Effects of long-term testosterone replacement therapy,with a temporary intermission,on glycemic control of nine hypogonadal men with type 1 diabetes mellitus – a series of case reports

Abstract

Type 2 diabetes mellitus (T2DM) is often associated with obesity and subnormal serum testosterone (T) levels. Until 5 years ago there was no indication that men with type 1 diabetes mellitus (T1DM) had subnormal serum T. But recent studies indicate that about 10% of men with T1DM suffer from hypogonadism, as a rule aged men and men with obesity. While hypogonadal men with T2DM benefit from normalization of their serum T, this has not been investigated in men with T1DM. Nine men with T1DM, erectile dysfunction and hypogonadism (total testosterone?≤?12?nmol/L) received testosterone replacement therapy (TRT). In seven men TRT was intermitted: one man with prostate malignancy and six men because of problems of reimbursement. Incidentally, this provided an opportunity to monitor the effects of withdrawal and of the reinstatement of TRT. In all men, glycemic control (serum glucose and HbA_1c), weight, waist circumference, lipid profiles and erectile function improved upon TRT. The seven men whose TRT was intermitted showed a deterioration which improved again upon reinstatement of TRT. The data suggest that aging and obese men with T1DM might have subnormal T levels and that their glycemic control, lipid profiles and erectile function might benefit from TRT.     

Effects of testosterone replacement therapy withdrawal and re-treatment in hypogonadal elderly men upon obesity,voiding function and prostate safety parameters

Whether testosterone replacement therapy (TRT) is a lifelong treatment for men with hypogonadism remains unknown. We investigated long-term TRT and TRT withdrawal on obesity and prostate-related parameters. Two hundred and sixty-two hypogonadal patients (mean age 59.5) received testosterone undecanoate in 12-week intervals for a maximum of 11 years. One hundred and forty-seven men had TRT interrupted for a mean of 16.9 months and resumed thereafter (Group A). The remaining 115 patients were treated continuously (Group B). Prostate volume, prostate-specific antigen (PSA), residual voiding volume, bladder wall thickness, C-reactive protein (CRP), aging male symptoms (AMS), International Index of erectile function – erectile function (IIEF-EF) and International Prostate Symptoms Scores (IPSS) were measured over the study period with anthropometric parameters of obesity, including weight, body mass index (BMI) and waist circumference. Prior to interruption, TRT resulted in improvements in residual voiding volume, bladder wall thickness, CRP, AMS, IIEF-EF, IPSS and obesity parameters while PSA and prostate volume increased. TRT interruption reduced total testosterone to hypogonadal levels in Group A and resulted in worsening of obesity parameters, AMS, IPSS, residual voiding volume and bladder wall thickness, IIEF-EF and PSA while CRP and prostate volume were unchanged until treatment resumed whereby these effects were reversed. TRT interruption results in worsening of symptoms. Hypogonadism may require lifelong TRT.     

Influence of testosterone substitution on glycemic control and endothelial markers in men with newly diagnosed functional hypogonadism and type 2 diabetes mellitus: a randomized controlled trial

Abstract

Effects of testosterone (T) on the cardiovascular system of men remain controversial. The impact of T-replacement therapy (TRT) in men with functional hypogonadism and type 2 diabetes mellitus (T2DM) has to be elucidated. This study included 80 men (mean age 51.5?±?6.3 years) with newly diagnosed T2DM (according to ADA criteria) and functional hypogonadism (according to EAU criteria). Randomization: Group1 (n?=?40): TRT using 1%-transdermal T-gel (50?mg/day), Group2 (n?=?40) no TRT (controls). Dietary treatment applied to both. Parameters at baseline/after 9?months: anthropometric parameters, lipids and indicators of carbohydrate metabolism (fasting glucose, insulin, HbA1c, HOMA-IR), markers of adipose tissue and EnD (leptin, resistin, p- and e-selectin, ICAM- 1, VCAM- 1 and CRP). ANCOVA for repeated measurements revealed TRT to cause a significant decrease in waist circumference (WC), HOMA-IR and HbA1c vs controls (p?<?.001, p?=?.002, p?=?.004, respectively). Leptin declined in subjects receiving TRT vs controls (p?=?.04). Concentrations of resistin, ICAM-1, p-selectin and CRP decreased significantly vs controls (all p?<?.001); no effects for e-selectin and VCAM-1. Advanced age attenuated effects, higher delta testosterone levels augmented effects. Decrement of WC was related to decreasing markers of adipose tissue secretion/EnD. TRT in men with functional hypogonadism and T2DM improved carbohydrate metabolism and markers of endothelial dysfunction.     

Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study

We evaluated the effects of long-term testosterone replacement therapy (TRT) on the bone mineral density (BMD) in obese patients with metabolic syndrome (MS) and late-onset hypogonadism (LOH). Sixty men (mean age 57 ± 10) with low serum testosterone (T < 320 ng/dL) and MS regardless the presence of osteoporosis were enrolled. Forty men received intramuscular T-undecanoate (TU) four times/year for 36 months and 20 age-matched hypogonadal men with MS in whom T treatment was contraindicated were used as controls. Hormonal, biochemical markers, vertebral and femoral BMD by dual-energy x-ray absorptiometry were measured. At baseline, overall patients had mild osteopenia (lumbar BMD= 0.891 ± 0.097 g/cm(2); femoral BMD= 0.847 ± 0.117 g/cm(2)). TU induced a significant improvement of bone mass after 36 months (lumbar BMD=1.053 ± 0.145 g/cm(2); p < 0.002; femoral BMD=0.989 ± 0.109; p < 0.003 g/cm(2)) with a 5%/year increase and a significant reduction in hs-CRP without changes in body mass index. A direct relationship between serum T and BMD increments at the lumbar (r(2)?= 0.66, p < 0.0001) and femoral (r(2)?=0.52, p < 0.0001) sites was demonstrated. Study adherence was 50% without serious side effects. Long-term TRT in middle-aged men with LOH and MS determines a significant increase in both vertebral and femoral BMD related to increased serum T levels, probably independently from estradiol modifications.     

Effects of testosterone replacement therapy on hypogonadal men with osteopenia or osteoporosis: a subanalysis of a prospective randomized controlled study in Japan (EARTH study)

Objective: We investigated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) among hypogonadal men with osteopenia/osteoporosis.

Methods: From our previous EARTH study population, 74 patients with a clinical diagnosis of osteopenia or osteoporosis and hypogonadism were included in this study, as the TRT (n?=?35) and control (n?=?34) groups. The TRT group was administered 250?mg of testosterone enanthate injection every 4 weeks for 12 months. The BMD, waist circumference, body mass index, body fat percentage, and muscle volume were measured at baseline and at 12 months. Blood biochemical data, including total cholesterol, triglycerides, HDL-cholesterol, hemoglobin A1c, and adiponectin values were also evaluated.

Results: At the 12-month visit, BMD significantly increased in both groups. However, comparisons on changes of parameter values from baseline to the 12-month visit between the TRT and control groups were significantly different in BMD (5.0?±?5.0 vs. 3.0?±?3.2; p?=?.0434) and in adiponectin value (?0.90?±?3.33 vs. 0.10?±?2.04; p?=?.0192). There were no significant changes in other parameters.

Conclusions: TRT for 12 months could improve BMD with a decrease in adiponectin levels among hypogonadal men with osteopenia/osteoporosis.     

Low-intermediate dose testosterone replacement therapy by different pharmaceutical preparations improves frailty score in elderly hypogonadal hyperglycaemic patients

Abstract

An open-label follow-up study of low-to-intermediate dose testosterone replacement therapy (TRT) was conducted in 64 overweight patients (aged 65–75 years) with late onset hypogonadism (LOH) and increased fasting plasma glucose (FPG). Patients were subdivided into four treatment groups: oral testosterone (T) (T undecanoate, 80?mg/d), transmucosal T (60?mg/d), transdermal T (30?mg/d) or no treatment (control), and evaluated at 0 and 6 months. FPG, hemoglobin (Hb), prostate-specific antigen (PSA) and total T were measured and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated. Body mass index (BMI), waist circumference, fitness level (6-min walking test), Aging Males’ Symptoms (AMS) scale, handgrip strength and energy expenditure with physical activity (Minnesota questionnaire for Leisure Time Physical Activity (LTPA)) were evaluated and a “frailty score” (based on: grip strength, gait speed and LTPA) was calculated. T levels increased in all treatment groups; the oral T group had values still in the hypogonadal range (5.9?±?1.1?nmol/L). PSA and Hb concentrations did not change in any group. BMI, waist circumference, FPG and HOMA-IR improved in all T-treated groups after 6 months, with a greater effect seen with transmucosal and transdermal T compared with oral T. This study indicates that low-to-intermediate dose TRT may be safely utilized in LOH patients to ameliorate somatic and psychological frailty symptoms in association with improved anthropometric and glycometabolic parameters in aging, overweight men with LOH and impaired fasting glucose.     

Comprehensive evaluation of androgen replacement therapy in aging Japanese men with late-onset hypogonadism

Abstract

Objective: This study assessed the efficacy and safety of testosterone replacement therapy (TRT) in aging Japanese men with late-onset hypogonadism (LOH).

Methods: This study included 50 (median age: 57.7 years) Japanese men with LOH, who were consecutively enrolled and treated with TRT for at least six months at our institution. We evaluated the following measurements before and after six months of treatment with TRT as follows: blood tests, prostate volume, residual urine volume, self-ratings for International Index of Erectile Function 5 (IIEF-5), International Prostate Symptom Score (IPSS), Self-Rating Depression Scale (SDS), Aging Male Symptom (AMS) and the Medical Outcomes Study 8-item Short-Form health survey (SF-8).

Results: Following six months of TRT, the levels of testosterone, red blood cells, hemoglobin and hematocrit were significantly increased from baseline, while total cholesterol level was significantly decreased from baseline. Furthermore, TRT led to a significant increase in IIEF-5 score and a significant decrease in IPSS score. Of 30 men who were diagnosed with depression at baseline, only 11 men (36.7%) were still suffering from depression after TRT, and SDS scores were significantly decreased from baseline at month six. Treatment with TRT led to a significant decrease in all scores of the AMS scale as well as a significant improvement in all scores of the SF-8 survey, with the exception of the bodily pain score.

Conclusion: These findings suggest that TRT is an effective and safe treatment for aging Japanese men with LOH. TRT improved depressive symptoms as well as health-related quality of life.     

The Freshman 15—A Closer Look

Abstract

Objectives and Participants: Changes in body weight, composition, and size were examined in college freshmen at the beginning (initial, n = 240) and end of fall semester 2007 (n = 214) and the end of spring semester 2008 (n = 205). Methods: Height, weight, body composition, and waist and hip measurements were assessed. Results: Mean weight, body mass index (BMI), absolute and percent body fat all increased significantly over fall semester and the academic year. About 31% of freshmen lost ≥5 lbs. Mean academic year weight gain was 2.6 lbs (entire group) and 6.0 lbs (weight gainers); body fat increased by 4.4 lbs in the weight gainers. A significant correlation (r = .509) was found between weight change and waist circumference change, but not between weight change and waist to hip ratio change. Conclusions: Freshmen weight gain is associated with increases in body fat and waist circumference, which may be troublesome should the trend continue throughout college.     

Effects of testosterone replacement therapy on nocturia and quality of life in men with hypogonadism: a subanalysis of a previous prospective randomized controlled study in Japan

Abstract

Objective: We investigated the effects of testosterone replacement therapy (TRT) on nocturia and general health among men with hypogonadism and nocturia.

Methods: From our previous EARTH study population, 64 patients with a clinical diagnosis of nocturia (two or more times per one night) and hypogonadism, comprising the TRT group (n?=?31) and controls (n?=?33), were included in this analysis. The TRT group was administered 250?mg of testosterone enanthate as an intramuscular injection every 4 weeks for 6 months. All patients responded to the following questionnaires: International Prostatic Symptoms Score (IPSS), Aging Male Symptoms (AMS) score and Short Form-36 health survey at baseline and 6-month visit. These categories were compared based on changes from baseline to the 6-month visit between TRT and control groups.

Results: At the 6-month visit, the TRT group had a significant decrease in IPSS question no. 7 and AMS question no. 4, whereas no significant changes were observed in the control group. Additionally, role limitation because of health program, vitality and mental health domains were significantly improved in the TRT group.

Conclusions: Six-month TRT may improve nocturia, sleep conditions and quality of life among men with hypogonadism and nocturia.     

Prevalence of low testosterone and its relationship to body mass index in older men with lower urinary tract symptoms associated with benign prostatic hyperplasia

Abstract

Purpose: We examined the prevalence of low testosterone (LT) and its relationship with body mass index (BMI) in men with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), who were enrolled in a clinical trial of drug therapy, the Medical Therapy of Prostatic Symptoms (MTOPS) Study.

Materials and methods: MTOPS enrolled 3047 men, and of these, 1896 had total testosterone (TT) measured at baseline. LT was defined as a single measurement of TT of <300?ng/dL.

Results: The overall prevalence of LT was 25.7%. Prevalence increased with increasing BMI; 14.7% among men who were normal weight (BMI <25?kg/m²) and 24.2% and 39.3% among overweight (BMI 25 to <30?kg/m²), and obese (baseline BMI ≥30?kg/m²) men, respectively.

Conclusions: LT was observed in about one in four MTOPS study participants with baseline TT measurements. The prevalence of LT increased markedly with increasing BMI. Our findings suggest a high prevalence of LT in obese men with LUTS/BPH. Physicians should be alert to the possibility of symptoms of hypogonadism in this population.     

The effect of testosterone treatment on prostate histology and apoptosis in men with late-onset hypogonadism

Objectives: To investigate the effect of testosterone replacement therapy (TRT) on prostate histology and apoptosis in men with late-onset hypogonadism (LOH).

Methods: The study included 25 men, having LOH with prostate-specific antigen (PSA) level of 4?ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline, and received testosterone undecanoate treatment for 1 year. Prostate biopsy was repeated at the end of 1 year of testosterone therapy. In addition to clinical and biochemical parameters, prostate histology and apoptotic index (AI) were compared before and after the TRT.

Results: The mean serum total testosterone significantly increased from 178.04?±?51.92 to 496.28?±?103.73?ng/dl (p?=?0.001). No significant differences were observed in serum total and free PSA level, prostate volume and maximal urinary flow rate. There were also no significant differences in AI, stroma/epithelial cells ratio, Ki-67 positive cells and atrophy score of prostate tissue before and after the TRT.

Conclusions: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development, because of no significant differences in prostate histology after TRT.     

Testosterone deficiency and the metabolic syndrome

Evidence is presented to link components of the metabolic syndrome to testosterone deficiency and obesity. Testosterone deficiency in hypogonadism or testosterone deprivation in normo-gonadotropic men increases fat mass as well as fasting insulin levels. Testosterone supplementation (TS) in a dose dependent manner, increase lean body mass (LBM), reduces fat mass, body mass index (BMI) and waist hip ratio in both young and elderly hypogonadal men. A negative association between T and insulin resistance as well as impaired glucose intolerance has been demonstrated and in type 2 diabetic men TS improves metabolic parameters. TS improves most components of the metabolic syndrome and also reduces inflammatory cytokines.     

Bone mineral density in men with and without the metabolic syndrome

The objective of this study was to measure bone mineral density (BMD) in middle-aged men with and without the metabolic syndrome according to the International diabetes federation (IDF) definition from 2005. We studied 80 men (mean age: 51.9 ± 9.0 y, mean body mass index (BMI): 32.0 ± 1.7 kg/m²) with and 92 men without the metabolic syndrome (mean age: 52.6 ± 15.1 y, mean BMI: 24.9 ± 2.8 kg/m²). Height (cm), weight (kg), waist circumference (cm) and blood pressure were measured. Fasting plasma glucose (FPG) and blood lipids were determined. BMD at the lumbar spine and total hip was measured by dual X-ray absorptiometry on a Hologic QDR 4500 bone densitometer. In men around 59.3% had a waist circumference > 94 cm (abdominal obesity). Among them 58.7% showed abnormal BP values. Around 30.7% had FPG ≥ 5.6 mmol/L and 22.7% had low high density lipoprotein (HDL)-cholesterol and 36.6% had hypertriglyceridemia. In men with the metabolic syndrome, mean lumbar spine BMD was 0.986 ± 0.210 g/cm² and total hip BMD – 1.012 ± 0.209 g/cm². The corresponding values in men without this syndrome were 0.934 ± 0.179 g/cm² and 0.894 ± 0.189 g/cm², respectively. The inter-group BMD difference reached statistical significance only at the hip (p = 0.039). Respectively, the prevalence of osteoporosis at the central sites was significantly higher in men without the metabolic syndrome (MS) (13.2 versus 20.8%, p = 0.03). Our data confirmed the trend for higher BMD in the studied men with the metabolic syndrome.     

Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study

This observational post-marketing study of parenteral testosterone undecanoate (TU) in a non-selected population aimed to: examine the effectiveness of TU as treatment of hypogonadism; record adverse drug reactions (ADR) quantitatively particularly regarding polycythemia, prostate safety and cardiovascular-related metabolic risk factors; and verify whether recommended injection intervals apply to routine clinical practice. Eight hundred and seventy subjects from 259 outpatient units scheduled to visit the clinic six times were included. Effectiveness and tolerability of TU administration were assessed on a 4-point scale. Body weight, waist girth, blood pressure, hemoglobin levels, hematocrit, prostate-specific antigen (PSA), and digital rectal prostate examination were assessed. Over 90% of subjects completed the observational duration of 52.8?±?9.7 weeks (mean?±?SD) and 56% judged effectiveness as very good, 30.8% as good. 63.1% judged tolerability as very good, and 24.4% as good. No adverse effects on indicators of cardiovascular risk were observed. Polycythemia occurred in one subject and a supranormal hematocrit in one subject. Four subjects developed supranormal PSA levels. Prostate carcinoma was found in one subject, one subject had recurrence of a previously surgically treated prostate carcinoma, and the other two showed no indication of malignancy. Parenteral TU is safe, effective, and well-tolerated in clinical practice proving a good therapeutic option for hypogonadism.     

Prevalence of overweight and obesity in collegiate American football players, by position

OBJECTIVE: The authors' purpose in this study was to determine overweight and obesity prevalence in a collegiate football team. PARTICIPANTS: Eighty-five National Collegiate Athletic Association (NCAA) Division I football players volunteered to participate. METHODS: The authors measured height, weight, and waist circumference (WC), and estimated body fat percentage (% BF) from bioelectrical impedance. RESULTS: Body mass index (BMI), WC, and % BF were all positively correlated (p < .01), but BMI overestimated the prevalence of overweight and obesity in 50.6% of the cases. Fourteen players (16%) qualified as obese under all 3 methods. Offensive linemen had significantly higher % BF (p < .01) than most other positions, and on average this group exceeded the at-risk criteria for BMI (> 30 kg/m2), WC (> 102 cm), and % BF (> 25%). CONCLUSIONS: BMI alone is not a valid indicator of overweight and obesity in a strength-trained athletic population. However, some collegiate football players, especially linemen, meet multiple criteria for obesity.     

Oral Abstracts

Hypogonadism is associated with a range of disease states that have significant effects on morbidity and mortality, and also affect quality of life. The ESPRIT study (Energy, Sexual desire and body PropoRtions wIth AndroGel®, Testosterone 1% gel therapy) is a 6-month, multinational, open label, observational study in hypogonadal men being treated with transdermal AndroGel® in usual daily clinical practice; 1,700–2,400 patients will be enrolled in Canada, Germany, Central and Eastern Europe, Russia and the Middle East. The main objective will be to evaluate the effect of AndroGel® on symptoms of hypogonadism and quality of life as assessed by the Aging Males' Symptoms scale. Further objectives include evaluating the effect and time to onset of improvement in erectile dysfunction and libido/sexual desire (International Index of Erectile Function), fatigue (Multi-dimensional Fatigue Index) and body composition (waist circumference, body mass index). Subgroup analyses will be performed: <50 years versus ≥ 50 years; absence versus presence of metabolic syndrome. The safety of AndroGel® will also be assessed. The study population will consist of newly diagnosed hypogonadal men (age ≥ 18 years), in whom testosterone deficiency has been confirmed by clinical features and biochemical tests according to international guidelines, who are currently being prescribed AndroGel® (testosterone 1% gel, starting dose 50 mg testosterone per day).     

Sleep disturbance as a clinical sign for severe hypogonadism: efficacy of testosterone replacement therapy on sleep disturbance among hypogonadal men without obstructive sleep apnea

Objective: The present subanalysis of the EARTH study investigates the effects of one year testosterone replacement therapy (TRT) on sleep disturbance among hypogonadal men without obstructive sleep apnea.

Methods: Sleep disturbance was defined as three or more points in question 4 of the aging males symptoms (AMS) questionnaire. All participants completed the AMS scale, International Prostatic Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) and Short Form 36 (SF-36) health survey at baseline and after 12?months. Sexual symptoms were also evaluated based on three AMS subscores (Q15, 16 and 17).

Results: We identified 100 patients with sleep disturbance, of whom 48 (24 each in the TRT and control groups) were ultimately included for analysis. All SF-36 categories , AMS scale, IPSS and SHIM score subdomains were significantly worse in patients with sleep disturbance than in those without disturbance. Statistically significant differences in sleep disturbance, erectile symptoms, sexual desire and some domains of the SF-36 were observed between the TRT and control groups after 12?months.

Conclusion: Sleep disturbance may be one of the clinical signs for severe hypogonadism. Moreover, TRT improved sleep conditions, sexual function and quality of life among hypogonadal men with sleep disturbance.     

Level of physical activity and anthropometric characteristics in old age—results from a national health survey

Advanced age is associated with degenerative changes in body composition. There is evidence suggesting that changes may vary upon differences in lifestyle, environment, or gender. Physical activity engagement is considered an important component of lifestyle definition. There are suggestions that engaging in physical activity might alleviate degenerative body compositional changes. The objective is to assess the relationship between adherence to recommended guidelines of physical activity and anthropometric parameters in Israeli older adults. Anthropometric measures, including height, weight, and waist circumference, were taken, and BMI was calculated, from a random sample of 1,663 elderly adults (799 men and 864 women), aged 74.31 (±6.05) years old. Participants reported their physical activity habits and, based on official guidelines recommendations, they were divided into sufficiently active, insufficiently active, and inactive groups. One-way ANOVA (level of physical activity) for both genders was conducted for each anthropometric variable. In both genders, an association between level of physical activity and weight, waist circumference, and BMI was found, with lower values among the sufficiently active. In addition, a relationship between level of physical activity and height was indicated among women, implying that the more active women were taller than the less active. In addition to the already known health benefits of physical activity in old age, it is possible that adherence to recommended guidelines of physical activity is associated with favorable anthropometric characteristics.     

Prevalence of low testosterone in aging men with benign prostatic hyperplasia: data from the Proscar Long-term Efficacy and Safety Study (PLESS)

Abstract

Objectives: We examined the prevalence of low testosterone (LT) in the subset of men in the Proscar Long-term Efficacy and Safety Study (PLESS) who had serum total testosterone (TT) measured at baseline.

Methods: PLESS enrolled 3040 men with benign prostatic hyperplasia (BPH). Of these men, 299 had TT and body mass index (BMI) measurements at baseline. Patients were classified as having LT if their baseline TT was <300?ng/dl.

Results: Of the 299 PLESS patients with baseline TT and BMI measurements, 65 (21.7%) had LT. The prevalence of LT increased with increasing BMI, occurring in 8/78 (10.3%) normal weight patients (baseline BMI <25?kg/m²), 35/160 (21.9%) overweight patients (baseline BMI ≥25–<30?kg/m²), and 22/61 (36.1%) obese patients (baseline BMI ≥30?kg/m²).

Conclusions: LT was observed in more than one in five PLESS patients with baseline TT and BMI measurements. The prevalence of LT increased with increasing BMI – more than one in three obese PLESS patients with baseline TT measurements had LT.