Treatment of isolated hypogonadotropic hypogonadism effect on bone mineral density and bone turnover

Isolated hypogonadotropic hypogonadism (IHH) presents with delayed puberty in the late teens or early twenties, with a period of testosterone deficiency during active growth. The aims of the study were to determine 1) whether long term treatment of IHH results in normalization of bone density (BMD) and bone turnover, and 2) whether BMD and bone turnover respond to increasing doses of hCG. We studied 10 men, aged 26-46 yr, with IHH who were treated with hCG or testosterone esters (Sustanon) for 2-22 yr, with age at the start of treatment between 17-29 yr, and 10 age- and body weight-matched normal men as a control group. At baseline, lumbar spine, femoral neck, trochanter, and Ward's triangle BMD values were decreased, and serum bone Gla-protein, bone alkaline phosphatase, and urinary pyridinoline, deoxypyridinoline, and N-terminal telopeptide of type I collagen were increased compared with control values (by paired t test, P = 0.02, 0.03, 0.01, 0.05, 0.002, 0.02, 0.02, 0.007, and 0.006, respectively). The age at initial therapy was significantly correlated with total body BMD (r = -0.73; P = 0.017) and lumbar spine BMD (r = -0.756; P = 0.0097). Serum free testosterone was correlated with total body and trochanter BMD (r = 0.635; P = 0.048 and r = 0.629; P = 0.05), and serum free estradiol was correlated with total body and trochanter BMD (r = 0.641; P = 0.045 and r = 0.634; P = 0.048). Six of the 10 patients were recruited for a longitudinal study in which the dose of hCG was increased monthly from 2000 i.u. twice per week to 6000 i.u. twice per week. After increasing doses of hCG, levels of serum testosterone and estradiol and total body BMD increased significantly (by paired t test P = 0.001, 0.003, and 0.01, respectively). Serum bone Gla-protein levels increased by the first month and then decreased (paired t test, corrected by Bonferroni's method). Serum bone alkaline phosphatase and urinary N-terminal telopeptide of type I collagen/creatinine levels decreased significantly after increasing the dose of hCG. We conclude that patients with IHH who have serum testosterone within the laboratory reference range may require a higher dose of hCG to normalize BMD and bone turnover.