Biomedical subjects

Nelly Pitteloud

Publications and source records attributed to Nelly Pitteloud.

6 recordsLinked to original sources

PubMed2005

Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men.

Insulin resistance is associated with low testosterone (T) levels in men, the mechanism of which is unclear. Thus, the aim of this study was to evaluate the hypothalamic-pituitary-gonadal axis in men with a spectrum of insulin sensitivity. Twenty-one men (aged 25-65 yr) had a glucose tolerance test and assessment of insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Insulin sensitivity, expressed as the M value (milligrams per kilograms(-1) per minute(-1)), was calculated from the glucose disposal rate during the final 30 min of the clamp. Eighteen subjects had blood sampling every 10 min for 12 h to assess LH pulsatility. Hypogonadism was then induced with a GnRH antagonist, followed by sequential stimulation testing with GnRH (750 ng/kg, iv) and human chorionic gonadotropin (hCG; 1000 IU, im) to assess pituitary and testicular responsiveness, respectively. Nine subjects had normal glucose tolerance, nine had impaired glucose tolerance, and three had diabetes mellitus. There was a positive relationship between M and T levels (r = 0.46; P < 0.05). No relationship was seen between M and parameters of LH secretion, including mean LH levels, LH pulse amplitude, LH pulse frequency, and LH response to exogenous GnRH administration. In contrast, a strong correlation was observed between M and the T response to hCG (r = 0.73; P < 0.005). Baseline T levels correlated with the increase in T after hCG administration (r = 0.47; P < 0.05). During the clamp, T levels increased from a baseline level of 367 +/- 30 to 419 +/- 38 ng/dl during the last 30 min (P < 0.05). From these data we conclude that insulin resistance is associated with a decrease in Leydig cell T secretion in men. Additional studies are required to determine the mechanism of this effect.

Adult↗

PubMed2005

Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men.

OBJECTIVE: The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men. RESEARCH DESIGN AND METHODS: A total of 60 men (mean age 60.5 +/- 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity (V(O2max)) and expression of oxidative phosphorylation genes in skeletal muscle. RESULTS: A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity (r = 0.4, P < 0.005). Subjects with hypogonadal testosterone levels (n = 10) had a BMI >25 kg/m(2) and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts (n = 50); this relationship held true after adjusting for age and sex hormone-binding globulin but not BMI. Testosterone levels also correlated with V(O2max) (r = 0.43, P < 0.05) and oxidative phosphorylation gene expression (r = 0.57, P < 0.0001). CONCLUSIONS: These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.

Adult↗

PubMed2004

Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene.

Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder. Recently, loss-of-function mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been shown to cause autosomal dominant KS. To date, the detailed reproductive phenotype of KS associated with mutations in the FGFR1 has yet to be described. We report a kindred comprising a male proband with KS and spontaneous reversibility, whose mother had delayed puberty and whose maternal grandfather isolated anosmia. The proband presented at age 18 yr with KS and was subsequently treated with testosterone (T) therapy. Upon discontinuation of T therapy, he recovered from his hypogonadotropic hypogonadism, as evidenced by a normal LH secretion pattern, sustained normal serum T levels, and active spermatogenesis. The three members of this single family harbor the same FGFR1 mutation (Arg(622)X) in the tyrosine kinase domain. This report demonstrates 1) the first genetic cause of the rare variant of reversible KS, 2) the reversal of hypogonadotropic hypogonadism in a proband carrying an FGFR1 mutation suggests a role of FGFR1 beyond embryonic GnRH neuron migration, and 3) a loss of function mutation in the FGFR1 gene causing delayed puberty.

Adult↗

PubMed2004

Acute stress masking the biochemical phenotype of partial androgen insensitivity syndrome in a patient with a novel mutation in the androgen receptor.

Hypogonadism has traditionally been classified as either hypogonadotropic or hypergonadotropic based on serum gonadotropin levels. However, when hypothalamic suppression of GnRH secretion occurs, it can mask an underlying hypergonadotropic state. In this report we document the unusual case of a 61-yr-old man with androgen insensitivity and coincidental functional hypogonadotropic hypogonadism (HH). Although functional HH is not a well-recognized entity in the male, major stress has been reported to cause transient suppression of the hypothalamic-pituitary-gonadal axis in men. The patient in question was noted to have undervirilization, minimal pubertal development, hypogonadal testosterone, and low gonadotropin levels consistent with congenital HH during a hospital admission for myocardial infarction. However, the patient had also had surgery for hypospadias, a clinical feature not typically part of the phenotypic spectrum of congenital HH. We therefore hypothesized that the combination of acute stress and chronic glucocorticoid administration for temporal arteritis induced transient HH in a patient with a disorder of sexual differentiation in whom gonadotropin levels would have otherwise been elevated. Using clinical, molecular, and genetic studies, the patient was found to have partial androgen insensitivity syndrome (PAIS) caused by a novel mutation (Ser(740)Cys) in the ligand-binding domain of the androgen receptor. Subsequent studies of the patient confirmed the characteristic gonadotropin and sex steroid abnormalities of PAIS. We describe for the first time a patient with PAIS presenting with a reversible hypogonadotropic biochemical profile triggered by an acute illness and corticosteroid therapy. This case highlights the necessity for caution when interpreting gonadotropin levels during acute stress.

Androgen-Insensitivity Syndrome↗

PubMed2002

Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism.

GnRH treatment is successful in inducing virilization and spermatogenesis in men with idiopathic hypogonadotropic hypogonadism (IHH). However, a small subset of IHH men, poorly characterized to date, fail to reach a normal testicular volume (TV) and produce sperm on this therapy. To determine predictors of outcome in terms of TV and sperm count, we studied 76 IHH men (38% with anosmia) undergoing GnRH therapy for 12-24 months. The population was stratified according to the baseline degree of prior pubertal development: absent (group 1, n = 52), partial (group 2, n = 18), or complete (adult onset HH; group 3, n = 6). Cryptorchidism was recorded in 40% of group 1, 5% of group 2, and none in group 3. Pulsatile GnRH therapy was initiated at 5-25 ng/kg per pulse sc and titrated to attain normal adult male testosterone (T) levels. LH, FSH, T, and inhibin B (I(B)) levels were measured serially, and maximum sperm count was recorded. A longitudinal mixed effects model was used to determine predictors of final TV. LH (97%) and T (93%) levels were normalized in the majority of IHH men. Groups 2 and 3 achieved a normal adult testicular size (92%), FSH (96%), I(B) levels (93%), and sperm in their ejaculate (100%). However, given their prior complete puberty and thus primed gonadotropes and testes, group 3 responded faster, normalizing androgen production by 2 months and completing spermatogenesis by 6 months. In contrast, group 1 failed to normalize TV (11 +/- 0.4 ml) and I(B) levels (92 +/- 6 pg/ml) by 24 months, despite normalization of their FSH levels (11 +/- 2 IU/liter). Similarly, sperm counts of group 1 plateaued well below the normal range (median of 3 x 10(6)/ml) with 18% remaining azoospermic. The independent predictors of outcome of long-term GnRH therapy were: 1) the presence of some prior pubertal development (positive predictor; group effect (beta) = 4.3; P = 0.003); 2) a baseline I(B) less than 60 pg/ml (negative predictor; beta = -3.7; P = 0.009); and 3) prior cryptorchidism (negative predictor; beta = -1.8; P = 0.05). Notably, anosmia was not an independent predictor of outcome when adjusted for other baseline variables. Our conclusions are: 1) pulsatile GnRH therapy in IHH men is very successful in inducing androgen production and spermatogenesis; 2) normalization of the LH-Leydig cell-T axis is achieved more uniformly than the FSH-Sertoli cell-I(B) axis during GnRH therapy; and 3) favorable predictors for achieving an adult testicular size and consequently optimizing spermatogenesis are prior history of sexual maturation, a baseline I(B) greater than 60 pg/ml, and absence of cryptorchidism.

Adolescent↗

PubMed2002

The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism.

As our knowledge of the molecular mechanisms underlying idiopathic hypogonadotropic hypogonadism (IHH) expands, it becomes increasingly important to define the phenotypic spectrum of IHH. In this study we examined historical, clinical, biochemical, histological, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. We hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context. Thirty-eight percent of the population had Kallmann syndrome (KS; IHH with anosmia), 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, KS represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty). Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Comparing IHH patients according to the absence (68%) or presence (24%) of some prior pubertal development revealed significant differences in testicular size (3.3 +/- 0.2 vs. 11.8 +/- 1.2 ml; P < 0.001), incidence of cryptorchidism (40% vs. 5%; P < 0.05), microphallus (21% vs. 0%; P < 0.05), inhibin B levels (45 +/- 4 vs. 144 +/- 20 pg/ml; P < 0.0001), and Mullerian inhibitory substance levels (9.8 +/- 1.4 vs. 2 +/- 0.5 ng/ml). Most familial cases had no pubertal development (95% vs. 5%; P < 0.001); males with mutations in the KAL gene displayed the most severe phenotype. Mean gonadotropins levels (LH, 1.8 +/- 0.1 vs. 2.9 +/- 0.4 IU/liter; FSH, 2.2 +/- 0.2 vs. 3.3 +/- 0.3 IU/liter; P < 0.05) and the finding of apulsatile LH secretion based on frequent sampling (80% vs. 55%; P < 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive. The use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism, and microphallus), biochemical markers of testicular growth and differentiation (inhibin B and Mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. Viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability.

Adult↗