Hypothalamus & Pituitary: Neuroendocrinology, Circadian Rhythms PDF

Hypothalamus & Pituitary: Neuroendocrinology, Circadian Rhythms Andrea C. Gore, PhD Professor, Division of Pharmacology and Toxicology [email protected] 1 Learning Objectives By the end of this lecture you will learn about and understand: Neuroendocrine systems and their functions. Intro...

Hypothalamus & Pituitary: Neuroendocrinology, Circadian Rhythms Andrea C. Gore, PhD Professor, Division of Pharmacology and Toxicology [email protected] 1 Learning Objectives By the end of this lecture you will learn about and understand: Neuroendocrine systems and their functions. Introduction to the hypothalamus and pituitary Hypothalamic-anterior pituitary hormones: properties and pathophysiology Hypothalamic-posterior pituitary hormones: properties and pathophysiology. Circadian rhythms. 2 Neuroendocrinology Link between nervous and endocrine systems. The driving force is typically the nervous system; the endocrine system responds to nervous system signal. Often a single cell can have both neuronal and endocrine qualities. The neural side allows for quick response, and the endocrine side allows for sustained response and restoration of homeostasis. 3 Hypothalamus Major controller of neuroendocrine function Integration center between the brain, autonomic nervous system, and endocrine glands Necessary for appropriate responses to environmental factors Maintenance of homeostasis Coordination of physiological functions and behaviors (e.g., reproduction, feeding, emotional, stress responses, temperature, etc.) 4 Hypothalamus – Pituitary relationship adenohypophysis neurohypophysis 5 6 Hypothalamic-anterior pituitary hormones Hypothalamus Pituitary Target, Function Thyrotropin-releasing hormone (TRH) Thyroid-stimulating hormone (TSH) Thyroid gland (T3, T4); Metabolism Corticotropin-releasing hormone (CRH) Adrenocorticotropic hormone (ACTH; corticotropin) Adrenal gland (cortisol/corticosterone; DHEA); Stress Gonadotropin-releasing hormone (GnRH) Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) Gonad (Sex steroid hormones – estrogens, progestins, androgens); Reproduction Growth hormone-releasing hormone (GHRH) ----------------------Somatostatin (GH-inhibiting hormone) Stimulates Growth hormone (GH) [somatotropin] ----------------------Inhibits GH Liver (IGF-I), bone, kidney, other organs; Growth, anabolic function Dopamine (prolactininhibiting hormone)* Prolactin Mammary gland (milk); lactation *ACG: There is no unique prolactin-stimulating hypothalamic hormone. The default state of prolactin is repression; it needs to be de-repressed to lactate. 7 Feed-forward and feedback regulation example – Hypothalamic-pituitary-adrenal (HPA) axis Feed forward: Drive from hypothalamus to pituitary to target Hypothalamic hormone à drives pituitary hormone Pituitary hormone à drives target (adrenal) hormone Negative Feedback: Input to hypothalamus & pituitary about the concentrations of a peripheral hormone ↑ target hormone à ↓ hypothalamic & pituitary hormone (receptor occupancy is high; inhibits hyp/pit output) ↓ target hormone à ↑ hypothalamic & pituitary hormones (receptor occupancy is low; stimulates hyp/pit output) 8 Assessing Pathophysiology Case study: diagnosis of Cushing’s Syndrome (hypersecretion of cortisol) “Challenge tests” (also called provocative tests) are often used to diagnose a problem, rather than measuring absolute levels. Give a stimulus à evoke response. Dexamethasone administration suppresses cortisol in a healthy individual. 9 Pathophysiology: Pituitary Adenoma Adenoma: Benign tumor of epithelial cell origin. Very common (1/6 autopsies) but most are non- or subfunctional. Symptoms relate to expanding intracranial mass (headache, diabetes insipidus (loss of vasopressin), vision changes) or to hormone excess/deficiency. 10 Etiology: Any pituitary cell type can undergo hyperplasia – – – – – GH - gigantism (childhood), acromegaly (adulthood) ACTH – Cushing’s disease – too much cortisol (8x more common in women than men) Prolactin – Galactorrhea TSH (rare) – Hyperthyroidism LH or FSH (rare) – Precocious puberty, ovarian hyperstimulation Pathophysiology: Typically arise from clonal expansion (one cell multiplies) Genetic causes, especially MEN-1 (multiple endocrine neoplasia-1) 11 Pathophysiology: Prolactinoma Most common anterior pituitary disorder – 40% of pituitary adenomas are prolactinomas. Most are asymptomatic Can be associated with galactorrhea in 30-80% women, 33% men. Other symptoms can include menstrual disturbances, infertility (both sexes) and loss of libido. Decreased bone density – mechanism not understood but suggests that PRL has effects on bone. Treatment of symptomatic tumors: surgery; dopamine agonists. 12 Hypothalamic-anterior pituitary hormones Hypothalamus Pituitary Target, Function Thyrotropin-releasing hormone (TRH) Thyroid-stimulating hormone (TSH) Thyroid gland (T3, T4); Metabolism Corticotropin-releasing hormone (CRH) Adrenocorticotropic hormone (ACTH; corticotropin) Adrenal gland (cortisol/corticosterone; DHEA); Stress Gonadotropin-releasing hormone (GnRH) Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) Gonad (Sex steroid hormones – estrogens, progestins, androgens); Reproduction Growth hormone-releasing hormone (GHRH) ----------------------Somatostatin (GH-inhibiting hormone) Stimulates Growth hormone (GH) [somatotropin] ----------------------Inhibits GH Liver (IGF-I), bone, kidney, other organs; Growth, anabolic function Dopamine (prolactininhibiting hormone) Prolactin Mammary gland (milk); lactation Increasing dopamine action with agonists inhibits prolactin release in prolactinoma. 13 Pathophysiology: Hypopituitarism Panhypopituitarism – complete loss of all pituitary hormones. Hypopituitarism – loss of one or more pituitary hormone. 14 Pathophysiology: Hypopituitarism Etiology: – Sudden onset due to trauma – pituitary stalk section, infarction, hemorrhage. – Gradual onset due to pituitary tumors or radiation therapy. Pathophysiology: – Low concentrations of pituitary hormones together with low concentrations of target hormones. Clinical Manifestations: – Dependent upon extent and duration of insufficiency; sometimes can be compensated (e.g. vasopressin deficiency is treated by increasing water intake). 15 Hypothalamus - Posterior Pituitary neuroendocrine systems Vasopressin and oxytocin neurons 1. Cell bodies are in two regions of the hypothalamus: the paraventricular nucleus (PVN) and supraoptic nucleus (SON). 2. These are very large neurons that project axons through the pituitary stalk into the posterior pituitary. 3. Nerve terminals in posterior pituitary are full of large secretory vesicles that store vasopressin or oxytocin. In response to a stimulus, the vesicles are released directly into the systemic circulation. ***Functionally and anatomically the posterior pituitary is an extension of the hypothalamus. -Note that there is no portal capillary vasculature. 16 Vasopressin (VP; AVP) Also called ADH (anti-diuretic hormone) and arginine vasopressin (AVP). Hypothalamic “osmostat” – osmoreceptors An increase in blood osmolality triggers thirst, together with release of vasopressin. Enhances water retention in collecting ducts of the kidneys, allowing for water conservation. Urine concentration increases. 17 Oxytocin (OXT) Stimulates uterine smooth muscle contraction during childbirth. During lactation, OXT is responsible for reflexive milk ejection during suckling. Within the brain, OXT is important to behaviors including maternal behavior and pair-bonding in monogamous species. – Controversial: autism in humans 18 Properties of Vasopressin and Oxytocin 9 amino acid peptides (nonapeptide) that are structurally similar. The hypothalamic cell bodies that synthesize vasopressin and oxytocin are very large, known as magnocellular neurons. There is one oxytocin receptor, on breast tissue, pituitary, brain, uterus, arterioles. Three types of vasopressin receptors: V1a: on smooth muscle, triggering vasoconstriction V1b or V3: on pituitary corticotropes, contribute to ACTH release (together with actions from CRH) and stress regulation V2: on distal nephrons, mediating VP’s effect on osmolality All these receptors are G-protein coupled receptors. 19 Pathophysiology of vasopressin: formerly known as Diabetes Insipidus (DI), now called AVP-deficiency (central) or AVP-resistant (nephrogenic) 20 Pathophysiology of vasopressin: formerly known as Diabetes Insipidus (DI), now called AVP-deficiency (central) or AVP-resistant (nephrogenic) Clinical Presentation: – Polyuria (increased water intake) that persists even under conditions of dehydration – up to 20 L/day – Thirst – Nocturia (adults) and Enuresis (children – bed-wetting) AVP deficiency (Central) – Loss of AVP, usually due to head trauma, intracranial tumor, or surgery. – Can be treated by increasing water intake; pharmacotherapy (e.g. desmopressin) Nephrogenic AVP resistance (Nephrogenic) – Kidney’s loss of ability to respond to circulating vasopressin by retaining water. – Usually due to a defect in vasopressin receptor or a water channel on renal collecting ducts (aquaporin-2) – Sometimes induced by drugs – Can be treated by low salt diet and drinking enough water to avoid dehydration – Sometimes treated with diuretics (paradoxical effect on urine output in some people) 21 Pathophysiology – Syndrome of Inappropriate Vasopressin (ADH) Secretion (SIADH) Clinical Presentation: Hyponatremia without edema; can be associated with confusion, lethargy and weakness, seizures, coma. Etiology: Vasopressin-secreting tumors (often non-hypothalamic or pituitary), CNS disorders, pulmonary disorders, drugs. Other disorders (adrenal insufficiency, hypothyroidism) can be associated with SIADH. Pathophysiology: Not well understood; involves serum Na+ imbalance through water intake, renal solute delivery, and VP-mediated distal renal tubular water retention. Management: Restriction of fluid and water intake. Removal of a tumor, if relevant Vasopressin antagonists are available but not widely used except in cases of congestive heart failure or extreme cases. 22 Circadian Rhythms Hypothalamus: suprachiasmatic nucleus - SCN (neural control) Pineal gland: Melatonin (hormonal control) Other cycles – – – – SCN of a mouse expressing luciferase under the control of a Hourly (hormone pulses) circadian clock gene (sped up – each cycle represents 24h) Daily (circadian/diurnal) Weekly/monthly (estrous/menstrual) Yearly (seasonal) Courtesy Dr. Fonken 23 Suprachiasmatic nucleus (SCN) the master circadian pacemaker atop a hierarchy of oscillators Light is the most potent ”zeitgeber” (time giver) for entraining the circadian system SCN Rods and Cones Image-forming 470 nm Retinohypothalamic tract (RHT) Melanopsin-containing ipRGCs Non image-forming, but light-sensitive 24 Pineal Gland & Melatonin Tiny, pinecone-shaped endocrine gland. Secretes melatonin, a tryptophan metabolite – Hormone of darkness – highest secretion at night 25 The roles of melatonin Sleep aid Inhibits reproductive activity (e.g., puberty, seasonal breeding) Seasonality Antioxidant Immune regulation Aging Learning, memory, cognition Photo courtesy of Randy Nelson 26 Circadian-related pathologies Disorders of circadian system are associated with increased: Sleep disturbances, sleep apnea Obesity Type 2 diabetes mellitus Cancers – specifically hormonally associated Cognitive dysfunction Alzheimer’s disease Neuropsychiatric disorders Circadian disruption due to jetlag, shift work, or even dim light at night can also increase risk for disorders of the circadian system. 27 Learning Objectives By the end of this lecture you will learn about and understand: Neuroendocrine systems and their functions. Introduction to the hypothalamus and pituitary Hypothalamic-anterior pituitary hormones: properties and pathophysiology Hypothalamic-posterior pituitary hormones: properties and pathophysiology. Circadian rhythms. 28