Activin A and activin receptors in the human thyroid: A link to the femalepredominance of goiter?

Activin A belongs to the TGF-beta family of growth factors involved in cont rol of tissue formation by growth inhibition and to a family of hormones in volved in human reproduction. Serum levels of dimeric activin A display a s exual dimorphism with significantly higher circulating hormone concentratio ns in men than in women after menopause. Since goiter is far more frequent in women than in men, we investigated the role of this sex-related growth f actor in the human thyroid. Primary cultures were obtained from 3 patients with goiter, and 4 with recurrent goiter. Activin A significantly inhibited the proliferation of human thyroid follicular epithelial cells in vitro in concentrations between 0.5 and 50 ng/ml and was almost as potent as TGF be ta -1. Analysis in native tissues from 12 normal thyroids, 16 goiters, and 5 Graves thyroids demonstrated mRNA expression of the activin subunit betaA , TGF beta -receptor type I and II, activin receptors type I receptors alk2 and alk4, and activin type II receptors actRII and actRIIb. Isoform analys is of the major functional type I activin receptor alk4 revealed the full-l ength transcript SKR2-1 and transcripts for the partially truncated protein s SKR2-2 and SKR2-3 in normal thyroids and goiters. Semi-quantitative RT-PC R revealed a significant 2.5-fold decrease of mRNA for alk4-1 type I activi n receptors in goiter as compared to normal thyroid (p < 0.05), whereas exp ression of the type II receptor actRII was unchanged. These data identify a novel growth inhibitory pathway by activin in the human thyroid. Down-regu lation of activin receptor type Ib in goiter hints towards end-organ change s which could contribute to deficient growth inhibition. These data provide a mechanistic model how the sexually dimorphic hormone activin A may prote ct males from goitrogenesis.