11th April 2024

Normal growth

Physiology of growth hormone

Released in a pulsatile manner, the production of HGH is controlled in a negative feedback loop, which can be influenced by behavioural factors such as sleep, stress and exercise. Growth hormone-releasing hormone (produced in the hypothalamus) and ghrelin (produced from the stomach when hungry) are the main stimulants that act on the somatotrophs located in the anterior pituitary, resulting in the production/secretion of HGH. Increased HGH levels, in turn, stimulate hepatocytes to produce insulin-like growth factor (IGF-1) which directly reduces the release of HGH and indirectly via somatostatin. HGH also self-regulates its release by inhibiting the production of GHRH.

HGH can directly and indirectly stimulate growth. HGH activates mitogen-activated protein kinases (MAPK), initiating a cascade of protein activations that eventually result in increased gene transcription, replication and cellular division. Indirectly, IGF activates tyrosine kinase-mediated pathways, inhibiting cell apoptosis and increasing cellular division.

Physiology of the thyroid hormones

Thyroid hormones have a wide range of effects across multiple organs and tissues in the body. Production of thyroid hormones starts with the release of thyrotropin-releasing hormone from the periventricular nucleus of the hypothalamus. TRH binds to G-protein coupled receptors in cells located in the anterior pituitary gland, activating a complex signalling cascade that ends with the activation of protein kinase C, which stimulates thyroid-stimulating hormone production. TSH is released into the blood, where it will bind to G-protein coupled receptors of thyroid follicular cells, initiating the production of thyroglobulins. It also activates protein kinase A, an important enzyme responsible for mediating iodide uptake and oxidation in thyroglobulins via NaI symporters and thyroid peroxidase, respectively. Coupling reactions occur between MIT and DIT, producing T3 and T4, which are released into the circulation in a 20:80 ratio.

Only a small proportion of thyroid hormone remains unbound (~0.2%). The rest react to and are carried by transporter proteins such as thyroxine-binding globulin and albumin. When required, T3/T4 dissociate themselves from their transporter protein and enter the targeted cells either by diffusion or surface carrier proteins. Like most hormones associated with hypothalamus-pituitary axis, the concentration of thyroid hormones is controlled by a negative feedback loop. High concentrations of T3/T4 inhibit the release of TRH and TSH. External influences can affect this system; hormones such as somatostatin and glucocorticoids can inhibit TSH production, while environmental factors such as stress and exercise can increase TRH release.

Physiology of glucocorticoids

Glucocorticoids are one of three steroids produced in the adrenal glands (zona fasciculata). The process starts with the release of corticotrophin-releasing hormone from the hypothalamus. This stimulates the production of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. ACTH has a dual function; it binds to melanocortin 2 receptors, initiating signalling cascades for steroid production (in the mitochondria) and increasing the cholesterol availability, activating HMG CoA reductase and activating hormone-sensitive lipase. Dependent on the enzymes exposed, the cholesterol can be converted into mineralocorticoids, glucocorticoids or sex hormones. Important enzymes involved in the production of glucocorticoids are cholesterol desmolase, 17a-hydroxylase, 21-hydroxylase and 11-beta-hydroxylase. The final product, cortisone, is an inactive steroid that is converted to cortisol (active form) in the liver by 11-beta hydroxysteroid dehydrogenase type 1. The release of glucocorticoids follows a pulsatile circadian pattern, with the highest concentrations found in the morning. High levels of glucocorticoids inhibit the release of CRH and ACTH, while environmental factors such as stress can stimulate release.

Cortisol has several functions within the body. It increases glucose and free fatty acids availability by activating hormone sensitive lipase (HSL), encouraging glucose production and inhibiting insulin. It plays an important role in the immune system, increasing the presence of white cells through accelerating proliferation and maturation and reducing migration and apoptosis. Though glucocorticoids have no direct effects on cell growth, the concentration of the hormone can impact the production of growth hormone via the hypothalamus-pituitary-axis, with high concentrations ultimately inhibiting its secretion.

References

• Shahid, M., Ashraf, M. and Sharma, S., 2022. Physiology, Thyroid Hormone. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK500006/
• Chourpiliadis, C. and Aeddula, N., 2022. Physiology, Glucocorticoids. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK560897/
• Brinkman, J., Tariq, M., Leavitt, L. and Sharma, S., 2022. Physiology, Growth Hormone. [online] Ncbi.nlm.nih.gov. Available at: <https://www.ncbi.nlm.nih.gov/books/NBK482141/>