Large divergence in testosterone concentrations between men and women: Frame of reference for elite athletes in sex-specific competition in sports, a narrative review.

OBJECTIVE: The purpose of this narrative review was to summarize available data on testosterone levels in normal, healthy adult males and females, to provide a physiologic reference framework to evaluate testosterone levels reported in males and females with conditions that elevate androgens, such as disorders of sex development (DSD), and to determine the separation or overlap of testosterone levels between normal and affected males and females. METHODS: A literature review was conducted for published papers, from peer reviewed journals, reporting testosterone levels in healthy males and females, males with 46XY DSD, and females with hyperandrogenism due to polycystic ovary syndrome (PCOS). Papers were selected that had adequate characterization of participants, and description of the methodology for measurement of serum testosterone and reporting of results. RESULTS: In the healthy, normal males and females, there was a clear bimodal distribution of testosterone levels, with the lower end of the male range being four- to fivefold higher than the upper end of the female range(males 8.8-30.9 nmol/L, females 0.4-2.0 nmol/L). Individuals with 46XY DSD, specifically those with 5-alpha reductase deficiency, type 2 and androgen insensitivity syndrome testosterone levels that were within normal male range. Females with PCOS or congenital adrenal hyperplasia were above the normal female range but still below the normal male range. CONCLUSIONS: Existing studies strongly support a bimodal distribution of serum testosterone levels in females compared to males. These data should be considered in the discussion of female competition eligibility in individuals with possible DSD or hyperandrogenism.

Safety, pharmacokinetics and pharmacological effects of the selective androgen receptor modulator, GSK2881078, in healthy men and postmenopausal women.

AIM: Selective androgen receptor modulators (SARMs) induce anabolic effects on muscle without the adverse effects of androgenic steroids. In this first-in-human study, we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of the SARM GSK2881078. METHODS: In Part A, healthy young men (n = 10) received a single dose of study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg GSK2881078 or matching-placebo). In Part B, repeat-dose cohorts in men (n = 65) were 0.05 mg, 0.2 mg then 0.08 mg, 0.24 mg, 0.48 mg, 0.75 mg, or placebo; in women (n = 24) they were 0.24 mg, 0.35 mg, or placebo (7 days for 0.5 mg, 14 days for other doses). RESULTS: PK analysis showed dose-proportional increases in exposure and a long >100-h half-life. No significant effects on vital signs, electrocardiograms, cardiac telemetry or standard clinical laboratory studies were observed. A dose-response effect was observed on lowering both high-density lipoprotein and sex hormone-binding globulin. In females at 0.35 mg, differences from placebo were -0.518 (95% confidence interval: -0.703, -0.334) mmol l-1 and -39.1 (-48.5, -29.7) nmol l-1 , respectively. Women showed greater sensitivity to these parameters at lower doses than men. Drug-related adverse events (AEs) were mild. One woman developed a drug rash and was withdrawn. Two men had elevated creatine phosphokinase after physical exertion during follow-up. A serious AE occurred in a subject on placebo. CONCLUSIONS: These data demonstrate pharmacodynamic effects with acceptable tolerability and support further clinical evaluation of this SARM.

Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release.

GSK-1614235 and KGA-2727 are potent, selective inhibitors of the SGLT1 sodium-dependent glucose transporter. Nonclinical (KGA-2727) and clinical (GSK-1614235) trials assessed translation of SGLT1 inhibitor effects from rats to normal human physiology. In rats, KGA-2727 (0.1 mg/kg) or vehicle was given before oral administration of 3-O-methyl-α-d-glucopyranose (3-O-methylglucose, 3-OMG) containing 3-[3H]OMG tracer. Tracer absorption and distribution were assessed from plasma, urine, and fecal samples. SGLT1 inhibition reduced urine 3-OMG recovery and increased fecal excretion. SGLT1 inhibitor effects on plasma glucose, insulin, gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were also measured during a standard meal. Incremental glucose, insulin, and GIP concentrations were decreased, indicating downregulation of ß-cell and K cell secretion. Minimal effects were observed in the secretion of the L cell product, GLP-1. With the use of a three-way, crossover design, 12 healthy human subjects received placebo or 20 mg GSK-1614235 immediately before or after a meal. Five minutes into the meal, 3-OMG was ingested. Postmeal dosing had little impact, yet premeal dosing delayed and reduced 3-OMG absorption, with an AUC0-10 of 231±31 vs. 446±31 µg·h(-1)·ml(-1), for placebo. Recovery of tracer in urine was 1.2±0.7 g for premeal dosing and 2.2±0.1 g for placebo. Incremental concentrations of insulin, C-peptide, and GIP were reduced for 2 h with premeal GSK-1614235. Total GLP-1 concentrations were significantly increased, and a trend for increased peptide YY (PYY) was noted. SGLT1 inhibitors block intestinal glucose absorption and reduce GIP secretion in rats and humans, suggesting SGLT1 glucose transport is critical for GIP release. Conversely, GLP-1 and PYY secretion are enhanced by SGLT1 inhibition in humans.

Clinical pharmacology of albiglutide, a GLP-1 receptor agonist.

UNLABELLED: Albiglutide is a glucagon-like peptide-1 analogue composed of tandem copies of modified human glucagon-like peptide-1 (7-36) coupled to recombinant human albumin that is approved in adults for the treatment of type 2 diabetes mellitus. After subcutaneous administration, albiglutide is likely primarily absorbed via the lymphatic circulation, with maximum concentrations being reached in 3 to 5 days; steady-state exposures are achieved following approximately 4 to 5 weeks of once-weekly administration. The elimination half-life of albiglutide is approximately 5 days. Clearance of albiglutide is 67 mL/h with between-subject variability of 34.9%; no covariates have been identified that would require dose adjustment of albiglutide. Albiglutide lowers the fasting plasma glucose and reduces postprandial glucose excursions. In addition, ß-cell secretion is enhanced by albiglutide during hyperglycemia, whereas secretion is suppressed during hypoglycemia; α-cell response to hypoglycemia is not impaired by albiglutide. Albiglutide does not prolong the corrected QT interval but has a modest effect on heart rate in patients with type 2 diabetes mellitus. Dose adjustment is not suggested in patients with renal impairment, but experience in patients with severe renal impairment is very limited, and it is recommended that albiglutide be used with care in such patients due to an increased frequency of diarrhea, nausea, and vomiting. No clinically relevant drug interactions have been observed in clinical trials. TRIAL REGISTRATION: NCT00938158, NCT01406262, NCT00537719, NCT01077505, NCT01147731, NCT01147718, NCT01147692, NCT00354536, NCT00394030, NCT00530309, NCT01357889, NCT00518115, NCT01098461, NCT01475734, NCT00849017, NCT00838916, NCT00839527, NCT01098539.

Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide.

BACKGROUND: Chronic kidney disease is frequently present in patients with type 2 diabetes mellitus (T2DM). New therapeutic options in this patient subpopulation are needed. OBJECTIVES: Assess the effect of renal impairment on the pharmacokinetics (PK), efficacy, and safety of albiglutide in single- and multiple-dose studies. METHODS: Pharmacokinetics, safety, and efficacy of once weekly albiglutide in patients with T2DM was assessed from a single-dose (30 mg), nonrandomized, open-label study (N = 41) including subjects with normal and varying degrees of renal impairment, including hemodialysis, and a pooled analysis of 4 phase 3, randomized, double-blind (1 open-label), active or placebo-controlled multiple-dose studies. The pooled analysis of the latter 4 studies (N = 1113) was part of the population PK analysis, which included subjects with normal and varying degrees of renal impairment (mild, moderate, severe) treated with albiglutide (30 to 50 mg) to primary end points of 26 to 52 weeks. RESULTS: Single-dose PK showed area-under-the-curve ratios (and 90% CIs) of 1.32 (0.96-1.80), 1.39 (1.03-1.89), and 0.99 (0.63-1.57) for the moderate, severe, and hemodialysis groups, respectively, relative to the normal group. Results indicate that modest increases in plasma concentration of albiglutide were observed with the severity of renal impairment. There was a trend for more glycemic lowering as the estimated glomerular filtration rate decreased. The severe group had a higher frequency of gastrointestinal (eg, diarrhea, constipation, nausea, and vomiting) and hypoglycemic (with background sulfonylurea use) events compared with patients with mild or moderate renal impairment. CONCLUSION: The PK, efficacy, and safety data indicate that albiglutide has a favorable benefit/risk ratio in patients with T2DM and varying degrees of renal impairment, and the need for a dose adjustment is not suggested. Experience in patients with more severe renal impairment is very limited, so the recommendation is to use albiglutide carefully in this population. CLINICAL TRIAL REGISTRATION: (ClinicalTrials.gov):NCT00938158, NCT00849017, NCT00838916, NCT00839527, NCT0198539.

GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.