An introduction to endocrinology
Doutor Pedro Silva
Several kinds of molecules are used by the organism as infromation carriers: autocrine agents act on the same cell that secretes them (or on identical adjacent cells), paracrine agents act on different neighboring cells, and neurotransmiters are released from neurones to the synaptic clefts.
In contrast, hormones are secreted by specialized glands into the bloodstream: unlike neurotransmitters, paracrine, or autocrine molecules, they can act on cells located very far from the original secreting tissue. The effects of the signalling molecules on their target cells may be very diverse, and always includes the binding of the signalling molecule to specialized proteins called "receptors".
The physico-chemical properties of the signalling molecule determine the location of the corresponding receptors. Lipophilic hormones may cross the phospholipid bilayer and bind to intra-cellular receptors. These receptors are trancription factors that change conformation upon binding. In their bound, activated, state, these receptors bind to specific regions in nuclear DNA, and activate (or deactivate) the transcription of genes, which leads to the change of the protein content and metabolic state of the cell. Since protein synthesis is a slow process, the effect of lipophilic hormones is not immediate, and may take hours (or days) to become noticeable.
In contrast, water-soluble hormones cannot cross the membrane and bind to the external face of membrane-spanning proteins. In this instance, the conformational changes brought about on the receptor upon ligand binding trigger fast processes of activation (or deactivation) of proteins already present in the cell. These hormones act therefore much faster (in second to minutes). The tranduction of the hormonal signal may occur in different ways:
| opening ionic (Na+, K+, Cl-, Ca2+) channels. The influx of ions modifies the cell membrane potential. Ca2+ also binds to a specific protein (calmodulin) and activates it. Activated calmodulin may itself activate a wide array of other proteins present in the cell.
| phosphorylation of specific intracellular proteins by an intercellular domain of the receptor with protein kinase activity. Many proteins may exist in two forms, either phosphorylated or dephosphorylated, only one of which is physiologically active. Kinases therefore activate (or deactivate) proteins already present in the cell, leading to a very fast change on the amount (and kind) of active enzymes in the cell.
| activation of cytoplasmic kinases by the intracellular domain of the activated receptor
| activation of G-proteins. G-proteins contain three subunits, one of which binds GDP. When a G-protein binds an activated receptor, its GDP-binding subunits undergoes a subtle conformational change, and exchanges its GDP nucleotide by a GTP. The GTP-bound subunit can no longer bind the other subunits, and separates. This isolated GTP-bound subunit may the activate different signal transduction mechanisms:
|      activation of adenylyl (or guanylyl) cyclases which produce the second messengers cAMP (or cGMP). These second messengers activate specific kinases, which in turn activate (or deactivate) a wide array of enzymes.
|      activation of phospholipase C. This enzyme kydrolyzes a specific phospholipid, yielding two second messengers: inositol triphosphate (IP3) and a diacylglycerol (DAG). DAG activates the (membrane-bound) protein kinase C, and IP3 triggers Ca2+ release from the endoplasmic reticulum.
The effects triggered by these hormones are transient: e.g. cAMP eventually is hydrolyzed by phosphodiesterase into AMP, terminating its activating effect, phosphatases remove the phosphate group from phosphorylated proteins, etc.
Hormones may also be removed from the bloodstream by enzymatic activities present in the liver, or through excretion by the kidneys. Water-soluble hormones are usually the easiet to remove, and most often disappear from the bloodstream in a few hours. On the other hand, lipid-soluble hormones are carried in the plasma by proteins, and remain in the bloodstream for a longer time.
Hormones which stimulate the secretion of additional hormones are called tropic hormones.
The pituitary (hypophysis) is a gland located under the hypothalamus. It contains two histologically different regions:
The hypothalamus controls the adenohypohysis through the secretion of several hypophysiotropic hormones :
GnRH - Gonadotropin releasing hormone
somatostatin (inhibts growth hormone secretion)
dopamine, also know as "prolactin-inhibiting factor" (inhibits prolactin secretion)
TRH - thyrotropin-releasing hormone (also stimulates prolactin secretion)
GHRH - growth hormone-releasing hormone
CRH - corticotropin-releasing hormone
Hormone disorders may be due to abnormal amounts of circulating hormones (either hypo- or hyper-secretion) or to abnormal target cell responses (hypo- or hyper-sensitivity). Anomalies of the amount of hormone may be due to malfunctioning of:
the secreting gland a (primary hypo- or hyper-secretion)
the gland (usually the pituitary) that secretes its tropic hormone( secondary hypo- or hyper-secretion)
the gland (usually the hypothalamus) that secretes the regulating hormone of its tropic hormone(tertiary hypo- or hyper-secretion)
Anomalies in the magnitude of the target cell response to hormone binding may be due to the amount of receptors present, to inhibition of cellurar mechanisms ellicited by receptor activation or to anomalous maturation of the hormone (several peptide hormones must be activated by hydrolysis after secretion to the bloodstream).
The thyroid gland, located in front of the trachea, weighs approximately one ounce. It is composed of several follicles, which contain an outer layer of secreting cells surrounding a solvent-filled cavity where proteins (mainly thyroglobulin) accumulate filled. The thyroid actively absorbs iodide from the bloodstraeam and transfers it (through the action of a peroxidase enzyme system) to specific tyrosine residues present in thyroglobulin. Eacy tyrosine may receive one or two iodine atoms (yielding either monoiodotyrosine -MIT_ or diiodotyrosine - DIT). Iodine-containing hormones produced in the thyroid are built from these iodinated tyrosine residues: thyroxine (T4) is built from two DIT molecules, and triiodothyronine (T3) is built from one DIT and one MIT. Both T4 and T3 are lipid-soluble hormones, and are carried in the bloodstream by specific proteins (like transthyrretin). T4 is much more abundant than T3, but only T3 is active: T4 must be deiodinated to the active form (T3) by the target cell.
Iodine-containing thyrois hormones induce the synthesis or respiratory enzymes, Na+-K+ ATPase, etc. induzem a síntese de enzimas respiratórias, da bomba de Na+-K+, etc., which causes a general increase of the metabolic rate and heat production. Their effects on the body also include appetite increase, decrease of adipose tissue, increased breaathing rate and urea excretion, etc.
Whenever the concentrations of T3 and T4 in the bloodstream are too low, TSH is secreted by the pituitary gland. TSH stimulates the thyroid to increase its protein production and size. Therefore, in the absence of iodine the size of thyroid gland increases considerably due to its continuous stimulation by TSH.
In the kydney's Bowman capsules, blood plasma is continuously filtered. Apart from the absence of proteins, the composition of the filtrate inside the capsule is identical to that of the plasma outside the capsule. The collected filtrate flows through the kydney tubules, where several molecules are either reabsorbed into the bloodstream, or secreted into the filtrate. The composition of the resulting outflow (urine) is therefore quite different from that of the original filtrate.
The filtrate concentration mechanism comprises two main processes:
active transport of Na+ towards the outside of the tubules, which creates a difference in osmotic pressure between the two sides of the tubular membrane.
passive transport of water out of the tubule, according to the osmotic pressure difference created by the previous process.
Accurate regulation of the amount of body water is necessary since excess water can cause edema and elevation of blood pressure (and consequently bleeding and stroke). On the other hand, if the volume of water is too low the blood pressure will be too low to adequately supply the organs. This regulation is performed by adjusting the urine concentration: hypervolemia causes the excretion of large amounts of dilute urine, and hypovolemia causes the excretion of very concentrated urine. This is achieved by adjusting the permeability of the collecting tubules, which is determined by the presence of a highly specific water channel (aquaporin). This protein is synthesized by collecting tubule cells and stored in endosomes present therein. Vasopressin (released by the neurohypophysis) induces the fusion of these endosomes with the cell membrane, allowing the water to exit the tubule through the aquaporins. The release of vasopressin occurs when the hypothalamus osmoreceptors detect high concentrations of solutes in the blood (i.e. after ingestion of salty foods, or in dehydration). If the neurohypophysis does not secrete enough ADH, or if the kidney is not sensitive to this hormone, no significant water reabsorption will occur at the tubule level, and continuous production of large amounts of extremely dilute urine (diabetes insipidus) will be observed.
Independent adjustment of sodium reabsorption is achieved through the intervention of aldosterone. This hormone is synthesized by the glomerulosa zone of the adrenal cortex, and causes synthesis of sodium pumps by the tubule cells, and consequent retention of sodium by the body. Aldosterone is released fundamentally in response to blood pressure lowering:
When blood pressure is low, the juxta-glomerular cells of the kidney secrete renin into the blood. This enzyme acts on a protein released by the liver (the angiotensinogen), producing
The angiotensin converting enzyme (ACE) converts angiotensin I into
angiotensin II, which stimulates the secretion of
Angiotensin II elevates blood pressure by other additional mechanisms: it stimulates cardiac output, thirst and secretion of ADH and causes vasoconstriction of arterioles.
When blood pressure is high, further distension of cardiac atrial cells causes the release of atrial natriuretic peptide (ANP). This increases the glomerular filtration rate and inhibits the secretion of aldosterone, renin and ADH, causing the excretion of sodium and water.
Maintaining Ca 2+ levels is very important for organism balance: low concentrations increase the excitability of nerve and muscle cell membranes, while too high concentrations cause cardiac arrhythmias and decrease neuromuscular excitability. Calcium homeostasis depends on the relationships between the kidneys, gastrointestinal tract and bones. These contain> 99% of the body's total calcium, and play a leading role in maintaining plasma Ca2+ levels. This role is critical, and takes precedence over the role of structural support played by the bone.
At the renal level, calcium is filtered, and then reabsorbed based on its plasma concentration. When it is very high, the resorption is reduced.
Bone is composed of several types of cells that surround a gelatinous matrix composed primarily of collagen, where calcium phosphates (collectively known as hydroxyapatite) are deposited. Other minerals (copper, zinc, boron, magnesium and silicon) also play important roles in bone formation. Non-erythropoietic bone cells can be of three types: osteoblasts (secrete collagen, where minerals deposit), osteoclasts (which dissolve minerals by H+ secretion and collagen by secretion of hydrolytic enzymes), and osteocytes (osteoblasts surrounded by calcified matrix).
A large number of factors affect the relative activities of osteoblasts and osteoclasts. Bone formation is favored by estrogen (and therefore the low levels of this hormone in menopause favors the onset of osteoporosis), testosterone, calcitonin, insulin and growth hormone, whereas its decomposition by osteoclasts is promoted by the thyroid hormones, cortisol (and hence the contraindication of corticoids in children) and parathyroid hormone.
The parathyroid hormone (or paratormone) is secreted by the parathyroid glands. Its secretion is stimulated by low extracellular concentrations of Ca2+ . Parathyroid hormone increases the plasma Ca2+ concentration in several ways:
It increases the activity of osteoclasts
It increases renal reabsorption of Ca2+
It stimulates the formation of 1,25-hydroxyvitamin D, which increases the intestinal absorption of 2+
It decreases renal phosphate reabsorption, which prevents phosphate levels from increasing as the phosphate release from bone increases.
Vitamin D deficiency prevents bone formation, causing rickets (in children) and osteomalacia (in adults), as it causes a decrease in the absorption of Ca2+ . Osteoporosis is caused by loss of minerals and bone collagen due to imbalances in the relative activity of osteoclasts and osteoblasts. Contrary to popular belief, most studies show that elevated calcium intake does not, by itself, slow the rate of osteoporosis. For example, high-protein diets increase Ca2+ excretion and so the prevalence of osteoporosis is higher in industrialized countries where meat and fish consumption is very high. Other habits affect osteoporosis: sulfur-containing amino acids (methionine and cysteine), caffeine, and sodium increase the rate of calcium excretion, whereas regular exercise (walking, or climbing stairs) may be more effective in preventing osteoporosis than calcium intake.
Human metabolism continually produces large amounts of CO2. Once CO2 reacts with water (forming carbonic acid), it must be removed so that no acidosis occurs. Removal occurs in the lungs, and is stimulated by low pH. In turn, excess HCO3- can cause alkalosis. HCO3- homeostasis is maintained by the kidneys, which filter HCO3- and then reabsorb it almost completely. The kidney also adjusts the pH directly by secretion of H+ (into the blood or into the tubule) in the distal and proximal tubules. The distal tubule may also secrete HCO3-.
The synthesis of urea, which occurs in the liver, uses HCO3-, which contributes to the decrease in blood pH. Situations of metabolic acidosis may therefore be aggravated by the action of the urea cycle. Under these circumstances, nitrogen is eliminated by the joint action of the liver and kidney: excess nitrogen is first incorporated into glutamine by glutamine synthase. The renal glutamine synthase then cleaves glutamine into glutamate and NH3, which is immediately excreted. This process allows the excretion of nitrogen without eliminating the bicarbonate anion.
Growth hormone (somatotropin)
Exercise, stress and sleep stimulate the secretion of GHRH, which directs the adenohypophysis to secrete somatotropin . Somatotropin (also know as growth hormone, or GH) has two types of effects:
in the short term, acts directly on adipose tissue, stimulating the release of fatty acids into the bloodstream, stimulates gluconeogenesis and protein synthesis in the liver, and decreases glucose entry (and increases protein synthesis) in the muscle. It's a diabetogenic effect. In the epiphyseal plaque of the bones, it stimulates the differentiation of pre-chondrocytes in chondrocytes. These cells are responsible for the formation of cartilage that osteoblasts subsequently convert into bone.
in the long run, it indirectly promotes bone growth: somatotropin induces the secretion of a hormone (somatomedin, or insulin-like growth factor (IGF-I) in the liver and bones, which stimulates chondrocyte division, allowing the bones to become longer.
In addition to the hypothalamic controls, other hormones (thyroid hormones, insulin, and sex hormones) influence the secretion of somatotropin. Sex hormones stimulate the secretion of somatotropin and IGF-I; however, in addition to this effect, sex hormones induce the complete conversion of epiphyseal plaque into bone, which causes the end of growth. This explains both the growth observed at puberty and the absence of growth in adulthood. Testosterone also exerts direct anabolic effects on various organs and tissues, causing p. ex. increase in muscle mass. In turn, high concentrations of cortisol inhibit DNA synthesis, stimulate catabolism and bone resorption, causing a decrease in growth rate. Somatotropin and thyroid hormones are responsible for extrauterine growth. Fetal growth does not depend on these hormones, but on insulin.
Glucocorticoids (cortisol and corticosterone) are synthesized mainly by the fasciculated zone of the adrenal cortex in situations of aggression to the body (physical trauma, prolonged exposure to cold, infection, loss of fluids, fear, pain, etc.). These stress situations usually also include release of adrenaline from the adrenal medulla. The release of cortisol is mediated by the hypothalamic-pituitary axis. In addition to CRH, the secretion of ACTH (and, by extension, cortisol) is also stimulated by other hormones, eg adrenaline and vasopressin.
Even in the absence of stress, cortisol plays important roles: it increases the action of adrenaline and noradrenaline on the vascular musculature, and maintains the cellular concentrations of various enzymes involved in maintaining circulating glucose levels. It increases the breakdown of triglycerides, diverts blood flow to the muscles and increases lung ventilation. It also has anti-inflammatory action (by inhibiting the production of leukotrienes and prostaglandins) and limits the immune system's performance (preventing it from disproportionately reacting to minor infections). Lack of cortisol can lead to the onset of autoimmune diseases. During fetal and neonatal development, it is also implicated in the differentiation of the adrenal medulla, lungs, intestine and certain regions of the brain.
Loss of adrenal cortical function (eg due to autoimmune diseases, infectious diseases, or, more rarely, invasive tumors) causes adrenal insufficiency: lowering cortisol levels causes a decrease in blood pressure, a reduction in glucose levels, weakness, lethargy and lack of appetite; additionally, loss of aldosterone (also secreted by the adrenal cortex) causes imbalances in sodium, potassium and water blood levels. Adrenal insufficiency may also be due to lack of ACTH. In this case, the symptoms are less severe, since the levels of aldosterone are not affected, because they are regulated by the renin-angiotensin system, and not by ACTH.
Adrenal insufficiency can be fatal if not treated aggressively. Its opposite (excess glucocorticoids), although less dangerous, can also be severe. In Cushing's syndrome, excessive secretion of cortisol (by adrenal tumors) or ACTH (by pituitary tumors) is observed. Elevated levels of cortisol stimulate uncontrolled catabolism of muscles, skin, bones, and other organs. Osteoporosis develops, and the skin becomes very sensitive to aggressions. Blood glucose may rise to levels normally associated with diabetes. Severe immunosuppression, hypertension (due to the permissive effect of cortisol on the action of adrenaline and noradrenaline on the vascular musculature) and obesity (due to the increased appetite caused by cortisol) may also occur.