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  1. 1. Nem’s Notes… Phase 1 ENDOCRINOLOGY 1 (page 1 of 3) Hormones Definitions Hormone Circulating messenger binding to specific receptor Endocrine Gland Gland producing and secreting hormone(s) to the blood Neurotransmitter Chemical substance transmitting impulse across synpase Neurosecretion Any substance produced within a nerve cell Endocrine Released into blood to act on distant cells Paracrine Released into extracellular space to act on neighbouring cells Autocrine Released by a cell to act on itself (not generally hormones) Hormones The three classes are: (a) Peptide/Protein Majority (eg TRH, LH, TSH) (b) Steroid from Cholesterol (eg Cortisol) (c) Others (eg NO, prostaglandins) Protein Production (a) DNA transcription in Nucleus Hormones (b) Translation on Ribosomes on RER (c) Formation of Prohormone in Golgi apparatus (d) Conversion of Prohormone to Hormone stored in granules (e) Exocytosis of secretory granules (dependent on calcium) Receptor (a) Tyrosine Kinase (eg insulin) Types more online at page 1 of 15
  2. 2. Nem’s Notes… Phase 1 ENDOCRINOLOGY 1 (page 2 of 3) Hormones Receptor (b) G-Protein Receptor Types (i) cAMP 2nd messenger (ii) IP3, DAG, Ca2+ 2nd messengers more online at page 2 of 15
  3. 3. Nem’s Notes… Phase 1 ENDOCRINOLOGY 1 (page 3 of 3) Hormones Steroid Production (a) Storage of cholesterol esters in lipid droplets Hormones (b) Droplet enters mitochodria and coverted to Pregnenolone (c) Pregnenolone converted to hormone in smooth ER (d) Hormone exits cell freely and binds to protein for transport Receptor Feedback Loops more online at page 3 of 15
  4. 4. Nem’s Notes… Phase 1 ENDOCRINOLOGY 2 (page 1 of 2) Diabetes Mellitus & The Islets of Langerhans Glucose Glucose is the main energy source for the body and is delivered to cells via the blood. Regulation To ensure a constant supply the blood glucose must be regulated. The hormones controlling blood glucose are: (a) Adrenaline [↑] (b) Glucagon [↑] (c) Cortisol [↑] (d) Growth Hormone [↑] (e) Insulin [↓] Metabolic Pathways (a) Carbohydrate and Protein more online at page 4 of 15
  5. 5. Nem’s Notes… Phase 1 ENDOCRINOLOGY 2 (page 2 of 2) Diabetes Mellitus & The Islets of Langerhans (b) Fats Langerhans Structure of the Islets of Langerhans (a) α cells secrete glucagon 20-25% (b) β cells secrete insulin 70-80% (c) δ cells secrete somatostatin <10% Insulin Release affected by: (a) Increased glucose (+) (b) Basic amino acids (+) (c) Growth hormone (+) (d) Parasympathetic innervation (ACh) (+) (e) Somatostatin (-) (f) Sympathetic (α receptors) (-) Glucagon Release affected by: (a) Decreased glucose (+) (b) Certain amino acids (+) (c) Insulin (-) (d) Somatostatin (-) more online at page 5 of 15
  6. 6. Nem’s Notes… Phase 1 ENDOCRINOLOGY 3 (page 1 of 1) Hypothalamus & Pituitary Hypothalamo-Adeno Hypothalamic hormones act on the adenohypophysis to trigger hypophysial Axis adenohypophysial hormone release. The signal is released by specialised hypothalamic nuclei which causes neurosecretions from the hypothalamic neurones at the median eminence. These neurosecretions enter the hypothalamo- hypophysial portal system at the capillary plexus of the median eminence. The portal system carries the hormones directly to the adenohypophysis rather than being carried through the systemic circulation. This means that the signal causes a rapid response and is not diluted by the systemic circulation. Hypothalamic Hormones Hypothalamic Hormone Adenohypophysial Hormone Somatotrophin Releasing Hormone ↑ Growth Hormone (GH) (GHRH) Somatostatin ↓ Growth Hormone (GH) and (TSH) (GHIH) Dopamine ↓ Prolactin (dominant) (DA) Thyrotrophin Releasing Hormone ↑ Prolactin and Thyrotrophin (TSH) (TRH) Gonadotrophin Releasing Hormone ↑ LH and FSH (GnRH) Corticotrophin Releasing Hormone ↑ Corticotrophin (ACTH) (CRH) Vasopressin ↑ Corticotrophin (ACTH) (VP) Adenohypophysial Hormones Hormone Effect Promotes growth in muscle and bone Growth Hormone (GH) Opposes action of insulin Initiates lactation and mammary glands Prolactin (PRL) Promotes gonadal steroid release Acts on the thyroid gland to release Thyrotrophin (TSH) thyroid hormones Acts on gonads to release sex steroids Luteinizing Hormone (LH) and affects ovarian cycle Acts on gonads to release sex steroids Follicle Stimulating Hormone (FSH) and affects ovarian cycle Acts on adrenal cortex to release Corticotrophin (ACTH) adrenal hormones esp cortisol Hypothalamo-Neuro- The neurohypophysis is innervated by the paraventricular and supraoptic hypophysial Axis neurones which originate in the hypothalamus and connect directly to the neurohypophysis. Neurohypophysial Vasopressin (ADH) Vasoconstriction Hormones Antidiuresis at the collecting duct of the nephron Oxytocin Stimulates labour contractions Stimulates milk ejection and maternal instinct more online at page 6 of 15
  7. 7. Nem’s Notes… Phase 1 ENDOCRINOLOGY 4 (page 1 of 2) Thyroid Anatomy 3 sections (a) left lobe (b) right lobe (c) central isthmus surrounding the trachea and larynx Parathyroid glands embedded in the thyroid Follicles The thyroid is made up of follices Iodothyronines Production (mainly T4) more online at page 7 of 15
  8. 8. Nem’s Notes… Phase 1 ENDOCRINOLOGY 4 (page 2 of 2) Thyroid Iodothyronines Main physiological actions (a) Increases Basal Metabolic Rate (b) Increases Protein, Carbohydrate and Fat Metabolism (c) Potentiates Catecholamines (eg tachycardia) (d) Interacts with other endocrine systems (eg oestrogen) (e) Has effects on the CNS (f) Increases Vitamin A synthesis Control Mechanisms Thyroid Affects 5% of population and 4 females to 1 male Disease Ratio of overactive to underactive thyroid is ~1:1 Overactive (Thyrotoxicosis/Hyperthyroidism) (a) Thyroid swelling (Goitre) (b) Weight Loss (c) Muscle weakness (d) Tremor (e) Anxiety & sweating (f) Palpitations and accelerated CVS disease (g) Altered bowel habit (Diarrhoea) Underactive (Hypothyroidism) (a) Lethargy and fatigue (b) Thickened tongue and oedema of eyelid (c) Bradycardia (d) Dry scaly skin (e) Altered bowel habit (Constipation) (f) Heavy periods (g) Cold intolerance TRH Pituitary Overactive Underactive Deficiency Tumour TSH ↓ ↑ ↓ ↑ T3/T4 ↑ ↓ ↓ ↑ Treatment Hypothyroid: Thyroxine replacement – dose monitored using TSH feedback. Hyperthyroid: PHASE 2 more online at page 8 of 15
  9. 9. Nem’s Notes… Phase 1 ENDOCRINOLOGY 5 (page 1 of 2) Gonads Anatomy Males Females Gonad Testis Ovary Efferent ductules Epididymis Uterine/Fallopian Tube Internal Duct System Vas deferens Uterus Seminal vesicles Vagina Urethra Penis External Genitalia Vulva Scrotum Male (a) Spermatogonia (diploid) on basement membrane of seminiferous tubules Gametogenesis (b) Primary Spermatocytes (diploid) undergo first meiotic division to become… (c) Secondary Spermatocytes (haploid) undergo second meiotic division to form… (d) Spermatids (haploid) matured in the Sertoli cells giving rise to… (e) Spermatozoa which are released into the lumen of the tubule & to the epididymis. Ovarian Cycle (a) Follicular Phase Several follicles grow rapidly due to LH and FSH. One is (days 1-13) selected and the others undergo atresia. The follicle secretes increasing oestrogen (17β-oestradiol). (b) Ovulation Once the 17β-oestradiol level exceeds a certain point and (day 14) LH surge occurs via positive feedback. This precedes the rupture of the follicle and ovulation. (c) Luteal Phase The remaining follicles form the corpus luteum which (days 15-28) produces progesterone which maintains the endometrium. If there is no implantation the corpus dies and LH and FSH levels rise. Endometrium (a) Proliferative Phase Under the influence of 17β-oestradiol from the ovarian (days 4-13) follicle, the endometrium thickens. (b) Secretory Phase Progesterone from the corpus luteum causes secretion of (days 14-28) glycogen and engorgement with blood. (c) Menstrual Phase Decreasing progesterone from the corpus luteum causes (days 1-4) vasoconstriction. This leads to ischaemia, infarction and necrosis in the top epithelium which is menstruated. more online at page 9 of 15
  10. 10. Nem’s Notes… Phase 1 ENDOCRINOLOGY 5 (page 2 of 2) Gonads Hypothalamo- HYPOTHALAMUS Pulse generator causes neuronal GnRH release hypophysial Axis ADENOHYPOPHYSIS GnRH acts on Gonadotrophs releasing LH and FSH Gonadal Androgens Made in Leydig cells of testes (M) or Follicular Thecal cells (F) Steroids In Men the main androgen is testosterone which has many effects: (a) development/maintenance of sexual organs (b) secondary male charecteristics (c) developmental effects (muscle building, puberty, fetal) (d) central actions (libido, behaviour) In Women the main use is as a precursor of the oestrogens Oestrogens Androgen from Leydig cells aromatised in Granulosa cells (F). Produced to a much lesser extent in men in adipose tissue. In Women the main oestrogen is 17β-oestradiol whose effects are: (a) cyclic development of tissues (uterus, cervix, vagina…) (b) proliferative phase of endometrial cycle (c) contributes to secretory phase (d) secondary sex characteristics (e) CVS effects (protection against heart disease) (f) Skeletal effects (protects bone) In Men the use of oestrogens is unknown Progestogens Precursor for other steroid hormones. Low levels in men. In women the main progestogen is progesterone which affects: (a) the luteal phase (b) the secretory phase (c) stimulates breast development (d) increased basal temperature after ovulation Hormonal (M): LH causes testosterone release from Leydig cells. Control Testosterone negatively feeds back into both the hypothalamus and pituitary FSH causes spermatogenesis in Sertoli cells as well as producing Inhibin. Inhibin negatively feeds back to the pituitary. (F): FSH and LH stimulate follicular development. The follicles then secrete 17β-oestradiol. At a certain 17β-oestradiol level positive feedback causes LH surge This causes ovulation. The ruptured follicle becomes the corpus luteum secreting progesterone Progesterone & 17β-oestradiol exert negative feedback directly and indirectly As the corpus luteum dies this negative feedback falls FSH and LH levels rise again. Puberty The stage in life where reproductive capability is achieved. Probably due to night-time release of LH and FSH from the adenohypophysis. This causes increased gonadal steroid production. Adrenarche is the release of adrenal androgens and occurs 2 years before puberty. Amenorrhoea Primary: Failure of first menarche to occur at pubery Secondary: Cessation of menstrual periods after puberty Infertility Inability to conceive after 1 year of unprotected intercourse Endocrine causes: (a) Low spermatogenesis due to GnRH deficiency (b) Female GnRH def due to stress, exercise, weight loss (c) Polycystic Ovarian disease (excess androgen) more online at page 10 of 15
  11. 11. Nem’s Notes… Phase 1 ENDOCRINOLOGY 6 (page 1 of 2) Adrenal Cortex Anatomy Adrenals are in pink Microanatomy Hormones Adrenal Cortex (Zona Glomerulosa): Mineralocorticoid (esp Aldosterone) (Zona Fasciculata): Glucocorticoid (esp Cortisol) (Zona Reticularis): Glucocorticoid and androgen Adrenal Medulla Catecholamine (esp Adrenaline) Steroid Hormone Cholesterol Pregnenolone Progesterone 17-OH Progesterone Sex Steroids Androgen Cortisol Aldosterone Oestrogen more online at page 11 of 15
  12. 12. Nem’s Notes… Phase 1 ENDOCRINOLOGY 6 (page 2 of 2) Adrenal Cortex Hypothalamo-Pituitary-Adrenal Axis (eg Cortisol Regulation) Cortisol Part of the normal stress response – is longer lasting than adrenaline/noradrenaline but also maintains metabolic balance. It is essential for life. Biological Actions: (a) Increased blood pressure (Glucocorticoid) (b) Increased blood glucose (c) Increased Fat deposition and weight (d) Muscle wasting (e) Decreased bone mass – osteoporosis (f) Anti-inflammatory (immunosuppressive) (g) Mood swings and depression Excess = Cushing’s syndrome Deficiency = Addison’s disease Cortisol is also dependent on the circadian rhythm. Aldosterone Biological Actions: (a) Reabsorption of Na+ ions (b) Secretion of K+ and H+ ions Stimulated by (a) Fall in Na+ ions (b) Increase in K+ ions (c) Corticotrophin (ACTH) (d) Angiotensin II Excess = Conn’s syndrome Deficiency = Addison’s disease more online at page 12 of 15
  13. 13. Nem’s Notes… Phase 1 ENDOCRINOLOGY 7 (page 1 of 3) Parathyroid & Calcium Metabolism Bone Structure Two types of bone: (a) Flat bone (eg skull, scapula, mandible) (b) Long bone (eg tibia, femur, humerus) Long Bones have: (a) Two extremities (epiphyses) (b) Cylindrincal mid-shaft (diaphysis) (c) Development zone inside mid-shaft (metaphysis) (d) Growth plate between epiphysis and metaphysis Bone can occur as: (a) Compact bone (cortex) (b) Spongy bone (trabecular bone) Filled with bone marrow The two surfaces are the: (a) Internal (b) External which are lined with layers of osteogenic cells Microstructure The three types of cell are: (a) Osteoblasts bone forming (b) Osteocytes osteoblasts encased in bone (c) Osteoclasts bone resorbing Remodelling A four-stage process: (a) Activation (b) Resorption – Osteoclasts (c) Formation – Osteoblasts (d) Quiescence Bone Disease Osteoporosis – osteoblasts form bone more slowly than osteoclasts resorb it leading to net bone loss. Paget’s Disease – over-activity of osteoclasts and osteoblasts leading to disorganised new bone formation. Calcium Role of calcium in the body: (a) Maintenance of neuromuscular excitability (b) Release of neurotransmitters and hormones (c) Intracellular messenger (d) Muscle contraction (e) Blood clotting (factor IV) Most is stored in the bone (90%). In the blood some is ionized as Ca2+, however only free unbound Ca2+ is bioactive. Total blood [Ca2+] = 2.5 mM 50% unbound and bioactive 45% bound to plasma protein 5% as diffusable salts Organs of (a) Gastro-Intestinal Tract Intake through food and excretion Calcium (b) Bone Storage and release Metabolism (c) Kidney Excretion and reabsorption Calcium Regulation ↑ [Ca2+] ↓ [Ca2+] Parathyroid Hormone (PTH) Calcitonin 1,25(OH)2 vitamin D3 (dehydroxycholecalciferol) more online at page 13 of 15
  14. 14. Nem’s Notes… Phase 1 ENDOCRINOLOGY 7 (page 2 of 3) Parathyroid & Calcium Metabolism Hormonal Parathyroid Hormone (PTH) is produced by the parathyroid glands Synthesis Calcitonin is produced by the parafollicular cells of the thyroid Vitamin D3 is synthesised from cholesterol under UV light and from diet PTH Parathyroid Hormone has the following effects: (a) Kidneys Increased Ca2+ and H+ absorption Increased HCO3- and PO43- excretion Increased synthesis of 1α-hydroxylase leading to increased vitamin D3 synthesis leading to increased Ca2+ absorption in GI tract (b) Bone Increased osteoclast activity Decreased osteoblast activity PTH directly negatively feeds back to the parathyroid glands Vitamin D3 Bioactive 1,25-(OH)2 Vitamin D3 has the following effects: (a) Bone Increased bone resorption (b) GI Tract Increased Ca2+ and PO43- reabsorption (c) Kidneys Increased Ca2+ and PO43- reabsorption Calcitonin Released from the parafollicular cells of the thyroid The effects of calcitonin are: (a) Bone Decreased bone resorption (b) Kidneys Decreased reabsorption of Ca2+. Gonadal The gonadal steroids protect against bone loss. Caucasian women over 35 lose Steroids bone at a rate of 2-5% per year. After the menopause decreased gonadal steroid synthesis will cause increased bone loss and further risk of osteomalacia (demineralisation of bone) and osteoporosis (lack of collagen matrix). Hypocalcaemia Causes (a) Renal Failure (most common) leading to increased phosphorus ([Ca2+] < 2.1) which binds to calcium and decreased vitamin D3 synthesis. (b) Hypothyroidism and decreased PTH (c) Vitamin D deficiency due to malabsorption or diet/daylight (d) PTH resistance (e) Vitamin D resistance more online at page 14 of 15
  15. 15. Nem’s Notes… Phase 1 ENDOCRINOLOGY 7 (page 3 of 3) Parathyroid & Calcium Metabolism Hypocalcaemia Symptoms (a) Paresthesias – numbness and tingling in extremities (b) Muscle cramp (c) Larynospasm (d) Tetany (spontaneous muscle contraction) (e) Seizure Signs (a) Increased neuromuscular irritability (Chvostek’s/Trousseau’s) Hypercalcaemia Causes (a) Hyperparathyroidism – oversecretion of PTH from adenoma ([Ca2+] > 2.1) (b) Hypercalcaemia due to malignancy – tumours may secrete parathyroid related peptide (PTHRP) which is similar to PTH. Common tumours are carcinoma of breast and squamous cell of the lung. Symptoms (a) Kidney stones, polyuria (b) Bone pain and fractures (c) Dyspepsia (indigestion) (d) Muscle weakness and joint pain (e) Depression, confusion. memory loss more online at page 15 of 15