Thyroid Stimulating Hormone Receptor

The TSHR (Thyroid Stimulating Hormone Receptor) is a receptor protein encoded by the TSHR gene, which is located on chromosome 14q24-q31. Three transcript variants have been found for the TSHR gene that encode different isoforms of the receptor protein.

The thyroid-stimulating hormone receptor (TSH-R) is a membrane protein and an important regulator of thyroid cell metabolism. Its ligands are thyrothropin and thyrostimulin. Defects in the coding gene are a cause of various types of hyperthyroidism.

The thyroid-stimulating hormone receptor (TSH-R) is predominantly expressed in the membrane of thyrocytes, where it stimulates almost every aspect of their metabolism. Several extrathyroidal localizations of the receptor have been found, including the pituitary gland, hypothalamus and other areas of the central nervous system, periorbital tissue, skin, kidney, adrenal gland, liver, immune system cells, blood cells and vascular tissue, adipose tissue, cardiac and skeletal muscle, and bone. Although the functionality of the receptor has been proven in most of these tissues, its physiological significance is not always clear.

Importance of the TSH receptor in extrathyroidal diseases: Graves' orbitopathy (GO) is an autoimmunity-related phenomenon caused by orbital lymphocytic infiltration with a predominance of T lymphocytes, edema and an increase in orbital connective tissue, adipose tissue and extraocular muscle volume. TSH-R is the target autoantigen in ophthalmopathy and periorbital fibroblasts are the substrate of the autoimmune attack. Stimulation of TSH-R in orbital fibroblasts by the autoimmunological response leads to activation of intracellular signaling pathways, production of glycosaminoglycans and an increase in proliferation, adipogenesis and myofibrillogenesis.

The TSH-R is also used as a target antigen in Graves' dermatopathy (pretibial myxedema = confusing term, as myxedema indicates hypothyroidism), is characterized by an infiltration of the subcutaneous tissue by glycoproteins (especially pretibial). It occurs very rarely without a basedow ophthalmopathy. The lesions are often itchy and reddened in the early stages and then turn brown. The dermatopathy can also precede or follow hyperthyroidism by years. (a confusing term, as myxedema indicates hypothyroidism), is characterized by an infiltration of the subcutaneous tissue by glycoproteins (especially pretibial). It occurs very rarely without a basedow ophthalmopathy. The lesions are often itchy and reddened in the early stages and then turn brown. Dermatopathy can also precede or follow hyperthyroidism by years. Thyroid hormone receptors have been found in skin fibroblasts, sebaceous glands, smooth muscle cells and Schwann cells. Similar to Graves' orbitopathy, this rare manifestation is associated with high titers of TSHRAbs and is characterized by a large amount of glycosaminoglycans distributed in the reticular part of the dermis. TSH-R immunoreactivity has been detected in the prepuce of patients with Graves' dermatopathy.

TSH-R and keratinocytes: Keratins are the major proteins produced by keratinocytes. The binding of T3 to thyroid receptors regulates gene expression in keratinocytes. This confirms that thyroid hormones play an important role in the proliferation of keratinocytes. In vitro analyses have shown that keratinocytes with a T3 deficiency have lower levels of plasminogen activator, an enzyme that plays a role in the shedding process of corneocytes. Human skin fibroblast cultures showed that other genes such as the RAS oncogene family (RAB3B), collagen (COLVIA3-CVIIIA1), hypoxia-inducible factor (HIF)-1A, the calcineurin inhibitor ZAKI4a and the AKR family, which respond to thyroid hormones, also play a role.

The effect of thyroid hormones on the skin is primarily mediated by TSH-R. The two isoforms of TSH receptors, thra and thrb, act as both positive and negative regulators in the skin. It has been shown that T3 stimulates the growth of both epidermal keratinocytes and skin fibroblasts. During embryogenesis, thyroid hormone plays an important role in establishing the barrier function of the epidermis by increasing the activity of the cholesterol sulfate cycle, and thyroid hormone accelerates barrier formation, which can impair the barrier function of the epidermis in hypothyroidism. Hyaluronic acid is the main glycosaminoglycan that accumulates in myxedema, which can affect multiple organs. Extravascular accumulation with inadequate lymphatic drainage results from transcapillary "leakage" of albumin. The appearance of the skin is cool and pale as the dermal mucopolysaccharides and water content are impaired in hypothyroidism.

1. Cohen B et al. (2023) Dermatologic manifestations of thyroid disease: a literature review. Front Endocrinol (Lausanne) 14:1167890.
2. Costagliola S et al. (2002) Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors. EMBO J 21:504-513.
3. Nakabayashi K et al. (2002) Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor. J Clin Invest 109:1445-1452.