NL Introduction to Endocrinology BMS200 2024 (1).pdf
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Introduction to Endocrinology BMS200 Dr. Lakshman, PhD September 16th, 2023 Learning Outcomes Describe the functional anatomy of the vascular and non-vascular elements of the endocrine hypothalamus, pituitary gland, thyroid gland, and adrenal glands Explain the regulation of the...
Introduction to Endocrinology BMS200 Dr. Lakshman, PhD September 16th, 2023 Learning Outcomes Describe the functional anatomy of the vascular and non-vascular elements of the endocrine hypothalamus, pituitary gland, thyroid gland, and adrenal glands Explain the regulation of the hypothalamic-pituitary-target gland axis, considering short and long feedback loops. Describe growth hormone synthesis, transport, function and regulation, including diurnal rhythms of secretion Analyze the regulation and biological actions of somatomedins in relation to growth hormone secretion. Predict complications associated with abnormal growth hormone production and function, such as acromegaly and gigantism. Describe the synthesis, regulation of secretion, and function of prolactin, including its role in cross-talk with other hypothalamic hormones. Pre-Assessment How does negative feedback work? What do you recall about the functionality of the growth hormone? Hypothalamus Anatomy The hypothalamus is composed of different types of neurons that are combined in various nuclei These receive input from various receptors of the body including information regarding thirst, blood pressure, appetite, light-dark, temperature, etc. Hypothalamic neurons send their output to centers in the brain, including pituitary gland Hypothalamic regulation The hypothalamus receives signals from the central nervous system and messengers that travel through the bloodstream: Situated in very close to the 3rd ventricle there are regions within the 3rd ventricular that allow somewhat selective passage of signals from blood ! ventricular fluid (known as circumventricular organs) Signals can be detected by neurons in the hypothalamic nuclei Can sense osmolarity, glucose, signal peptides (short loop feedback, appetite mediators)… many Extensive communication between the brainstem, limbic areas, and cortex (as already seen during our discussion of homeostatic pathways of appetite regulation) Magnocellular and Parvocellular Neurons Magnocellular neurons are located within the supraoptic and paraventricular nuclei Large, produce large quantities of neurohormones Neurohormones: oxytocin, vasopressin Output: posterior pituitary – release neurohormones into systemic circulation Parvocellular neurons are located within multiple different nuclei Small size Neurohormones: CRH, TRH, GHRH, GHIH, DA, GnRH/LHRH, PRH Output: median eminence (portal vein towards anterior pituitary), brainstem, spinal cord Hypothalamic-pituitary system (AP) The hypothalamus secretes releasing or inhibiting hormones into 1st set of capillaries These travel down to the anterior pituitary and modulate hormone secretion from those cells Anterior pituitary hormones control several other endocrine glands Thyroid, adrenal gland, gonads, liver Cranial anatomy – the hypophyseal fossa Note how the pituitary is almost completely surrounded by bone (sella turcica), and how close it is to the optic chiasm Basic Function of Hypothalamic Neurohormones Neurohormone Function Magno Oxytocin (via posterior pituitary) Stimulate uterine contractions cellula Vasopressin (ADH) (via posterior pituitary) Promote water reabsorption r Stimulate thirst neuro n Parvoc Corticotropin Releasing Hormone (CRH) Stimulate ACTH release; AP ellular Thyrotropin Releasing Hormone (TRH) Stimulate TSH release; AP neuro Gonadotropin Releasing Hormone (GnRH)/ Stimulate Gonadotropin release n Luteinizing Hormone Releasing Hormone (LHRH) (LH and FSH); AP Growth Hormone Inhibiting Hormone (GHIH)/ Inhibit GH release from anterior somatostatin pituitary (AP) Growth Hormone Releasing Hormone (GHRH) Stimulate GH release from anterior pituitary (AP) Prolactin Releasing Hormone (PRH) Stimulate prolactin release; AP Prolactin Inhibiting Hormone (PRIH)/ Dopamine Inhibit prolactin release; AP Hypothalamus and Pituitary Median Posterior Pituitary eminence Composed of axon terminals Infundibulum of magnocellular neurons and arteries forming inferior hypophyseal artery Anterior Pituitary Composed of endocrine tissues (responsible for producing ACTH, GH, TSH, etc.) Hypothalamic- Receives hypothalamic neurohormones via the secondary hypophyseal capillary plexus that receives blood from portal vein tract (hypothalamic parvocellular neurons release hormones into the primary capillary plexus within median eminence) Superior hypophyseal artery ! primary capillary plexus ! portal vein ! secondary capillary plexus Releases hormones into the hypophyseal veins (into systemic circulation via internal jugular vein) Hypothalamic Regulation Receives input from: CNS, intestines, heart, liver, stomach Contain specialized neurons that are able to detect different senses: glucose-sensing neurons, osmoreceptors Various hormones and signals from periphery can regulate hypothalamus via positive and negative feedback loops Negative loop: CRH stimulates ACTH release from anterior pituitary, ACTH inhibits hypothalamus from releasing more CRH Positive loop: Oxytocin stimulates uterine contractions, fetal head descends and stretches the cervix, triggering hypothalamus to release more oxytocin Hypothalamus is constantly integrating multiple different signals and adjusting its output accordingly Hypothalamic & Pituitary Regulation Most feedback is via negative feedback May be homeostatic or non-homeostatic mechanisms Oxytocin release during childbirth main example of positive feedback (more in BMS 250) – cervical thinning ! oxytocin release ! increased uterine contractions ! increased cervical thinning Definitions: Long loop: target endocrine gland ! hypothalamus or pituitary Short loop: pituitary ! hypothalamus We won’t discuss ultra-short Review: Short and Long Feedback Loops Lon Short loop Hypothalamus CRH GHRH TRH GnRH g Pituitary ACTH GH TSH FSH, LH Loo Target Gland Cortisol Insulin-like T3, T4 Estrogen, p growth progesterone, factor testosterone Growth Hormone (GH) Similar in structure to prolactin Produced by somatotrophs within the anterior pituitary Released in pulsatile bursts, major burst at night (nocturnal) during slow-wave sleep Transported with majority bound to growth-hormone binding protein to act as reservoir and to prolong half-life (protects against degradation) Half-life is 6-20 minutes Stimulates insulin-like growth factor 1 (IGF-1) release from liver Most important function: stimulation of postnatal longitudinal growth (anabolic and mitogenic effects) Production increases after 1-2 years, peaks in puberty, begins to decline in adulthood and continues with aging GH Regulation: Stimulation GH secretion is stimulated by: GHRH (hypothalamus) Hypoglycemia (promotes GHRH release) Arginine Catecholamines (also reduce GHIH/somatostatin) Dopamine Cortisol, thyroid hormones and androgens also influence GH by modifying the responsiveness to GHRH and GHIH Ghrelin (stomach, pancreas, kidney, liver, hypothalamus) GH Regulation: Inhibition GH secretion is inhibited by: Somatostatin / GHIH Hyperglycemia Increase in non-esterified fatty acids Insulin-like growth factor 1 (IGF-1) Directly inhibits somatotrophs Stimulates GHIH (which further inhibits somatotrophs) Somatostatin: Synthesized by many parts of the brain and organs (pancreas, stomach, others) Binds to (1) Galpha-i somatostatin receptor and promote tyrosine phosphatase activity (2) K+ channels resulting in hyperpolarized cell (stops release of GH) GH Secretion Patterns In the adult, GH levels are reduced as a result of smaller pulse width and amplitude rather than a decrease in the number of pulses. GH Receptor: Class 1 Cytokine Receptor Family: Location: liver, bone, kidney, adipose tissue, muscle, brain, eye, heart and immune cells There are 2 bindings sites which allow the GH receptors to dimerize once GH binds Dimerization resulting in increased JAK activity which leads to phosphorylation of tyrosine residues These will allow the release of activators of transcription proteins, which will promote the expression of GH- regulated genes (genes that are influenced by growth hormone) GH Functions: Organ/ System Impact Bone Increase formation of new bone and cartilage resulting in longitudinal growth (peaks in puberty), in adults promotes bone turn over and bone formation to maintain healthy bones Adipose Tissue Lipolysis: release and oxidation of fatty acids by reducing lipoprotein lipase Skeletal Muscle Increases amino acid uptake, protein synthesis, cell proliferation Liver IGF-1 production and release, gluconeogenesis, reduce glucose uptake; promotes hepatic glucose output Immune System Influences B cells, antibody production, NK activity, macrophages and T cells CNS Influences mood and behavioural changes Metabolism Increase lipolysis, reduce skeletal muscle glucose utilization GH and IGF-1 IGF-1 (somatomedin) Regulated by GH, PTH and reproductive hormones (in bone) Function: stimulates bone formation, protein synthesis, glucose uptake into muscles, neuronal survival, myelin synthesis, bone turn over, collagen synthesis, linear growth, mitogen (DNA, RNA and protein synthesis) Low at birth, increases during childhood/puberty, begins to decline in 3rd decade IGF-2: function postnatally is unknown Too much GH – What would you expect? What symptoms or problems would you expect to see clinically given the functions of growth hormone, if it were to be produced in significant excess? Acromegaly Most often acromegaly is due to somatotrope adenoma resulting in over secretion of GH Bone: Acral bony overgrowth result in frontal bossing Increased hand and foot size Mandibular enlargement with prognathism Wide space between incisor teeth Soft tissue: Increased heel pad thickness, increased shoe size, coarse facial features, large fleshy nose Acromegaly – Neoplastic Complications GH – increase JAK/STAT pathway ! proliferation BRCA1 – breast cancer Suppression of regulatory proteins ! they typically stop inappropriate DNA and cell replication ! colon and pituitary cancers Mitogen Acromegaly – Metabolic Complications Promote gluconeogenesis Reduction in insulin signaling pathway Insulin Resistance Acromegaly – Neurologic Complications If the somatotrope adenoma (aka AP tumour) grows large enough, it can: Impinge on the optic nerve (at the optic chiasm ! bitemporal hemianopsia) left eye right eye Increase intracranial pressure (headaches, eventually impacting cortical function, selected cranial nerves) Acromegaly and Cardiovascular Impact Cardiomyopathy with arrhythmia’s Left ventricular hypertrophy Decreased diastolic function Hypertension Upper airway obstruction with sleep apnea (common) Central sleep dysfunction Soft tissue laryngeal airway obstruction Diabetes Gigantism If increased GH secretion occurs before epiphyseal long bone closure (in children or adolescents) this results in gigantism Gigantism has the same etiology and almost all the same clinical features/ complications as acromegaly However, GH secretion is elevated prior to closure of the epiphyseal plate ! greatly increased height Prolactin Synthesized by the lactotrophs (15-20% of anterior pituitary); amount of lactotrophs increases in response to estrogen (i.e. pregnancy) Secretion increases during sleep and reduces during wake hours Function: development of mammary glands and milk production Under tonic inhibition from the dopamine binding to D2 receptors on the lactotrophs; dopamine released from hypothalamus Somatostatin and GABA also exert inhibitory impact Stimulated by suckling and increased estrogen Suckling results in reduction of dopamine release from hypothalamus GnRH, serotonergic and opioidergic pathways also promote release as do Prolactin Releasing Factors (TRH, oxytocin, vasoactive intestinal peptide) Prolactin Function Prolactin Receptor: Location: mammary gland, ovary, brain Function: Develop mammary glands Milk synthesis Maintenance of milk synthesis Milk synthesis is prevented during pregnancy by high progesterone levels Inhibit GnRH What is the primary hormone responsible for stimulating both the synthesis and secretion of GH from somatotrophs? A. Somatostatin B. Insulin C. Ghrelin D. Growth hormone-releasing hormone (GHRH) What is the primary physiologic effect of growth hormone? A. Stimulation of brain function B. Suppression of immune response C. Promotion of adipocyte differentiation D. Stimulation of postnatal longitudinal growth Which family of receptors do growth hormone cell surface receptors belong to? A. G-protein couple receptors B. Class 1 cytokine receptors C. Tyrosine kinase receptors D. Steroid receptors What is the primary physiologic role of prolactin in the mammary gland? A. Inhibition of mammary gland development B. Suppression of milk synthesis C. Stimulation of milk production D. Regulation of lactose metabolism References The Hypothalamus and Posterior Pituitary Gland. In: Molina PE. eds. Endocrine Physiology, 5e. McGraw Hill; 2018. Accessed July 25, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx? bookid=2343§ionid=183488081 Anterior Pituitary Gland. In: Molina PE. eds. Endocrine Physiology, 5e. McGraw Hill; 2018. Accessed July 25, 2023. https://accessmedicine- mhmedical-com.ccnm.idm.oclc.org/content.aspx? bookid=2343§ionid=183488163 Melmed S, Jameson J. Pituitary Tumor Syndromes. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed August 08, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx? bookid=3095§ionid=265439651
