Adrenal 101

The adrenal glands also known as the suprarenal glands. Supra meaning above, and renal meaning kidneys. So these glands are situated on top of the kidneys. These are endocrine glands that produce a variety of hormones, but most notable adrenaline, and the steroids aldosterone and cortisol. Each gland has an outer cortex which is divided into three different zones and an inner medulla. The three zones of the cortex are the zone glomerulosa, zone fasciculate, and zone reticularis.

This article will go briefly touch on the structure of the adrenal gland, including each zone of the cortex. Then it will dive into the function of the adrenal gland and the hormones it produces along with their specific cellular target. Finally the article will conclude with an overview of adrenal insufficiency and cortisol overproduction and diseases that illustrate those two conditions.

Structure

adrenal gland sections

As mentioned earlier, the gland is composed of an outer cortex, and an inner medulla. The outer cortex can be further divided into three zones that each have a specific function.

Zona Fasciculata

The zona fasciculata sits between the other two zones (zona glomerulosa, and zona reticularis) and consists of cells responsible for producing glucocorticoids such as cortisol. Its the largest of the three zones consisting of about 80% of the space in the cortex.

Zona Glomerulosa

The zona glomerulosa is the outermost zone of the adrenal cortex. The cells that are situated in this zone are responsible for the production of mineralocorticoids such as aldosterone. Aldosterone is an important regulator of blood pressure. Review the article covering the Renin-Aldosterone system.

Zona Reticularis

The zona reticular is the innermost cortical layer which is primarily responsible for producing androgens. Its main component synthesized is dehydroepiandrosterone (DHEA), and androstenedione, which is the precursor to testosterone.

Medulla

The medulla is in the centre of each adrenal gland with the cortex around the entire periphery. The chromatin cells within the medulla are the bodies main source of catecholamines. Catecholamines produced in the medulla are adrenaline (epinephrine), and noradrenaline (norepinephrine). Regulation of the synthesis of these catecholamines is driven by the sympathetic nervous system via the preganglionic nerve fibers stemming from the thoracic spinal cord (T5-T11) to the adrenal glands. When the medulla gets stimulated to produce these hormones it secretes them directly into the cardiovascular circulation system, which is unusual of sympathetic innervation as they usually have distinct synapses on specialized cells.

Mineralocorticoids

Mineralocorticoids such as aldosterone are named according to its function. They regulate minerals, such as salt and regulate blood volume (blood pressure). Aldosterone, the most prominent mineralocorticoid acts on the distal convoluted tubules and the collecting ducts by increasing the reabsorption of sodium and the excretion of both potassium and hydrogen ions. The amount of salt present in the body affects the extracellular volume, which influences the blood pressure.

Glucocorticoids

Glucocorticoids are also named due to its function. Cortisol is a prominent glucocorticoid that regulates the metabolism of proteins, fats and sugars (glucose). Cortisol increases the circulating level of glucose. They cause protein catabolism into amino acids and the synthesis of glucose from the amino acids in the liver. They also increase the concentration of fatty acids by increasing lipolysis (fat breakdown) which cells can use as an alternative energy source in situations of glucose absence. Glucocorticoids also play a role in suppression of the immune system. They induce a potent anti-inflammatory effect.

Cortisol

Cortisol is the prominent glucocorticoid produced by the adrenal gland. The adrenal gland secretes a basal level of cortisol depending on the time of day it is. Cortisol concentrations in the blood are highest in the early morning and lowest in the evening as part of the circadian rhythm of adrenalcorticotropic hormone (ACTH) secretion. The article on general endocrinology explains what ACTH is and how it affects the adrenal gland. Basically what happens is the hypothalamus secretes corticotropin releasing hormone that acts on the pituitary to produce ACTH that acts on the adrenal gland cortex to produce cortisol.

Androgens and Catecholamines

The primary androgen produced by the adrenal gland is DHEA, which is converted to more potent androgens such as testosterone, DHT, and estrogen in the gonads. DHEA acts as a precursor. Androgens drive sexual maturation.

Catecholamines are produced by the chromaffin cells from tyrosine. The enzyme tyrosine hydroxyls converts tyrosine to L-DOPA. L-DOPA is then converted to dopamine before it can be turned into norepinephrine. Norepinephrine is then converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT). Epinephrine and norepinephrine act as adrenoreceptors throughout the body, whose primary effect is to increase the blood pressure and cardiac output by way of vasoconstriction. Catecholamines play a huge role in the fight-or-flight response.

Corticosteroid Overproduction

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The normal function of the adrenal gland can be impaired from infections, tumors, autoimmune diseases, or from previous medical therapy such as radiation and chemotherapy. Cushing’s syndrome is the manifestation of glucocorticoid excess. Symptoms and sign are a direct result of chronic exposure to glucocorticoids. Diagnosis is difficult because the symptoms are often nonspecific and pathognomonic of the syndrome in isolation. Symptoms include proximal (distant) muscle weakness, wasting of the extremities, increased fat in the abdomen and face often leading to a moon face, bruising without trauma, and a buffalo hump. A buffalo hump is fat on the back of the neck and supraclavicular pads. In women, menstrual irregularities are common such as oligomenorrhea (infrequent menstrual periods), amenorrhea (absence of menstrual periods), and variable menses. Hyperpigmentation can occur by increased secretion of cortisol. Cortisol acts on the melanocyte-stimulating hormone receptors.

Glucose intolerance is common in Cushing’s syndrome. Primarily due to stimulation of gluconeogenesis by cortisol and insulin resistance caused by the obesity. This leads to hyperglycemia, which can exacerbate any diabetic patient.

Bone loss and osteoporosis is common in patients with Cushing’s syndrome because there is less intestinal calcium absorption. Calcium is vital to bone health and growth. The decrease in bone formation is coupled with an increased rate of bone reabsorption which can lead to more pathological fractures.

Adrenal Insufficiency

Addison’s disease is considered primary hypoadrenalism. There is an inherent deficiency of glucocorticoids and mineralocorticoids. Most commonly caused by an autoimmune condition. Autoimmune means that the body is attacking itself by production of antibodies against cells of the adrenal cortex. In cases of adrenal crisis due to autoimmune primary adrenal insufficiency clinical presentation is usually the patient presenting in a state of shock. Abdominal tenderness upon deep palpation is common. Patients present with hyperpigmentation due to chronic ACTH release by the pituitary. Proopiomelanocortin is overproduced which is a pro hormone that is cleaved into its biologically active hormones corticotropin and melanocyte-stimulating hormone (MSH). This causes increased melanin synthesis, causing the hyperpigmentation. Other non-specific symptoms such as lethargy, fatigue, weakness, confusion, anorexia, nausea, vomiting, or even coma can occur. One of the most commonly presented symptoms is fever and infection, which can be exaggerated by the hypocortisolemia.

Its important to take this article slowly. There a lot of different parts, but the aim was to look at the hormones themselves and how they physiologically act on the body, then take what was learned about those and apply them to two scenarios, hypo/hyperadrenalism and how it affects the body. Cushing’s syndrome is where there is hyperproduction of cortisol primarily leading to many disastrous effects on the body. Addisons disease is an autoimmune disease where the body produces antibodies against the cells of the adrenal cortex, causing destruction of the gland itself, again leading to detrimental effects on the body.

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Pheochromocytoma Workup

A pheochromocytoma is a catecholamine-secreting tumor that arises from the chromatin cells of the adrenal medulla. Extraadrenal pheochromocytoma arise from the sympathetic ganglia and are referred to as catecholamine-secreting paragangliomas. These neoplasms are very rare, occurring in less than 0.2% of the patients. Most catecholamine-secreting tumors are sporadic and occur in the fourth to fifth decade of life, effecting both men and women equally. However, about 40% of the patients that present with a pheochromocytoma there is a familial inheritance. These familial tumors arise earlier in life and typically associated with several familial disorders. Such disorders are Von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2), and neurofibromatosis (NF1).

Clinical Presentation

Symptoms and signs only occur in about 50% of patients and paroxysmal in nature. There is a classic triad of symptoms that is observed which consists of episodic headache, sweating, and tachycardia with either paroxysmal hypertension or primary hypertension. Paroxysmal hypertension is the most common sign of pheochromocytoma. The headache associated with pheochromocytoma can vary from mild to severe and occurs in 90% of patients. Generalized sweating occurs accompanied by forceful palpitations, tremors, dyspnea, fatigue, and often anxiety and panic attack-type symptoms. There is increased secretion of catecholamines; epinephrine, norepinephrine, and dopamine which cause abnormalities in carbohydrate metabolism which leads to insulin resistance, and an impaired fasting glucose which mimics type 2 diabetes mellitus. In rare cases there is episodic hypotension and rapid cyclic fluctuations of hypertension and hypotension.

Initial Evaluation

The diagnosis of pheochromocytoma is made upon biochemical testing for catecholamine hypersecretion, followed by imaging studies to identify an adrenal tumor. There are many indications for testing that a physician may take into consideration before subjecting patients to many tests and appointments. Some of the indications for testing include the classic triad of symptoms (headache, sweating, and tachycardia), hyperadrenergic spells (palpitations, diaphoresis, tremor, pallor), onset of paroxysmal hypertension or primary hypertension at an early age, or any familial syndromes or history of pheochromocytoma.

Biochemical Testing

The range of biochemical testing that is performed is based upon the index of suspicion that the patient in fact has a pheochromocytoma. Low index of suspicion includes a 24-hour urinary fractionated catecholamines and metanephrines. If there is a high index of suspicion, it is recommended to use a plasma fractionated metanephrines. These tests are performed by high-performance liquid chromatography (HPLC) with tandem mass spectroscopy or electrochemical detection. The more recent techniques have overcome the traditional problems that are associated with drug interference and contrast agents.

Catecholamines

Catecholamines are an organic compound that are derived from the amino acid tyrosine. Tyrosine can either be derived from diet or synthesized from phenylalanine. Epinephrine, norepinephrine, and dopamine are the primary catecholamines that are secreted from the adrenal medulla during the sympathetic flight-or-fight response.

Norepinephrine is a neuromodulator and a hormone that circulates in the blood. Its primary function is to mobilize the brain and the body for action as part of the peripheral sympathetic system. In the flight-or-fight response norepinephrine causes arousal and alertness. It enhances the formation and retrieval of memory, and focuses attention. As a hormone it increases cardiac output by increasing the heart rate and blood pressure. It triggers glycolysis and increases vascular blood flow to the skeletal muscles.

Dopamine functions as a neurotransmitter that is released by neurons to send signals to other functioning nerve synapses. Dopamine plays a critical role in reward-motivated behavior. The anticipation of most types of rewards increase the levels of dopamine in the brain. Many addictive drugs mimic this pathway while simultaneously blocking the reuptake of it. Dopamine is also functional in the motor control pathway as a neuromodulator which controls the release of many other hormones. In circulation outside of the brain, dopamine functions as a chemical messenger. It inhibits norepinephrine release and acts as a vasodilator. It increases renal excretion of sodium. It acts to reduce insulin secretion and gastrointestinal motility.

Epinephrine, also known as adrenaline or adrenalin functions as a neurotransmitter, hormone, and as a medication. It plays an important role in increasing cardiac output, pupil dilation, and increasing insulin release to stimulate glycolysis. It acts on the alpha and beta receptors to ultimate activate the flight-or-fight response. Epinephrine is also used medically to treat a number of conditions including anaphylaxis, cardiac arrest, and bleeding.

General Endocrinology

Hormones make up the endocrine system and act on almost every tissue in the body. Hormones are substances that are produced by a specialized cell that circulates in the blood. The best example of this is insulin which is secreted by the beta cells in the pancreas.

hormoneoverview

Credit for the photo goes to Pearson Education, Inc.

There are multiple forms of chemical signaling that hormones utilize. The first is autocrine where the cell targets itself. Signaling across gap junctions occurs when a specialized cell targets another cell that is connected via a gap junction. Paracrine is when the targeted cell is nearby. Endocrine which will be the primary focus for today is when the cell produces hormones or chemical signals that have to travel through the blood stream to act on distant cells. Depending on the receptor type to these hormones distinguishes the action it has on the recipient tissue or cell. Receptors can by cytoplasmic, ion channels, tyrosine kinase receptors, or a G-protein coupled receptor. There can also be different types of hormones. Protein hormones utilize calcium as a secondary messenger. The action potential of protein hormones is quick as opposed to steroid hormones. The action of steroid hormones is slow as steroids are not as membrane permeable as protein hormones. Its important to note that hormones are released in pulses. Each pulse has an amplitude and period.

The endocrine system needs feedback control loops to function properly. Negative control loops maintain hormonal balance. Positive control loops are actually what causes physiological changes in the tissues involved.

The endocrine system starts in the hypothalamus. The hypothalamus releases releasing hormones to stimulate the anterior and posterior pituitary to secrete effector hormones that act on various sites of the body.

The anterior pituitary otherwise known as the adenohypophysis secretes the majority of the hormones. Releasing hormones are secreted by the hypothalamic neurons into the hypothalamopituitary portal system. These hormones are then carried down the pituitary stalk by this portal system into the adenohypophysis. The anterior pituitary secretes adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), prolactin (PRL), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). These all act on their respectable tissues/cells to secrete specific hormones. ACTH acts on the adrenal gland, which sits on top of the kidneys. The adrenal gland is responsible for secretion of catecholamines (epinephrine/norepinephrine) that influences the flight or fight response as well as glucocorticoids such as cortisol which have physiological effects throughout the entire body. TSH acts on the thyroid gland to secrete the thyroid hormones T3 and T4. These hormones also have wide-spread physiological function throughout the body. GH acts on the liver and influences bone, muscle, and tissue growth. PRL acts on the mammary glands such as the breast glands to stimulate growth and to start lactation. FSH and LH act on the testes of males to secrete inhibin and testosterone as well on the ovaries in females to secrete estrogen, progesterone, and inhibin. Decreased or elevated levels of any of these hormones can have detrimental effects on normal physiological processes. These discrepant levels can either be from primary disease (In the organ where the hormones are produced) or it can be secondary disease, i.e. from the hypothalamus, or pituitary.

Oxytocin and vasopressin (ADH) are the hormones secreted by the posterior or neurohypophysis pituitary. These are synthesized in the paraventricular supraoptic nuclei of the hypothalamus and are carried down the pituitary stalk by axonal transport. These hormones are then released into the general circulation in the neurohypophysis. Oxytocin works in females and males. It effects the uterine smooth muscle and mammary glands in females and in males it effects the smooth muscle in the ductus deferens and the prostate gland. Vasopressin or ADH promotes water retention in the distal tubules and collecting ducts of the kidneys. SIADH is excess ADH secretion and results in concentrated urine, and a low serum concentration. In other words there is low serum sodium which is bad! Diabetes insipidus on the other hand is deficiency in ADH.

-Caleb