Charles H. Emerson

Recombinant human thyroid-stimulating hormone : pharmacology, clinical applications and potential uses

The major functions of pituitary thyroid-stimulating hormone (TSH) are to maintain the biosynthesis and secretion of the thyroid hormones L-thyroxine (T4) and L-3,5,3′triidothyronine (T3). The TSH core contains two apoproteins, the α and β subunits. The α subunit is identical to that of pituitary follitropin, pituitary lutropin and placental chorionic gonadotropin, whereas the β subunit is unique. TSH is a glycoprotein; the glycoprotein components of the a and β subunits account for more than 10% of their mass and are essential for normal thyrotropic action and intravascular kinetics. The hypothalamic tripeptide, TSH-releasing hormone (TRH) is required for optimum TSH biosynthesis, particularly as far as addition of the glycoprotein components is concerned. TRH deficiency is associated with secretion of TSH molecules that are appropriately measured in most assays but have reduced bioactivity. In previous years the TSH used in clinical practice was obtained and purified from bovine pituitaries. Bovine TSH was used to test thyroid function and to augment the uptake of radioiodine in patients with thyroid cancer. Bovine TSH has been largely abandoned as a clinical agent because of adverse immune reactions.A recombinant human TSH (rhTSH; Thyrogen®1), has been approved by the US FDA for diagnostic use in patients with thyroid cancer. The a and β subunits of Thyrogen® are identical to those of human pituitary TSH. Thyrogen® has a specific activity of approximately 4 IU/mg and is a potent stimulator of T4, T3 and thyroglobulin (Tg) secretion in healthy volunteers. It also increases thyroid iodide uptake in patients with thyroid cancer or multinodular goitre and in volunteers, even those exposed to large amounts of stable iodide. Thyroid cancer patients who have been treated by thyroidectomy and radioiodine ablation but are at risk of harbouring residual thyroid cancer are candidates for Thyrogen® administration to prepare them for whole body iodide scans and serum Tg measurements. In thyroidectomised thyroid cancer patients who are unable to secrete pituitary TSH upon thyroid hormone withdrawal, Thyrogen® is the only acceptable method to prepare them for these procedures. Thyrogen® has been used on a compassionate basis to prepare patients for radioiodine ablation. rhTSH, in addition to being useful in the management of patients with thyroid cancer, is potentially useful to test thyroid reserve and to aid in thyroid-related nuclear medicine procedures. In the future, TSH analogues that have superagonist or antagonist properties may become available as therapeutic agents.

Role of the Placenta in Fetal Thyroid Homeostasis

The placenta is usually regarded as a conduit through which maternal nutrients pass to the fetus, or as a barrier that allows for fetal development in an insulated environment. Thus, with respect to thyroid function, it is well known that the placenta transfers iodide to, and excludes thyrotropin from, the fetal circulation. It is less recognized that the placenta is a metabolically active organ, and that this activity is important for the conversion of fetal substrates. In order to relate this aspect of placenta physiology to fetal thyroid homeostasis it is necessary to first review thyroid hormone profiles and pharmacokinetics in the fetus.

Thyroid Function and Disease in the Female

The thyroid has attracted the interest of observers for centuries. Goiter in women is depicted in artwork from the ancient Egyptians, the Aztecs, and many other cultures. In 1656, Warton suggested that the gland was more prominent in women because its role was to round out and beautify the neck.1 Gull’s report in 1874 “On a cretinoid state supervening in adult life in women,” was one of the first descriptions which drew attention to similarities between myxedema and cretinism. A few years later, Ord provided the first comprehensive description of myxedema.1 Its title emphasized the point that this disease was seen predominantly in women. It is now clear that women are more susceptible than men to all the common thyroid diseases including autoimmune disorders (Graves’ disease, Hashimoto’s thyroiditis), simple goiter, and thyroid neoplasia.