RCSI Hypothalamus-Pituitary Target Organ Axes: Feedback Control 2 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Hypothalamus - Pituitary Target Organ Axes: Feedback Control 2 Class Year 2 Course Endocrine and Breast Module Lecturer Dr. Brona Murphy / Dr. Ebrahim Rajab Date January 2024  LEARNING OUT...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Hypothalamus - Pituitary Target Organ Axes: Feedback Control 2 Class Year 2 Course Endocrine and Breast Module Lecturer Dr. Brona Murphy / Dr. Ebrahim Rajab Date January 2024  LEARNING OUTCOMES Describe the role of Growth Hormone in the body Describe how defects in the levels of Growth Hormone in the body can cause disease Outline the role of prolactin in the body Describe how defects in the levels of Prolactin in the body can cause disease Outline the role of Oxytocin in the body Outline the role of ADH/Vasopressin in the body Describe how the defects in the levels of ADH/Vasopressin in the body can cause disease  ANTERIOR PITUITARY HORMONES In general, clinically there are specific hypo- and hyper- secretory conditions for most of the anterior pituitary hormones They are caused by either: – Hypo or hypersecretion of the anterior pituitary cells (primary) – Hypo or hypersecretion of hypophysiotropic hormones (secondary)  GROWTH HORMONE (SOMATOTROPIN) Single chain – 191 amino acids Essential for growth, but not wholly responsible for determining rate and final magnitude of growth – Genetic determination – Adequate diet – Freedom from chronic disease/stressful environment – Normal levels of growth-influencing hormones Secretion is pulsatile –serum concentration varies – Amplitude and frequency is regulated by age, gender, nutrition, sleep, body composition, stress, exercise. Random serum measurement of GH concentration can be misleading CONCENTRATION OF GROWTH HORMONE IN THE BODY Most abundant hormone produced by anterior pituitary Age ng/ml As one ages the average plasma (years) concentration of GH in an otherwise normal person drop 5-20 6 Continued secretion of GH 20-40 3 beyond growing period implies GH has other effects such as metabolic 40-70 1.6  GROWTH PROMOTING EFFECTS OF GROWTH HORMONE THROUGH SOMATOMEDINS GH does not act directly on it target cells to https://s3.amazonaws.com/healthtap-public/ht-staging/user_answer/reference_image/3888/large/Human_growth_hormone.jpeg?1349189255 exert its growth promoting actions Instead exerts majority of its growth- promoting effects indirectly by stimulating somatomedins – Insulin-like growth factors (IGFs) – Structurally and functionally similar to insulin – Most important is IGF-1 (Somatomedin C) – Major source of circulating IGF-1 is liver Released into blood on GH stimulation – Also produced by most other tissues ROLE OF GROWTH HORMONE IN THE BODY 1. Stimulates Linear Growth: Growth promoting effects through hyperplasia (increased cell division) and hypertrophy (increased protein synthesis) – Promotes growth of visceral organs directly and via IGF-1 – Bones: GH effect is to increase growth of skeletal frame GH causes the growth of bone in thickness and length Acts directly and indirectly on long bone epiphyseal plates via IGF-1 synthesis. Increases deposition of protein by chondrocytic and osteogenic cells Increases the rate of proliferation of these cells Stimulates differentiation of chondrocytes producing deposition of new bone* ROLE OF GROWTH HORMONE IN THE BODY 2. Metabolic Actions in Adults: Acts directly on liver, muscle and adipose tissue to shift metabolism to lipid use for energy, thereby conserving carbohydrates and proteins – Increases lipolysis and lipid oxidation; increases fatty acids in blood – Stimulates protein synthesis in most cells, especially in the muscles – Conserves glucose for brain – Raises blood glucose (i.e. antagonizes insulin action) Increases hepatic output of glucose Decreases peripheral insulin sensitivity & reduces glucose uptake by muscles ❖ Because GH produces insulin insensitivity/resistance it is considered a diabetogenic hormone. ❖ Excess GH secretion can produce metabolic disturbances very similar to type II diabetes. – Promotes phosphate, water, and sodium retention GH secreted when body’s energy needs exceed available glucose stores such as during prolonged fasting * ROLE OF GROWTH HORMONE IN THE BODY 3. Overall Functions: – Maintains adult cardiac function (i.e. contractility) and glucose homeostasis – Supports bone mineralization, adipose balance, and muscle anabolism Biological actions of Growth Hormone  Growth Hormone Axis Growth Hormone (GH)/Somatotropic Hormone/Somatotropin Hypothalamus GHRH: Stimulatory factor for somatotrope cells Somatostatin in anterior pituitary to release GH; GHRH (-) GH episodic release. (+) (-) Stimulators: hypoglycemia, dietary protein, exercise Inhibitors: IGF-1, GH. Anterior Somatostatin (GHIH): pituitary Inhibitory factor for somatrope cells (opposes GHRH action; inhibits GH release IGF1 SST receptors (G-protein coupled) are GH (-) present in many tissues: hypothalamus, GI (+) tract, Pancreas Also inhibits: TSH, PRL in pituitary; glucagon and insulin in pancreas liver Octreotide and Lantreotide are FDA approved analogs  CHANGES IN THE LEVEL OF GH IN THE BODY CAN CAUSE DISEASE http://2.bp.blogspot.com/-BnBWyjA6jvA/Tfg49z6pk3I/AAAAAAAAAA0/9Q4S2l6FU8w GH is necessary for growth before adulthood. Growth hormone deficiency produces dwarfism Hypersecretion of Growth hormone can produce gigantism (Normal growth also requires normal levels of thyroid hormones, insulin and sex steroids)  CAUSES OF GH DEFICIENCY Causes – Hypothalamic dysfunction Defect in the mechanisms that control GH secretion e.g. Lack of GHRH not stimulating the anterior pituitary – Pituitary defect Defect in the production of GH by somatotrophs – mutations in GH receptor Target cells for GH fail to respond normally due to mutations in the receptor. SYMPTOMS OF GROWTH HORMONE DEFICIENCY Symptoms dependent on age Hyposecretion of GH in a child – Dwarfism Short stature Poorly developed muscles Excess subcutaneous fat – Laron Dwarfism Blood levels of GH normal to high Abnormal GH receptors on tissues; GH response impaired – African Pygmies GH levels & target cell responsiveness normal Lack IGF-1 GH deficiency in adults Reduced skeletal mass & strength; increase in % body fat Decreased bone density Increased risk of heart failure  MEASURING GH DEFICIENCY Test IGF-1 first. If low, provocative testing (insulin- Serum Glucose levels induced hypoglycemia) is done to confirm diagnosis Response when GH levels normal Response when GH deficiency present TREATMENT RECOMBINANT FORMS OF HUMAN GH  CAUSES OF GROWTH HORMONE EXCESS Taught further in “Conditions Due to Excess/Deficiency of Pituitary Hormones” lecture Tumour of GH producing cells of anterior pituitary Symptoms depend on the age of the individual when the abnormal secretions begin SYMPTOMS OF GROWTH HORMONE EXCESS Overproduction in childhood results in Gigantism Rapid growth in height without distortion of body proportions Hyperglycaemia; cardiac hypertrophy; susceptible to infection; rarely live past their 20’s. Source: Endocrine and Reproductive Physiology. White, Bruce A., PhD; Harrison, John R., PhD; Mehlmann, Lisa M., PhD. 2019 FIG. 5.23 Robert Wadlow, later known as the “Alton Giant.” Although he weighed only 9 lb at birth, he grew rapidly, and by 6 months of age, he weighed 30 lb. A. Robert with his father at age 10; B. With a friend at age 16; C. Shortly before his death at age 22 years from cellulitis of the feet, he was 8 ft, 11 in tall and weighed 475 lb.  SYMPTOMS OF GROWTH HORMONE EXCESS GH hypersecretion after adolescence (Acromegaly) Due to a pituitary adenoma secreting excess GH GH acts directly and indirectly to stimulate soft tissues growth; also, appositional bone growth (i.e. thickness) Increased cardiovascular mortality with reduced life expectancy in non- cured individuals Jaw and cheekbones become more prominent from thickening of bones & skin The hands and the feet enlarge and fingers and toes greatly thickened Peripheral nerve disorders often occur as nerves trapped by overgrown connective tissue or bone or both Frontal bossing (= prominent forehead), prognathism (= protrusion of mandible)  MEASUREMENT & TREATMENT Best single test for the diagnosis of acromegaly is measurement of IGF-1. – An elevated IGF-1 confirms the diagnosis. A normal level rules it out. Confirmation testing: If the serum IGF-1 concentration is equivocal, serum GH should be measured after oral glucose tolerance test (OGTT) – Non-Suppressed GH levels after OGTT confirms the diagnosis – (Typically, GH should respond to high blood glucose by dropping in concentration) Treatment – Surgery is first line -> pituitary surgery to remove the tumor – If there is residual tumor that is not resectable -> medical therapy with somatostatin (i.e.- GH inhibitory hormone) analog (e.g.- octreotide) or pegvisomant (GH receptor antagonist)  PROLACTIN Prolactin (PRL) secreted from lactotropes in anterior pituitary 199-amino acid single chain protein Primary role is stimulation of milk production Lactrotropes differs from other endocrine cell types of the anterior pituitary in two major ways: 1. The lactrotrope is not part of an endocrine axis. PRL acts directly on neuroendocrine cells to induce physiological changes 2. Production and secretion of PRL is predominantly under tonic inhibitory control by the hypothalamus through dopamine. Disruption of the pituitary stalk and hypothalamohypophyseal portal vessels (e.g. surgery or physical trauma) results in an increase in PRL, but a decrease in other anterior pituitary hormones. Several prolactin-releasing factors (PRFs) have been identified in the hypothalamus that may play a role under certain conditions such as suckling or stress. Prolactin (PRL) Axis Tonically inhibited by Hypothalamus Dopamine – Also by dopamine agonists (e.g. bromocriptine) PRL (-) Dopamine “PRFs” Stimulated by PRFs under (-) certain conditions (breast stimulation, stress, estrogen, sleep, TRH Neural Anterior – Also by dopamine Stimulus pituitary antagonists (e.g. anti- (+) psychotics) negatively regulates LH and PRL E2 (+) FSH via hypothalamus (GnRH) (+) does not stimulate a hormone Mammary – not a subject to feedback Gland Ovary MILK  PROLACTIN Women – Stimulated by elevated serum estrogens (during pregnancy) – Inhibits GnRH synthesis & secretion -> inhibits ovulation – level increases steadily during pregnancy – Stimulates breast development & milk production – Suckling maintains elevated levels of PRL secretion by nipple stimulation Men (less significant role) – Not part of the normal male reproductive hormone feedback loop – Inhibits GnRH causing inhibitory influence on spermatogenesis  BIOLOGICAL EFFECTS OF PROLACTIN Before & after puberty - stimulates proliferation & branching of ducts in female breast During pregnancy - causes development of lobules of alveoli within which milk is produced After parturition - stimulates milk synthesis & secretion Reproduction - excess PRL blocks synthesis & release of GnRH Prevents ovulation in women Prevents normal sperm production in men Immunity (extent & nature of effects are still under research) – Synthesised by maternal uterine cells during pregnancy – Suggests role in immunological balance required for acceptance of foetal tissue by mother & protection of maternal tissues from foetal invasion CHANGES IN THE LEVEL OF PRL IN THE BODY CAN CAUSE DISEASE Prolactin Deficiency Prolactin Excess – Cause – isolated prolactin Causes deficiency is rare Physiologic (pregnancy, breastfeeding, stress) – Most patients with prolactin Pathologic (pituitary deficiency have evidence adenoma, drugs (e.g.- of other pituitary hormone dopamine receptor deficiencies antagonists) (panhypopituitarism- Symptoms discussed in later slides) Women (Galactorrhoea*, amenorrhea**, Infertility) – Symptoms – Decreased Men (decreased libido, lactation decreased fertility) *Galactorrhoea - milk production from the breast unrelated to pregnancy or lactation **Amenorrhea – absence of menstruation  LACTOTROPH ADENOMA Commonest pituitary tumour Common cause of female infertility Treatment – First Line is medical therapy with dopamine agonists- Cabergoline (preferred), Bromocriptine – Second line- Surgery: Transsphenoidal resection – Radiation- Generally reserved for resistant or aggressive tumors  SUMMARY- PITUITARY HORMONE EXCESS Pituitary Site Hormone Symptom/Sign Clinical Best test to Excess Condition order Anterior ACTH Moon face, Cushing’s 24 hr UFC, central obesity, Disease (ACTH LNSC, 1 mg DST striae, DM, secreting HTN adenoma) Anterior GH Enlarged Acromegaly IGF-1 level for hands, feet, screening, tongue, head OGTT for confirmation Anterior PRL Galactorrhea/a Prolactinoma Serum menorrhea prolactin level 24 hr UFC (urine free cortisol) LNSC -> Late night salivary cortisol DST -> Dexamethasone suppression test OGTT -> Oral glucose tolerance test HORMONES OF THE POSTERIOR PITUITARY  OXYTOCIN Oxytocin increase gradually in pregnancy & then sharply during labour Stimulates contraction of the uterus – myometrium As baby moves towards the birth canal → triggers pressure receptors in the cervix → evoke release of oxytocin →  muscular contraction → facilitates labour → baby delivered (example of a positive feedback loop) Promotes milk ejection from mammary glands (= Letdown reflex) Also important for social interactions - shown to be important in human behaviours including sexual arousal, recognition, trust, anxiety and mother–infant bonding. No deficiency disease and no excess disease  ARGININE VASOPRESSIN (ADH) (Arginine) Vasopressin (AVP)/Antidiuretic hormone (ADH)- Primarily formed in the supraoptic nuclei (hypothalamus) Regulates urinary water loss, extracellular fluid (ECF), and osmolarity Two major effects: – Enhances the retention of water by kidneys in distal tubule and collecting ducts resulting in decreased urinary output – ANTIDIURETIC EFFECT – Causes contraction of arteriolar smooth muscle – PRESSOR EFFECT  ROLE OF VASOPRESSIN/ADH IN THE ANTI- DIURETIC EFFECT ADH release controlled by hypothalamic osmoreceptors & systemic barorceptors Hypothalamic osmoreceptor neurons able to maintain ECF within narrow range (280-295 mOsm/kg) – within this range a rise of 1% in serum osmolality stimulates a rise in ADH secretion Volume receptors are less sensitive than osmoreceptors and a change of 10-15% in volume is required to produce measurable change in ADH – Very high concentrations of ADH stimulate receptors (v1) in the skin and mesenteric blood vessels causing vasoconstriction and increased blood pressure Cortisol and thyroid hormone restrain release of ADH -> patients with hypothyroidism and adrenal insufficiency have increased ADH release -> hyponatremia FIG. 5.8 Anatomy of the hypothalamus and pituitary gland (midsagittal section) depicting the pathways for antidiuretic hormone secretion. The closed box illustrates an expanded view of the hypothalamus and pituitary gland. From Koeppen BM, Stanton BA: Renal Physiology, 3rd ed., St. Louis, 2001, Mosby.  REGULATION OF VASOPRESSIN (ADH) SECRETION Secretion of ADH is primarily regulated by osmotic & volume stimuli ADH secretion stimulated by – Plasma hyperosmolality – Plasma hypovolemia (i.e.- volume depletion) – Angiotensin II ADH secretion inhibited by – Plasma hypoosmolality – Plasma hypervolemia Summary: Severe volume loss (e.g.- hypovolemic shock) results in a hypertonic state that triggers ADH release in an attempt to maintain volume  DEFICIENCY IN ADH SECRETION Most common is diabetes insipidus (DI)* 1. Deficiency in ADH secretion from posterior pituitary Hypothalamic “central” DI Causes: tumours of hypothalamus, autoimmune disease, head trauma 2. Kidney unable to respond to ADH Nephrogenic DI Causes: renal disease, mutations in ADH receptor gene or in gene coding for water channels in kidneys, drugs (lithium) Major symptoms of either type: Polyuria, polydipsia (excess thirst) & nocturia Treatment for central DI - Exogenous ADH *Diabetes insipidus is a disorder characterized by the inability of the kidneys to conserve water, leading to excessive urination (polyuria) and increased thirst (polydipsia). Thus, diabetes insipidus literally means "tasteless passing through," highlighting its key feature of excessive but dilute and non-sweet urine.  OVERSECRETION OF ADH: SYNDROME OF INAPPROPRIATE ADH SECRETION (SIADH) Causes – CNS damage (head injury), – Secretion of ADH from abnormal sites such as lung cancer (paraneoplastic) – Drugs or infections (TB) Major effect – Electrolyte disturbance – Hyponatraemia  ADH →  increased H2O reabsorption →dilution of plasma Na →  plasma Na (hyponatraemia) → hypo-osmolar plasma In SIADH -> hyper-osmotic urine is produced inappropriately Symptoms – Initial mild CNS symptoms (lethargy, nausea and muscle cramps) Further drop in sodium levels (drowsiness, confusion, seizures and coma) & low urinary output Treatment - Fluid (water) restriction (first line treatment) & ADH antagonists (second line) TABLE FOR REVISION! Hormone Function Disorders Essential for growth via IGF-1, promotes bone and Deficiency: Short stature in children, Growth Hormone (GH) muscle growth, increases bone density and muscle strength issues lipolysis, protein synthesis, in adults; Excess: Gigantism in children, antagonizes insulin action acromegaly in adults Stimulates milk Deficiency: Rare, lack of lactation production, regulates postpartum; Excess: Galactorrhea, Prolactin reproductive health amenorrhea, infertility (women), decreased libido and fertility (men) Crucial for childbirth (uterine contractions), milk Dysregulation: Affects labor and Oxytocin ejection, social bonding maternal behaviors, no specific diseases and behavior from deficiency or excess Regulates water balance via kidneys, affects blood Deficiency: Diabetes insipidus (excessive ADH/Vasopressin pressure through urination, thirst); Excess: SIADH (water vasoconstriction retention, hyponatremia) SUMMARY: HYPOTHALAMUS-PITUITARY- TARGET ORGAN AXES Growth Hormone (GH): Essential for growth, acts through IGF-1. Promotes bone and muscle development, lipid metabolism, and antagonizes insulin. Disorders: Deficiency → dwarfism, reduced muscle strength (adults); excess → gigantism, acromegaly. Prolactin (PRL): Stimulates milk production and regulates reproductive functions. Disorders: Excess → galactorrhea, amenorrhea, infertility (women); decreased libido, infertility (men). Oxytocin: Important for labor and milk ejection; social bonding no major deficiency or excess disorders. Antidiuretic Hormone (ADH/Vasopressin): Regulates water balance and blood pressure via kidney action and vasoconstriction. Disorders: Deficiency → diabetes insipidus; excess → SIADH (water retention, hyponatremia).  Recommended Reading Medical Sciences. Jeannette Naish. Chapter 10. Endocrinology and the Reproductive System. Or, Endocrine and Reproductive Physiology. Bruce White, John Harrison, Lisa Mehlmann. Chapter 5. Hypothalamus-Pituitary Complex Or, Master Medicine: Physiology. J McGeown. Chapter 8. Endocrine physiology. Multiple Choice Questions A 10-year-old boy presents with rapid growth over the past year, with a height greater than the 97th percentile for his age. On examination, he has coarse facial features and large hands and feet. Laboratory investigations reveal elevated serum IGF-1 levels and poor suppression of growth hormone following an oral glucose tolerance test. What is the most likely diagnosis? A. Acromegaly B. Gigantism C. Laron Dwarfism D. Cushing Syndrome E. Marfan Syndrome **Correct Answer**: B. Gigantism Multiple Choice Questions A 35-year-old woman presents with complaints of irregular menstruation and spontaneous milk discharge from her breasts, despite not being pregnant or breastfeeding. She also reports difficulty conceiving over the past two years. Her serum prolactin level is significantly elevated, and imaging reveals a pituitary adenoma. Which of the following is the most appropriate initial treatment? A. Transsphenoidal surgery B. Dopamine agonist therapy C. Somatostatin analog therapy D. Radiation therapy E. Thyroid hormone replacement **Correct Answer**: B. Dopamine agonist therapy Multiple Choice Questions A 50-year-old man presents with fatigue, increased thirst, and excessive urination. His serum sodium is elevated, and urine osmolality is low despite hypernatremia. Following administration of desmopressin, his urine osmolality increases significantly. What is the most likely diagnosis? A. Nephrogenic diabetes insipidus B. Syndrome of inappropriate ADH secretion (SIADH) C. Central diabetes insipidus D. Psychogenic polydipsia E. Addison’s disease **Correct Answer**: C. Central diabetes insipidus Multiple Choice Questions A pregnant woman in her third trimester experiences strong uterine contractions. Her cervix is fully dilated, and her physician explains that a hormone is responsible for enhancing these contractions in a positive feedback manner. Which hormone is being referred to? A. Prolactin B. Oxytocin C. ADH D. Cortisol E. Estrogen **Correct Answer**: B. Oxytocin