Testosterone replacement therapy: improved sexual desire and erectile function in men with type 2 diabetes following a 30-week randomized placebo-controlled study.

Although testosterone replacement treatment (TRT) can improve sexual function in many hypogonadal (HG) men with type 2 diabetes (T2DM), some show either no improvement or only in a limited number of domains. Indeed, it is often difficult for the clinician to offer an indication of the likely efficacy of TRT as little data exist on the proportion of TRT-treated men who will demonstrate improvement in domains such as sexual desire (SxD) and erectile function (EF). We describe in men with T2DM: firstly, the likelihood of improved sexual desire (SxD) and erectile function (EF) following TRT at various time points, and secondly, if probability of SxD change predicted likelihood of subsequent EF change. During a 30-week randomized controlled study of testosterone undecanoate (TU), 199 T2DM men with HG (189 men completing) identified from primary care registers (placebo (P): 107, TU: 92) were stratified using baseline total testosterone (TT)/free testosterone (FT) into Mild (TT 8.1-12 nmol/L or FT 0.18-0.25 nmol/L) and Severe HG groups (TT ≤8 nmol/L and FT ≤0.18 nmol/L) and placebo (P)- and TU-treated groups. Associations between TU, SxD and EF were investigated using chi-square and logistic regression analysis. The proportion of men with improved SxD after 6 weeks and EF improvement after 30 weeks was significantly higher following TU treatment compared to P, this particularly evident in Severe HG men. Changes in SxD and EF were significantly associated in all groups. Logistic regression showed that SxD change at 6 weeks predicted of EF change after 30 weeks. Our study confirms TRT leads to changes in SxD and EF at different time points and suggests SxD and EF changes are related. SxD change after 6 weeks predicting EF change at 30 weeks is possibly a useful clinical finding.

The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study).

BACKGROUND: The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established. Current Endocrine Society and European Association of Urology guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes and in men suffering from erectile dysfunction. It is recognised that a range of physical symptoms appear as the testosterone level falls but few studies have addressed the threshold at which symptoms improve with physiological replacement. We report the first double-blind placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess the metabolic changes with testosterone replacement. METHODS: The type 2 diabetes registers of seven general practices were screened to establish the prevalence of low testosterone and the associations with diabetes control. Of 550 eligible patients approached, 488 men (mean age 62.6) consented to take part in screening with a morning testosterone level, assessed between 8 and 11 am. This identified 211 patients for a double-blind placebo-controlled study of long acting testosterone undecanoate (TU) 1000 mg lasting 30 weeks followed by 52 weeks of open label use. The population was divided into a SEVERE group with either total testosterone (TT) of 8 nmol/l or less or free testosterone (FT) 180 pmol/l or less or a MILD group with TT 8.1-12 nmol/l or FT 181-250 pmol/l. RESULTS: Men in the SEVERE group increased mean through TT from 7.73 nmol/l at baseline to 9.93 at 30 weeks and the MILD group from 10.47 to 11.94. The SEVERE group showed marked improvement in sexual function, but no significant improvement in metabolic parameters. The MILD group showed no improvement in sexual function, but significant improvement in weight, body mass index, waist circumference and Hospital Anxiety and Depression Scale. Improvement was seen in all parameters during 52 weeks open label treatment where trough TT levels approached 15 nmol/l. Baseline prostate-specific antigen (PSA) was lower in the SEVERE group and increased with TU for 30 weeks and then stabilised. There was no increase in PSA with treatment in the MILD group. CONCLUSIONS: Testosterone undecanoate significantly improves sexual parameters and Ageing Male Symptom Score, but not metabolic factors at 30 weeks in men with SEVERE testosterone deficiency syndrome (TDS). In men with MILD TDS, significant improvements in metabolic but not sexual parameters were seen, suggesting that there are threshold levels for response to testosterone replacement therapy and that trials of therapy need to achieve sustained therapeutic levels to be effective. PSA showed minor rises, but only for 30 weeks in the SEVERE group.

Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study.

Bronchiolitis obliterans (BO) is a serious noninfectious pulmonary complication following allogeneic bone marrow transplantation (BMT). Azithromycin, a macrolide antibiotic, may have a beneficial effect in BO through its anti-inflammatory effect. The aim of the current study was to investigate the potential effect of azithromycin on pulmonary function tests (PFTs) in BO complicating BMT. PFTs of 153 post-BMT patients were followed; eight patients out of 153 (12%) developed obstructive airway disease on their PFTs, along with characteristic findings of BO on high-resolution computed tomography of the chest. These patients were given azithromycin 500 mg q.d. for 3 days, followed by 250 mg three times a week for 12 weeks. Clinically significant improvements were achieved both in forced vital capacity, where the mean (95% confidence interval) increase reported was 410 mL (0.16-0.65), which was an average improvement of 21.57%, and in the forced expiratory volume in one second, where the mean increase noticed was 280 mL (0.10-0.44), which was an average improvement of 20.58%. In conclusion, the potential role of azithromycin in the treatment of bronchiolitis obliterans is intriguing and it warrants further testing.

Modifications of eukaryotic initiation factor 4F (eIF4F) in adult cardiocytes by adenoviral gene transfer: differential effects on eIF4F activity and total protein synthesis rates.

In adult feline cardiocytes, increases in eukaryotic initiation factor 4F (eIF4F) activity are correlated with accelerated rates of total protein synthesis produced in response to increased load. Adenoviral gene transfer was employed to increase either eIF4F complex formation or the phosphorylation of eIF4E on Ser-209. To simulate load,cardiocytes were electrically stimulated to contract (2 Hz,5 ms pulses). Non-stimulated cardiocytes were used as controls.Adenovirus-mediated overexpression of wild-type eIF4E increased the total eIF4E pool by 120-140% above endogenous levels after 24 h and produced a corresponding increase in eIF4F content.However, it did not accelerate total protein synthesis rates inquiescent cardiocytes; neither did it potentiate the increase produced by contraction. To modify the affinity of eIF4F, cardiocytes were infected with a mutant (eIF4E/W56F) with a decreased binding affinity for the mRNA cap. Overexpression of eIF4E/W56F increased the quantity of eIF4F but the rate of total protein synthesis was decreased inquiescent and contracting cardiocytes. Overexpression of a mutant that blocked eIF4E phosphorylation (eIF4E/S209A) increased the quantity ofeIF4F without any significant effect on total protein synthesis rates in quiescent or contracting cardiocytes. Overexpression of the eIF4Ekinase Mnk-1 increased eIF4E phosphorylation without a corresponding increase in eIF4F complex formation or in the rate of total protein synthesis. We conclude the following: (1) eIF4F assembly is increased by raising eIF4E levels via adenoviral gene transfer; (2) the capbinding affinity of eIF4F is a rate-limiting determinant for total protein synthesis rates; and (3) increases in the quantity of eIF4Falone or in eIF4E phosphorylation are not sufficient to accelerate total protein synthesis rates.

Postprandial changes in superoxide dismutase activity in subjects with Gilles de la Tourette syndrome and controls.

Erythrocyte measures of copper-zinc superoxide dismutase (CuZnSOD) were performed on 11 subjects with a clinical diagnosis of Gilles de la Tourette syndrome (GTS) and 6 healthy controls at specified intervals throughout the day. There were no significant differences between GTS subjects and controls but in both subjects and controls there was a significant increase in SOD, 75 min postprandially, which decreased to baseline 135 min postprandially. This has implications for the timing of biological samples in future studies of SOD. Possible reasons for the increase are discussed.