Student-2023-PHA3114 Patho II_Disorders of the HP axis.pptx

Disorders of Endocrine Function (Hypothalamus-Pituitary Axis) Dr. Coucha Department of Pharmaceutical Sciences South University School of Pharmacy [email protected] Office: 348 (Savannah) (912) 201-8146 Porth’s Pathophysiology, tenth edition, Chapters 40, 41. Pathophysiology of Disease: An...

Disorders of Endocrine Function (Hypothalamus-Pituitary Axis) Dr. Coucha Department of Pharmaceutical Sciences South University School of Pharmacy [email protected] Office: 348 (Savannah) (912) 201-8146 Porth’s Pathophysiology, tenth edition, Chapters 40, 41. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e 1 ____ Hormone Gland releasing the hormone Hormone regulation Stimulants • _____ • ______ Inhibitors • ______ • ______ Actions of the hormone Secretion disorders Excess Low Name of the disorder Causes Manifestations Diagnosis Treatment 2 Disorder Hormone Diagnosis (SS-Lab tests) Acromegaly Hashimoto thyroiditis Graves Disease Thyroid storm Myxedematous coma Cushing disease Addison’s disease SIADH Diabetes Insipidus 3 Learning Objectives LO1: Describe the mechanisms of endocrine hypofunction and hyperfunction. LO2: Describe the function of the anterior pituitary gland. LO3: Describe the actions and regulation of the growth hormone. LO4: Describe the difference between the negative and positive feedback. LO5: Explain the manifestations, diagnosis and treatments of short stature/Dwarfism. LO6: Explain the manifestations, diagnosis and treatments of GH deficiency in adults. 4 Learning Objectives LO7: Explain the manifestations, diagnosis and treatments of gigantism. LO8: Explain the manifestations, diagnosis and treatments of acromegaly. LO9: Describe the function of the posterior pituitary gland. LO10: Describe the actions and regulation of the anti-diuretic hormone. LO11: Explain the manifestations, diagnosis and treatments of diabetes insipidus. LO12: Explain the manifestations, diagnosis and treatments of Syndrome of Inappropriate ADH (SIADH) 5 Endocrine system: Endocrine Cells Hormones • • • • are released to circulation to act on a target organ circulate as either free, unbound molecules or as hormones attached to transport carriers The extent of protein carrier binding influences the rate at which hormones leave the blood and enter the cells. Drugs that compete with a hormone for binding with transport carrier molecules ___ hormone action by _____ the availability of the active unbound hormone. Hormone Free Hormone Carrie r protei Bound Hormone n Target Cells Biologic effects LO1: Describe the mechanisms of endocrine hypofunction and hyperfunction GENERAL ASPECTS OF ALTERED ENDOCRINE FUNCTION Disturbances of endocrine function can usually be divided into two categories— hypofunction and hyperfunction Hyperfunction usually is associated with excessive hormone production. This can result from excessive stimulation and hyperplasia of the endocrine gland or from a hormone-producing tumor. LO1: Describe the mechanisms of endocrine hypofunction and hyperfunction GENERAL ASPECTS OF ALTERED ENDOCRINE FUNCTION Absence or Impaired development of a gland Receptor Defects Deficiency or lack of an enzyme that is needed for hormone synthesis Hypofunct ion Receptors may be absent Receptor binding of hormones may be defective Impaired cellular responsiveness to the hormone Aging or gland Atrophy due to drug therapy or for unknown reason Gland Destruction BF disruption Infection, Inflammation Autoimmune response, Neoplastic growth LO1: Describe the mechanisms of endocrine hypofunction and hyperfunction 8 Hypothalamic–Pituitary Regulation • The hypothalamus and pituitary gland form a functional unit that exerts control over the activities of several endocrine glands, and thus a wide range of physiologic functions. • The hypothalamus is located centrally in the brain and serves as the coordinating center of the brain for endocrine, behavioral, and autonomic nervous system function. 9 Hypothalamic–Pituitary Regulation • The pituitary gland, or hypophysis, is a peasized gland located at the base of the brain • A short funnel-shaped stalk, the infundibulum, connects the pituitary gland with the hypothalamus. The pituitary gland has two components • Posterior lobe (neurohypophysis) or neural component • Anterior lobe (adenohypophysis) or glandular component. www.merckmanuals.c 10 Hypothalamic–Pituitary Regulation Hormones produced by the anterior pituitary • LH and FSH: Luteinizing hormone and Folliclestimulating hormone • GH: Growth Hormone • ACTH: Adrenocorticotropic hormone • TSH: Thyroid Stimulating Hormone • Prolactin 2: Describe the function of the anterior pituitary gland. 11 Hormones produced by the anterior pituitary control • Function of the Gonads (FSH and LH) • Body growth and metabolism (GH) • Adrenal glands-Glucocorticoid hormone levels (ACTH) • Function of the Thyroid gland (TSH) • Milk production and Breast growth (prolactin) 2: Describe the function of the anterior pituitary gland. 12 Growth Hormone Actions Growth hormone (somatotropin) is synthesized and secreted by special cells in the anterior pituitary called somatotropes somatomedins LO3: Describe the actions and regulation of the growth T or F • GH cannot directly cause bone growth • The rate of GH production in adults is almost as great as it is in children. 13 Growth Hormone Actions somatomedins It enhances fatty acid mobilization, increases the use of fatty acids for fuel, and maintains or increases blood glucose levels by decreasing the use of glucose for fuel. LO3: Describe the actions and regulation of the growth 14 Hormone Regulation Two hypothalamic hormones regulate the secretion of GH: Hypothala mus GHR Somatost H atin • GH-releasing hormone (GHRH), which increases GH release. Anterior Pituitary gland • Somatostatin, which inhibits GH release. Growth Hormone Liver ostatin, Somatotropes, Somatotropin, Somatomedins LO3: Describe the actions and regulation of the growth hormone. IGF-1 15 Things to Remember • Somatotropes, Somatotropin, Somatostatin, Somatomedins • Somatotropes (from the Greek sōmat meaning "body" and tropikós meaning "of or pertaining to a turn or change") are cells in the anterior pituitary that produce growth hormone. • Tropin: stimulate, act on • Statin: pertaining to stopping • Medi: middle • Somatomedin a hormone which acts as an intermediate in the stimulation of tissue growth by growth hormone. 16 Growth Hormone Secretion • The secretion of GH fluctuates over a 24-hour period, with peak levels occurring 1 to 4 hours after onset of sleep. LO3: Describe the actions and regulation of the growth hormone. https://www.precisionnutrition.com/all-about-gh17 LO3: Describe the actions and regulation of the growth hormone. Hypothalamic–Pituitary Axis Hormone Regulation GH secretion is stimulated by hypoglycemia, fasting, starvation, increased blood levels of amino acids (particularly arginine), and stress conditions such as trauma, excitement, emotional stress, and 1. Stress & Low blood glucose stimulate release heavy exercise. of GHRH and decrease release of the inhibiting hormone (somatostatin) from hypothalamus 2. GHRH increases GH secretion from the anterior pituitary. 3. When GH is released, it acts on its target tissues. 18 LO3: Describe the actions and regulation of the growth hormone. Hypothalamic–Pituitary Axis Hormone Regulation GH increases somatomedins release, protein synthesis, and blood glucose. 19 Hypothalamic–Pituitary Axis Hormone Regulation GH is inhibited by increased glucose levels, free fatty acid release, LO3: Describe the actions and regulation of the growth hormone. cortisol, and obesity. • Negative Feedback Loops 20 Hypothalamic–Pituitary Axis Hormone Regulation • The regulation of hormones (especially the Hypothalamic-Pituitary system) occurs primarily via feedback loops • Positive and Negative Feedback Loops Some feature of hormone action directly or indirectly inhibits further hormone secretion so that the hormone level returns to an ideal level or set point. LO4: Describe the difference between the negative and positive 21 GH disorders • • GH Deficiency in Children and adults GH Excess in Children and adults GH Deficiency Children • in Short stature is a condition in which height is less than the third percentile on the appropriate growth curve Child with GH deficiency a 5.5 year old boy (left) with GH deficiency was a significantly shorter than his fraternal twin sister (right) Neuroendocrinology and Pituitary Disease LO:5 Explain the manifestations, diagnosis and treatments of short stature 22 Red dot is plotted on the 95th percentile line, which means that the kid is taller than 95 percent of all other kids of the same sex. Yellow dot is plotted on the 25th percentile line, which means that the kid is ____ than 75 percent of all other kids of the same sex. 23 LO:5 Explain the manifestations, diagnosis and treatments of short stature https://doctorlib.info/pediatric/case-files-pediatrics/25 Knowledge check • Which of the following can lead to short stature in kids? A. IGF deficiency B. Damage to the posterior pituitary gland C. Damage to the hypothalamus D. Deficiency of receptors for GH 24 GH deficiency Diagnosis Causes • Primary GH deficiency • Secondary GH deficiency (panhypopituitarism) • Biologically inactive GH production • Deficient IGF-1 production in response to normal or elevated GH Hypothala mus GHR Somatost H atin Anterior Pituitary gland Growth Hormone Liver LO:5 Explain the manifestations, diagnosis and treatments of short stature IGF-1 25 GH deficiency Diagnosis • Physical examination • N.B: Diagnosis of short stature is not made on a single measurement but is based on sequential height measurements, velocity of growth, and parental height. • Radiologic films are used to assess bone age, which often is delayed • MRI of the hypothalamic–pituitary area • Treatment with recombinant DNA GH LO:5 Explain the manifestations, diagnosis and treatments of short stature 26 Growth Hormone Deficiency in Adults There are two categories of GH deficiency in adults: 1. GH deficiency that was present in childhood 2. GH deficiency that developed during adulthood, mainly as the result of hypopituitarism resulting from a pituitary tumor or its treatment The GH deficiency syndrome is associated with a cluster of cardiovascular risk factors including: • central adiposity (associated with increased visceral fat) • insulin resistance • dyslipidemia • a higher prevalence of atherosclerotic plaques • endothelial dysfunction LO6: Explain the manifestations, diagnosis and treatments of GH deficiency in adults. 27 GH deficiency Diagnosis in adults • • A low IGF-1 level in the presence of low levels of three or more pituitary hormones indicates GH deficiency Subnormal serum GH responses to provocative stimuli • a pharmacological agent acutely stimulates pituitary GH secretion, and peak serum GH levels detected by sequential blood sampling of serum GH levels after administration of the GH provocative agent Hypothala mus GHR H Anterior Pituitary GH IGF LO6: Explain the manifestations, diagnosis and treatments of GH deficiency in adults. 28 GH deficiency Diagnosis in adults • If hypofunction of an endocrine tissue is suspected: Stimulation test If a prompt rise in GH is realized, the patient is considered normal. Stimulant s??? Hypothala mus GHR H Anterior Pituitary GH LO6: Explain the manifestations, diagnosis and treatments of GH deficiency in adults. IGF 29 GH deficiency Diagnosis • Tests can be performed using Stimulate GH secretion • Insulin tolerance test so that GH reserve can • Arginine-GHRH be evaluated } • Two or more tests are usually performed to ensure accuracy GH replacement therapy is the treatment of choice. GH secretion is stimulated by hypoglycemia, fasting, starvation, increased blood levels of amino acids (particularly arginine), and stress conditions such as trauma, excitement, emotional stress, and heavy exercise. LO6: Explain the manifestations, diagnosis and treatments of GH Low BG/Argin ine Hypothala mus GHR H Anterior Pituitary GH IGF 30 GH Excess in children • GH excess occurring before puberty and the fusion of the epiphyses of the long bones results in pituitary gigantism • Fortunately, the condition is rare because of early recognition and treatment of the adenoma.  Excessive growth in height, muscles, and organs, making the child extremely large for his or her age.  large hands and feet  delayed puberty  prominent forehead and prominent jaw  increased sweating A 22 year old man with gigantism due to excess gh is shown to the left of his identical twin 31 LO7: Explain the manifestations, diagnosis and treatments of N Eng J Med. 1999;340:524 GH excess in adults • When GH excess occurs in adulthood or after the epiphyses of the long bones have fused, the condition is referred to as acromegaly. • Acromegaly (from the Greek words acros “end portion”, and megalos “large”) • The most common cause of acromegaly is a GH-secreting somatotrope adenoma in the pituitary gland. • The other causes of acromegaly are • hypothalamic tumors that result in excess secretion of GHRH, • ectopic secretion of GHRH by nonendocrine tumors (such as small cell lung cancers) 32 Clinical manifestations of acromegaly result from the effects on body cells from excess circulating blood levels of GH and IGF-1 AC cromegalic facies RO ardiomegaly/ atherosclerosis/ hypertension M eproductive dysfunction EG ALbstructive sleep apnea, deep Y voice etabolic effects leading to impaired glucose regulation and diabetes m nlarged hand and Excessive sweating with an feet unpleasant odor reasy skin rthritis arge lips, broad nose, prominent supraorbital ridge and a protruding LO8: Explain the manifestations, diagnosis and treatments of acrom Spl ed teeth 33 Diagnosis • Facilitated by the typical features of the disorder. • MRI scanning • Serum IGF-1 testing is the recommended initial lab test. • If the serum IGF-1 is elevated, then the confirmatory test is • Oral Glucose Tolerance Test LO8: Explain the manifestations, diagnosis and treatments of acromegaly. 34 Diagnosis Oral Glucose Tolerance Test/ GH suppression test • Oral glucose solution is administered • Normal: • Acromegaly: • GH is inhibited by increased glucose levels, free fatty acid release, cortisol, and obesity. LO8: Explain the manifestations, diagnosis and treatments of acromegaly. 35 wth Hormone Excess in Adults Acromegaly Treatment • Surgical ____ of the tumor. • GH receptor ___ (Pegvisomant) • Somatostatin ____ produce feedback inhibition of GH (Octreotide) By Philippe Chanson and Sylvie Salenave - Acromegaly. Orphanet Journal of Rare Diseases 2008, 3:17. doi:10.1186/1750-1172-3-17, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=15072129 36 LO8: Explain the manifestations, diagnosis and treatments of acromegaly. 37 • A 43-year-old man complains of increased hat size and headaches when he wakes up in the morning. Physical exam reveals mild hypertension, prominent jaw with spaces between the teeth, large hands and feet, and generalized muscle What are the weakness. reasons for his signs and symptoms? What will be the treatment goals? https://step2.medbullets.com/endocrine/120094/pituitary-adenoma--acromega ly 38 The Posterior Pituitary (Neurohypophysis) It secretes two hormones: oxytocin and antidiuretic hormone (ADH) or vasopressin. Oxytocin Physiological Functions: • It stimulates milk ejection from the breast in response to suckling (milk ejection reflex). • It stimulates uterine contraction during labor to expel the fetus and placenta. Don’t forget!!! Oxytocin: stimulates milk ejection Prolactin: stimulates milk Production 9: Describe the function of the posterior pituitary gland. 39 The Posterior Pituitary (Neurohypophysis) Antidiuretic Hormone (ADH) or Vasopressin • ADH, also known as arginine vasopressin, is formed in the hypothalamus and stored in the posterior pituitary. ADH has two principle sites of action: the kidney and blood vessels. Vasopressin binds to V1 receptors on vascular smooth muscle to cause vasoconstriction Vasopressin V1 recept or Vasoconstriction Increased blood pressure LO10: Describe the actions and regulation of the anti-diuretic 40 Antidiuretic Hormone (ADH) or Vasopressin This figure shows the structure of the nephron, which filters waste from the body's blood supply. Each nephron is composed of a glomerulus and a tubule. The glomerulus filters wastes and excess fluids, while the tubules modify the waste to form urine. Cleaned blood returns back to the circulation via a renal vein. 41 http://southshorenephrology.com/education/nephron-structure Antidiuretic Hormone (ADH) or Vasopressin • ADH acts on renal collecting ducts via V2 receptors • Vasopressin increases the number of active water channels in the cell membranes of renal collecting duct cells • Increasing water reabsorption • Decreasing urine formation • Increasing the concentration of the urine. • Increasing arterial pressure “Why?” Tubular Fluid Collecting duct ADH Aquaporin ADH receptor 42 1 2 Tubular Fluid luminal membrane Collecting duct 1-Without ADH, the luminal membranes of the tubular epithelial cells of the collecting ducts are almost impermeable to water. ADH Aquaporin ADH receptor 2-In the presence of ADH, pores or water channels, called aquaporins, are stimulated to move into the membrane of these tubular cells, making them 43 permeable to water. ADH/Vasopressin Regulation Tubular Fluid Collecting duct The main function of ADH is osmoregulation • Slight elevations in blood osmolarity result in the secretion of ADH. ↑Plasma Osmolarity • ADH acts primarily in the kidneys to increase water reabsorption, thus returning the osmolarity to baseline ↑ ADH secretion ↑ water Reabsorption T or F Hypervolemia promotes ADH secretion ↓ Plasma Osmolarity LO10: Describe the actions and regulation of the anti-diuretic 44 Diabetes insipidus • caused by a deficiency of or a decreased response to ADH • The kidneys make a lot urine • Manifested by: • Polyuria: 3-20 L/day (reference: 0.5–2 L/day) • Polydipsia (excessive thirst  increased fluid consumption) 45 Diabetes insipidus = Dehydrated Diagnosis: • Medical/family history and Physical exam • Magnetic resonance imaging (MRI) • Urinalysis • High amount of urine • hypo-osmolality • Blood tests (hypernatremia) The hallmark of diabetes insipidus is dilute urine 46 Diagnosis Fluid deprivation test Water Deficit • Patient with no DI:  rapid ____ in urine volume & ____ urine osmolality • (Normal ADH response) ↑Plasma Osmolarity ↑ ADH secretion ↑ water Reabsorption • Patient with DI:  no change in urine volume or osmolality (no ADH effect) ↓ Urine volume & ↑ osmolality LO11: Explain the manifestations, diagnosis and treatments of diabetes 47 Diabetes insipidus: Etiology • Disease of the CNSNeurogenic/central DI: Defect in the synthesis or release of ADH. • Disease of the kidneyNephrogenic DI: kidneys do not respond to ADH. 48 Diabetes insipidus: Desmopressin Test •Desmopressin test to distinguish nephrogenic from neurogenic (central) DI • Desmopressin is a synthetic analogue of arginine vasopressin • Administer desmopressin • If ____________DI, urine osmolality should rapidly increase by > 50%. Desmopre ssin (D=Decrea se Urine Output) • If __________DI, urine osmolality may not increase or may increase only slightly. 49 Diabetes insipidus: Treatment • Patients should have access to water • The volume of urine produced in the total absence of vasopressin may reach 10–20 L/d (if no adequate fluid intake dehydration can develop and may rapidly progress to coma). • Desmopressin acetate if severe (neurogenic) 50 Syndrome of Inappropriate ADH (SIADH)= (Stop urination) Excessive amount of ADH hormone resulting in water retention The manifestations of SIADH • Urine output decreases despite adequate or increased fluid intake. • Urine osmolality is high • • Hyponatremia Serum osmolality is low. LO12: Explain the manifestations, diagnosis and treatments of Syndrome of 51 SIADH Treatment • Correct underlying cause • Fluid restriction (mild cases) goal  to restore Na+ plasma concentration to normal • Diuretics (moderate cases) • Hypertonic saline IV (severe cases) • Specific ADH V2 receptor antagonists V2 receptor antagonist LO12: Explain the manifestations, diagnosis and treatments of Syndrome of 52 Diabetes Insipidus SIADH ADH levels Urine Osmolality Serum Sodium 53 Case • A 23-year old male was seen in the emergency department after suffering a concussion and head trauma from a motor vehicle accident. The patient was stabilized in the emergency and transferred to the intensive care unit (ICU) for observation. The patient had CT scan of the head that revealed a small amount of cerebral edema but was otherwise normal. During the second day in the ICU, the nurse informed that the patient had a large amount of urine output in the last 24 hrs. The nursing records reported his urine output over the previous 24 hrs to be 5000cc. He has not been given any diuretic medications. A urine osmolality was ordered and was found to be low. His physician remarked that the kidneys were not concentrating urine normally. • What is the most likely diagnosis for the increasing dilute 54