Clinical Information

The 3 human pituitary glycoprotein hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin, and the placenta-derived chorionic gonadotropin, are closely related tropic hormones. They signal through G-protein-coupled receptors, regulating the hormonal activity of their respective endocrine target tissues. Each is composed of an alpha- and a beta-subunit, coupled by strong noncovalent bonds. The alpha-subunits of all 4 hormones are essentially identical (92 amino acids; molecular weight [MW] of the "naked" protein:10,205 Da), being transcribed from the same gene and showing only variability in glycosylation (MW of the glycosylated proteins: 13,000-18,000 Da). The alpha-subunits are essential for receptor transactivation. By contrast, all the different beta-subunits are transcribed from separate genes, show less homology, and convey the receptor specificity of the dimeric hormones.

Under physiological conditions, alpha- and beta-chain synthesis and secretions are tightly coupled, and only small amounts of monomeric subunits are secreted. However, under certain conditions, coordinated production of intact glycoprotein hormones may be disturbed and disproportionate quantities of free alpha-subunits are secreted. In particular, some pituitary adenomas may overproduce alpha subunits. Although most commonly associated with gonadotroph- or thyrotroph-derived tumors, alpha-subunit secretion has also been observed in corticotroph, lactotroph, and somatotroph pituitary adenomas. Overall, depending on cell type and tumor size, 5% to 30% of pituitary adenomas will produce sufficient free alpha-subunits to result in elevated serum levels, which usually fall with successful treatment. Stimulation testing with hypothalamic releasing factors (eg, gonadotropin-releasing hormone [GnRH] or thyrotropin-releasing hormone [TRH]) may result in further elevations disproportionate to those seen in individuals without tumors.

Measurement of free alpha-subunit after GnRH-stimulation testing can also be useful in the differential diagnosis of constitutional delay of puberty (CDP) versus hypogonadotrophic hypogonadism (HH). CDP is a benign, often familial, condition in which puberty onset is significantly delayed, but eventually occurs and then proceeds normally. By contrast, HH represents a disease state characterized by lack of gonadotropin production. Its causes are varied, including hypothalamic and pituitary inflammatory or neoplastic disorders, a range of specific genetic abnormalities, as well as unknown causes. In children, HH results in complete failure to enter puberty without medical intervention. In children with CDP, in normal pubertal children, in normal adults and, to a lesser degree, in normal prepubertal children, GnRH administration results in increased serum LH, FSH, and alpha-subunit levels. This response is greatly attenuated in patients with HH, particularly regarding the post-GnRH rise in alpha-subunit concentrations.