Introduction
Leda, a 38-year-old woman, attended a medical appointment reporting weakness, mood swings, weight gain, and irregular periods. Taking into consideration that these symptoms may be connected with the patient’s level of cortisol, I ordered an overnight dexamethasone suppression test and a 24-hour free cortisol urine test along with the measurement of serum adrenocorticotrophic hormone (ACTH) levels. The results indicated the presence of Cushing disease as a result of ACTH’s hypersecretion that causes elevated cortisol levels produced by adrenal glands and may lead to serious health complications, including osteoporosis, type 2 diabetes, cognitive difficulties, and high blood pressure. As this condition is traditionally associated with a tumor, I ordered a cranial MRI in order to identify its presence.
Dexamethasone Suppression Test
In general, a dexamethasone suppression test (DST) is used to detect Cushing disease associated with the insufficient suppression of the hypothalamic-pituitary-adrenal (HPA) axis. This primary neuroendocrine system is responsible for the body’s stress response and homeostatic function (Dogra & Vijayashankar, 2021). Synthesized by the hypothalamus’s neurons, corticotropin-releasing hormone (CRH) goes to and stimulates the anterior pituitary that produces ACTH (Dogra & Vijayashankar, 2021). In turn, ACTH stimulates the production of cortisol by the adrenal cortex in the adrenal glands. The main cause of Cushing disease is a tumor that causes the over-secretion of hormones. Being non-cancerous, it anyway may lead to severe comorbidities, such as cardiovascular morbidity, metabolic syndrome, infections, musculoskeletal abnormalities, fatigue, and depression (Theodoropoulou & Reincke, 2018). In general, treatment presupposes the detection of a tumor using a cranial MRI and pituitary surgery.
A DST implies taking dexamethasone, cortisol’s manmade version, to detect whether the body produces less cortisol as it should be. Traditionally, the test is made overnight and includes two types: a low-dose DST and a high-dose DST (Dogra & Vijayashankar, 2021). A low-dose DST implies the oral administration of dexamethasone 1 mg overnight with a morning check of serum cortisol levels to confirm the existence of Cushing disease (Dogra & Vijayashankar, 2021). If the disease is confirmed, a high-dose DST that presupposes dexamethasone 8 mg overnight should be made to categorize it (Dogra & Vijayashankar, 2021). Thus, ACTH-independent Cushing disease indicates an adrenal source, while ACTH-dependent Cushing disease shows that it has pituitary etiology.
In general, a low-dose DST does not presuppose adverse effects, as corticosteroids may be harmful if taken in high doses for a long period of time. Thus, even a high-dose DST may be associated with mild side effects, such as headache and poor sleep, that disappear without intervention. Nevertheless, if chest pain or other more serious symptoms appear, Lead should contact me in a time-sensitive manner.
Metabolism of Steroid Hormones
Synthesized from cholesterol, steroid hormones are produced in the adrenal glands. Their cortex is responsible for the synthesis of glucocorticoids, including cortisol, mineralocorticoids, androgens, and adrenal androgen precursors (Schiffer et al., 2019). It is divided into three zones on the basis of produced steroid classes: zona glomerulosa, zona fasciculata, and zona reticularis (Schiffer et al., 2019). In zona fasciculate, cortisol is produced as a result of glucocorticoid biosynthesis from 17α-hydroxyprogesterone received from cholesterol (Schiffer et al., 2019). In turn, cortisol is metabolized in the body both irreversibly and reversibly. Irreversible metabolism involves A-ring reductases, while reversible metabolism implies deactivating cortisol to cortisone in the liver and vice versa by 11β-hydroxysteroid dehydrogenases (Schiffer et al., 2019). Cortisol is excreted predominantly in the urine, however, it has a diurnal secretion rhythm that presupposes a distinct pattern of concentrations. In other words, a healthy individual has a higher serum cortisol concentration in the morning and a lower concentration at midnight. A loss of rhythm may indicate the presence of a disease – that is why it was essential to order a 24-hour free cortisol urine test for Leda in order to detect her pattern.
Advantages of a 24-Hour Urine Test
As previously mentioned, the excretion of cortisol has a distinct pattern of its concentration in the urine. That is why a 24-hour free cortisol urine test that presupposes the patient’s collection of all urine during the day helps not only measure the total amount of hormone produced during a day but assess whether the rhythm of its concentration is healthy. In general, it is possible to say that a 24-hour urine test may be regarded as a highly accessible and comprehensive method that, in combination with other tests, allows to detect the occurrence of Cushing disease and other disorders associated with a level of cortisol. It is applied when the symptoms of high or low cortisol level are observed, however, other factors that impact it, such as emotional stress, pregnancy, infections, hyper- or hypothyroidism, the administration of glucocorticosteroids, or obesity, are absent.
Cellular Responses
It goes without saying that protein-based and steroid-based hormones trigger cellular responses in different ways. Thus, synthesized in the anterior pituitary, ACTH participates in the production of cortisol through the stimulation of glucocorticoid steroid hormone secretion from the cells of the adrenal cortex, especially in the zona reticularis and zona fasciculata of the adrenal glands. For this, ACTH binds with G protein-coupled receptors located on the extracellular membranes of adrenocortical cells (Allen & Sharma, 2021). This leads to the activation of adenylyl cyclase and protein kinase A and the increase in the production of intercellular cyclic adenosine monophosphate (cAMP) (Allen & Sharma, 2021). By this, ACTH regulates the secretion of androgen and cortisol and participates in immune function and glucose metabolism.
In turn, for cells, cortisol and other steroid hormones act as primary messengers. Due to its fat-soluble properties, cortisol may cross a cell’s cytoplasmic membrane to bind to the cytoplasm’s specific glucocorticoid receptors dissociating the cytosol’s Hsp90 chaperone protein (Thau et al., 2021). Subsequently, the cortisol-receptor complex affects gene transcription entering the cell’s nucleus. As glucocorticoid receptors are present in the majority of the body’s tissues, cortisol is able to impact almost all organ systems. In addition, cortisol increases lipolysis associated with the release of free fatty acids that provide energy for other cells.
Conclusion
As Leda came with particular symptoms that indicated a high level of cortisol while other factors that may impact its secretion were absent, tests that were prescribed for her may be regarded as fully reliable. In particular, a 24-hour free cortisol urine test indicated a high concentration of cortisol produced during a day and the change in the rhythms of its secretion. Subsequently, an overnight dexamethasone suppression test, together with the measurement of serum adrenocorticotrophic hormone (ACTH) levels, detect the presence of Cushing disease, traditionally caused by a tumor. In this case, a cranial MRI is required for its detection. If the presence of a tumor is confirmed, pituitary surgery will be required.
References
Allen, M. J., & Sharma, S. (2018). Physiology, adrenocorticotropic hormone (ACTH). In StatPearls [Internet]. StatPearls Publishing. Web.
Dogra, P., & Vijayashankar, N. P. (2021). Dexamethasone suppression test. In StatPearls [Internet]. StatPearls Publishing. Web.
Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K. H. (2019). Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review. The Journal of Steroid Biochemistry and Molecular Biology, 194, 105439.
Thau, L., Gandhi, J., & Sharma, S. (2021). Physiology, cortisol. In StatPearls [Internet]. StatPearls Publishing. Web.
Theodoropoulou, M., & Reincke, M. (2019). Tumor-directed therapeutic targets in Cushing disease. The Journal of Clinical Endocrinology & Metabolism, 104(3), 925-933.