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

Disclosures

Clin Endocrinol. 2016;84(1):107-114. 

In This Article

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 analysed 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 apnoea.

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 analysed 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.

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