Klinefelter syndrome is characterized by a vast range of phenotypes related to androgen effects. Testosterone (T) acts via the X-linked androgen receptor gene carrying the CAG repeat (CAGn) polymorphism, the length of which is inversely associated with androgen action and might account for the marked variation in phenotypes. In 77 newly diagnosed and untreated Klinefelter patients with a 47,XXY karyotype we assessed phenotype and social traits in relation to X-weighted biallelic CAGn length using X-chromosome inactivation analysis after digestion of leukocyte DNA with methylation-sensitive HpaII. Forty-eight men were hypogonadal and received T substitution therapy; in these, pharmacogenetic effects were investigated. The shorter CAGn allele was preferentially inactive. CAGn length was positively associated with body height. Bone density and the relation of arm span to body height were inversely related to CAGn length. The presence of long CAGn was predictive for gynecomastia and smaller testes, whereas short CAGn were associated with a stable partnership and professions requiring higher standards of education also when corrected for family background. There was a trend for men with longer CAGn to be diagnosed earlier in life. Under T substitution, men with shorter CAGn exhibited a more profound suppression of LH levels, augmented prostate growth, and higher hemoglobin concentrations. A significant genotype-phenotype association exists in Klinefelter patients: androgen effects on appearance and social characteristics are modulated by the androgen receptor CAGn polymorphism. The effects of T substitution are pharmacogenetically modified. This finding is magnified by preferential inactivation of the more functional short CAGn allele.
Testosterone (T) substitution in hypogonadal men results in growth of the prostate gland. T effects are mediated via the androgen receptor (AR). The length of the (CAG)n polymorphism of the AR gene is negatively associated with transcriptional activity and might account for variations in prostate growth during substitution therapy. In 131 hypogonadal men aged 18-69 yr, we assessed prostate volume longitudinally by transrectal ultrasonography and determined AR (CAG)n, sex hormone levels, and anthropometric measures. Sixty-nine men with primary and 62 with secondary hypogonadism began substitution therapy with im injections of T enanthate (n = 81), transdermal T preparations (n = 19), sc injections of human chorionic gonadotropin (n = 17), or oral T undecanoate (n = 14) for 2.4 +/- 0.8 yr. Average prostate size increased from 15.8 +/- 6.1 ml to 23.0 +/- 6.8 ml. ANOVA including covariates revealed initial prostate size to be dependent on age (P < 0.001) and baseline T levels (P = 0.01) but not on number of (CAG)n (ranging from 13-30; mean, 21.4 +/- 3.5). Prostate growth per year and absolute prostate size under substituted T levels (6.1 +/- 3.3 to 21.6 +/- 10.3 nmol/liter) were strongly dependent on (CAG)n, with lower treatment effects in longer repeats (both P < 0.001). Other significant predictors were initial prostate size (negative for growth rate and positive for absolute size) and age (positive for both growth rate and absolute size). The odds ratio for men with (CAG)n less than 20, compared with those with (CAG)n of 20 or more to develop a prostate size of at least 30 ml under T substitution, was 8.7 (95% confidence interval, 3.1-24.3; P < 0.001). This observation was strongly age dependent with a more pronounced odds ratio in men older than 40 yr. This first pharmacogenetic study on androgen substitution in hypogonadal men demonstrates a marked influence of the AR gene (CAG)n polymorphism on prostate growth.
Objective: It is generally accepted that both gonadotropins LH and FSH are necessary for initiation and maintenance of spermatogenesis. We investigated the relative importance of FSH for the maintenance of spermatogenesis in hypogonadotropic men. Subjects and methods: 13 patients with gonadotropin deficiency due to idiopathic hypogonadotropic hypogonadism (IHH), Kallmann syndrome or pituitary insufficiency were analyzed retrospectively. They had been treated with gonadotropin-releasing hormone (GnRH) ðn ¼ 1Þ or human chorionic gonadotropin/human menopausal gonadotropin (hCG/hMG) ðn ¼ 12Þ for induction of spermatogenesis. After successful induction of spermatogenesis they were treated with hCG alone for maintenance of secondary sex characteristics and in order to check whether sperm production could be maintained by hCG alone. Serum LH, FSH and testosterone levels, semen parameters and testicular volume were determined every three to six months. Results: After spermatogenesis had been successfully induced by treatment with GnRH or hCG/hMG, hCG treatment alone continued for 3 -24 months. After 12 months under hCG alone, sperm counts decreased gradually but remained present in all patients except one who became azoospermic. Testicular volume decreased only slightly and reached 87% of the volume achieved with hCG/ hMG. During treatment with hCG alone, FSH and LH levels were suppressed to below the detection limit of the assay. Conclusion: Once spermatogenesis is induced in patients with secondary hypogonadism by GnRH or hCG/hMG treatment, it can be maintained in most of the patients qualitatively by hCG alone, in the absence of FSH, for extended periods. However, the decreasing sperm counts indicate that FSH is essential for maintenance of quantitatively normal spermatogenesis.
Mutations in the leptin gene can result in profound obesity in both rodents and humans. 1-3 In humans, serum leptin levels correlate with body mass index 4 (BMI: kg m −2 ). However, in patients with anorexia nervosa (AN) leptin levels are lower than in BMI-matched healthy controls. 5 We had previously argued that genes involved in weight regulation should be considered as candidate genes for AN. 6 To investigate this hypothesis we screened the coding region of the leptin gene and part of the leptin gene linked upstream region (LEGLUR) in 49 patients with AN and 315 children and adolescents with extreme obesity. Two novel mutations in the coding region (Ser-91-Ser; Glu-126-Gln), each found in a single proband, and a novel polymorphism in the LEGLUR (position −1387 G/A; frequency of both alleles approximately 0.50) were identified. Tests for association of LEGLUR polymorphism alleles were negative by comparing allele frequencies between 115 AN patients, 71 bulimia nervosa patients, 315 extremely obese children and adolescents, 141 healthy underweights and 50 controls that were not selected for body weight. Tests for transmission disequilibrium were also negative. Hence, an influence of variations in the leptin gene on eating disorders or extreme early onset obesity could not be detected.
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