Endocrinology Surrey 2024.ppt

Overview of Endocrinolog y Dr Agnieszka Falinska Consultant Endocrinologist Royal Surrey County Hospital Endocrinology studies hormones A hormone is a chemical messenger that travels from one cell to another. Hormones are biologically active substances released in one part of the body, travel in the...

Overview of Endocrinolog y Dr Agnieszka Falinska Consultant Endocrinologist Royal Surrey County Hospital Endocrinology studies hormones A hormone is a chemical messenger that travels from one cell to another. Hormones are biologically active substances released in one part of the body, travel in the blood stream and have an effect on other part (often remote) of the body. This helps different parts of the human body to communicate with each other and integrate body functions Hormones are found in all organisms with more than one cell, both in plants and animals. We will concentrate on human endocrinology Hormones described first in 1905 Hormones are secreted by endocrine glands but also by other organs : - Gut and liver produces gut hormones regulating our digestion and contributing to appetite control, obesity… - Heart produces Atrial natriuretic peptide controlling body fluid volume and blood pressure - Kidney produces renin regulating blood pressure - Adipose tissue – leptin – decreases appetite and increases metabolism - Placenta – human chorionic gonadotropin (hCG) Hormones control our life Essential for our every-day survival and control: our temperature, sleep, mood, level of alertness Blood pressure, heart rate sugar regulation, appetite, hunger, metabolism and obesity growth, puberty, fertility, pregnancy bone growth and calcium metabolism Chemical structure of hormones Amino Acid Derivatives Peptides Proteins Steroid It affects hormone’s distribution, the type of receptors it binds to and other aspects of its function. Amine hormones derived from the modification of single amino acids such as tryptophan, tyrosine Melatonin (pineal gland) regulates circadian rhythm (synthetic form taken as tablets) Thyroid hormones (thyroid gland) -metabolismregulating thyroid hormones Catecholamines (adrenals) such as epinephrine, norepinephrine play a role in the fight-or-flight response, Dopamine (hypothalamus) inhibits the release of certain anterior pituitary hormones. Peptide and Protein Hormones consist of multiple amino acids linked to form an amino acid chain. synthesized like other body proteins: DNA is transcribed into mRNA, which is translated into an amino acid chain. Peptide hormones - short chains of amino acids Antidiuretic hormone (ADH) -pituitary -important in fluid balance Atrial-natriuretic peptide (ANP) – heart – reduces blood pressure Protein hormones - longer polypeptides Growth hormone (pituitary gland) Follicle-stimulating hormone (FSH) – pituitary - glycoprotein (attached carbohydrate group) - stimulate the maturation of eggs in the ovaries and sperm in the testes. Steroid hormones Derived from the lipid cholesterol Testosterone and the estrogens (testes and ovaries) Aldosterone (adrenal) involved in osmoregulation Cortisol (adrenals)- regulates metabolism Not soluble in water - they are hydrophobic Blood is water-based - steroid hormones require a transport protein (eg Sex Hormone Binding Globulin) This complex structure extends the half-life (time required for the half of the hormone to be degraded) of steroid hormones much longer than that of hormones derived from amino acids. Cortisol has a half-life of approximately 60 to 90 minutes Epinephrine has a half-life of approximately one minute. Mode of action Non-steroid hormones: amino acid, peptides, protein hormones water soluble & lipid insoluble - cannot pass through the cell membrane act through second messengers – bind to receptors on cell membranes Steroid hormones: lipid soluble and can pass through the cell membrane directly enter the cell. !!!!! Thyroid hormones that are amine derivatives but are lipid soluble Non-steroid Hormone action Effects target tissues by binding to the receptors - specific for a hormone Receptors are extra cellular (surface) protein molecules in the cell membrane associated with G-proteins (GDP) and Adenyl cyclase Hormones (First messenger) bind to the receptor and produces Second Messengers with the help of receptors Hormone bind to receptor causing activation of G-protein which further activates Adenyl cyclase that converts ATP to Cyclic AMP (Adenosine monophosphate). This causes a signaling pathway. The cAMP activates the Kinase enzyme which triggers specific intracellular biochemical changes like enzyme activation, secretion, ion channel changes etc. Steroid Hormone action Diffuse through the cell membrane of the target cell Bind to intracellular receptors in either the cytoplasm or within the nucleus creating hormone-receptor complex which moves to the cell nucleus and binds to a particular segment of the DNA It triggers transcription of a target gene to mRNA, which moves to the cytosol and directs protein synthesis. These proteins promote specific to hormones metabolic reactions in the cell. Actions are slower but last longer Endocrine control system AUTOCRINE PARACRINE ENDOCRINE Regulation of hormone release Humoral - changes in ion/nutrient levels in the blood Hormonal - changes in hormone levels that initiate or inhibit the secretion of another hormone Neural - a nerve impulse prompts the secretion or inhibition of a hormone NEGATIVE FEEDBACK LOOP Portal Circulation PITUITARY NEGATIVE FEEDBACK Main endocrine glands Hypothalamus/pituitary axis Thyroid gland Adrenals Pancreas Gonads – ovaries and testes Hypothalamus Part of limbic system in the brain Body homeostasis Controls the release of hormones from the anterior and posterior pituitary Small peptide hormones and dopamine The first hypothalamic releasing hormone (Thyrotropinreleasing hormone – TRH) was isolated and purified from tons of pig and sheep brains in the late 1960s. The research teams of Andrew Schally and Roger Guillemin shared a Nobel Prize in 1977. They also described the blood supply connecting hypothalamus and pituitary called the portal system. Hypothalamus – hormones Corticotropin-releasing hormone (CRH) – stimulates production of ACTH activating cortisol axis Gonadotropin-releasing hormone (GnRH) stimulates production of LH/FSH stimulating further gonads – ovaries and testis Thyrotropin-releasing hormone (TRH) stimulates production of TSH stimulating thyroid hormone production Growth Hormone Releasing Hormone (GHRH) – stimulates GH production Antidiuretic hormone/Vasopressin (ADH) increases how much water is absorbed into the blood by the kidneys Oxytocin - release of a mother’s breast milk, moderating body temperature, and regulating sleep cycles Pituitary gland - Hypophysis Weight 1g and 1cm diameter Hypothalamo-pituitary relationship Pituitary Hormones Anterior Pituitary  Thyroid Stimulating Hormone (TSH)  Adrenocorticotropic Hormone (ACTH)  Growth Hormone (GH)  Follicle Stimulating Hormone (FSH)  Luteinizing Hormone (LH)  Prolactin (Prl) Posterior Pituitary  Antidiuretic hormone - Vasopressin (AVP)  Oxytocin Pituitary Hormones HYPOTHALAMUS Tertiary Portal Circulation Secondary PITUITARY END ORGAN Primary HYPOTHALAMUS HYPOTHALAMIC FACTOR Portal Circulation PITUITARY END ORGAN HYPOTHALAMUS HYPOTHALAMIC FACTOR Portal Circulation PITUITARY PITUITARY HORMONE END ORGAN HYPOTHALAMUS HYPOTHALAMIC FACTOR Portal Circulation PITUITARY PITUITARY HORMONE END ORGAN END ORGAN HORMONE The Hypothalamic- Pituitary Axes Prolactin PROLACTIN is 199 amino acid peptide, synthesised in the lactotrophe cells of the anterior pituitary. major function of prolactin is milk production – oxytocin stimulates ejection release is tonically inhibited by dopamine from hypothalamus Inhibits gonadal function (nature’s contraceptive!) Posterior Pituitary Hormones synthesized in the hypothalamus (neurons) are transported down the axons to the endings in the posterior pituitary Hormones are stored in vesicles in the posterior pituitary until release into the circulation Principal Hormones: Antidiuretic hormone & Oxytocin Secretion of Posterior Pituitary Hormones Synthesis, storage, and release of posterior pituitary hormones Antidiuretic Hormone (ADH) Antidiuretic actions - V2 receptors - increases permeability of the collecting ducts to water – retaining water Vasopressor actions - V1 receptors - constricts vascular smooth muscle cells Oxytocin Breast-feeding -Promotes milk ejection as a reflex to baby cry Childbirth (parturition) - in late pregnancy, uterine smooth muscle (myometrium) becomes sensitive to oxytocin - positive feedback Endocrine Control: Three Levels of Integration Hormones of the hypothalamic-anterior pituitary pathway Thyroid gland Small gland in the neck Release thyroid hormones: Thyroxine (T4) Triiodothyronine (T3) Tyrosine based hormones Partially composed of iodine Increases Basal Metabolic Rate and thermogenesis Increases sympathetic nerve activity Regulation of thyroid synthesis and secretion hypothalamic-pituitarythyroid axis Hypothalamus  TRH  anterior pituitary  TSH  thyroid  T3 & T4  negative feedback on the hypothalamus and the anterior pituitary Adrenal glands Glucocorticoids (cortisol) Gonads – testes and ovaries Lecture 6 Male reproductive endocrinology LH – acts on Leydig cells to stimulate Testosterone production FSH - with Testosterone act on Sertoli cells to stimulate spermatogenesis Testosteroneproduced in Testes (Leydig Cells) and adrenal glands (zona reticularis) Female reproductive endocrinology Female reproductive endocrinology LH – stimulates androgen and progesterone production Stimulates ovulation FSH – stimulates oestrogen production Oestrogen – Endometrial Proliferation Breast Development Progesterone Increases Body temperature Secretory endometrium Pancreas Beta cells in the islets of Langerhans produce insulin in response to rising glucose/food. Promote the storage of glucose in fat, muscle, liver and other body tissues Alpha cells produce glucagon in response to lowering glucose Disorders of endocrine systems Related to excess of hormones – hyper.... Hyperprolactinemia – raised prolactin due to pituitary overgrowth Treatment based on hormonal production block Cabergoline is a dopamine receptor agonist on D2 receptors Dopamine inhibits prolactin production Other options include surgery to remove overgrowth Lack of hormones – hypo…… Treatment based on hormonal replacement Hypopituitarism Progressive loss of Anterior Pituitary function: FSH/LH and GH; TSH; ACTH. Tumors (Pituitary Adenomas), Trauma, Inflammatory/Infiltrative, Vascular (inc. Apoplexy) Rare - congenital defects - Kallman’s syndrome, Pituitary Aplasia Treatment – replacement of all the hormones Pituitary Tumour Cortisol excess Central - Cushing’s Disease Excess cortisol in the blood due to an ACTH secreting pituitary tumour High cortisol, high ACTH Adrenal - Cushing’s Syndrome Excess cortisol in the blood due to overproduction of cortisol in the adrenals High Cortisol, low ACTH nciples of endocrine investigations Based on negative feedback – the hormone suppresses its own production Administer supra-physiologcal levels of hormones – eg 1mg Dexamethasone Healthy response – endogenous cortisol low - suppressed Abnormal response – cortisol not suppressed suggesting lack of physiological control Overnight Low Dose Dexamethasone Suppression Test Dexamethasone 1mg is given at 11pm the night before Cortisol is measured at 8am the next morning Cortisol suppression to 4 L/d) of hypotonic urine in absence of glycosuria. Hypothalamic/ Central (lack of ADH) Nephrogenic DI (V2 receptors not working) Serum Sodium is usually maintained in the normal range. Diagnosis is suggested by inappropriately low Urine Osmolality in relation to the Serum Osmolality. Test – water deprivation test Hypothyroidism Low thyroid hormones T4/T3 and high TSH (periphery cause) Thyroiditis (automimmune – Hashimoto) Clinical Features Insidious onset, tiredness, lethargy, cold intolerance, constipation, weight gain, bradycardia, loss of hair/eyebrow, slow relaxing reflex Treatment Thyroxine replacement Hyperthyroidism High thyroid hormones T3/T4, Low TSH, Thyroid antibodies positive Autoimmune–Grave’s disease or toxic solitary adenoma Clinical features Excess sweating, weight loss, diarrhoea, heat intolerance, palpitations, atrial fibrillation (irregular Heart rate), heart failure, anxiety, eye signs, goitre Treatment – surgery, radioactive iodine, Carbimazole – prevents iodinating tyrosine by thryroid peroxidase reducing levels of hormones After the catastrophe at Chernobyl, iodine-131 was released in high doses from the reactor for about 40 days and it took about seven months for it to decay to a safe level. That increased the risk of thyroid cancer (100 times) and hypothyroidism Addisons Disease Autoimmune destruction of adrenal cortex Low cortisol, aldosterone, high ACTH Clinical Features Pigmentation – from ACTH excess Lethargy, malaise, weight loss “salt wasting” - hyponatraemia (low sodium), hyperkalemia (high potassium which could be potentially life-threatening) Hypoglycaemia, vomiting, low blood pressure along with hyponatraemia and hyperkalemia = Addisonian Crisis – Medical emergency Female infertility amenorrhea Central Pituitary Destruction – tumour, trauma Hyperprolactinaemia – high prolactin inhibits LH/FSH Genetic syndromes - Kallman’s Syndrome Anorexia Nervosa Ovarian Polycystic Ovarian Syndrome Ovarian Failure – tumour, trauma Ovarian dysgenesis – genetic syndromes Male infertility Central Pituitary Destruction – tumour, trauma Hyperprolactinaemia – high prolactin inhibits LH/FSH Genetic syndromes - Kallman’s Syndrome Anorexia Nervosa Testicular Tumour, torsion, varicele, orchitis, trauma Testicular dysgenesis due to genetic disorders Diabetes Mellitus Chronic diseases characterised by abnormalities of metabolism (carbohydrate, fat and protein) resulting from either Deficiency of insulin (type 1) Resistance to the actions of insulin (type 2) Damage to pancreas (type 3c) One of the most common disease in the world One of the major health burdens of the NHS Management of diabetes Diagnosis - HbA1c (glycolated haemoglobin) cut point of ≥6.5% (48mmol/mol) Type 1 diabetes requires insulin from the moment of diagnosis Type 2 diabetes treatment focuses on improved insulin sensitivity using Metformin GLP-1 analogues SGLT2 inhibitors Insulin at later stages Diabetes is dangerous due to complications Microvascular complication Retinopathy – retinal vessel damage leading to blindness Neuropathy – nerve damage leading to loss of sensation Nephropathy – kidney damage leading to failure and the need for dialysis Macrovascular complications Myocardial Infarction Stroke Peripheral Vascular Disease Type 1 Diabetes Onset typically