Within the thyrotropic control loop, the Brokken-Wiersinga-Prummel control loop is an on-off feedback loop from TSH to its own formation. With the help of this control loop, TSH formation is limited. It has significance for the interpretation of TSH levels in Graves’ disease.
What is the Brokken-Wiersinga-Prummel regulatory loop?
With the help of the regulatory loop, TSH formation is limited. TSH is produced in the pituitary gland and controls the formation of thyroid hormone thyroxine, for example. The Brokken-Wiersinga-Prummel feedback control loop is an ultrashort feedback mechanism of the TSH level to its own TSH secretion. The more TSH is secreted, the more TSH formation is inhibited. However, it is a downstream regulatory circuit within the main thyrotropic regulatory circuit. TSH is a proteinogenic hormone called thyrotropin. Thyrotropin is produced in the pituitary gland and controls the formation of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). The two hormones stimulate the metabolism. If their concentration is too high, hyperthyroidism (hyperthyroidism) occurs with accelerated metabolic processes, palpitations, sweating, tremors, diarrhea and weight loss. In the opposite case, there is hypothyroidism (underactive thyroid gland) with slowing down of all metabolic processes and weight gain. The main control loop causes an increase in T3 and T4 concentrations to decrease thyrotropin release via a negative feedback loop. In addition to the thyrotropic master control loop, there are other downstream slave control loops. These include the Brokken-Wiersinga-Prummel feedback control loop as an ultrashort feedback mechanism by which TSH synthesis is additionally limited.
Function and task
The biological significance of the Brokken-Wiersinga-Prummel regulatory circuit is, in all likelihood, to prevent excessive TSH release. It provides a pulse-like fluctuation in TSH levels. Overall, the processes within the thyrotropic control loop are complicated and, due to their complexity, require several downstream control loops. Thus, in addition to the ultrashort feedback mechanism, there is also the long feedback of thyroid hormones on the release of TRH (thyrotropin releasing hormone) and control circuits for adjusting the plasma protein binding of T3 and T4. In addition, TSH levels are linked to the activity of deiodinases, which convert inactive T4 to activated T3. The thyrotropic master control loop also includes the activity of TRH (thyrotropin releasing hormone). Thyrotropin releasing hormone is secreted in the hypothalamus and regulates the formation of TSH. With the help of this hormone, the hypothalamus establishes the target value for the thyroid hormones. To do this, it constantly determines the actual value. The target value must be in reasonable proportion to the corresponding physiological conditions. When the demand for thyroid hormones increases, the formation of TRH is stimulated, which in turn stimulates the formation of TSH. Elevated TSH levels produce increased levels of the thyroid hormones T4 and T3. This requires activation of deiodinases to induce conversion of T4 to T3. In addition, iodine uptake is also regulated by TSH. However, it is also subject to its own iodine-dependent regulation. T4 provides the most important feedback for the synthesis of TSH. T3 acts only indirectly by binding to a thyrotropin receptor or a receptor for TRH. Thus, the secretion of TSH is influenced by TRH, thyroid hormones, and also by somatostatin. Furthermore, neurophysiological signals also influence the formation of TSH. Via the downstream Brokken-Wiersinga-Prummel regulatory circuit, the TSH concentration is additionally limited by its own TSH secretion. This probably occurs via the peptide hormone thyrostimulin. The function of this hormone is currently unknown. Like TSH, it docks at the TSH receptor and seems to act similarly. Therefore, it may play a mediating role in the Brokken-Wiersinga-Prummel regulatory circuit. However, these complexities do not allow for a simple correlation between concentrations of TSH and thyroid hormones.
Diseases and disorders
The complex relationship is particularly evident in the treatment of hyperthyroidism and hypothyroidism.Thus, hypothyroidism may be due to several causes, such as destroyed thyroid tissue, absent thyroid gland, deficiency of TSH due to hypopituitarism or deficiency of TRH due to hypothalamic insufficiency. Hyperthyroidism can result from autoimmune diseases of the thyroid gland, in TSH-producing tumors, or in excess TRH. These diseases lead to the thyrotropic control circuit not being able to function properly. The importance of the Brokken-Wiersinga-Prummel control loop is particularly evident in the so-called Graves’ disease. Here, the ratio of the concentrations of TSH and the thyroid hormones no longer matches. Graves’ disease is characterized by hyperthyroidism due to autoimmunological reactions. In this disease, the immune system attacks the receptors for TSH in the follicular cells of the thyroid gland. These are IgG-type antibodies that bind to the TSH receptor. These autoantibodies thereby permanently stimulate the receptors and thus mimic the natural effect of TSH. The permanent stimulation also results in the permanent production of thyroid hormones. A growth stimulus of thyroid tissue is initiated, so that it becomes larger by growth of a (goiter). The existing TSH is no longer effective because it cannot bind to the receptors. Due to the increased levels of thyroid hormones, the concentration of TSH becomes even lower. This effect is further enhanced by the fact that the autoantibodies also act directly on the pituitary gland, thereby inhibiting the release of TSH. Despite low TSH concentration, hyperthyroidism is present in Graves’ disease. The antibodies also attack the retroorbital eye muscles, which can cause the eyes to protrude. Diagnostically, increased values for the thyroid hormones T3 and T4 and suppressed values for TSH can be detected. This correlation is typical for Graves’ disease. Usually, there is a correlation between elevated thyroid levels and elevated TSH levels.
