Lecture 6.1 - The Hypothalamic-Pituitary Axis and Growth Hormone PDF

The hypothalamic pituitary axis: ◦The hypothalamic and pituitary gland form a complex functional unit that serves as the major link between the endocrine and nervous systems ◦The hypothalamus and pituitary gland modulate a wide variety of processes ‣ Body growth ‣ Re...

The hypothalamic pituitary axis: ◦The hypothalamic and pituitary gland form a complex functional unit that serves as the major link between the endocrine and nervous systems ◦The hypothalamus and pituitary gland modulate a wide variety of processes ‣ Body growth ‣ Reproduction ‣ Adrenal gland function ‣ Water homeostasis ‣ Milk secretion ‣ Lactation ‣ Thyroid gland function ‣ Puberty The pituitary gland consists of two parts: ◦Anterior pituitary gland - adenohypophysis (endocrine tissue) ◦Posterior pituitary gland - neurohypophysis (nerve tissue) ◦The anterior and posterior pituitary glands have distinct embryological origins and distinct functions - completely separate tissues ‣ Anterior pituitary arises from evagination of oral ectoderm (Rathke's pouch) - primitive gut tissue ‣ Posterior pituitary originates from neuroectoderm - primitive brain tissue ◦The posterior pituitary gland is physically connected to the hypothalamus, since the hypothalamus drops down through the infundibulum (stalk) to form the posterior pituitary Neurocrine function of the posterior pituitary: ◦Hormones are produced in the hypothalamus ◦Oxytocin and antidiuretic hormone (vasopressin) produced by neurosecretory cells in the supraoptic and paraventricular nuclei of the hypothalamus ◦Transported down nerve cell axons in vesicles to the posterior pituitary ◦Stored and released from posterior pituitary nerve endings into the general circulation to act on distant targets ‣ NOTE: the posterior pituitary gland does not synthesise these hormones, it just releases them  Anterior pituitary function: ◦Hormones synthesised in hypothalamus are transported down axons and stored in median eminence before release into hypophyseal portal system ◦These hormones stimulate (or inhibit) target endocrine cells in the anterior pituitary gland (neurocrine function) ◦Endocrine cells of anterior pituitary secrete a variety of hormones into the bloodstream to act on distant target cells (i.e. endocrine function) Tropic hormones of the hypothalamus: ◦6 tropic hormones (stimulating) produced in the hypothalamus ◦These have direct effects on the release of anterior pituitary hormones ‣ TRH - thyrotropin releasing hormone - can also cause release of prolactin ‣ PRH - prolactin releasing hormone = TRH (minor +ve control on prolactin) ‣ PIH - prolactin release-inhibiting hormone (dopamine) ‣ CRH - corticotropin releasing hormone - affects adrenal glands ‣ GnRH - gonadotropin releasing hormone - affects reproductive organs ‣ GHRH - growth hormone releasing hormone ‣ GHIH - growth hormone-inhibiting hormone (Somatostatin) RH - releasing hormone IH - inhibitory hormone ◦Tropic hormones affect the release of other hormones in the target tissue Hormones produced by the anterior pituitary: ◦TSH - thyroid stimulating hormone (secretion of thyroid hormone from thyroid gland) ◦ACTH - adrenocorticotropic hormone (secretion of hormones (cortisol) from adrenal cortex) ◦LH - luteinising hormone (ovulation and secretion of sex hormones) ◦PRL - prolactin (mammary gland development and milk secretion) ◦GH - growth hormone (growth and energy metabolism, Stimulates IGFs (Insulin-like growth factors)) Negative feedback: ◦The pathways by which hypothalamic and anterior pituitary hormones are produced are often regulated by negative feedback ◦Short loop or long loop negative feedback pathways  Example - The hypothalamic pituitary adrenal axis: Endocrine control of growth: Growth hormone: ◦Produced in the anterior pituitary: ‣ Stimulated by hypothalamic GHRH ‣ Inhibited by hypothalamic somatostatin ◦Protein hormone (191 aa) has signal peptide that must be cleaved before proper folding ◦Growth-promoting effects mainly exerted indirectly via insulin-like growth factors (somatomedins) ◦In response to GH cells of the liver and skeletal muscle produce and secrete IGFs GH is essential for normal growth during childhood and teenage years: ◦GH stimulates long bone growth ‣ Length and wider prior to epiphyseal closure ‣ Width after epiphyseal closure ◦IGFs stimulate both bone and cartilage growth ◦In adults: ‣ GH and IGFs help maintain muscle and bone mass and promote healing and tissue repair as well as modulating metabolism and body composition Control of GH secretion: ◦Principle control is via the hypothalamus ‣ GHRH -> increases GH secretion ‣ Somatostatin -> decreases GH secretion ◦CNS regulates GH secretion via inputs into the hypothalamus effecting GHRH and somatostatin ◦GH secretion is regulated by long loop and short loop and negative feedback ◦Long loop negative feedback: ‣ Mediated by IGFs:  Inhibit release of GHRH from hypothalamus Stimulates the release of somatostatin from hypothalamus Inhibit release of GH from anterior pituitary ◦Short loop negative feedback - mediated by GH itself via stimulation of somatostatin release Growth hormone deficiency: ◦In childhood, results in pituitary dwarfism ◦Proportionate type of dwarfism ◦Complete or partial deficiency ◦Both types respond to GH therapy ◦Height below 3rd percentile on standard growth charts ◦Growth rate slower than expected for age ◦Delayed or no sexual development during teen years Growth hormone excess: ◦In childhood, results in GIANTISM ‣ Rare (~3 cases per 10,000,000 people) ‣ Often caused by pituitary adenoma ◦In adulthood, leads to acromegaly: ‣ Literally means large extremities: Hands Feet Lower jaw How does GH exert its effects on cells?: ◦GH receptors activate Janus kinases (JAKs) Insulin-like growth factors (IGFs): ◦2 IGFs in mammals (IGF1 and IGF2) ‣ IGF2 mainly involved in foetal growth ‣ IGF1 major growth factor in adults ◦Binding proteins modulate their availability in the blood ◦Actions of IGFs can be paracrine and autocrine as well as endocrine ◦IGFs act through IGF receptors (distinct from GH receptors) to modulate: ‣ Cell growth (hypertrophy) ‣ Cell number (hyperplasia) ‣ Increase in the rate of protein synthesis ‣ Increase in the rate of lipolysis in adipose tissue  Other hormones also influence growth: