Usefulness of the free alpha-subunit to diagnose hypogonadotropic hypogonadism

Differentiating constitutional delay of growth and puberty from hypogonadotropic hypogonadism is still a problem in clinical practice. Our previous study demonstrated that the peak/basal ratio of the free alpha-subunit of the glycoprotein hormones is higher in normal prepubertal boys than in male adults with hypogonadotropic hypogonadism. The objective of this study was to assess the performance of this ratio in normal male patients at different ages and levels of pubertal development, and in patients with hypogonadotropic hypogonadism, both isolated and combined with other pituitary hormone deficiencies.

Cohort study.

Twenty-eight normal prepubertal males between 6 and 8 years; 20 normal prepubertal males between 9 and 13 years; 18 males with constitutional delay of growth and puberty; 26 normal pubertal males; 13 adult men with isolated hypogonadotropic hypogonadism; 21 adult men with complete hypogonadotropic hypogonadism combined with other hormone deficiencies; and 11 adult men with partial hypogonadotropic hypogonadism combined with other hormone deficiencies.

Serum levels of free alpha-subunit immediately before (basal), and 30 and 60 min after 100 micro g intravenous GnRH were measured by immunofluorimetry. Median and P25-P75 range of the peak/basal ratio of the free alpha-subunit was determined for each group. A receiver operating characteristics curve was calculated. Results were compared using the Kruskal-Wallis test.

The peak/basal ratio of the free alpha-subunit was higher in patients with constitutional delay of growth and puberty (7.46) than in those with isolated hypogonadotropic hypogonadism (2.73), complete combined hypogonadotropic hypogonadism (1.58), and partial combined hypogonadotropic hypogonadism (2.61; P < 0.001). A peak/basal ratio < 3.26 identified hypogonadotropic hypogonadism with 93.2% sensitivity and 94.4% specificity when compared to constitutional delay of growth and puberty. There was no statistical difference between the peak/basal ratio of prepubertal patients between 6 and 8 years (7.20), patients between 8 and 13 years (8.71), normal pubertal males (8.10) and those with constitutional delay of growth and puberty (7.46). In a group of boys with delayed puberty, a cut-off point of 3.69 defined hypogonadotropic hypogonadism with 95.6% sensitivity and 94.4% specificity. A cut-off point of 4.81 gave 100% sensitivity (88.9% specificity), and 3.09 gave 100% specificity (86.7% sensitivity).

The peak/basal ratio of the free alpha-subunit can be used for the differential diagnosis of constitutional delay of growth and puberty and hypogonadotropic hypogonadism, irrespective of age. This distinction allows early investigation and treatment of patients with hypogonadotropic hypogonadism and reassurance for those with constitutional delay of growth and puberty.