The secretion of human chorionic gonadotropin (hCG) from a nonseminomatous germ-cell tumor activates luteinizing hormone (LH) receptors in testicular Leydig cells and promotes the secretion of both testosterone and estradiol, subsequently leading to the development of gynecomastia and the suppression of gonadotropin-releasing hormone (GnRH) and LH levels.
Markedly elevated hCG levels also activate thyrotropin receptors in the thyroid, resulting in diffuse uptake of iodine and increased synthesis and release of thyroid hormones (T4 and T3) and subsequently leading to the development of hyperthyroidism and the suppression of thyroid-releasing hormone (TRH) and thyrotropin levels.
hCG Clinical Pearls
· What types of tumors secrete hCG?
Germ-cell tumors are the neoplasms that are most likely to secrete hCG, but other nontrophoblastic tumors that originate in the lungs, liver, stomach, or kidneys have also been associated with ectopic hCG production.
· Among patients with hCG-secreting tumors, the prevalence of hyperthyroidism increases when the hCG level rises above what threshold?
HCG has low affinity for the thyrotropin receptor, and thyroid activity is correlated to hCG level. A very high hCG level, which can be present in persons who are pregnant or have certain tumors, may cause clinical manifestations of hyperthyroidism.
In the absence of thyrotropin-receptor mutations, the combination of frank hyperthyroidism and undetectable thyrotropin levels is typically seen only when hCG levels are higher than 50,000 IU per liter. Several case series involving pregnant patients and patients with hCG-secreting tumors have shown that the prevalence of hyperthyroidism increases when the hCG level rises above the threshold of 50,000 IU per liter and that hyperthyroidism occurs in up to two thirds of patients with hCG levels higher than 200,000 IU per liter.
· Do both pure seminomas and nonseminomatous germ-cell tumors produce hCG?
Germ-cell tumors are either pure seminomas or nonseminomatous germ-cell tumors.
Seminomas do not commonly produce hCG, and if they do, the levels are typically lower than 1000 IU per liter.
In contrast, approximately 20 to 40% of nonseminomatous germ-cell tumors produce hCG, and levels can exceed the threshold of 50,000 IU per liter. Most nonseminomatous germ-cell tumors are composed of a mix of different cell types, including elements of seminoma, choriocarcinoma, teratoma, yolk-sac tumor, and embryonal cancers.
Choriocarcinoma elements are the most aggressive and most often associated with high secretion of hCG and no production of alpha-fetoprotein. Approximately 10% of germ-cell tumors are extragonadal. Several studies have shown that 3 to 5% of patients with nonseminomatous germ-cell tumors have high hCG levels and hyperthyroidism.
· What are some features of testicular choriocarcinoma?
In men, especially young men, choriocarcinoma is usually detected as a component of a testicular mixed germ-cell tumor and is exceedingly rare in its pure form.
Choriocarcinoma has a propensity to metastasize to the central nervous system. In some orchiectomy specimens, metastatic choriocarcinoma appears only as a regressed germ-cell tumor.
Choriocarcinoma is the germ-cell tumor that is most likely to have spontaneous regression because of its aggressive nature and tendency to outgrow the blood supply, but regression can be seen in seminomas and embryonal carcinomas.
The diagnosis of choriocarcinoma is primarily based on the presence of intermixed mononuclear trophoblasts and syncytiotrophoblasts, a finding that distinguishes this tumor from other germ-cell tumors with only scattered syncytiotrophoblasts.
Occasionally, persons with very high hCG levels have been noted to have hemorrhage from metastatic sites of choriocarcinoma, a feature that is referred to as the choriocarcinoma syndrome.
