Adrenocortical hormone

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In humans and other animals, the adrenocortical hormones are hormones produced by the adrenal cortex, the outer region of the adrenal gland. These polycyclic steroid hormones have a variety of roles that are crucial for the body's response to stress (for example, the fight-or-flight response), and they also regulate other functions in the body. Threats to homeostasis, such as injury, chemical imbalances, infection, or psychological stress, can initiate a stress response. Examples of adrenocortical hormones that are involved in the stress response are aldosterone and cortisol. These hormones also function in regulating the conservation of water by the kidneys and glucose metabolism, respectively. [1]

Contents

Classes

Adrenocortical hormones are divided into three classes by function: mineralocorticoids, glucocorticoids, and androgens.

  1. Mineralocorticoid hormones are synthesized in the outermost layer of the adrenal cortex known as the zona glomerulosa. [2] Their function is to regulate the concentration of electrolytes circulating in the blood. [1] For example, aldosterone functions to raise blood sodium levels and lower blood potassium levels by targeting the kidneys. Specifically, it binds receptors of cells that comprise the distal tubules of the kidneys which then stimulate ion channels to conserve sodium and excrete potassium. [3] Additionally, the ion gradient initiates conservation of water.
  2. The glucocorticoid family of hormones is synthesized in the middle layer of the adrenal cortex known as the zona fasciculata. These hormones regulate the processing of proteins, fats, and carbohydrates by the human body. They also play a role in maintaining a normal stress response cycle.
  3. Androgens, or sex hormones, are synthesized in the innermost layer of the adrenal cortex known as the zona reticularis. These hormones, such as estrogen in females and testosterone in males, are commonly known for promoting sexual characteristics and the maturation of reproductive organs of the respective gender. [2]

Structure

Adrenocortical hormones are considered steroid hormones because of the shared characteristic of a cholesterol backbone. The structures of different steroids differ by the types and locations of additional atoms on a cholesterol backbone. [4] The cholesterol backbone consists of four hydrocarbon rings, three cyclohexane rings and one cyclopentane, that contribute to its insolubility in aqueous environments. However, the hydrophobic nature allows them to readily diffuse through the plasma membrane of cells. [3] This is important to the function of steroid hormones as they rely on cellular response pathways to restore the homeostatic imbalance that initiated the hormone release.

Synthesis

The synthesis of adrenocortical steroid hormones involves a chain of oxidation-reduction reactions catalyzed by a series of enzymes. Synthesis begins with a molecule of cholesterol. Through shared intermediates and pathways branching off those shared intermediates, the different classes of steroids are synthesized. Steroids are synthesized from cholesterol in their respective regions of the adrenal cortex. The process is controlled by steroidogenic acute regulatory protein (StAR) which sits in the mitochondrial membrane and regulates the passage of cholesterol. [3] This is the rate-limiting step of steroid biosynthesis. Once StAR has transported cholesterol into the mitochondria, the cholesterol molecule undergoes a string of oxidation-reduction reactions catalyzed by a series of enzymes from the family of cytochrome P450 enzymes. A coenzyme system called adrenodoxin reductase transfers electrons to the P450 enzyme which initiates the oxidation-reduction reactions that transform cholesterol into the steroid hormones. [5] Though synthesis is initiated inside mitochondria, precursors are shuttled to the endoplasmic reticulum for processing by enzymes present in the endoplasmic reticulum. The precursors are shuttled back to the mitochondria in the region of the adrenal cortex within which synthesis initially began and it is there that synthesis is completed. [6]

Pathology

Cushing's Syndrome

Cushing's syndrome arises from the repeated hypersecretion of glucocorticoids. It can be caused by either an adrenal tumor or by hypersecretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. [2] It is predominantly due to an excess of the glucocorticoid cortisol. Secretion is typically regulated by the hypothalamus which secretes corticotropin-releasing hormone (CRH) to the pituitary gland, stimulating the pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH then travels to the adrenal glands and induces the release of cortisol into the bloodstream. [7] In Cushing's syndrome, this process occurs in excess. Some symptoms of an individual with Cushing's syndrome include low tissue protein levels, due to muscle and bone atrophy, and high blood glucose levels. Sodium levels also see an increase which results in fluid retention in tissues and elevated blood pressure. In addition to hypersecretion of cortisol, excess androgens are secreted. [8] In females, increased secretion of androgens, such as testosterone, results in masculinization which may present as facial hair growth and a deepened voice. [2]

Treatment for Cushing's syndrome aims to reduce the high levels of cortisol circulating through the human body. The course of action ultimately depends on the cause of the hypersecretion. Cushing's can be induced by repeated synthetic steroid use to treat inflammatory diseases, or it can also be caused by a tumor in the pituitary gland or adrenal gland. In either case, treatment may rely on removal of the tumor or of the adrenal glands. [8] Without the adrenal glands, the human body is unable to supply the hormones it produces and therefore requires hormone replacement therapy.

Addison's Disease

Addison's disease is an autoimmune disorder that affects the adrenal cortex such that it is unable to efficiently secrete hormones. The immune system specifically targets the cells of the adrenal cortex and destroys them, but Addison's disease can also be caused by a severe infection such as tuberculosis. Some symptoms include hypoglycemia and decreased blood sodium levels and increased blood potassium levels caused by a deficiency of aldosterone. These electrolyte imbalances induce nerve and muscle issues. Other symptoms include fatigue, salt cravings, weight loss, and increased skin pigmentation. [2] Increased skin pigmentation is caused by a deficiency of the adrenocortical hormone hydrocortisone. Its normal behavior would be as negative feedback at the pituitary gland, stimulating the pituitary gland to decrease secretion of corticotropin. Because hydrocortisone is not able to be produced in Addison's disease, the pituitary gland continues to secrete corticotropin which binds to the receptor for melanocyte-stimulating hormone. It then causes melanocytes to produce more pigment, thus darkening the skin tone. [9]

The standard treatment for Addison's disease is hormone replacement therapy for the mineralocorticoids and glucocorticoids that are no longer able to be synthesized.[12] Former U.S. President John F. Kennedy is a well-known individual who suffered from Addison's disease throughout his presidency. Due to the availability of hormone replacement therapy, he and his staff were able to cover up his condition. [2]

Stress and immunity

Recent studies have discovered a pathway that links stress to the onset of disease through the activation of certain genes. [10] The experience of psychological stress activates transcription factors that activate genes. In a study by Cole et al., it was concluded that GABA-1 transcription factor activates the interleukin-6-gene. This gene codes for a protein that activates the inflammatory response which directs an immune response to the site of the inflammation. [9] Chronic inflammation makes an individual more susceptible to diseases such as cancer, heart disease, and diabetes.

Another study found that physical stress caused increased cortisol:DHEAS (dehydroepiandrosterone sulphate) molar ratios which may contribute to reduced immunity, especially in the elderly for whom cortisol:DHEAS ratios are already increased. This is because DHEAS levels decrease with age while cortisol levels do not. This high ratio was found to suppress the activity of neutrophils and raise susceptibility for infection. [11]

Related Research Articles

<span class="mw-page-title-main">Adrenal gland</span> Endocrine gland

The adrenal glands are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which produces steroid hormones and an inner medulla. The adrenal cortex itself is divided into three main zones: the zona glomerulosa, the zona fasciculata and the zona reticularis.

<span class="mw-page-title-main">Endocrine system</span> Hormone-producing glands of a body

The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems.

<span class="mw-page-title-main">Adrenocorticotropic hormone</span> Pituitary hormone

Adrenocorticotropic hormone is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol and androgens by the cortex and medulla of the adrenal gland, respectively. ACTH is also related to the circadian rhythm in many organisms.

<span class="mw-page-title-main">Cushing's syndrome</span> Symptoms from excessive exposure to glucocorticoids such as cortisol

Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a round red face due to facial plethora, a fat lump between the shoulders, weak muscles, weak bones, acne, and fragile skin that heals poorly. Women may have more hair and irregular menstruation. Occasionally there may be changes in mood, headaches, and a chronic feeling of tiredness.

<span class="mw-page-title-main">Hypothalamic–pituitary–adrenal axis</span> Set of physiological feedback interactions

The hypothalamic–pituitary–adrenal axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands. These organs and their interactions constitute the HPA axis.

<span class="mw-page-title-main">Adrenal cortex</span> Cortex of the adrenal gland

The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is also a secondary site of androgen synthesis.

<span class="mw-page-title-main">Anterior pituitary</span> Anterior lobe of the pituitary gland

A major organ of the endocrine system, the anterior pituitary is the glandular, anterior lobe that together with the posterior lobe makes up the pituitary gland (hypophysis) which, in humans, is located at the base of the brain, protruding off the bottom of the hypothalamus.

<span class="mw-page-title-main">Cortisol</span> Human natural glucocorticoid hormone

Cortisol is a steroid hormone, in the glucocorticoid class of hormones and a stress hormone. When used as a medication, it is known as hydrocortisone.

<span class="mw-page-title-main">Addison's disease</span> Endocrine disorder

Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adrenal glands, causing adrenal insufficiency. Symptoms generally come on slowly and insidiously and may include abdominal pain and gastrointestinal abnormalities, weakness, and weight loss. Darkening of the skin in certain areas may also occur. Under certain circumstances, an adrenal crisis may occur with low blood pressure, vomiting, lower back pain, and loss of consciousness. Mood changes may also occur. Rapid onset of symptoms indicates acute adrenal failure, which is a clinical emergency. An adrenal crisis can be triggered by stress, such as from an injury, surgery, or infection.

<span class="mw-page-title-main">Aldosterone</span> Mineralocorticoid steroid hormone

Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a central role in the homeostatic regulation of blood pressure, plasma sodium (Na+), and potassium (K+) levels. It does so primarily by acting on the mineralocorticoid receptors in the distal tubules and collecting ducts of the nephron. It influences the reabsorption of sodium and excretion of potassium (from and into the tubular fluids, respectively) of the kidney, thereby indirectly influencing water retention or loss, blood pressure, and blood volume. When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and kidney disease. Aldosterone has exactly the opposite function of the atrial natriuretic hormone secreted by the heart.

<span class="mw-page-title-main">Adrenal insufficiency</span> Medical condition

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids, mineralocorticoids, and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes to organ failure and shock. Adrenal crisis may occur if a person having adrenal insufficiency experiences stresses, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow.

Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

<span class="mw-page-title-main">Endocrine gland</span> Glands of the endocrine system that secrete hormones to blood

Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testicles, thyroid gland, parathyroid gland, hypothalamus and adrenal glands. The hypothalamus and pituitary glands are neuroendocrine organs.

3β-Hydroxysteroid dehydrogenase/Δ5-4 isomerase (3β-HSD) is an enzyme that catalyzes the biosynthesis of the steroid progesterone from pregnenolone, 17α-hydroxyprogesterone from 17α-hydroxypregnenolone, and androstenedione from dehydroepiandrosterone (DHEA) in the adrenal gland. It is the only enzyme in the adrenal pathway of corticosteroid synthesis that is not a member of the cytochrome P450 family. It is also present in other steroid-producing tissues, including the ovary, testis and placenta. In humans, there are two 3β-HSD isozymes encoded by the HSD3B1 and HSD3B2 genes.

The ACTH test is a medical test usually requested and interpreted by endocrinologists to assess the functioning of the adrenal glands' stress response by measuring the adrenal response to adrenocorticotropic hormone or another corticotropic agent such as tetracosactide or alsactide (Synchrodyn). ACTH is a hormone produced in the anterior pituitary gland that stimulates the adrenal glands to release cortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and aldosterone.

Hypoadrenocorticism in dogs, or, as it is known in people, Addison's disease, is an endocrine system disorder that occurs when the adrenal glands fail to produce enough hormones for normal function. The adrenal glands secrete glucocorticoids such as cortisol and mineralocorticoids such as aldosterone; when proper amounts of these are not produced, the metabolic and electrolyte balance is upset. Mineralocorticoids control the amount of potassium, sodium, and water in the body. Hypoadrenocorticism is fatal if left untreated.

<span class="mw-page-title-main">Adrenal gland disorder</span> Medical condition

Adrenal gland disorders are conditions that interfere with the normal functioning of the adrenal glands. Your body produces too much or too little of one or more hormones when you have an adrenal gland dysfunction. The type of issue you have and the degree to which it affects your body's hormone levels determine the symptoms.

Glucocorticoid remediable aldosteronism also describable as aldosterone synthase hyperactivity, is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient.

<span class="mw-page-title-main">Amphenone B</span> Chemical compound

Amphenone B, or simply amphenone, also known as 3,3-bis(p-aminophenyl)butan-2-one, is an inhibitor of steroid hormone and thyroid hormone biosynthesis which was never marketed but has been used as a tool in scientific research to study corticosteroids and the adrenal glands. It acts as competitive inhibitor of 11β-hydroxylase, 17α-hydroxylase, 17,20-lyase, 21-hydroxylase, and 3β-hydroxysteroid dehydrogenase, as well as of cholesterol side-chain cleavage enzyme, thereby inhibiting the production of steroid hormones including glucocorticoids, mineralocorticoids, androgens, and estrogens. In addition, amphenone B inhibits the production of thyroxine by a thiouracil-like mechanism, specifically via inhibition of organic binding of iodine and uptake of iodide by the thyroid gland.

<span class="mw-page-title-main">Adrenalism</span>

Adrenalism describes the condition of an excessive or substandard secretion of hormones related to the adrenal glands, which are found directly superior to the kidneys. Adrenalism can be further distinguished as hyperadrenalism, referring to the excessive secretion of hormones, and hypoadrenalism, referring to the insufficient secretion of hormones.

References

  1. 1 2 Genest, J., Biron, P., Koiw, E., Nowaczynski, W., Chretien, M., & Boucher, R. (1961). Adrenocortical hormones in human hypertension and their relation to angiotensin. Circulation Research, 9, 775-791.
  2. 1 2 3 4 5 6 Shier, D., Butler, J., Lewis, R. “Adrenal Glands.” Hole’s Human Anatomy & Physiology. 12th ed. New York: McGraw-Hill, 2010. 504-508.
  3. 1 2 3 [Connell, J. M. C., & Davies, E. (2005). The new biology of aldosterone. Journal of Endocrinology, 186, 1-20.]
  4. ↑ Nelson, D. L., Lehninger, A. L., and Cox, M. M. “Hormones are Chemically Diverse.” Lehninger Principles of Biochemistry. 6th ed. New York: W.H. Freeman, 2013. 908.
  5. ↑ Sushko, T. A., Gilep, A. A., & Usanov, S. A. (2012) Mechanism of intermolecular interactions of microsomal cytochrome P450s CYP17 and CYP21 involved in steroid hormone biosynthesis. Biochemistry, 77(6), 585-592.
  6. ↑ Duarte, A., Poderoso, C., Cooke, M., Soria, G., Cornejo Maciel, F., et al. (2012). Mitochondrial fusion is essential for steroid biosynthesis. PLoS ONE, 7(9): e45829.
  7. ↑ Porterfield, J. R., Thompson, G. B., Young, W. F., et al. (2008). Surgery for cushing’s syndrome: An historical review and recent ten-year experience. World J. Surg., 32, 659-677.
  8. 1 2 Low, G., & Sahi, K. (2012). Clinical and imaging overview of functional adrenal neoplasms. International Journal of Urology, 19, 697-708.
  9. 1 2 Winqvist, O., Rorsman, F., & Kampe, O. (2000). Autoimmune adrenal insufficiency. BioDrugs, 13(2), 107-114.
  10. ↑ Cole, J.T., Mitala, C. M., Kundu, S., Verma, A., Elkind, J.A., Nissim, I., & Cohen, A.S. (2010). Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proceedings of the National Academy of Sciences, 107, 366-371.
  11. ↑ Butcher, S. K., Killampalli, V., Lascelles, D., Wang, K., Alpar, E. K., & Lord, J. M. (2005). Raised cortisol:DHEAS ratios in the elderly after injury: potential impact upon neutrophil function and immunity. Aging Cell, 4, 319-324.
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