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Transcript
ENDOCRINOLOGY 1. Hormones can be classified according to different aspects, either according to chemical composition (lipid derived, protein derived and amino acid derived) their action, solubility (Group I and Group II, or sites where they are secreted (thyroid and adrenal hormones). Important notes about hormones: A slight alteration in structure of a hormone brings about significant physiologic activities e.g. estradiol (E2) and estriol (E3), both are estrogens but the former is most potent while estriol is the most inert and the difference is only the – hydroxy group which is absent in estriol. Hormone concentration in blood can be present in three forms; protein bound hormone [bound to a specific plasma protein] and this form is functionally inactive, free hormone [unbound to protein] which is functionally active and total hormone that represents both bound and free. The neural crest is the embryonic origin of some endocrine cells, this means that there's connection between the CNS and the endocrine system, and ectopic (abnormal) production of hormones from a wrong tissue can be used as tumor markers, e.g. Parathyroid H (PTH) and ACTH are produced by cells of lung cancer. High levels of hormones at tissue level than plasma is needed for certain functions for e.g. testosterone is higher in scrotal tissue than in plasma since it's required for spermatogenesis. Hormone Biosynthesis and Modification:This differs from one hormone to another and as the following: 1. They are derived from different chemical precursors e.g. steroids are lipid derivatives while Triiodothyronine (T3) and Tetraiodothyronine (Thyroxin=T4) are tyrosine derivatives. In contrast, other hormones secreted from different tissues and they act on different target cells but have similar chemical structures. For e.g. TSH that stands for thyroid stimulating hormone (or called Thyrotropin) is secreted from the pituitary gland and acts on the thyroid tissue whereas human chorionic gonadotropin (hCG) is secreted from the placenta and acts on the ovaries; however both hormones have similar chemical structures as both are glycoproteins with two subunits and, in which subunit is identical in both of them (also for LH and FSH). 2. Some hormones are secreted in their final forms. For e.g. Aldosterone and Cortisol, while others need modification after their secretion into the blood—that's to say they are synthesized and secreted in inactive forms called pro-hormones. Example is insulin which comes from pro-insulin in plasma.{ A+B+C (A+B) + C} Pro-insulin which has three peptides, by the action of proteolytic enzymes in blood it's converted to insulin (A+B) peptides the active form and leaving C-peptide functionless but used in laboratory to differentiate exogenous from endogenous insulin in cases of hypoglycemic coma. If the level of C-peptide and insulin are both high, they indicate endogenous source. Contrarily if insulin increased only while C-peptide is low it indicates exogenous source. (Why?) 1 Target gland or tissue; The tissue that has a biochemical and physiological response to hormone is called target tissue. For e.g. thyroid gland is the target tissue for TSH that is secreted by the pituitary gland, this hormone has specific receptors on thyroid cells acts by increasing both size and number of thyroid cells and also stimulates their function. The target tissue responses to its hormone affected by several factors: 1. Concentration of hormone at tissue level (not in plasma) 2. Normal binding of hormone to its receptors in that tissue 3. Normal post-receptor response Defect in any of these factors changes the normal hormonal response in that tissue. Control Mechanisms:The mechanisms that maintain normal level of hormones both in serum and tissues are: 1. Feedback mechanism: in which the product of one or a given endocrine axis (a hormone) affected by increase or decrease the earlier parts of that axis which will alter the rate of production of target tissue product. It is of two types: Negative feedback inhibition; it is the commonest type in which increase in product of axis more than normal level will inhibit the whole axis activity. For e.g. the hypothalamus-pituitary-adrenal axis (HPA axis). Any increase in its level (cortisol for example) will inhibit the secretion of hypothalamic hormone which is CRH (corticotropin-releasing hormone) and this in turn, will not stimulate pituitary hormone ACTH (adrenocorticotropin hormone) any longer. This is called long loop inhibition. While when pituitary hormones increase, they will inhibit hypothalamus secretion. This is called short loop inhibition. This mechanism is lost in patients with Cushing's syndrome in which case cortisol secretion is huge. Positive feedback; or called feed-forward in which increase in product, increases the axis of activity for e.g. estrogen secreted from follicular cells of ovary at the day 14 of menstrual cycle will result in increase of Luteinising hormone (LH) for higher levels (LH-surge) which is important to induce ovulation. 2. Neural stimulation: physical or emotional stress may result in transmission of neural signals from higher centers in the brain to hypothalamus and therefore there's increase in pituitary hormone secretion as well as the target gland which will stimulate the axis. This is called (open loop control system) may result in clinical findings similar to endocrine diseases. 3. Inherent rhythm (circadian rhythm); intermittent release of hypothalamic hormones or pituitary hormones results in regular daily secretion of target hormones. Example is cortisol—it is higher at morning and lower at night. This rhythm is lost in patients of Cushing's syndrome. Hormone Action:Hormones are classified into two groups according to their receptor location (action): 1. Group I: these diffuse through the membrane of cells forming HR-complex inside the cells which undergo structural changes that enhance the binding of complex to 2 DNA of the cell results in gene transcription (mRNA production) which affects metabolic response. 2. Group II: protein-derived hormones that are water-soluble compounds so they cannot diffuse to inside the cell but they do their response by binding to surface receptors and the signals transmitted intracellularly through the second messenger, the hormone is the first messenger. This group can be classified according to their second messengers into 4 subgroups: Subgroup (A) has cAMP as a second messenger and they act by increasing cAMP level inside the cells through activation of cell membrane enzyme (adenylate cyclase); in the first step HR-complex is formed, which will activate C-protein of adenylate cyclase that catalyses formation of cAMP from ATP. Thereafter; activity of GTPase enzyme of Gprotein of adenylate cyclase will inactivates the adenylate cyclase enzyme. The second step occurs when cAMP is produced that'll act on protein kinase—this enzyme acts by transferring phosphate group from ATP to the target enzyme in cascade thereby activating the enzyme which will induce cellular response. Termination of hormonal response occurs by 2 ways 1) the HR-complex dissociated due to release of hormone from its receptors, this termination will result in reduction of cAMP level and 2) by the action of phosphodiesterase on cAMP which converts cAMP to 5ʹ-AMP which is inactive. NB: Caffeine which is Xanthine derivative inhibits phosphodiesterase activity therefore causes prolonged hormonal action. Subgroup (B) includes one hormone only called atrial natruretic factor (ANF) which is produced by atrial tissue of heart and causes natruresis, vasodilation and inhibition of aldosterone secretion, therefore; results in decreased sodium (Na⁺↓ and BP↓) which causes decrease in surface receptors as well as blood pressure. This hormone acts by binding to surface receptors and the HR complex formation results in activation of guanylate cyclase enzyme which increases cGMP production from GTP leading to effective physiologic response (decrease blood pressure). cGMP breaks down by the action of cGMP 3 phosphodiesterase. Therefore, drugs that activate guanylate cyclase increase cGMP level, such as Nitroprusside and Nifedipine (Adalat) are used in treatment of hypertension. Subgroup (C) the second messenger is phosphoinositol e.g. ADH, when this hormone attaches to its receptor on the cell surface, it will activate an enzyme called phospholipase C, which acts on PI on the cell membrane, resulting in production of diacyl glycerol and inositol triphosphate (ITP), which effectively release calcium from ECF storage sites and influx calcium from ECF to inside the cells, ending with increased calcium ion levels intracellularly. This ion binds to specific protein called calmodulin, forming calciumcalmodulin complex, which are similar to cAMP (activate enzymatic cascade). Subgroup (D) this including insulin, GH, prolactin (PRL) and hCG. There is no a definitive messenger for them but they act almost all over the body. Hypothalamic Hormones: The hypothalamus produces two groups of hormones that are associated with posterior and anterior pituitary. The first group includes 3 peptide hormones that travel down to the posterior pituitary through nerve fibers where they are stored there. These hormones are: 1. Arginine-vasopressin (or known as ADH): when there is hyperosmolality e.g. during dehydration, this hormone is released from posterior pituitary and acts on renal tubule through special receptors enhancing water reabsorption from tubules to the blood (without salts). This means that it will dilute the blood and therefore corrects osmolality, but concentrated urine is produced. The reverse is true, that is to say when the subject drinks a lot of water/fluid, this will decrease blood osmolality and inhibits ADH secretion, with more loss of water in urine (dilute urine is produced), so disease or trauma that causes damage of posterior pituitary causes deficiency of ADH resulting in a syndrome called diabetes insipidus. Also, congenital absence of tubular receptors of ADH (renal cause), results in a similar syndrome called nephrogenic diabetes insipidus. 2. Oxytocin: a hormone similar in structure to ADH, controls ejection of milk from lactating breasts. It also initiates uterine contraction during labour. It can be used in obstetrics to induce labour, in the form of drugs called Pitocin. 3. Neurophysin: its function is not clear but it may transport and restore the above two hormones. The second group includes small molecules called regulatory hormones that are produced in the hypothalamus and are transported through blood network to anterior pituitary. These are of 2 types: Releasing hormones (RH) Releasing hormone-inhibitory hormones (RHIH) The RH stimulates release of anterior pituitary hormones, whilst RHIH inhibits them. Normally, all pituitary hormones undergo stimulation, except prolactin (PRL), which undergoes inhibitory effect (its release is normally inhibited). 4 Mechanisms in Endocrine Axis:The mechanism starts with neural signals which stimulate the production of releasing hormones (RH) from the hypothalamus. Each of these RH triggers its target cell in anterior pituitary gland to produce its corresponding tropic hormone. These tropic hormones circulate in blood and act on their target gland or tissue to produce their effects. Neural Signals (Brain centre) ⁺ TRH CRH GnRH GHRH ⁺ ⁺ ⁺ ⁺ TSH ACTH FSH &LH GH Thyroid Adrenal Gonads Bone & Cortex Cartilage Note: prolactin is the exception because its secretion is normally inhibited (RHIH is high). But when there are tumour called chromophobes adenoma, or when there is pregnancy and lactation, the RH of prolactin is dominant, which results in increased level of prolactin in blood, results in galactorrhoea¹ or normal lactation respectively. ¹: galactorrhoea: spontaneous secretion of milk in nursing mothers, sometimes related to hyperprolactinaemia. Hormones Not Under Axis Control:This group includes hormones not under the control of hypothalamic and pituitary hormones, such as calcitonin produced by C-cells of thyroid gland and parathyroid hormone that's produced by parathyroid glands. Both of these hormones are controlled by serum calcium level. Insulin and glucagon are secreted from and cells of the pancreas. They are under the control of blood glucose level. Epinephrine and norepinephrine are secreted from adrenal medulla in response to stress conditions. Classification of Anterior Pituitary Hormones:According to their chemical composition, these hormones are of 2 types: 1. Simple polypeptides: such as GH and prolactin, both secreted from acidophilic cells of pituitary, both of them have no specific target endocrine tissues, but they act directly to do their effects, e.g. GH enhances bone and cartilage growth, while prolactin stimulates lactation. 2. Glycoproteins: such as LH, FSH, TSH and ACTH which are produced by basophilic cells of pituitary. This group is more resistant to heat or temperature outside the body. (Why?) 5 Growth Hormone:The highest blood level of this hormone occurs after severe exercise, deep sleep, and hypoglycemia. These three factors have been used in laboratories to estimate growth hormone level after stimulation or provocation, to diagnose growth hormone deficiency. Its growth function occurs through specific factors called somatomedins (IGF I and IGF II)—stands for insulin-like growth factors, which are produced from liver cells in response to GH. These factors are also called sulphation factors because they incorporate sulphate to cartilage. They promote their growth effect on target tissues (bone and cartilage) through specific cell membrane receptors. Other functions of GH are metabolic as it enhances protein synthesis and lipolysis (results in increased FFA in blood), but it inhibits glucose uptake by peripheral cells, therefore causing hyperglycaemia, (it acts as antagonist of insulin), preventing insulin binding to its receptors. Growth hormone disorders: Growth hormone undergoes two important abnormalities. These are increased GH secretion due to pituitary cell tumors, this results in increased GH level in blood and if it occurs during childhood, shows a disease called gigantism, while if it occurs during adulthood, it is called acromegaly. But in GH defect which is called dwarfism (short stature), it is due to either deficiency of GH (decreased secretion from pituitary), because of pituitary gland damage, or due to target tissue resistance to growth hormone—called Laron-Pygmies dwarf. This is caused by absence of hepatic receptors of GH and not related to GH level in blood. Hence we have two pathologically different types of dwarfism that's caused by defect of GH. Hypopituitarism:Defect in secretion of pituitary hormones, which is of two types: 1. Isolated hormonal deficiency: in which only one or two hormones are deficient while the other hormones are normal, because usually congenital abnormalities in hypothalamic centres results in deficient releasing hormones. The usual hormones affected are gonadotropins and GH. 2. Panhypopituitarism: in which all hormones of anterior pituitary are deficient due to pituitary tumours or infarction (which means loss of blood supply to the organ). In infarction, it may occur due to post-partum haemorrhage (after-delivery bleeding) and the syndrome produced is called Sheehan's syndrome. Clinical and biochemical consequences of hypopituitarism: the features are usually due to target gland failure e.g. deficiency of LH or FSH causes secondary hypogonadism, which results in amenorrhoea (absence of menses), infertility, atrophy of secondary sex characters, impotence in male and loss of libido. Deficiency of GH and TSH causes growth retardation (dwarfism). Deficiency of ACTH causes secondary adrenocortical hypo-function. This type should be differentiated from the primary cause that's called Addison's disease, in which the adrenal gland itself is destroyed by bacterial infection or by auto-immune disease (auto-antibodies) which means loss of cortical or adrenocortex function (cortisol↓). In Addison's disease, there are low 6 levels of cortisol with a very high level of ACTH. In contrast, in the secondary type, both of these hormones (cortisol and ACTH) are on low levels. The second difference is that in primary, there is hyperpigmentation while in secondary there is no pigmentation (why?); because the low level of cortisol in Addison's there is loss of negative feedback inhibition, which results in excessive secretion of CRH and in turn ACTH. But this latter is also stimulator of melanocytes (cells of melanin) which are important for melanin production that gives us dark pigmentation of skin and mucous membranes. Endocrine Disease:It is of two types: 1. Primary endocrine disease: in which there is failure of target glands/tissues to respond to hypothalamic or pituitary hormones, which are normal. This means that there is low levels of target gland hormones, results from the damage of gland, leading to loss of negative feedback inhibition, therefore there is excessive uncontrolled production of pituitary hormones e.g. ovarian failure leading to very low or no oestrogen, leading to stimulation of hypothalamic (GnRH) or pituitary (LH and FSH). Ovarian failure No oestrogen Loss of negative feedback inhibition GnRH↑ Adrenal failure No cortisol No of negative feedback inhibition CRH↑ ACTH↑ Hypothyroidism T3↓, T4↓ 2. Secondary endocrine disease: deficiency of higher level gland hormones (hypothalamus and pituitary) which results in deficiency of target gland hormones as well. H H ⁺ P ⁻ P ⁺ T ⁻ T (not produced) Normal Abnormal Damage to hypothalamus causes deficiency of GnRH. So there is no stimulation for pituitary hormone production, i.e. low levels of LH and FSH which leads to no hormonal action on target tissues such as testes and ovaries, resulting in low level of serum testosterone (in male) or low levels of serum oestrogen and progesterone (in female). Adrenal Glands:This gland is divided into two regions; the cortex and medulla. The cortex is part of the hypothalamic-pituitary-adrenal adrenal axis and consists of 3 layers called zona granulosa which produces mineralocorticoids, for example aldosterone. The inner 2 layers are zona fasiculata and zona reticularis which are responsible for production of two types of hormones, glucocorticoids (e.g. cortisol) and androgens (e.g. dehydroepiandrosterone— 7 DHEA), respectively. Excess or deficiency in serum level of any of these layers results in serious complications. Steroidogenesis (Biosynthesis of Steroid Hormones):Steroid hormones, bile salts and vitamin D all are derived from cholesterol that's why the steroid-producing tissues are all rich in cholesterol. Cholesterol is a 27C molecule; its derivative steroids contain either of 18, 19 or 21C molecules according to its type: 21C- progesterone, glucocorticoids and mineralocorticoids , 19C-androgens 18Coestrogens The rate-limiting step is the first step which is the conversion of cholesterol to pregnenolone, the final products depend on the tissue and enzyme they contain, but generally, the most significant products are cortisol, aldosterone and androgens—DHEA, and oestrogen (oestrone). The pituitary hormone ACTH is stimulator of the inner two layers but not on the outer layer; therefore it stimulates production of cortisol and androgen. The outer layer of this gland is controlled by another system in the body called renin-angiotensin system which stimulates production of aldosterone (mineralocorticoid derivative). Adrenal hormones are classified into 3 groups depending on their physiologic function: Glucocorticoids: these include cortisone and cortisol. Cortisol stimulates gluconeogenesis, lipolysis and protein breakdown (catabolic hormone) and antagonises the action of insulin. That's why they are called diabetogenic agents. Cortisol is normally involved in retention of water and electrolytes from renal tubules to ECF (blood and interstitial compartment). This explains hypertension, therefore deficiency of this enzyme results in hypotension, while excess amounts in hypertension. Cortisol also suppresses the immune and inflammatory responses (anti-inflammatory), because it decreases the number of leucocytes and also their migration and inhibits phospholipase A2, which is important for production of inflammatory molecules (prostaglandins and leucotrienes). For this reason, this hormone is used as a drug in the treatment of inflammatory conditions such as allergy and rheumatic diseases in form of cortisone (Hydrocortisone™) which converts inside the body to cortisol—the active form. In blood, 95 per cent of cortisol is bound to cortisol-binding protein (CBP), commonly globulin (CBG). The other 5 per cent of hormone is unbound to protein (free). In certain conditions e.g. CBG↑ due to genetic causes or pregnancy, or if the patient is on contraceptive pills so the total cortisol in serum is high due to high level of bound form only. That is why the patients have no symptoms or signs. In contrast, other conditions lead to loss of CBG, like nephrotic syndrome, androgen therapy or genetic defect in production of CBG, leading to decrease in total level of hormones, due to a decrease in the bound form only, while the free form is normal in both cases (no symptoms). The hormone is inactivated by liver cells through conjugation with sulphate or glucoronate to sulphated or glucoronated hormone which are water soluble (not toxic) and can be excreted in urine. Among other steroids, cortisol is the only one involved in adrenal gland secretion through HPA axis. Cushing's syndrome:Increased serum cortisol level is due to several causes, such as: 8 ACTH↑ (common): is part of a syndrome due to pituitary adenoma (Cushing's disease). It is either caused by non-pituitary carcinoma or by ACTH therapy as a drug. Cortisol↑: due to tumour in adrenal cortex, when there is ACTH↓, again it is either of two; adrenal tumours or by cortisol therapy as a drug¹ ¹: cortisol as a drug is known as Dexamethasone (or trademark Dexon or Dexone). Metabolic consequences: 1. Glucocorticoid activity of high cortisol results in hyperglycaemia and glucosuria, because cortisol, like other stress hormones antagonises the activity of insulin (inhibits cellular glucose uptake), and also increases protein breakdown and lipolysis, therefore increases the activity of gluconeogenesis. 2. Protein breakdown also causes the nitrogen balance (increased loss of nitrogen in urine) loss of bone matrix is due to defect in collagen and this results in osteoporosis. Also, protein breakdown results in muscle wasting and thin skin with bruising. (striae atrophicae). 3. High levels of cortisol acts like aldosterone, therefore it enhances sodium ion reabsorption in exchange to hydrogen and potassium ions in the renal tubules. This means it causes hypernatraemia (Na⁺↑) and increased loss of potassium and hydrogen in urine, therefore results in hypokalaemia (K⁺↓) and alkalosis (pH>7.45), respectively. 4. If the cause of Cushing's syndrome is increased ACTH, this hormone will stimulate androgen production as well as cortisol. This explains hirsutism and virilism in female subjects with menstrual disturbances. Laboratory features: Serum cortisol: we should measure this hormone in the morning and evening to see if there is any defect in circadian rhythm, which is a diagnostic feature of Cushing's syndrome. However, the presence of significantly high serum cortisol levels in the evening sample is also diagnostic. Urine cortisol: in 24hr urine samples is diagnostic when it is at very high levels. Tests for HPA axis: by checking both serum cortisol and serum ACTH, in order to differentiate the cause of disease (primary or secondary). If both are increased, this indicates secondary (explain how). If one of them (only cortisol) is high and ACTH is undetectable, this indicates primary endocrine disease. If both are low, it indicates drug therapy. Mineralocorticoids: the most important hormone is aldosterone which stimulates exchange of sodium with potassium and hydrogen ions across the cell membranes, especially of renal tubules. Production and secretion of this hormone from glomerulosa (the outermost layer) is under the control of renin-angiotensin system, which is involved in regulation of blood pressure and electrolyte balance. 9 Low blood pressure stimulates production of renin from renal tubules, the enzyme acts on angiotensinogen converts into angiotensin I, then to angiotensin II. This production occurs in lung tissue. Angiotensin II acts on special receptors on the adrenal cortex. The second messenger is calcium, which will stimulate the enzymatic cascade that are responsible for activation of the first enzyme in steroidogenesis, that acts on cholesterol, converting it into pregnenolone which by several steps converts to aldosterone, which has specific receptors on renal tubules which enhances exchange of Na⁺ to K⁺ and H⁺. This rise in serum sodium ion level indicates increased salting of blood which will increase blood pressure back to normal (corrects hypotension). Aldosterone disorders: Deficiency of aldosterone is of two types: Primary adrenal hypo-function (called also adrenal insufficiency or Addison's disease): this occurs due to damage of the adrenal cortex by chronic bacterial infections (tuberculosis) or by autoimmune disease. This results in deficiency of all hormones including aldosterone, cortisol and androgens. Aldosterone deficiency causes defect in exchange mechanism of Na⁺ to K⁺ and H⁺ in renal tubules. This leads to hypotension, hypokalaemia and acidosis (pH<7.35), while low cortisol level results in loss of negative feedback inhibition of HPA axis, leading to increased level of serum ACTH, melanin pigment production is also increased. Secondary adrenal hypo-function: due to damage of hypothalamus or pituitary gland but there is no adrenal dysfunction but a loss of stimulation factor of adrenal gland. In this disease only serum cortisol and androgen are low or affected, while aldosterone is in normal range. Excess of aldosterone; this is also of two types—primary and secondary: Primary aldosteronism (Conn's disease): in which adrenal cortex tumour secretes large amounts of aldosterone, which enhance exchange mechanism with subsequent hypernatraemia, hypokalaemia and alkalosis. Secondary aldosteronism: or oedema in which there is a long-standing disease e.g. low renal blood flow due to cardiac failure or liver cirrhosis that stimulates reninangiotensin system, with production of large quantities of aldosterone. The features are the same as primary aldosteronism—namely; hypernatraemia, hypokalaemia and alkalosis. Congenital Adrenal Hyperplasia (CAH):Normally steroidogenesis involves several enzymatic reactions, with different enzymes, such as hydroxylases, dehydrogenases, and isomerases. Abnormalities in hydroxylation reactions are the most common e.g. cortisol is synthesised by 3 subsequent hydroxylases, which are 17-, 21- and 11-hydroxylases. 21-hydroxylase but not 17- or 11-hydroxylases are also involved in aldosterone production. Congenital deficiency of 17- or 11-hydroxylase is very rare and involves only cortisol production. 21hydroxylase is most common and affects both cortisol and aldosterone. If there is deficiency of 21-hydroxylase, there is low cortisol, resulting in loss of negative feedback 10 inhibition, with production of large quantities of ACTH. ACTH increases the size and number of adrenal cortex cells (hyperplasia), with increased precursors of cortisol and aldosterone before enzymatic block. These precursors may be metabolised by an alternative pathway, especially androgen (its level rises), resulting in hermaphroditism in childhood with ambiguous genitalia of either sex. Thyroid Gland It is an endocrine gland, located in the anterior triangle of the neck and consists of two lobes connected by the narrow isthmus. It consists of two types of cells: Acinar (follicular) cells Parafollicular cells (C-cells) The first type secretes thyroid hormones T3 and T4. The C-cells secrete calcitonin. T3 and T4 are important for general metabolic pathways, while calcitonin is important for calcium metabolism. The production and release of thyroid hormones are controlled by anterior pituitary hormone TSH, which is a glycoprotein. This TSH is controlled by hypothalamic hormone TRH. The whole control system is called HPT axis. The blood level of T4 is higher than of T3, but T3 is 3 to 4 times more potent than T4 at tissue level. So T4 is the storage type, while T3 is the active form. This is because T4 should be deiodinated at this level and be converted to T3. T3 has receptors on all body tissues and its function is to stimulate general metabolism (speeds up the metabolic pathways), growth and differentiation. Therefore deficiency of this hormone is a cause of dwarfism, this is because growth hormone production at gene level requires T3 hormone as stimulator. Tyrosine is the precursor of thyroid hormone (as well as epinephrine and norepinephrine). Iodination at position 3 will result in production of 3,5-diiodotyrosine (DIT). Condensation of two molecules of DIT results in production of thyroxine or called 3,5,3′,5′-tetraiodothyronine—or T4. While condensation of 1mole of 3-monoiodotyrosine (MIT) and 1mole of DIT results in production of 3,5,3′-triiodothyronine or called T3. Removal of iodine from 5′- carbon of the ring of T4 by deiodinase enzyme could also result in production of T3, while removal of iodine from carbon 5- position of the ring of T4 will result in production of this compound; 3,3′,5′-triiodothyronine (reverse T3 or rT3). Q) Which of them is active; T3 or rT3? A) T3 is more active than rT3 (inactive). But it is produced in the body (why?) Some conditions that need reservation of energy e.g. chronic illness or the use of drugs e.g. Inderal (propranolol) is used for control of the heartbeat. Both these factors will enhance deiodination from position carbon 5- of ring of T4, therefore produce inactive hormone rT3. In this way it will preserve energy. Other conditions such as the use of the drug phenytoin (antiepileptic drug), stimulates the liver enzymes (by induction)— deiodinase to remove iodine from 5′- of ring. This results in production of high level of serum T3, with low level of serum T4. 11 Q) Why patients should be asked about their drug history when we need to perform hormonal analyses? Process of Thyroid Hormone Synthesis:Anti-thyroid drugs are of different types: Thiourea e.g. thiocyanide, perchlorate act on the first step (trapping step) Carbimazole Thiouracil; both with carbimazole act on the second step, the step of tyrosine iodination (iodination step), therefore they prevent iodination. Normally, more T4 than T3 is produced from the thyroid gland in ratio of 7:1. This ratio is decreased when there is iodine deficiency. In blood, 99 per cent of T3 and T4 are transported as protein-bound forms. The proteins responsible are TBG (stands for thyroxine-binding globulin) mainly and to a less extent albumin and prealbumin (as does retinol). Only about 1 per cent is unbound and it is the active form. Therefore conditions that increase serum protein level e.g. pregnancy and oestrogen therapy results in increased serum level of protein-bound forms so also increasing the total form. But it does not affect the active free form. However, most laboratory methods measure the total hormone level, which will give the physician misinterpretation of results (that the patient has hyperthyroidism), which is a false interpretation. The reverse is also true; patient has low protein level, or androgen therapy, decreasing protein levels, causing a false interpretation of hypothyroidism. In both conditions, we should measure the free hormone level in blood to confirm or exclude hyper/hypothyroidism. A normal level of free hormone indicates the patient is normal i.e. euthyroid. Note (NB): Each step of thyroid hormone biosynthesis is controlled by a specific enzyme; therefore congenital deficiencies of these enzymes can lead to Goitre (enlargement of thyroid gland). But If the deficiency is so severe, it may result in hypothyroidism. The iodide uptake/trapping (step 1) as well as biosynthesis and secretion of thyroid hormones and the growth of thyroid tissue itself is controlled or regulated by TSH of pituitary. T3 and T4 in blood can be catalysed by proteolytic enzymes and deiodination, that is to say T4 converts to T3 which in turn, converts to DIT, then MIT leaving tyrosine (amino acid) which can be destroyed by proteolytic enzymes. Disorders of thyroid gland: enlargement of thyroid gland is of two types; diffuse or nodular (appearance of nodes on the lobes, giving the gland an irregular shape). They can either be simple or multi-nodular goitre. This classification does not give an idea about the functional properties of the gland; therefore we should classify thyroid disorders according to their functions as follows: 1. Hyperthyroidism (Thyrotoxicosis): this is hyper-function of the gland caused by Grave's disease (diffuse goitre), ore due to toxic nodular goitre. In both conditions, 12 there is an increased level of serum T3 and T4, this high level will act on hypothalamus and pituitary, preventing the production of TSH. The picture will be very high level of T3 and T4, associated with very low or undetectable levels of TSH in blood. This shows that the condition is primary. This high level of T3 and T4 will speed up the metabolic pathway, resulting in toxic symptoms and signs, such as: Tremor Loss of weight Tachycardia Sweating Good appetite Anxiety and irritability All of these will finally lead to a condition called thyrotoxicosis. 2. Hypothyroidism (Myxoedema): results from low levels of T3 and T4 in the blood. It is either due to thyroid gland damage by autoimmune disease or inflammatory disorder, or it is due to genetic deficiency of one of the enzymes responsible for thyroid hormone synthesis which affects children. The disease is called Cretinism. All these types are primary hypothyroidism, but if the low levels of T3 and T4 are due to releasing hormone—TRH deficiency or TSH deficiency due to damage of hypothalamus or pituitary glands respectively, the disorder is called secondary hypothyroidism. In both cases, there is low level of T3 and T4, but the difference is in TSH, if it is very low i.e. undetectable, it is called secondary, but if TSH is very high (more than 60mmol/dL) it is primary disorder. The signs and symptoms of hypothyroidism are quite opposite to goitre: Physical slowness Cold sensation Masked face (no expression) Mental retardation Gaining weight Anorexia (loss of appetite) Normal function of the gland; Euthyroidism (compensatory enlargement) occurs due to iodide deficiency, which initially leads to decrease in T3 and T4 production. This low level will stimulate HPT axis and stimulate secretion of large quantities of TSH by feedback mechanism. TSH stimulates production of T4 to maintain normal production of T3 and T4, associated with large gland size. This is euthyroid goitre. Thyroid Function Test (TFT): Total T3 + free T3 Total T4 + free T4 TSH T3 uptake FTI (free thyroxine index) 13 Generally, we measure total T3 and total T4 and TSH in order to diagnose the function of thyroid gland, but we cannot give the cause of the disease. If all three parameters are normal, it is called euthyroidism which is usually due to iodide deficiency (iodine supplementation fixes it). If serum T3 and T4 are high, whilst serum TSH is very low (<0.05mg/ml) this is the typical picture of thyrotoxicosis but if serum t3 and T4 are very low while TSH is very high, this is the typical picture of primary hypothyroidism but in one case if T3, T4 and TSH are all low, this is a typical picture of secondary hypothyroidism. In cases where we suspect an increase or decrease in the levels of proteins (e.g. pregnancy, androgen therapy, etc.) we should either perform a measurement of free T3 or free T4 plus TSH. If the free levels increase or decrease it is associated with an inverse change in TSH this is a pathological problem, if free form of T3 and T4 is not available in the laboratory, we should make an estimation of T3 uptake, total levels of T3 and T4, in addition to TSH. Then we calculate the FTI which equals: FTI = (total thyroid hormone level ∕ T3 uptake) X 100 FTI will give us nearly the approximate level of free hormones. Gonads:According to both sexes, the gonads are two: Ovaries (female) secrete: o Progesterone o Oestrogen: (higher than progesterone because oestrogen has receptors on hypothalamus so has positive feedback. It is the end product that can control secretion of hypothalamus and pituitary. Testes (male): the main secretion is testosterone Secretion of these glands is controlled by hypothalamic-pituitary gonadal axis (HPG axis). A decrease in œstrogen or testosterone levels in blood results in loss of negative feedback mechanism, resulting in stimulation of GnRH from hypothalamus which will stimulate gonadotropins i.e. LH and FSH from the pituitary gland. LH and FSH have receptors on testicular and ovarian tissues which will stimulate secretion of target hormones— testosterone and oestrogen respectively. In females; Levels of LH and FSH (therefore oestrogen and progesterone) are different according to the period of menstrual cycle (Menstrual cycle phase). At the time of menstruation, the first day of the cycle represents the first day of bleeding. A typical cycle consists of 28 days. The first phase of cycle is called (follicular phase), starting from day 1 until day 14 (half the menstrual cycle time). About 48 hrs after day 14 is called the (ovulatory phase). The remaining time until the end of the cycle is called (luteal phase) when LH action is up. 14 At the first day (time of bleeding), there is low levels of oestrogen and progesterone. This low level of oestrogen results in loss of negative feedback mechanism with subsequent, gradual increase in pituitary hormones (LH and FSH). FSH will act on several ovarian follicles (about 5 to 6), but it results in development of a single follicle (Graafian follicle), which becomes mature and prepares the ovum. LH at the same time stimulates secretion of oestrogen from developing follicles. This oestrogen increases to a very high level (peak) 12 hrs before the day 14. This peak of oestrogen undergoes positive feedback stimulation of LH secretion and results (during 1248 hr period) in peak increase in LH level. This is called LH-surge which is critical for ovulation. After ovulation, the empty follicle (without ovum) is called corpus luteum or yellow body, which releases progesterone and oestrogen (but progesterone more obviously). Progesterone prepares the uterus for implantation of fertilised ovum if present. This is the luteal phase. If there is no implantation, the endometrium shedding occurs and the cycle takes place again. Disorders of the gonads: Primary ovarian fauilure: low oestrogen levels, high levels LH and FSH. Occurs due to loss of negative feedback mechanism e.g. menopause Secondary ovarian failure: due to diseases in hypothalamus and/or pituitary results in low levels of LH and FSH resulting in low levels of oestrogen e.g. panhypopituitarism. Both of these conditions can result in amenorrhoea and even infertility. In males; LH stimulates Leydig's cells of testes to secrete testosterone (androgen). This hormone is responsible for male secondary sex characteristics, and gives male characters in general. It inhibits gonadotropin secretion by negative feedback inhibition, similar to that of ovarian hormones in females. If there is testicular failure due to any cause it is called primary endocrine disease, where there is low level of testosterone, resulting in loss of negative feedback mechanism, with stimulation of LH secretion, so the level of LH will be very high in blood. if there is hypothalamic or pituitary diseases, level of LH and FSH are low, so level of testosterone is also within low limits this is secondary testicular failure (secondary endocrine disease). FSH stimulates spermatogenesis and its level is not controlled by testosterone, but by another factor called inhibin, which is secreted from Sertoli's cells (in testes) or from mature sperm. Therefore if there is low FSH this will result in oligospermia or azoospermia and of course infertility in males. The indicators of defect in spermatogenesis are high levels of FSH (in blood), with very low level of inhibin (glycoprotein secreted by seminiferous tubules). Androgens: These are a group of 19C steroids, required for differentiation of male genital tract and development of secondary male sex characteristics. They also influence muscle bulk, bone mass and sexual performance in males. 15 In females, androgens act as precursors of oestrogen (18C steroids). There are several types of androgens: Testosterone (most important androgen in blood): In male it is secreted from Sertoli cells, whilst in females 50 per cent testosterone is derived from peripheral conversion of androstenedione, 25 per cent originate from ovaries and 25 per cent from the adrenal glands. Structurally, testosterone is a 19C steroid and has unsaturated bond between C 4and C 5- and a ketone group at C 17-, ring position. Testosterone is converted to a more potent steroid called dihydrotestosterone (DHT) by the enzyme 5-reductase, which is present in prostate, genital skin and seminal vesicles. Androstenedione: produced from testosterone in peripheral tissues, it may also be produced by adrenal or ovaries, or peripheral conversion of plasma dehydroepiandrosterone (DHEA). Androstenedione and DHEA are weak androgens they act more as pre-hormones for testosterone. Biosynthesis occurs in testis and adrenals by two pathways: 1. Pregnenolone is transformed to 17-hydroxypregnenolone and then to DHEA, later on to androstenedione and testosterone. 2. Pregnenolone to progesterone, then to androstenedione. This pathway is more active. Metabolism: in blood, testosterone is bound to plasma protein, mainly sex hormonebinding globulin (SHBG) or to testosterone esterdiol-binding globulin. In women, 80 per cent of testosterone is bound to SHBG, 19 per cent to albumin and only 1 per cent remains free—the active form. In males, 78 per cent bonds to SHBG, 19 per cent loosely bound to albumin and 3 per cent of total is free, which is the biologically active form. The main metabolites of androstenedione and testosterone are produced by reduction of ketone group at carbon 3- and also carbon 7- positions. Most of these androgens are converted irreversibly to 17-ketone steroids which conjugate with sulphuric acid and glucoronic acid, excreted as water-soluble substances in urine. Several methods have been used to detect androgens in serum and urine, the main one is radioimmunoassay (RIA) and enzyme-linked fluoroimmunoassay (ELFIA). Normal range in male adult is (300-1000) ng/dL, while in females it is (30-70) ng/dL. The highest level of testosterone in males occurs in the morning and gradually decreases to 25% in evening. Slow and progressive decline occurs after 5 th decade of life. In females, highest level is during puberty or 1 to 2 days at mid cycle. Clinical disorders: there are two types of disorders that affect androgen level, depending on the tissue affected; theses are primary or secondary endocrine diseases. Progesterone: during menstrual cycle, progesterone in conjugation with oestrogen regulates function of sex characteristics. It is important for preparing uterus for implantation and maintenance in pregnancy. In non-pregnant women, progesterone is secreted from corpus luteum whilst during pregnancy it is secreted from placenta, the main sources. 16 Minor sources also occur in adrenal cortex and testes in male. Structurally, progesterone is a 21C steroid contains keto group at carbon 3-, double bond between carbon 4- and carbon 5-. Both of these structural characters are essential for progesterone activity. Synthetic compounds called 19-nortestosterone that is widely used as an oral contraceptive, which is more potent than progesterone itself. Metabolism: the production of progesterone in ovaries occurs the same as for steroidogenesis in adrenal cortex, in which acetate converts to cholesterol, then enters through the pathway of pregnenolone. In luteal tissue the precursor is LDL cholesterol, from which the secretion of progesterone is under the control of LH. In blood, progesterone is bound to CBG; this indicates it doesn't have a specific binding protein. The free level is 10-20% of total cholesterol, which remains constant throughout the normal menstrual cycle. Its peak level occurs at luteal production, reaching 30mg/d (in nonpregnant women) from placenta and third trimester (last 3 months) of pregnancy the level reaches 300mg/d. inactivation of this hormone occurs through two procedures: 1. Reduction of pregnenidiol (conjugated form with glucoronic acid) then excreted out as water-soluble substance in urine. This urine pregnenidiol is used as index of endogenous production of progesterone. 2. Conjugated with sulphuric acid and excreted outside the body. Clinical significance: during follicular phase of cycle, serum level is 1ng/mL, but after ovulation, production of progesterone from corpus luteum increases to a maximum of (1020) ng/mL in the fourth to seventh day of luteal phase. This level remains elevated for four to six days, and then decreases suddenly to baseline level at about 24hr before bleeding. Since the increase or decrease in progesterone level is related to corpus luteum, therefore ovulation in non-pregnant females, we can use progesterone as indicator of ovulation. If the level of progesterone at luteal phase is similar to that of follicular phase, or the summation of three consequent measures at the last seven days of cycle, is less than 15ng/mL, this indicates that the cycle is un-ovulatory cycle, which could be the cause of infertility. Approximately after the end of fourth week of pregnancy, progesterone is produced by the placenta. Oestrogen: responsible for development and maintenance of female sex hormones and secondary sex characteristics of females. It is important in regulation of menstrual cycle, and maintenance of pregnancy, important for prevention of lactation during pregnancy, as it prevents lactating glands. Most oestrogens are produced in corpus luteum and (during pregnancy) from placenta. Oestradiol (E2) is the most potent oestrogen. Structurally, oestrogen consists of an 18C and has the following features: Aromatic ring A Presence of ketone/hydroxyl group (oestradiol) at carbon 17-, or hydroxyl group at carbon 16- (in case of oestriol). Phenolic hydroxyl group at carbon 3- gives the compound its acidic properties. Absence of methyl group at carbon 10-. 17 The phenol ring A and oxygen at carbon 17- are essential for biological activity. Any substituents at other positions will diminish the feminising activity of this hormone. Biosynthesis: the three classes are produced by ovarian tissue which has active aromatase system that converts androgens to oestrogens. In menopausal women (ovarian failure), the main source of oestrogen is from peripheral adrenal conversion of androstenedione to oestrone¹. The major site for conversion is adipose tissue, explaining high levels of oestrone in post-menopausal women and also the uterine bleeding that occurs in such women. In blood, oestradiol² is strongly bound to SHBG and loosely to albumin, while only 2-3% is free (active). In contrast, oestrone is almost always bound to albumin. During pregnancy the major source of oestrogen is the placenta, which secretes large quantities in milligrams; the main oestrogen produced is oestriol³ (during pregnancy). Metabolism: oestradiol forms reversible redox system with oestrone, which is metabolised through two pathways; 2-hydroxylation pathway, with production of catecholestrogen and 16-hydroxylase pathway with formation of oestriol. Some pathological conditions, such as in hyperthyroidism, the 2-hydroxylation pathway is increased. During liver disease or hypothyroidism the reverse occurs. Oestrogen is inactivated in liver and excreted in urine (like all other steroids). Clinical significance: oestradiol is almost always secreted from ovaries, therefore is essential for evaluation of ovarian function. Oestriol is of limited diagnostic use, but we use it in diagnosis of post-menopausal bleeding and menstrual dysfunction. Oestriol is only used during pregnancy to evaluate the foeto-placental dysfunction. ¹: denoted E1 ²: denoted E2 ³: denoted E3, also one other derivative is oestetrol (E4). 18 19 20 21 22