogonadism in most studies, but could not be proven to be a risk factor.[2] In statistical analysis, diseases such as coronary heart disease, hypertension, stroke and peripheral arterial disease were not predictive of hypogonadism, but they could be shown to correlate with incident low T. There is now substantial evidence that low levels of T are associated with significant long-term negative health consequences. [8] In the ongoing European Male Ageing Study (EMAS), it was found that more than 50% of subjects with LOH had one or more common morbidities. Most prevalent were hypertension (29%), obesity (24%) and heart diseases (16%). [9] In a follow-up of the same study, obesity, weight gain and increased waist circumference were identified as the predictors of incident hypogonadism. [10] Remarkably, in the EMAS sexual symptoms are powerful indicators of LOH. This was demonstrated in one study that established an inverse relationship between an increasing number of sexual symptoms and a decreasing testosterone level. The authors attributed great value to these sexual symptoms and concluded that LOH can be defined by the presence of at least three sexual symptoms when also total testosterone levels are <11 nmol/l (3·2 ng/ml) and free testosterone levels are <220 pmol/l (64 pg/ml). [11]

Upon normalization of serum T levels following administration of T, a number of beneficial effects particularly on weight, fat distribution and metabolic factors have been observed. [12,13] While treatment of obesity is commonly a frustrating experience for patient and doctor, several studies indicate now that normalizing serum T levels may produce substantial and sustained effects on weight reduction, associated with a number of benefits on lipids and glycaemic control. [14–17]

This study reports the effects of long-term testosterone replacement treatment (TRT) in a cohort of elderly men. In a subgroup of these men, there was an intermission of T treatment because costs of the T preparation were no longer reimbursed and in a small group because of an incidental prostate carcinoma. In all of these men, T treatment could be reinstated. So, we present a comparison of data for a group of men who were continuously treated with T treatment and a group who had a temporary intermission of T treatment but eventually resumed treatment.

Back to Top

Patients and Methods

In an ongoing registry study in a urology clinic, 262 hypogonadal men received testosterone for a maximum of 11 years representing 2088·5 patient-years. There was a small number of men with Klinefelter’s syndrome (n = 5), unilateral orchiectomy (n = 4), bilateral testicular atrophy (n = 2) and anorchia (n = 1). They were younger (mean 49·23 ± 6·72 years) than most of the other patients (mean age 62·28 ± 7·34 years). All subjects had sought urological consultation for erectile dysfunction. A threshold of 12·0 nmol/l and the presence of symptoms as assessed by the Aging Males’ Symptoms (AMS) scale were used for the definition of hypogonadism. [18] All men received treatment with parenteral T undecanoate 1000 mg (Nebido®; Bayer Pharma, Berlin, Germany), administered at baseline and 6 weeks and thereafter every 12 weeks for a maximum of 11 years.

After having been on TRT for a mean duration of 65·5 ± 14·1 months, TRT was temporarily intermitted for a mean of 16·9 ± 3.3 months in 147 patients (designated as Group I) (period I). In 140 men, this was due to cost reimbursement issues for T treatment, and in an additional seven men, prostate cancer had been diagnosed, but they could safely resume T treatment after appropriate curative treatment. All men resumed TRT thereafter for up to 18 months (mean period: 14·5 ± 5·8 months). Data were collected for up to 18 months after resumption of T treatment (period P).

Of the cohort, 115 men were treated continuously (designated as Group C). To be able to compare on-treatment to off-treatment periods, three periods of equal duration were defined: pre-intermission (on TRT), during intermission (off TRT) and post-intermission (on TRT after resumption of TRT). The 18 months prior to intermission were designated as Period A, data for the following 16·9 months were designated as Period I, and data for the following 14·5 months (or up to baseline) were designated as Period P. Following this designation, for each patient, data for Period A, Period I and Period P were averaged, resulting in 3 data points for each patient.

Four patients dropped out of the study, and their data up to their last visits were analyzed in Group C. Hormonal and anthropometric parameters were measured at every other visit.

Exclusion criteria for testosterone administration included previous treatment with androgens, prostate cancer or any suspicion thereof, such as prostate-specific antigen (PSA) levels >4 ng/ml, International Prostate Symptom Score (IPSS) >19 points, breast cancer or severe untreated sleep apnea.

Back to Top

Statistical Analysis

When the study started, it was not clear that a number of men (n = 147), later designated as Group I, would have an intermission of their T treatment while the remaining 115 men would continue treatment uninterruptedly (Group C). To arrive at a valid comparison between Group C and Group I, data for Group C and Group I were separately analyzed in all three phases of the study (before intermission, during intermission and after intermission). Subjects who dropped out of the study or are currently under observation were included in Group C, as the comparator group.

For each subject in Group I, along with their data collected during the discontinuation period (Period I), we included data for the 18 months (or up to their end of follow-up, whichever came first) following their resuming the treatment (Period P) and 18 months (or baseline whichever came first) prior to their discontinuation (Period A). For subjects in Group C, their follow-up was partitioned into three periods by starting in reverse order from their last visit. The first 18 months were designated as Period A, data for the following 16·9 months were designated as Period I, and data for the following 18 months (or up to baseline) were designated as Period P. Following this designation, for each patient, data for Period A, Period I and Period P were averaged, resulting in 3 data points for each patient.

Baseline characteristics and clinical outcomes for patients in Group C and Group I were summarized using means and standard deviations and compared using t-tests. Similarly, outcome data for Period P were compared between the two groups using t-tests. Clinical parameters across Period A, Period I and Period P were compared across Group I and Group C using a mixed-effects repeated-measures model with period, group and their interaction as fixed effects. A random effect was included in the intercept. Time effects were assessed by comparing means in Period I and Period A with data for Period P in both Group I and Group C. Group effects were assessed by comparing Group I and Group C in each Period A, Period I and Period P. For continuous variables, the mean, standard deviation and sample size for the overall sample and various groups were reported at each time point. For categorical variables, the frequency distribution was reported. We tested the hypotheses regarding change in outcome scores across the study period by fitting a linear mixed-effects model to the data. Time (to indicate follow-up interviews) was included as fixed effect in the model. A random effect was included in the model for the intercept. Estimation and test of change in scores were determined by computing the differences in least-square means at baseline vs the score at each follow-up interview.

Ethical guidelines as formulated by the German ‘Ärztekammer’ (the German Medical Association) for observational studies in patients receiving standard treatment were followed. All subjects consented to be included in the research of their treatment protocol which is in accordance with the Declaration of Helsinki (http://www.wma.net). All procedures were carried out with the adequate understanding and written consent of the subjects.

Results

Results are presented in and Figs 1-5. Serum total and free T levels increased significantly in both Group C and Group I (Fig. 1). In Group C, the achieved serum T levels were maintained over the study period, while in Group I, these levels returned to baseline to reach pre-intermission levels after the resumption of T treatment. Sex hormone binding globulin (SHBG) declined modestly in the C Group and then remained stable in the further course of T administration, but in the last part of the observation period, a further modest but significant decrease was noted. In the I Group, SHBG levels declined significantly upon T administration, increased significantly during the intermission period and decreased significantly again during the resumption of T (Fig. 1).

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

Back to Top

Fig 1 A Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 1 B Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 1 C Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Figure 1. Hormones

Back to Top

Fig 2 A Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 2 B Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 2 C Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Figure 2. Anthropometry

Back to Top

Fig 3 A Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 3 B Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Figure 3. Glycemic Control

Back to Top

Fig 4 A Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 4 B Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Figure 4. Blood Pressure

Back to Top

Fig 5 A Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 5 B Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 5 C Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Fig 5 D Effects of Long-term Testosterone Replacement Therapy Cenegenics Phoenix Arizona

Figure 5. Lipids

In the C Group, body weight, BMI and waist circumference declined progressively and significantly over the study period (and Fig. 2). In the I Group, a similar pattern was observed before the intermission. During the intermission, these variables increased significantly and declined significantly again when T treatment was reinstated but the lower values of the pre-intermission period were not attained.

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

Fasting glucose levels declined significantly upon the initiation of T treatment in both groups ( and Fig. 3). In the C Group, these levels remained stable but upon longer-term treatment, there was a further decline. In the I Group, serum glucose increased significantly upon withdrawal of T treatment and returned again to pre-intermission values when T was reinstated. A similar pattern was observed for HbA1c ( and Fig. 3).

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

Serum cholesterol, LDL cholesterol and triglycerides declined progressively in the C Group over the study period and so did the ratio of total cholesterol: HDL as well as non-HDL cholesterol. In the I Group, there was a similar decline before the intermission and levels increased again during the intermission to return again to levels before the intermission when T treatment was resumed. HDL moved into opposite directions (and Fig. 5).

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

The pattern observed for total cholesterol was also encountered with the serum transaminases.

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

Systolic and diastolic blood pressure decreased and stabilized in the C Group. In the I Group, there was a significant increase in systolic blood pressure during the intermission, but not in diastolic blood pressure that remained stable. Pulse pressure decreased in both groups before the intermission period. In the I Group, pulse pressure increased during the intermission and returned to pre-intermission values after the resumption of T treatment (and Fig. 4).

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

Serum C-reactive protein (CRP) showed an initial decline in the C Group. In the I Group, levels declined during T administration, moderately increased during the intermission and declined again when T administration was reinstated ().

Back to Top

Table 1.  Testosterone, free testosterone, SHBG, weight, BMI, waist circumference, glucose, HbA1c, serum lipids, liver transaminases, blood pressure and CRP in men receiving continuous testosterone treatment vs intermitted treatment

Baseline Before intermission End of intermission P before vs end of intermission End of observation after resumption P at the end of intermission vs end of observation after resumption
Continuous Testosterone (nmol/l) 7·84 ± 2·34 19·61 ± 0·28 19·76 ± 0·22 NS 19·65 ± 0·23 NS
Intermitted 7·65 ± 1·83 16·54 ± 0·25 7·50 ± 0·20 <0·0001 18·50 ± 0·20 <0·0001
Continuous Free T (pmol/l) 144·78 ± 63·06 418·98 ± 9·55 429·04 ± 7·62 NS 447·41 ± 7·96 0·0439
Intermitted 161·26 ± 71·12 375·16 ± 8·44 149·35 ± 6·74 <0·0001 466·24 ± 7·04 <0·0001
Continuous SHBG (nmol/l) 40·12 ± 20·73 36·84 ± 1·31 35·57 ± 1·31 NS 32·27 ± 0·91 0·0010
Intermitted 34·34 ± 20·75 29·85 ± 1·15 33·77 ± 1·16 <0·0001 24·80 ± 0·81 <0·0001
Continuous Weight (kg) 97·3 ± 12·88 87·67 ± 1·00 86·15 ± 0·98 <0·0001 84·37 ± 0·85 <0·0001
Intermitted 102·5 ± 14·53 92·12 ± 0·89 97·35 ± 0·86 <0·0001 94·42 ± 0·75 <0·0001
Continuous BMI (kg/m2) 30·81 ± 4·33 27·67 ± 0·32 27·26 ± 0·31 0·0012 26·70 ± 0·28 <0·0001
Intermitted 32·47 ± 4·37 29·20 ± 0·28 30·80 ± 0·28 <0·0001 29·95 ± 0·24 <0·0001
Continuous Waist (cm) 106·47 ± 8·72 98·42 ± 0·85 97·20 ± 0·80 <0·0001 95·75 ± 0·71 <0·0001
Intermitted 108·71 ± 10·93 100·16 ± 0·75 105·42 ± 0·71 <0·0001 102·30 ± 0·63 <0·0001
Continuous Glucose (mg/dl) 111·46 ± 35·67 92·65 ± 2·38 88·34 ± 3·42 NS 80·20 ± 1·30 0·0043
Intermitted 112·99 ± 38·63 104·14 ± 2·10 116·95 ± 3·02 <0·0001 89·23 ± 1·15 <0·0001
Continuous HbA1c (%) 6·38 ± 1·06 5·77 ± 0·07 5·72 ± 0·09 NS 5·58 ± 0·06 0·0012
Intermitted 6·69 ± 1·29 5·94 ± 0·06 6·71 ± 0·08 <0·0001 5·97 ± 0·06 <0·0001
Continuous Cholesterol (mg/dl) 251·15 ± 46·77 197·33 ± 3·25 185·97 ± 3·24 0·0004 173·74 ± 2·16 <0·0001
Intermitted 260·81 ± 54·58 223·71 ± 2·88 284·41 ± 2·87 <0·0001 200·92 ± 1·91 <0·0001
Continuous HDL (mg/dl) 42·41 ± 12·61 54·44 ± 0·98 55·45 ± 0·71 NS 58·42 ± 0·72 0·0002
Intermitted 40·4 ± 11·69 50·71 ± 0·87 38·14 ± 0·63 <0·0001 57·48 ± 0·63 <0·0001
Continuous LDL (mg/dl) 156·9 ± 25·43 119·56 ± 2·3 110·81 ± 1·78 <0·0001 101·66 ± 1·88 <0·0001
Intermitted 157·31 ± 30·7 131·06 ± 2·11 163·04 ± 1·58 <0·0001 116·17 ± 1·66 <0·0001
Continuous Triglycerides (mg/dl) 235·72 ± 89·26 177·01 ± 5·26 159·83 ± 4·81 <0·0001 148·04 ± 3·41 0·0012
Intermitted 265·63 ± 97·57 223·05 ± 4·65 289·00 ± 4·25 <0·0001 191·62 ± 3·01 <0·0001
Continuous Total cholesterol:HDL ratio 6·59 ± 2·82 3·82 ± 0·11 3·64 ± 0·19 NS 3·03 ± 0·05 0·0008
Intermitted 7·07 ± 2·85 4·89 ± 0·09 7·75 ± 0·17 <0·0001 3·60 ± 0·05 <0·0001
Continuous Non-HDL (mg/dl) 208·74 ± 52·35 143·11 ± 3·35 130·52 ± 3·40 0·0001 115·32 ± 2·17 <0·0001
Intermitted 220·4 ± 58·21 173·09 ± 2·97 247·00 ± 3·01 <0·0001 144·24 ± 1·92 <0·0001
Continuous AST (U/l) 28·33 ± 13·02 29·10 ± 0·89 27·09 ± 0·78 0·0081 23·87 ± 0·46 <0·0001
Intermitted 26·55 ± 8·41 30·81 ± 0·79 34·91 ± 0·69 <0·0001 24·43 ± 0·41 <0·0001
Continuous ALT (U/l) 34·62 ± 23·49 36·13 ± 1·41 33·49 ± 1·27 0·0073 28·18 ± 0·90 <0·0001
Intermitted 30·42 ± 18·61 36·46 ± 1·24 39·21 ± 1·12 0·0017 27·38 ± 0·80 <0·0001
Continuous Systolic BP (mmHg) 135·24 ± 12·77 118·86 ± 0·58 117·33 ± 0·80 0·0096 116·29 ± 0·45 NS
Intermitted 139·31 ± 13·19 124·89 ± 0·52 137·13 ± 0·71 <0·0001 120·64 ± 0·40 <0·0001
Continuous Diastolic BP (mmHg) 82·71 ± 7·87 75·17 ± 0·37 73·30 ± 0·36 <0·0001 72·19 ± 0·29 0·0019
Intermitted 81·72 ± 9·74 76·54 ± 0·33 76·88 ± 0·32 NS 74·10 ± 0·26 <0·0001
Continuous Pulse pressure 52·53 ± 12·1 43·94 ± 0·59 44·69 ± 0·89 NS 44·10 ± 0·42 NS
Intermitted 57·52 ± 12·88 48·08 ± 0·52 60·18 ± 0·79 <0·0001 46·52 ± 0·37 <0·0001
Continuous CRP (mg/dl) 1·39 ± 0·69 1·07 ± 0·09 0·88 ± 0·02 0·0359 0·87 ± 0·02 NS
Intermitted 1·45 ± 0·74 1·02 ± 0·08 1·05 ± 0·01 NS 0·99 ± 0·01 0·0001
Continuous AMS 53·52 ± 8·35 30·28 ± 0·62 27·78 ± 0·63 <0·0001 25·53 ± 0·37 <0·0001
Intermitted 54·8 ± 8·43 36·51 ± 0·54 57·67 ± 0·56 <0·0001 31·88 ± 0·33 <0·0001

AMS, Aging Males’ Symptom; BMI, body mass index; CRP, C-reactive protein; SHBG, sex hormone binding globulin.

The AMS questionnaire (assessing health-related quality of life and symptoms in ageing men) showed an improvement when men received T, which was lost during the intermission, but regained after the resumption of T treatment.

Back to Top

Discussion

In this observational study of 262 elderly men with hypogonadism (defined as a combination of symptoms of T deficiency with a serum T level ≤12·0 nmol/l), receiving treatment with T undecanoate injections, 147 men had an intermission of their T administration for reasons of reimbursement of costs or prostate cancer for a mean of 16·9 months. This intermission was not designed, but its occurrence provided an opportunity to monitor the effects of withdrawing T treatment on measures of obesity, metabolic factors and well-being. These effects could be set against the course in men who continued their T administration uninterruptedly.

As expected, in Group I serum total and free T levels returned to the levels before T administration, while levels of SHBG increased to pretreatment values. Body weight, BMI and waist circumference increased significantly but did not quite return to pretreatment values. Fasting glucose and serum HbA1c returned to baseline levels or were even higher. Similar patterns were observed for serum cholesterol, LDL cholesterol, triglycerides, HDL cholesterol, total cholesterol/HDL ratio and non-HDL cholesterol, as well as systolic blood pressure, pulse pressure and liver transaminases. The effects on diastolic blood pressure and on the inflammation marker CRP were more benign. Upon the resumption of T administration, serum levels of total and free T reached similar levels as before the intermission but serum SHBG declined further. Over the post-intermission observation period of mean 14·5 months, body weight, BMI and waist circumference declined but did not reach the lower levels achieved over 65·5 months before the intermission, but serum glucose and HbA1c did. This was also the case with serum lipids and systolic blood pressure and pulse pressure, and liver transaminases.

Our results strongly indicate that the beneficial changes induced by normalization of serum T are not sustained when T administration is halted and serum levels return to hypogonadal values. But these beneficial effects do manifest themselves again upon the resumption of T administration restoring serum T to normal.

There are almost no studies monitoring the effects of halting T administration to men with hypogonadism, particularly in the middle-aged and elderly. In a recent study, we compared the effects of T administration to two groups of men: a group of 450 men between the ages of 32 and 65 years (mean 56·10 ± 6·29) and a group of 111 men >65 years (mean 68·45 ± 2·91).[19] The symptoms of T deficiency and the benefits of restoring serum T in men were not different between younger men and men >65 years of age. We interpreted this to indicate that age is not a significant factor in the symptomatology and benefits that men receive from restoring their T levels to normal.

In a Japanese study, beneficial psychological effects were maintained over a period of 55 months following cessation of T administration. [20] But in a study of middle-aged hypogonadal severely obese men, 1-year T treatment improved cardio metabolic and hormonal parameters. Upon withdrawal of T, a return back to hypogonadism occurred within 6 months, with loss of beneficial effects on cardiovascular and body composition improvements that had been attained. [21] The results of this study [21] and ours would seem to argue that the hypogonadism encountered in elderly men is truly a state of hypogonadism where the effects of restoring T levels to normal are lost when serum T falls back to hypogonadal values. The effects of T withdrawal manifested themselves indeed within a short interval of approximately 6 months which is in agreement with the study by Francomano et al. [21]

The results of our study would seem to imply that T replacement in hypogonadal men is long-term. This has been accepted for young men but has raised concerns for men over 50–60 years of age. Of late, particularly, the implications of T treatment for cardiovascular disease have been hotly debated. The data are not sufficient to arrive at a final verdict, [6,22] but critical analysis of literature does not give rise to immediate concerns. [23] The same applies to the risks of prostate cancer. Also with regard to prostate disease, analysis of the data is reassuring. [24]

There are now guidelines [5,25] that help physicians to let elderly men benefit from T treatment while prudently avoiding pitfalls that may occur in the course of T administration, be they related or not to T treatment.

Our study has methodological shortcomings. First of all, the study is observational and not placebo-controlled. The intermission in T administration was not randomized but dictated by insurance policy (no reimbursements of costs) or incidental prostate disease. During the intermission, anthropometric values, blood pressure, glycemic control and lipids returned to their less favorable pretreatment levels. Whether (drug) interventions or changes in medication dosage took place during this interval was not assessed in this study.

Nevertheless, our observations are unambiguous and point in the expected direction and should be followed up by studies with a better design.

Back to Top

References

  1. Huhtaniemi, I. (2014) Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment. Asian Journal of Andrology, 16, 192–202.
  2. Biswas, M., Hampton, D., Newcombe, R.G. et al. (2012) Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clinical Endocrinology (Oxford), 76, 665–673.
  3. Goncharov, N.P., Katsya, G.V., Chagina, N.A. et al. (2008) Three definitions of me syndrome applied to a sample of young obese men and their relation with plasma testosterone. Aging Male, 11, 118–122.
  4. Muraleedharan, V. & Jones, T.H. (2014) Testosterone and mortality. Clinical Endocrinology (Oxford), 81, 477–487.
  5. Lunenfeld, B., Mskhalaya, G., Zitzmann, M. et al. (2015) Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male, 18, 5–15.
  6. Jones, T.H. (2014) Testosterone and cardiovascular disease. The Lancet. Diabetes & Endocrinology, 2, 612–613.
  7. Pye, S.R., Huhtaniemi, I.T., Finn, J.D. et al. (2014) Late-onset hypogonadism and mortality in aging men. The Journal of Clinical Endocrinology and Metabolism, 99, 1357–1366.
  8. Zarotsky, V., Huang, M.Y., Carman, W. et al. (2014) Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology, 2, 819–834.
  9. Corona, G., Lee, D.M., Forti, G. et al. (2010) Age-related changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS). The Journal of Sexual Medicine, 7, 1362–1380.
  10. Rastrelli, G., Carter, E.L., Ahern, T. et al. (2015) Development of and recovery from secondary hypogonadism in ageing men: prospective results from the EMAS. The Journal of Clinical Endocrinology and Metabolism, 100, 3172–3182.
  11. Wu, F.C., Tajar, A., Beynon, J.M. et al. (2010) Identification of late-onset hypogonadism in middle-aged and elderly men. The New England Journal of Medicine, 363, 123–135.
  12. Corona, G., Rastrelli, G. & Maggi, M. (2013) Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-analysis of TRT outcomes. Best Practice and Research Clinical Endocrinology and Metabolism, 27, 557–579.
  13. Cai, X., Tian, Y., Wu, T. et al. (2014) Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Asian Journal of Andrology, 16, 146–152.
  14. Haider, A., Saad, F., Doros, G. et al. (2014) Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study. Obesity Research & Clinical Practice, 8, e339–e349.
  15. Saad, F., Haider, A., Doros, G. et al. (2013) Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring, Md.), 21, 1975–1981.
  16. Traish, A.M., Haider, A., Doros, G. et al. (2014) Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. International Journal of Clinical Practice, 68, 314–329.
  17. Francomano, D., Lenzi, A. & Aversa, A. (2014) Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. International Journal of Endocrinology, 2014, Article ID 527470.
  18. Heinemann, L.A., Saad, F., Zimmermann, T. et al. (2003) The Aging Males’ Symptoms (AMS) scale: update and compilation of international versions. Health Quality of Life Outcomes, 1, 15.
  19. Saad, F., Yassin, A., Haider, A. et al. (2015) Elderly men over 65 years of age with late-onset hypogonadism benefit as much from testosterone treatment as do younger men. Korean Journal of Urology, 56, 310–317.
  20. Taniguchi, H., Kawa, G., Kinoshita, H. et al. (2011) Symptomatic change in Japanese hypogonadal patients several years after androgen replacement therapy. Aging Male, 14, 190–194.
  21. Francomano, D., Bruzziches, R., Barbaro, G. et al. (2014) Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. Journal of Endocrinological Investigation, 37, 401–411.
  22. Yeap, B.B. (2015) Testosterone and cardiovascular disease risk. Current Opinion in Endocrinology, Diabetes, and Obesity, 22, 193–202.
  23. Morgentaler, A., Feibus, A. & Baum, N. (2015) Testosterone and cardiovascular disease – the controversy and the facts. Postgraduate Medicine, 127, 159–165.
  24. Khera, M., Crawford, D., Morales, A. et al. (2014) A new era of testosterone and prostate cancer: from physiology to clinical implications. European Urology, 65, 115–123.
  25. Dean, J.D., McMahon, C.G., Guay, A.T. et al. (2015) The International Society for sexual medicine’s process of care for the assessment and management of testosterone deficiency in adult men. The Journal of Sexual Medicine, 12, 1660–1686.

Clin Endocrinol. 2016;84(1):107-114. © 2016 Blackwell Publishing

Dr. C.B. Daniel Cenegenics AZ Elite Health and Age Management
Send