Effects of long-term oral testosterone undecanoate therapy on urinary symptoms: data from a 1-year, placebo-controlled, dose-ranging trial in aging men with symptomatic hypogonadism.

BACKGROUND: There has been a longstanding question as to whether testosterone therapy could precipitate or worsen urinary symptoms in aging men. We investigated the effects of 1-year oral testosterone undecanoate (TU) therapy on urinary symptoms in aging, hypogonadal men. METHODS: A total of 322 men ≥50 years with symptomatic testosterone deficiency participated in a 1-year, randomized, multicenter, double-blind trial. Patients received placebo or oral TU 80 mg/day, 160 mg/day, or 240 mg/day. RESULTS AND LIMITATIONS: Compared with placebo, treatment with oral TU at doses of 80 mg/day and 160 mg/day resulted in no significant change in IPSS urinary symptoms or quality of life (QoL) scores. Treatment with oral TU 240 mg/day led to a statistically significant, but clinically insignificant, improvement in IPSS total score and a significant improvement in IPSS QoL score. None of the TU doses tested had a significant effect on PSA or PV. CONCLUSIONS: Long-term oral TU therapy had no deleterious effects on IPSS total score and did not change PV and PSA in aging, hypogonadal men. Oral TU therapy at a dose of 240 mg/day may even improve IPSS QoL score.

Effects of oral testosterone undecanoate therapy on bone mineral density and body composition in 322 aging men with symptomatic testosterone deficiency: a 1-year, randomized, placebo-controlled, dose-ranging study.

OBJECTIVE: We investigated the effects of oral testosterone undecanoate (TU) on bone mineral density (BMD), lean body mass (LBM) and body fat mass (BFM) in aging men with symptomatic testosterone deficiency (TD). METHODS: Three hundred twenty-two men ≥50 years with TD symptoms and calculated free testosterone <0.26 nmol/L participated in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to placebo, oral TU 80 mg/d, oral TU 160 mg/d, or oral TU 240 mg/d, administered as divided doses with normal meals. BMD of the hip and lumbar spine were evaluated by dual energy X-ray absorptiometry (DEXA), and body composition (LBM and BFM) by whole body DEXA. RESULTS: Oral TU significantly increased BMD at Month 12 at the lumbar spine (240 mg/d), total hip (240 mg/d), and trochanter and intertrochanter (160 and 240 mg/d) compared with placebo. Oral TU significantly increased LBM at Months 6 and 12 for all oral TU groups compared with placebo. BFM significantly decreased at Month 6 (all oral TU groups) and Month 12 (160 mg/d) compared with placebo. The effects on BMD and body composition showed a clear dose response. CONCLUSIONS: Treatment with oral TU led to improvement in BMD, LBM and BFM in aging men with symptomatic TD.

Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.

OBJECTIVE: To investigate the effects of oral testosterone undecanoate (TU) on symptoms associated with late-onset hypogonadism (LOH). Design Multicenter, randomized, double-blind, placebo-controlled. METHODS: The study was performed in 14 study centers in seven European countries. Men > or =50 years (n=322) with symptoms of hypogonadism and testosterone deficiency (calculated free testosterone <0.26 nmol/l) were randomized and treated for 12 months with placebo or oral TU 80, 160 or 240 mg/day. Primary outcome was the total score on the Aging Males' Symptoms (AMS) rating scale after six months of treatment. RESULTS: Treatment of mild-to-moderate LOH symptoms in subjects with borderline hypogonadism with oral TU resulted in an improved total AMS score at month 6, but differences between groups were not statistically significant. There was greater improvement in subjects <60 years when compared with subjects > or =60 years (P=0.001), but baseline testosterone level had no influence on treatment response. The AMS sexual symptoms domain improved with oral TU 160 mg/day at months 6 (P=0.008) and 12 (P=0.012) compared with placebo, but not with 80 and 240 mg/day. Treatment was well-tolerated and there were no between-group differences in adverse events or drop-out rates. CONCLUSIONS: In one of the largest placebo-controlled studies of testosterone therapy in LOH, oral TU did not improve total AMS score in subjects with mild-to-moderate symptoms compared with placebo, except the sexual symptom sub-domain where a modest improvement was reported with oral TU 160 mg/day.

Serum IGF-I levels and IGF-I gene splicing in muscle of healthy young males receiving rhGH.

OBJECTIVE: Elevated growth hormone (GH) levels lead to increased circulating insulin-like growth factor-I (IGF-I), but the effects on localised muscle IGF-I splice variant expression is not known. The effects of rhGH administration, with or without an acute bout of high resistance exercise, were measured on serum IGF-I and on the mRNA levels of IGF-I splice variants in the vastus lateralis muscle of healthy young men. DESIGN: The study was a randomised double blind trial with a crossover design. Seven subjects were randomly assigned to a group receiving daily injections of rhGH (0.075IU kg(-1)day(-1)) or placebo for a two week period. Following a one month washout, the groups were reversed. RESULTS: Administration of rhGH increased circulating IGF-I from 31.8+/-3.2 to 109+/-5.4 nmol/L (p<0.05). There was no effect of the exercise bout. RNA was extracted from muscle biopsies obtained from exercised and non-exercised legs 2.5h after the cessation of the exercise. Transcript expression was measured using Real-time QPCR. There was no effect of either exercise or rhGH administration on IGF-I 5' (Class 1 or Class 2) or 3' (IGF-IEa, or MGF) transcripts. CONCLUSION: Although rhGH administration has an effect on liver IGF-I expression, as shown by increase in circulating IGF-I, muscle IGF-I expression is unaffected in young healthy subjects with normal GH profile. The findings contrast with those of a previous study in which GH deficient elderly men showed higher muscle IGF-I 3' splice variant levels following rhGH administration with and without resistance training. Unlike in the liver, muscle Class1 and 2 IGF-I expression do not change significantly following administration of rhGH.

Extended and flexible domain solution structure of the extracellular matrix protein anosmin-1 by X-ray scattering, analytical ultracentrifugation and constrained modelling.

Kallmann's syndrome corresponds to a loss of sense of smell and hypogonadotrophic hypogonadism. Defects in anosmin-1 result in the X-linked inherited form of Kallmann's syndrome. Anosmin-1 is an extracellular matrix protein comprised of an N-terminal, cysteine-rich (Cys-box) domain and a whey acidic protein-like (WAP) domain, followed by four fibronectin type III (FnIII) domains. The solution structures of recombinant proteins containing the first three domains (PIWF1) and all six domains (PIWF4) were determined by X-ray scattering and analytical ultracentrifugation. Guinier analyses showed that PIWF1 and PIWF4 have different radii of gyration (R(G)) values of 3.1 nm and 6.7 nm, respectively, but similar cross-sectional radii of gyration (R(XS)) values of 1.5 nm and 1.9 nm, respectively. Distance distribution functions showed that the maximum lengths of PIWF1 and PIWF4 were 11 nm and 23 nm, respectively. Analytical ultracentrifugation gave sedimentation coefficients of 2.52 S and 3.55 S for PIWF1 and PIWF4, respectively. The interpretation of the scattering data by constrained modelling requires homology models for all six domains in anosmin-1. While models were already available for the WAP and FnIII domains, searches suggested the Cys-box domain may resemble the cysteine-rich region of the insulin-like growth factor receptor. Automated constrained molecular modelling based on joining the anosmin-1 domains with structurally randomised linkers resulted in 10,000 models for anosmin-1. A trial-and-error search showed that about 0.1-1.4% of these models fitted the X-ray data. The best models showed that the three domains and six domains in PIWF1 and PIWF4, respectively, were extended. The inter-domain linkers in anosmin-1 could not all be extended at the same time, and there was evidence for inter-domain flexibility. Models with folded-back domain arrangements do not fit the data. These solution structures account for the known biological function of anosmin-1, in particular its ability to interact with its three macromolecular ligands.

GnRH neuronal development: insights into hypogonadotrophic hypogonadism.

Pulsatile secretion of the hypothalamic decapeptide gonadotrophin-releasing hormone (GnRH) regulates activity of the pituitary-gonadal reproductive axis. Defects of this neuroendocrine axis necessarily result in hypogonadotrophic hypogonadism. In many vertebrate species studied, the main population of GnRH neurones originates extracranially within the olfactory system. In humans, both olfactory and GnRH systems are affected in Kallmann's syndrome--resulting in isolated hypogonadotrophic hypogonadism (IHH) combined with anosmia (loss of sense of smell). Familial IHH is also caused by other genetic conditions, which prevent GnRH from activating luteinizing hormone/follicle-stimulating hormone release from pituitary gonadotrophs. However, many cases of IHH have no defined chromosomal abnormality and, in the absence of pedigree analysis, studying the biological mechanisms controlling migration of GnRH neurones through the olfactory system into the developing central nervous system might reveal additional genetic pathways that play a role in the pathogenesis of IHH.

Hypogonadotropic hypogonadism.

Hypogonadotropic hypogonadism is characterized by failure of gonadal function secondary to deficient gonadotropin secretion, resulting from either a pituitary or hypothalamic defect, and is commonly seen in association with structural lesions or functional defects affecting this region. Although the genetic basis for idiopathic hypogonadotropic hypogonadism is largely unknown, mutations in several genes involved in the hypothalamo-pituitary-gonadal axis development and function have recently been implicated in the pathogenesis of this condition. Genes currently recognized to be involved include KAL-1 (associated with X-linked Kallmann Syndrome), gonadotropin-releasing hormone (GnRH) receptor, gonadotropins, pituitary transcription factors (HESX1, LHX3, and PROP-1), orphan nuclear receptors (DAX-1, associated with X-linked adrenal hypoplasia congenital, and SF-1), and three genes also associated with obesity (leptin, leptin receptor, and prohormone convertase 1 [ PC1]). Study of these mutations provides an important contribution in the understanding of the different stages of the reproductive axis development and physiology. Treatment options currently available for puberty induction, maintenance replacement therapy, and fertility induction are considered here. Gametogenesis can be induced with either exogenous gonadotropin or pulsatile GnRH therapy, depending on the etiology.