In humans and other animals, the adrenocortical hormones are hormones produced by the

adrenal cortex The adrenal cortex is the outer region and also the largest part of an 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 ...

, 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 An injury is any physiological damage to living tissue caused by immediate physical stress. An injury can occur intentionally or unintentionally and may be caused by blunt trauma, penetrating trauma, burning, toxic exposure, asphyxiation, o ...

, chemical imbalances, infection, or

psychological stress In psychology, stress is a feeling of emotional strain and pressure. Stress is a type of psychological pain. Small amounts of stress may be beneficial, as it can improve athletic performance, motivation and reaction to the environment. Exces ...

, can initiate a stress response. Examples of adrenocortical hormones that are involved in the stress response are

aldosterone 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 c ...

and

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

. These hormones also function in regulating the

conservation of water Conservation is the preservation or efficient use of resources, or the conservation of various quantities under physical laws. Conservation may also refer to: Environment and natural resources * Nature conservation, the protection and manageme ...

by the kidneys and glucose metabolism, respectively.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.

Classes

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

Mineralocorticoid Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mi ...

hormones are synthesized in the outermost layer of the

known as the zona glomerulosa.Shier, D., Butler, J., Lewis, R. “Adrenal Glands.” Hole’s Human Anatomy & Physiology. 12th ed. New York: McGraw-Hill, 2010. 504-508. Their function is to regulate the concentration of electrolytes circulating in the blood. For example,

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 Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...

to conserve sodium and excrete potassium. onnell, J. M. C., & Davies, E. (2005). The new biology of aldosterone. Journal of Endocrinology, 186, 1-20./ref> Additionally, the ion gradient initiates conservation of water. # The glucocorticoid family of hormones is synthesized in the middle layer of the

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. # Androgens, or sex hormones, are synthesized in the innermost layer of the

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.

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.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. The cholesterol backbone consists of four hydrocarbon rings, three

cyclohexane Cyclohexane is a cycloalkane with the molecular formula . Cyclohexane is non-polar. Cyclohexane is a colorless, flammable liquid with a distinctive detergent-like odor, reminiscent of cleaning products (in which it is sometimes used). Cyclohexan ...

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 The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

of cells. 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 Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

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

. The process is controlled by

steroidogenic acute regulatory protein The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is p ...

(StAR) which sits in the

mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...

membrane and regulates the passage of cholesterol. This is the rate-limiting step of

steroid biosynthesis A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

. Once StAR has transported cholesterol into the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

, the cholesterol molecule undergoes a string of

reactions catalyzed by a series of enzymes from the family of

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

enzymes. A coenzyme system called adrenodoxin reductase transfers electrons to the P450 enzyme which initiates the

reactions that transform cholesterol into the steroid hormones.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. Though synthesis is initiated inside

, precursors are shuttled to the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

for processing by enzymes present in the

. The precursors are shuttled back to the

in the region of the

within which synthesis initially began and it is there that synthesis is completed.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.

Pathology

Cushing's Syndrome

Cushing’s syndrome 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 ...

arises from the repeated

hypersecretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...

of glucocorticoids. It can be caused by either an adrenal tumor or by

of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. It is predominantly due to an excess of the glucocorticoid

. 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

into the bloodstream.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. In

, this process occurs in excess. Some symptoms of an individual with

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

, excess androgens are secreted.Low, G., & Sahi, K. (2012). Clinical and imaging overview of functional adrenal neoplasms. International Journal of Urology, 19, 697-708. In females, increased secretion of androgens, such as testosterone, results in

masculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...

which may present as facial hair growth and a deepened voice. Treatment for

aims to reduce the high levels of

circulating through the human body. The course of action ultimately depends on the cause of the

. Cushing’s can be induced by repeated synthetic steroid use to treat

inflammatory diseases Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

, 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. 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 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 ...

is an autoimmune disorder that affects the

such that it is unable to efficiently secrete hormones. The immune system specifically targets the cells of the

and destroys them, but

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

. These electrolyte imbalances induce nerve and muscle issues. Other symptoms include fatigue, salt cravings, weight loss, and increased skin pigmentation. Increased skin pigmentation is caused by a deficiency of the adrenocortical hormone hydrocortisone. Its normal behavior would be as

negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...

at the pituitary gland, stimulating the pituitary gland to decrease secretion of corticotropin. Because hydrocortisone is not able to be produced in

, the pituitary gland continues to secrete corticotropin which binds to the receptor for melanocyte-stimulating hormone. It then causes

melanocytes Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and heart. ...

to produce more pigment, thus darkening the skin tone.Winqvist, O., Rorsman, F., & Kampe, O. (2000). Autoimmune adrenal insufficiency. BioDrugs, 13(2), 107-114. The standard treatment for

is hormone replacement therapy for the mineralocorticoids and glucocorticoids that are no longer able to be synthesized. 2Former U.S. President John F. Kennedy is a well-known individual who suffered from

throughout his presidency. Due to the availability of hormone replacement therapy, he and his staff were able to cover up his condition.

Stress and immunity

Recent studies have discovered a pathway that links stress to the onset of disease through the activation of certain genes.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. 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.

Chronic inflammation Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions s ...

makes an individual more susceptible to diseases such as cancer,

heart disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...

, and diabetes. Another study found that physical stress caused increased

DHEAS Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepiand ...

(dehydroepiandrosterone sulphate) molar ratios which may contribute to reduced immunity, especially in the elderly for whom

ratios are already increased. This is because

levels decrease with age while

levels do not. This high ratio was found to suppress the activity of

neutrophils Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

and raise susceptibility for infection.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.

References

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