Guide to the Endocrine System: Anatomy, Physiology, and Clinical Insights

The Endocrine System Dr Sarah Jones Reader in Pharmacology 4PY019 Pharmacy Stage 1 The Endocrine System Over 2 weeks we shall cover; The Anatomy & Physiology of the endocrine system including The Hypothalamus and the Pituitary The Thyroid Gland The Hypothalamic Pituitary Adrenal (HPA) Axis The Endocrine Pancreas and control of blood glucose The Female Reproductive System The Parathyroid Gland and Calcium Homeostasis. Endocrine Physiology Hormones Neurotransmitters Oestrogen,Testosterone Glucocorticoids Thyroxine Insulin Noradrenaline Acetylcholine Pass into the bloodstream and act at distant targets Act over small nerve synapses Anatomy of the Endocrine System 4 The Hypothalamus & Pituitary Gland The hypothalamus talks to the pituitary 5/1/2024 The Anterior Pituitary (Adenohypophysis) Hypophyseal Portal System – a system of blood vessels connecting the hypothalamus to the anterior pituitary Hormone secretion from the anterior pituitary is largely regulated by hypothalamic releasing factors from the hypothalamus. Hypothalamic releasing factors reach the anterior pituitary through the blood stream – the hypophyseal portal system Hypothalamic Releasing Factors TRH CRF GnRH Prolactin releasing factor Growth hormone releasing factor MSH releasing factor Hormones TSH ACTH FSH LH Prolactin GH MSH SAMPLE FOOTER TEXT 6 Hormones of the Anterior Pituitary (Adenohypophysis) Hypothalamic releasing factor HORMONE TARGET EFFECTS Thyrotrophin releasing hormone (TRH) TSH Thyroid gland Secretion of TH Corticotrophin releasing factor (CRF) ACTH Adrenal cortex Glucocorticoid secretion Gonadotrophin releasing hormone (GnRH) FSH Ovaries/testes Follicle development Sperm maturation GnRH LH (ICSH) Ovaries/testes Ovulation Testosterone secretion Prolactin releasing factor Prolactin Mammary glands Milk production Growth hormone releasing factor GH All cells Growth MSH releasing factor MSH Melanocytes Melanin synthesis Secretion from the anterior pituitary is largely regulated by the release from the hypothalamus of “factors” Factors reach the pituitary through the blood stream Hormones of the Posterior Pituitary (Neurohypophysis) HORMONE TARGET EFFECTS ADH (vasopressin) V2 (Gs) receptors in the distal kidney tubule Reabsorption of H2O V1a (Gq) receptors (vascular smooth muscle) Vasoconstriction increase in BP Oxytocin OT (Gq) receptors in Labour the Myometrium contractions • The posterior pituitary (neurohyophysis) consists largely of nerve terminals of nerve cells which originate in the supraoptic and paraventricular nuclei of the hypothalamus. • The axons of these neurons form the hypothalamichypophyseal tract and terminate in close proximity to the capillaries of the posterior pituitary. • Peptides synthesized in the hypothalamic nuclei, pass down these axons into the posterior pituitary, where they are stored and eventually secreted Endocrine Control of Thyroid Hormone Secretion Hypothalamus Negative Feedback (-) Thyrotrophin Releasing Hormone (TRH) (+) Anterior Pituitary (-) Thyroid Stimulating Hormone (TSH) (+) Thyroid Gland Thyroid Thyroxine Thyroxine Physiological control systems – we don’t want to produce too much thyroxine! Anatomy & Physiology of Thyroid Hormone Biosynthesis Triiodothyronine (T3) Tetraiodothyronine (T4) or Thyroxine 1. TSH binds to TSH receptor (TSH-R) on the follicular cells of the thyroid. This increases the production of thyroglobulin (TG) made by the follicular cells. Thyroglobulin is then released into the colloid. 2. TSH also stimulates the uptake of iodide from the blood into the follicular cell. Iodide uses a Na+/ I- symporter to get into the cell. Colloid (follicle lumen) I2 I2 TG Follicular cell Na+ • Na+ • • Proteases separate the thyroglobulin “scaffold” from T3 and T4. Thyroxine binding globulin (TBG) transports T4 and T3 to peripheral tissues. TG Thyroperoxidase T4 T4 T3 Thyroglobulin I- 3. Thyroperoxidase is also responsible for coupling MIT with DIT (T3) or DIT with DIT (T4). Endocytosis Y TG I- TG Endocytosis Y 1. Thyroperoxidase coverts iodide into iodine (oxidation as iodide loses electrons to form iodine). DIT T3 I- 3. TSH also increases the activity of thyroperoxidase. 2. Thyroperoxidase facilitates the incorporation of iodine onto the tyrosines (Y) of thyroglobulin (iodination). Y Y Thyroperoxidase I- MIT Coupling Thyroid Hormone Biosynthesis T3 TSH-R I- I- TSH Blood capillaries T4 T3 T4 TBG KEY: Thyroid hormone receptor (TR) Retinoid X Receptor (RXR) T4 and T3 in Peripheral Tissues Plasma Membrane T4 T3 T4 TR 2 deiodinase (D2) or monodeiodinase RXR RXR-TR heterodimer Thyroid Response Element (TRE) T3 mRNA Transcription RER Extracellular Intracellular Protein Translation Thyroid hormones, tri-iodothyronine (T3) and thyroxine (T4), • There is a large pool of T4 in the body found mainly in the circulation. • There is a small pool of T3 in the body found mainly in the intracellular environment • Within target cells, the T4 is converted to T3, which interacts with a nuclear receptor to regulate gene transcription. • Cellular uptake of thyroid hormones is by transmembrane transporters. • T4 is mainly converted to T3 by 2 deiodinase (D2) located on the endoplasmic reticulum. • T3 translocates to the nucleus and binds to the thyroid hormone receptor and complexes with the Retinoid X Receptor (RXR-TR heterodimer) • This complex binds to the Thyroid hormone Response Element (TRE) • Induction of transcription • T3 and T4 actions: • Stimulation of metabolism, causing increased oxygen consumption and increased metabolic rate and regulation of growth and development Thyroid disorders Hyperthyroidism (thyrotoxicosis) Symptoms: high metabolic rate, increase in skin temperature, sweating, sensitivity to heat, tremor, tachycardia, increased appetite, weight loss. 2 Types: Diffuse toxic goitre (Graves’ disease) • Organ specific auto-immune disease • Thyroid stimulating immunoglobulins directed at the TSH receptor (increasing thyroxine secretion) • Patients exhibit protruding eyeballs Toxic nodular goitre • Caused by a benign neoplasm or adenoma Thyroid disorders Hypothyroidism (myxoedema) • Auto-immune disease • Causes low metabolic rate, slow speech, lethargy, bradycardia, sensitivity to the cold, mental impairment and characteristic thickening of the skin. • Hashimoto’s thyroiditis – a chronic autoimmune disease against thyroglobulin and thyroid tissue • Thyroid deficiency during development (1 in 3000/4000 births) retardation of growth and mental deficiency Self-Test Question Which of the following statements is incorrect regarding the synthesis of T3 and T4? a.) TSH binds to the TSH receptor (TSH-R) on the follicular cells of the thyroid which consequently increases the production of thyroglobulin made by follicular cells. b.) TSH stimulates the uptake of iodide from the blood into the follicular cell. using a Na+/ I- symporter c.) Thyroperoxidase facilitates the incorporation of iodine onto tyrosines of thyroglobulin d.) Thyroperoxidase coverts iodine into iodide e.) TSH increases the activity of thyroperoxidase. 5/1/2024 The Hypothalamic Pituitary Adrenal Axis SAMPLE FOOTER TEXT 18 Adrenal Glands • 2 Adrenal glands above the kidneys in capsules of fat • 2 Endocrine organs one around the outside of the other Adrenal Cortex Zona glomerulosa Mineralocorticoids Aldosterone • Tubular reabsorption of Na+, Cl- and K+ excretion • Osmotic retention of H2O ; increase in blood pressure Zona fasciculata Glucocorticoids Hydrocortisone (cortisol) • Controls metabolism • Stress response • Anti-inflammatory • Immunosupressive Regulation of synthesis and secretion of adrenal corticosteroids. The HPA Axis Hypothalamus CRF Anterior Pituitary ACTH Negative Feedback • Adrenocorticotrophic hormone (ACTH) stimulates synthesis and release of glucocorticoids (e.g. cortisol) from the adrenal cortex (zona fasciculata) • Corticotrophin-releasing factor (CRF) from the hypothalamus regulates ACTH release and is regulated in turn by neural factors and negative feedback from plasma glucocorticoids. • Mineralocorticoid (aldosterone) release from the adrenal cortex (zona glomerulosa) is predominantly controlled by the reninangiotensin system Adrenal Cortex Endogenous Glucocorticoids (cortisol) Exogenous Glucocorticoids (e.g. prednisolone) Aldosterone 5/1/2024 Prednisolone tablets (an exogenous glucocorticoid) are commonly used to treat inflammatory conditions. What do you think might happen if prednisolone is administered over a long period of time in high doses? Clue: Think about negative feedback! SAMPLE FOOTER TEXT 22 5/1/2024 The Endocrine Pancreas Endocrine tissue which is NOT under the control of the hypothalamus or pituitary 3 The Hormone Insulin and its Secretion Insulin is a polypeptide hormone (6,000 MW) that is produced in beta cells within the islets of Langerhans of the endocrine pancreas. Insulin is important in regulating blood glucose levels and high blood sugar levels stimulate its secretion. What happens to insulin once it leaves pancreatic beta cells? Insulin and its Targets Muscle Liver Fat • Insulin enters the blood stream • Insulin binds to insulin receptors on insulin responsive tissue (muscle, liver and fat) • This facilitates the uptake of glucose into insulin responsive tissue • Blood glucose is consequently lowered. Insulin Production and Type 1 Diabetes The Insulin Receptor - a Receptor Tyrosine Kinase The insulin receptor is a complex of two α- and two β- subunits These are held together by disulphide bridges. The α-subunits are extracellular. The β-subunits are transmembrane spanning proteins. The α-subunits form the insulin binding site. The intracellular portion of the β-units possess intrinsic tyrosine kinase activity. Insulin binding promotes auto-phosphorylation of Tyr residues on the intracellular domains. Rapid Tyr phosphorylation of adaptor proteins also occurs The best characterised substrate is IRS-1 (insulin receptor substrate-1), which contains 22 tyrosine residues. Phosphorylated Tyr residues act as docking sites for a repertoire of signalling proteins which relay the message from the activated receptor into the cell – such consequences include recruitment of glucose transport channels into the membrane. Occupied receptors aggregate into clusters which are subsequently internalised into vesicles, resulting in downregulation. Ultimately, these receptors are recycled back to the plasma membrane. Cellular events triggered by activated insulin receptors have both short- and longterm actions. The short-term actions are the immediate metabolic effects • Recruiting glucose transport channels (GLUT4) • ↑ glucose uptake into cells • ↑ glycogen synthesis (insulin converts glucose into glycogen) • ↓ both gluconeogenesis and glycogen breakdown. Fat/muscle cells These effects are generally governed by regulating kinase and phospholipase enzymes. Cellular events triggered by activated insulin receptors have both short- and long-term actions. Insulin receptor activation also signals, via a series of signal transduction proteins, to the nucleus to promote gene expression. •To modulate the synthesis of key enzymes involved in the regulation of blood glucose •To promote cell growth and division Type 2 Diabetes: Associated with both insulin resistance and impaired insulin secretion 1. A diet high in sugars and carbohydrates may precipitate elevated insulin levels. You will recall that blood glucose is the most important factor in the stimulation of insulin secretion (lipids too!) 2. The tissues upon which insulin exerts its effects become unresponsive following bombardment of their respective insulin receptors with elevated blood insulin levels owing to; a) Down-regulation of the insulin receptor (a loss of insulin receptors from the cell surface). Remember, insulin receptors internalize following ligand binding. b) Impaired signalling mechanisms which recruit the transporter GLUT-4 3. Insulin sensitive tissues are now unresponsive and resistant to the effects of insulin. Glucose can no longer enter the cell leading to a further rise in blood glucose. 4. In an attempt to drive glucose uptake into cells, the pancreatic β cells (which respond to elevations in blood glucose) produce yet more insulin which results in hyperinsulinaemia. 5. Gradually, the β cells of the pancreas become depleted of insulin (supply cannot keep up with demand) and impaired insulin secretion ensues Self-Test Question Which statement is FALSE? a) The insulin receptor is a complex of two alpha and two beta subunits b) The insulin receptor possesses intrinsic serine kinase activity c) Insulin binding to insulin receptors promotes auto-phosphorylation of tyrosine residues on the intracellular domains and the insulin receptor substrate (IRS) d) The activated insulin receptor promotes recruitment of GLUT 4 into the plasma membrane e) GLUT 4 is a glucose specific channel which permits entry of glucose into the cell. Anatomy of the Female Reproductive System Oral Contraceptives The Menstrual Cycle • Menstruation (lasting 3-6 days) marks the beginning of the menstrual cycle, during which the superficial layer of the endometrium is shed. • The Follicular Phase-the endometrium regenerates after menstrual flow ceases. • GnRH is secreted from the hypothalamus and stimulates the anterior pituitary to release FSH and LH • These act upon the ovaries to promote the development of small groups of follicles each of which contains an ovum. • One follicle develops faster than the others to form the Graafian follicle (GF), which secretes oestrogen (the remainder degenerate) The Proliferative Phase • Oestrogens are responsible for endometrial regeneration (day 5,6 to mid cycle) • The endometrium increases in thickness and vascularity • At peak oestrogen levels, there is a prolific cervical secretion of mucus (pH 8-9, alkaline), rich in protein and carbohydrate which facilitates entry of the sperm. • High endogenous oestrogen secretion just before mid-cycle sensitizes LH releasing cells of the anterior pituitary to the action of GnRH to cause the mid-cycle surge in LH secretion. • This in turn causes rapid swelling and rupture of the Graafian follicle resulting in ovulation • If fertilisation occurs, the fertilised ovum passes down the fallopian tube to the uterus. Luteal Phase • The ruptured follicle proliferates and develops into the corpus luteum, which secretes progesterone • Progesterone acts on the oestrogen-primed endometrium to render the endometrium suitable for implantation of the fertilized ovum. • Also, cervical mucous is less welcoming to sperm. • Progesterone exerts a negative feedback on the hypothalamus and the pituitary, thus decreasing the release of LH • If fertilization and implantation do not occur, progesterone secretion stops, triggering menstruation. • If fertilization and implantation does occur, the corpus luteum continues to secrete progesterone which negatively feeds back to the hypothalamus and pituitary to prevent ovulation The Menstrual Cycle The horrors of the Menopause • The menopause is the end of the female reproductive life. • It is a physiological process which begins as perimenopause at around the age of 45 and progresses until the final menarche and the end of fertility (UK average age is 51) • The menopause is defined when a woman has had amenorrhoea (no menstruation) for 12 months • The menopause comes with a range of classical symptoms which are experienced by most women Hormonal Changes during the Menopause Hypothalamus Hormonal Changes • Levels of FSH and LH increase significantly during the menopause • Low levels of circulating oestrogen and progesterone are unable to negatively feedback to the hypothalamus and anterior pituitary. • Oestrogen decreases as the ovaries run out of eggs. • In the absence of ovulation, the corpus luteum does not form so circulating levels of progesterone decline. • Elevated FSH and LH can be used to diagnose the menopause GnRH -ve Anterior pituitary -ve FSH Granulosa cells Aromatase Oestrogen Graafian Follicle LH Theca cells Androgens Progesterone Corpus Luteum Consequences Changes to the Menstrual Cycle • Women progressing toward the menopause (perimenopausal) often experience irregular vaginal bleeding. • Some of this bleeding is the result of menstruation from ovulatory cycles. • Other bleeds are from anovulatory cycles were endometrium has proliferated under oestrogen without the balance of progesterone from the corpus luteum after ovulation. - Progesterone is required to support the endometrium so when ovulation does not occur the endometrial lining breaks down. (Remember, progesterone comes from the corpus luteum, formed after ovulation) - This is termed oestrogen breakthrough bleeding and can happen as frequently as every fortnight in perimenopausal women. • As levels of oestrogen decrease further both of these types of bleeding gradually cease. Vasomotor Changes • 75% of women going through menopause experience hot flushes. • These occur with a red flush starting on the face and spreading down the neck and chest. • These are associated with peripheral vasodilation and a transient rise in body temperature. • The exact mechanism is unknown but it is thought to be due to pulsatile LH release influencing central temperature control. Or Is It? New evidence regarding neurokinin B. Novel drug target Urogenital Changes • The uterus and vagina are both tissues which are maintained by circulating oestrogen. • After menopause there is marked atrophy of the vagina and thinning of the myometrium. • There is also thinning of vaginal walls and dryness. • This can result in dyspareunia (pain during sex). • The bladder and urethra share embryological derivation with the uterus and vagina and these tissues also atrophy with the decrease in circulating oestrogen leading to symptoms of urinary incontinence and an increase in urinary tract infections. Bone Density • Oestrogen protects bone mass and density through reducing the activity of oesteoclasts. • With the drop in oestrogen this balance is tipped and there is an increase in bone resorption resulting in an acceleration of age-related loss of bone density and increased frequency in fractures especially of the wrist and hip Ischaemic Heart Disease • Oestrogen offers a protective effect against heart disease. • It is thought that oestrogen reduces levels of LDL cholesterol whilst raising HDL cholesterol. • After the menopause women experience the same frequency of cardiovascular disease as men. Parathyroid Hormone The polypeptide PTH is the main physiological regulator of Ca2+ in the blood. It’s secretion from parathyroid chief cells is stimulated by a reduction in ionised Ca2+ in the plasma. PTH secretion is inhibited when plasma Ca2+ concentration rises. 1. Stimulates the synthesis of the biologically active form of vitamin D (calcitriol) in the kidney. Kidney Ca2+ reabsorption PO4-excretion 2. Enhances reabsorption of Ca2+ from the kidney distal tubules and enhancement of urinary phosphate Bone resorption is resorption of excretion. bone tissue, the process by which osteoclasts break down the tissue2+ Ca 3. Mobilisation of release Ca2+ in bones and the minerals, and phosphate from resulting in a transfer of calcium bone through from bone tissue to the blood. stimulation of Resorptionwhich = loss osteoclasts increases bone resorption. Ca2+ reabsorption PTH and Calcium Homeostasis Increased absorption of Ca2+ and PO4- Gut Corrects fall in plasma Ca2+ Calcitriol (D3) Ca2+ Blood PTH secretion Parathyroid Blood Corrects fall in plasma Ca2+ Increased mobilisation of Ca2+ Bone The Unequivocal Importance of Calcium Calcium ions play integral roles in cellular activities including; • • • • Stimulus response coupling in striated and smooth muscle and endocrine and exocrine glands Intracellular signalling A cofactor for numerous intracellular enzymes Cofactor for blood clotting. 98% Calcium is in the form of crystals deposited on the protein matrix of bone, which provides its mechanical strength Calcium in the Circulation • Calcium circulates in plasma partly bound to protein (50%) • The remainder is in the free ionised and active form • The free fraction is maintained precisely within narrow limits principally by the actions of parathyroid hormone (PTH) and Vitamin D3 (calcitriol). Calcitonin secretion also reacts to changes in plasma [Ca2+], but is less important regarding overall Ca2+ homeostasis. Without enough vitamin D or calcium, your parathyroid glands compensate by producing too much PTH, a condition called hyperparathyroidism. This can lead to bone weakening (osteoporosis) and increased fracture risk.