Human chorionic gonadotropin stimulates thyroid hormone secretion, iodide uptake, organification, and adenosine 3',5'-monophosphate formation in cultured human thyrocytes.
Despite extensive studies, the issue of whether hCG possesses intrinsic thyrotropic activity remains unresolved. This is mainly because in the experimental systems used so far, the parameters measured did not include the thyroid-specific functions of iodine organification and the hormonal end-point response, T3 secretion, and cells of nonhuman origin were employed, constituting a major drawback in view of the wide variation in sensitivity of thyroid responsiveness to hCG in different species. We investigated the thyrotropic activity of hCG, using for this purpose a novel homologous assay system consisting of human thyroid follicles cultured suspended in collagen gel in serum-free medium. Under these conditions, the cells are organized as follicular three-dimensional structures with normal polarity, enabling enhanced responsiveness to hormonal stimulation. The parameters measured were the thyroid-specific functions of iodide uptake, organification, and T3 secretion, as well as formation of the second messenger, cAMP. Purified hCG (biological potency, 21,700 IU/mg; with no detectable TSH by immunoradiometric TSH assay) did indeed exhibit thyroid stimulatory activity. At doses ranging from 10-400 mg/L, hCG induced a dose-dependent increase in the parameters measured. The rise from basal to maximal levels achieved after hCG stimulation was 1.3 to 3.6 pmol/well for cAMP formation, 34 to 21,408 cpm/well for iodide uptake, 261 to 20,167 cpm/well for iodide organification, and 40 to 927 fmol/well for T3 secretion. Maximal levels elicited by hCG (200 mg/L) relative to maximal values achieved with bovine TSH were 49%, 56%, and 42% for iodide uptake, organification, and T3 secretion, respectively, and only 5% for cAMP. Iodide uptake proved to be the most sensitive indicator of the thyrotropic activity of hCG, with increases occurring at a concentration of 10 mg/L. Acting as a partial agonist, hCG was also capable of dose-dependently inhibiting TSH-stimulated cAMP formation. The free alpha- and beta- subunits of hCG, at doses as high as 200 mg/L, had no thyroid-stimulating effect. The present data thus clearly demonstrate that hCG is a human thyroid stimulator. Moreover, hCG managed to elicit substantial biological cell responses in human thyrocytes while evoking minimal amounts of cAMP, illustrating the concept of cAMP superfluity and highlighting the potential pitfalls of using cAMP as a reliable measure of hormonal bioactivity.
Kraiem
Z
Z
Endocrine Research Unit, Carmel Medical Center, Haifa, Israel.
Sadeh
O
O
Blithe
D L
DL
Nisula
B C
BC
D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000008:administration & dosage / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007454:Iodides / Q000378:metabolism*; D007457:Iodine Radioisotopes; D013961:Thyroid Gland / Q000187:drug effects / Q000502:physiology*; D013972:Thyrotropin / Q000494:pharmacology; D014284:Triiodothyronine / Q000378:metabolism*
D006063:Chorionic Gonadotropin; D007454:Iodides; D007457:Iodine Radioisotopes; D014284:Triiodothyronine; D013972:Thyrotropin; D000242:Cyclic AMP