Erythropoietin (EPO)

The role of red blood cells is to carry oxygen. Just like anything in the body, this is tightly regulated by a mechanism that monitors whether or not there is adequate oxygen getting to tissues and other cells. Hypoxia is detected by the peritubular fibroblasts of the kidneys which causes erythropoietin (EPO) to be released. The EPO gene has a hypoxia-sensing region in its 3’ regulatory component which causes hypoxia inducible factor-1 (HIF-1) transcription factor to be assembled and it interacts with the 3’ enhancer of the gene causing increased EPO mRNA and production of more EPO.  EPO is a true hormone, being produced in the kidneys, and acting upon another distant location being the bone marrow. When EPO binds to its ligand (receptor) on red blood cell progenitors it initiates a cascade which is mediated through the JAK2 signal transducers which ultimately effects the gene expression. EPO has three main physiological effects on the body; it allows early release of reticulocytes from the bone marrow, prevents apoptosis, and reduces the time needed for cells to mature in the bone marrow before release into the periphery. 

There are two mechanism for which EPO stimulates early release of red cell precurors into the bone marrow. It induces changes in the adventitial cell layer of the marrow sinuses that increases the width of the spaces that the red cells squeeze out of. It also down regulates red blood cell surface receptors for adhesive molecules that are located on the bone marrow stroma. As a result the red cells are able to pass through without the receptor so that they won’t bind to the stroma and delay release.

Apoptosis is programmed cell death. EPO inhibits apoptosis by removing the induction signal. Under normal physiology the bone marrow produces more CFU-Es than needed that are stored in the bone marrow which have a “head start” in the maturation process. About a 10 day head start in maturation. The CFU-Es (Colony-forming unit-erythroid) are red blood cell progenitor cells that develop from BFU-Es (Burst-forming unit-erythroid). Both BFU-E and CFU-E are red blood cell progenitor cells that develop into the pronormoblast, which is the first morphologically identifiable red blood cell precursor. If healthy, those cells live out there life span and undergo apoptosis. If there is a deficiency of red blood cell mass, those cells undergo maturation to be released, while simultaneously the apoptosis induction signal is inhibited. The normal death signal consists of a death receptor being FAS, on the membrane of the earliest red blood cell precursors (CFU-Es/BFU-Es), and FASL ligand on the maturing red blood cells precursors. When EPO levels are low, because there is adequate oxygen delivery the older FASL bearing cells cross-link with earlier FAS precursors which stimulates apoptosis. EPO is able to subdue apoptosis by stimulating the more mature precursors to be released from the marrow, especially in times of hypoxia. At which point there will no FASL bearing cells to cross-link the early FAS bearing precursors. Its a two fold effect, the more mature cells are released to help increase red cell mass in times of need, and the early precursor are allowed to mature and be released without undergoing apoptosis. When EPO binds to its ligand on the red blood cell activates the JAK2-STAT pathway, which ends in and up-regulation of transcription for BCL-2, which is an anti-apoptotic protein. This anti-apoptotic protein rests on the cell membrane and prevents the release of cytochrome c, which initiates apoptosis. 

JAKSTAT

EPO has an effect on the bone marrow transit time of a red blood cell precursor in two different ways; increased rate of cellular processes, and decreased cell cycle times. What this means is that EPO stimulates synthesis of red cell RNA, such as the production of hemoglobin. It also stimulates the production of egress-promoting surface molecules within the bone marrow which allow the red blood cells to flow through the marrow easier. EPO stimulates cells to enter cell cycle arrest earlier than normal, and as a result, spend less time maturing and are able to be released. These cells may appear larger in size and have a bluish tinge to their cytoplasm because of this.

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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.

Aspirin as a blood thinner?

Most people who have had previous cardiac issues, those who have even had a minor heart attack or survived a major infarction have often been prescribed to take an aspirin daily. To tackle this issue, its important to understand what a heart attack or an infarction actually is. Usually blood travels to the lungs, it gets oxygenated, and then travels through the coronary arteries to oxygenate the heart muscle itself. People over time can develop plagues that thin the artery lumen, or opening, eventually to the point where only a small amount of oxygenated blood can actually pass through. As a result, the heart can’t keep itself oxygenated. Without oxygen, tissues become hypoxic and die. When they die they release toxic cytokines and chemicals that damage tissue further, which coincidently we can objectively measure to determine whether an individual has experienced a heart attack. Heart attacks can come from a deep vein thrombosis, or an emboli as well. In that scenario, the clot actually happens somewhere else in the body and a piece of it breaks off and circulates until it gets to the heart and blocks the blood flow in the heart, causing an infarct.

Aspirin works as a blood thinner. It impairs the bodies ability to form a clot. What is a clot formed out of? Platelets. So aspirin directly targets a precursor to thromboxane A2, which activates downstream signaling to aggregate platelets and form a clot in primary hemostasis.

Synthesis of TXA2

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The synthesis of thromboxane A2 is through the Arachidonic Acid, Cyclooxygenase (COX) pathway. Phospholipids are converted to Arachidonic Acid catalyzed by phospholipase C or phospholipase A2. Arachidonic acid can at that point go to two pathways; the Lipooxygenase pathway, or the Cyclooxygenase pathway. There are two Cyclooxygenase peroxidase; COX-1 and COX-2. COX-1 mediates the pathway through which thromboxane A2 is going to be synthesized, and COX-2 mediates another pathway that works to synthesize prostaglandins which directly counteract the function of thromboxane A2. Its the bodies way of keeping homeostasis. For every action, there has to be an equal reaction. In the next step in the pathway, Arachidonic Acid is converted to Prostaglandin H2 (PGH2) by PGH2 synthase and COX-1/COX-2 working synergistically. Prostaglandin H2 is then converted to thromboxane A2 (TXA2) by thromboxane synthase. TXA2 is a vasoconstrictor and potent hypertensive agent.

So, how does aspirin come into play at all? Good thing you asked. Aspirin as it turns out irreversibly binds to COX-1. This antagonist effect stops the pathway and does not allow for the synthesis of thromboxane A2. Without TXA2, there will be no platelet aggregation, and no clot. Without primary hemostasis being established, coagulation, or secondary hemostasis, can’t take over to stabilize the clot with fibrin.

 

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