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Objective: TSH receptor (TSHr) mediates the activating action of TSH on the thyroid gland resulting in the growth and proliferation of thyrocytes and thyroid hormone production. TSHr is a major autoantigen in Graves' disease (GD) and is the target for TSHr antibodies. In GD, thyroid-stimulating antibodies (TSAb) are competitive agonists of TSH. In atrophic thyroiditis (AT), thyroid-stimulating blocking antibodies (TSHBAb) are TSH antagonists. The TSHr together with the LH receptor (LHr) and FSH receptor (FSHr) are G-protein-coupled receptors with considerable amino acid homologies in the extracellular domain. We studied the cross-reactivity of the antibodies measured in sera from patients with GD or AT on the LHr and FSHr function., Methods: We tested the activity of TSAb and TSHBAb in cell lines expressing the LHr and the FSHr. To this purpose a pSVL-FSHr construct was transfected in CHO cells and one clone was used., Results: Twenty-eight sera from patients with GD and four from patients with AT, known to contain TSHr antibodies measured with a radioreceptor assay, were selected. TSAb and TSHBAb activities were measured in CHO cells expressing the TSHr (CHO-TSHr). TSAb and TSHBAb were then tested with the cell lines expressing the LHr and the FSHr for their ability to elicit cAMP accumulation or inhibit FSH/LH-induced cAMP production. None of the TSAb identified was able to stimulate cAMP increase in CHO-LHr or CHO-FSHr. Similarly, none of the TSHBAb was able to block the cAMP response induced by FSH or LH in the respective cell lines., Conclusions: Our results confirm the notion of the organ-specific nature of the TSHr antibodies.