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Hypothalamus and the Pituitary Gland EPK Objectives Describe the anatomic connections between the hypothalamus and the pituitary gland and the functional significance of each connection. Name the hypophysiotropic hormones, and outline the effects that each has an anterior pituitary function. Describe the synthesis, processing, storage, and secretion of the hormones of the posterior pituitary. Objectives Discuss the effects of vasopressin, the receptors on which it acts, and how its secretion is regulated. Discuss the effects of oxytocin, the receptors on which it acts, and how its secretion is regulated. Hypothalamus and pituitary Pituitary gland Anatomy Anatomy Pituitary lies in the sella turcica of sphenoid bone below hypothalamus at base of brain Blood supply is from the superior and inferior hypophyseal arteries There is a portal system from the median eminence Pituitary has two lobes the anterior and the posterior Anterior pituitary Traditionally cells are divided into chromophobes and chromophils Chromophobes contain and secrete IL6 Chromophils are further divided into basophils and acidophils Acidophils secrete GH and Prolactin while basophils secrete ACTH, TSH, LH, and FSH Posterior pituitary-histology Post lobe: endings of SON and PVN can be observed in close relation to the blood vessels Pituicytes (modified asrocytes) are also present Hypothalamus and pituitary This consortium forms the most complex and dominant portion of entire endocrine system Output of this unit regulates the function of the thyroid gland, adrenal gland and also shares in control of somatic growth, lactation, milk secretion and water metabolism Hypothalamic function Plays a key role in the regulation of pituitary function It receives afferents from ◦ ◦ ◦ ◦ ◦ Thalamus reticular formation Limbic system Eyes Neocortex Neuroendocrine roles 2 hormones ADH and oxytocin are synthesised in the hypothalamus,stored and secreted by posterior pituitary A group of tropic hormones are synthesised, stored and released by anterior pituitary A set of releasing and inhibiting hormones are synthesised in the hypothalamus, travel to ant. Pituitary to regulate the synthesis and secretion of these tropic hormones cntd Close connections with the ANS allow coordination btwn ANS and pituitary function Therefore pituitary function can be influenced by pain, sleep, emotion, light and possibly thought HP axis is under the influence of blood borne substances and neural input Hypophysiotropic hormones These are hormones secreted by the hypothalamus which influence pituitary function They are either releasing or inhibiting factors The hormones include CRH, TRH, GHRH, GnRH, Dopamine, serotonin Anterior pituitary is exposed to higher concentration of these hormones than blood Most are peptides except dopamine It was once believed that each factor was responsible for release of one pitiutary hormone. However, this is not the case TRH increases prolactin release and somatostatin can inhibit release of TSH in addition to GH Dopamine (PIF) inhibit prolactin secretion Hypothalamic Pituitary Axis Posterior Pituitary Post Pituitary It is responsible for secretion of vasopressin and oxytocin These are nonapeptides or octapeptides depending on whether cysteine or cystine is considered The structures of the two hormones are similar, with 2 different amino acid residues They are synthesised in the hypothalamus Post Pituitary Vasopressin is synthesised mainly in the SON and oxytocin is synthesised mainly in the PVN, although both nuclei produce each hormone Due to the similarity in structure vasopressin has 20% of the activity of oxytocin and oxytocin has 0.5% to 1% of the activity of vasopressin Arginine vasopressin and oxytocin What would happen to the secretion of posterior pituitary hormones if there was transection of the connection between the hypothalamus and pituitary gland? Arginine vasopressin(ADH) Basically involved in the regulation of water balance and blood pressure Acts on 3 receptors V1a, V1b(V3) and V2 V2 is through the mediation of cAMP and V1 (IP3 and DAG) Physiological effects of ADH Increases permeability of collecting ducts to water Increases urea reabsorption in the inner medullary collecting duct Increase sodium absorption in TAL by activating the NaK-2 Cl transporter Physiological effects of ADH Vasoconstriction Increases glycogenolysis in the liver Depresses the cardiovascular centres Increases ACTH secretion from corticotrophes Increases synthesis of factor VIII and vWF Increasing permeability of collecting ducts to water Through V2 receptors(cAMP) Involves insertion of water channels in the luminal membrane known as aquaporins There are several types of aquaporins: 1, 2, 3, 6 and 7 are found in the kidney, 4 in the brain and 5 in salivary glands Vasopressin acts to increase the concentration of aquaporin 2 on membranes Stimuli which increase the secretion of vasopressin Increased osmotic pressure of plasma Decreased ECF volume(at least 20 %), (via cardiopulmonary receptors) Angiotensin II, Pain, emotion,stress Stimuli which increase the secretion of vasopressin include Nausea and vomiting Standing, Adrenergic stimuli Nicotine, Morphine, Carbamazepine Exercise Factor decreasing secretion Decreased effective osmotic pressure Increased ECF volume Alcohol Parasympathetic innervation Stretching of the atrial baroreceptors Atrial natriuretic peptide Clonidine Haloperidol Clinical Correlates Excess ADH leads to SIADH Insufficient ADH leads to Diabetes Insipidus Syndrome of Inappropriate ADH secretion (SIADH) Due to inappropriately elevated ADH that cause water retention in excess of Na+ Excess water causes dilutional hyponatremia Causes of SIADH Malignancy eg lung , gastrointestinal,renal Trauma –head injury , post surgery Cerebrum diseases eg infections like meningitis Stimulation of volume receptors like in artificial ventilation Drug induced eg thiazides,chlorpropamide Infections eg pneumonia (SIADH) Diseases in the lung also decrease tonic inhibition of ADH secretion leading to an increase in ADH secretion This will result in hyponatremia Excessive ECF volume will be lowered by the ‘escape phenomenon’ It is treated using demeclocycline Features of the syndrome Hyponatremia (Na+ < 135 mmol/L) Hypotonicity ( osmolality <280moSm/kg ) Urine osmolality (>100moSm/kg) Increased urinary Na+ excretion(>40mmol/L) Diabetes Insipidus Is due to deficient secretion of ADH The symptoms are polyuria and polydipsia It can be neurogenic or nephrogenic Nephrogenic DI One interesting form of this condition is inherited X – Linked receessive Gene for V2 is located on the X chromosome It can also be due to lithium or hypercalcemia oy hypokalemia It does not respond to desmopressin (a vasopressin analogue) It can be treated using thiazide diuretics Nephrogenic DI It can be treated using thiazide diuretics How do thiazides act??? Oxytocin Is derived from oxy- meaning rapid and tocia meaning labour Acts on oxytocin receptors(PLC) which uses Ca ++ as a second messenger Actions of Oxytocin On the mammary gland: it is important for the milk let down reflex Augmentation of labour by increasing uterine contractions Ejaculation in males May be involved in luteolysis May be responsible for propulsion of sperms in the female during or after intercourse In pharmacological doses can cause transient vasodilation Secretion can be increased by Suckling Stimulation of female external genitalia and cervix Thought of the baby, (tender thoughts) Cervical dilatation Pregnancy Progesterone decreases synthesis of oxytocin receptors Towards labour estrogen increases the synthesis of oxytocin receptors in the myometrium Side effects of oxytocin overdose Water intoxication Neonatal jaundice Uterine overstimulation-uterine rupture Hypotension (transient) Secretion decreased by Pain or physical discomfort Breast feeding under embarrassing circumstances Fear and anger Clinical correlates Deficiency of this hormone has no known problems Anterior Pituitary Hormones secreted by the gland appear to divide into 3 groups A) ACTH Related peptides e.g. ACTH, B endorphin, B Lipotropin , B MSH B) Glycoproteins eg FSH, TSH and LH C) Somatomammotropins Glycoproteins They have two subunits an alpha and beta Alpha subunits are identical or closely similar and they do not have biological activity Beta chains confer hormone specificity Beta chains alone have little biological activity c) Somatomammotropins Prolactin GH Growth Hormone GH Secreted by somatomammotrophs of pituitary Wide range of metabolic activity which may involve every type of cell Some of its effects are mediated by somatomedins GH release is controlled by GHRH and GHIH (somatostatin) GH secretion rate reflects Metabolic requirements (decreased glucose, increased Aas) Neural factors (eg stress, circadian rhythms) Structure Gene for GH is on chr 17 hGH has intrinsic lactogenic activity GH is bound to a protein in plasma that is a large fragment of EC domain of receptors Concentration of fragment is an index of number of GH receptor in the tissues About half of GH is protein bound and the T1/2 is 6 – 20 mins Effects of GH In liver ◦ ◦ ◦ ◦ ◦ ◦ ◦ RNA synthesis is increased Increased protein synthesis Increased gluconeogenesis, glycogenolysis Increased somatomedin In Adipose tissue Decreased glucose uptake Increased lipolysis; hence decreased adiposity In Muscle Decreased glucose uptake Increased amino acid uptake Increased protein synthesis Anti insulin effect in muscle Increased lean body mass Increased calcium absorption in Gastrointestinal tract and decreased sodium and potassium excretion in kidney Somatomedins Polypeptide growth factors secreted by liver and other tissues Principal circulation somatomedins are - IGF I (somatomedin C) - IGF II They are closely related to insulin but C chains are not separated Somatomedins (cont.) There are 6 binding proteins IGF I is mainly bound to IGFBP 3 (95%). GH increases synthesis of this protein The protein directs IGF to their specific receptors IGF receptor is similar to that of insulin IGFs are essential for embyronic development Effects of Somatomedins Increase protein sythesis Increase RNA synthesis Increase DNA synthesis Increase cell size and number This leads to increased organ size and function Effects on chrondrocytes Increased amino acid uptake Increase protein synthesis Increase RNA synthesis Increase DNA synthesis Increase collagen Increase chrondoiton sulfate Increase cell size and number This increases linear growth Other effects of Somatomedins Stimulate neuronal survival Stimulate myelin synthesis Control of GH release Stimulation ◦ ◦ ◦ ◦ ◦ Glucose and free fatty acid decrease Increase in amino acids Fasting and prolonged caloric deprivation Deep sleep Exercise Cntd Estrogens and androgens Dopamine and serotonin Alpha adrenergic agonists Enkephalins Stress (due to pain, surgery, psychogenic) Inhibition Glucose increase Free fatty acid increase Cortisol Obesity Pregnancy Somatostatin hGH Control of GH secretion Physiology of growth Growth is a complex process It is also affected by thyroid hormones, insulin, glucocorticoids, nutrition and genetic factors Role of nutrition Food supply is the most important extrinsic factor affecting growth A diet should be adequate in proteins, vitamins and calories Fasting and protein deprivation decreases IGF secretion Age at which deficiency occurs is of importance Growth Periods In humans there are two periods of rapid growth which are i) Infancy and ii) Late puberty before growth stops The 2nd growth spurt is due to GH, sex hormones, and cessation of growth due to closure of epiphyses Sex hormones increase spikes of IGF I release In infants there is episodic growth Thyroid hormones are critical during this period Thyroid hormones potentiate the action of IGF I and are permissive to the effects of GH. They are necessary for normal GH secretion Insulin is also important for growth. When deficient, IGF I secretion is decreased Adrenocortical hormones other than androgens have a permissive effect on growth However, Glucocorticoid treatment can slow or stop growth in children Catch Up Growth In periods of severe stress like illnesses children do not grow They will be below the expected averages compared to peers of the same age They will, after they recover, experience a period of growth which is greater than average to catch up with their peers – catch up growth Short Stature Short stature can be due to i) GHRH deficiency ii) GH deficiency iii) Deficient secretion of IGF I iv) Other causes Isolated GH deficiency is usually due to deficient GHRH Laron Dwarfs Is due to GH insensitivity due to loss of function mutation in the receptor The plasma IGF I and IGFBP 3 are decreased, while the concentration of GH is either normal or increased African Pygmies They have a normal GH level and a modest decrease in plasma level of GHBP Plasma [IGF I] fails to increase at the time of puberty However, they experience less growth than non pygmy controls throughout the pre pubertal period Explanation for short stature is still unsettled Other Causes of short stature Cretinism Precocious Puberty Gonadal dysgenesis (Turner’s Syndrome) Chronic abuse and neglect can cause dwarfism (Psychosocial dwarfism – Kasper Hauser Syndrome) Achondroplasia Achondroplasia It is the most common form of dwarfism in humans It is characterised by short limbs and a normal trunk It is inherited Autosomal Dominant with complete penetranc It is due to a mutation that codes for fibroblast growth factor receptor 3 (FGFR3) Achondroplasia Prolactin Prolactin Is a hormone principally concerned with stimulating breast development and milk production It is secreted by acidophils and it has receptors which resemble those for GH It is unique in that it is under predominant inhibition from the hypothalamus by dopamine Control of Secretion Secretion is stimulated by ◦ ◦ ◦ ◦ ◦ ◦ Sleep Nursing Breast stimulation in non lactating women Stress Hypoglycemia Exercise cntd Pregnancy TRH (hypothyroidism) Estrogens Sexual intercourse in women Histamine antagonists (H2) eg cimetidine -Dopamine antagonists Factors decreasing secretion Dopamine L Dopa Apomorphine Bromocriptine and related ergot derivatives Prolactin Effects of Prolactin Stimulating breast development (done in concert with other hormones like estrogens, progesterone, cortisol, GH) Causes milk production secretion from breast after estrogen and progesterone priming (increases synthesis of casein and lactalbumin) Inhibits action of gonadotropins Effects of prolactin dysfunction In women prolactin deficiency produces an inability to lactate Hypersecretion of prolactin causes hyperprolactenemia Hyperprolactinemia Is caused by chromophobe adenoma, damage to pituitary stalk and tumors secreting prolactin It is characterised by ◦ ◦ ◦ ◦ Loss of menses, decreased libido Anovulation Infertility and less often Galactorrhea (lactation unassociated with pregnancy). Gynecomastia is uncommon Excessive production of GH Leads to either gigantism or acromegaly Gigantism occurs when there is an excessive secretion before epiphyses close and acromegaly occurs after epiphyseal closure Is usually due to microadenomas of the GH secreting cells in the pituitary Acromegaly-features Enlarged hands and feet (spade like hands) Prognathism,coarse facial features, bulbous nose, prominent bony ridges Hirsutism -Gynecomastia and lactation Osteoarthritic vertebral changes Visual field changes (bitemporal hemianopia) Carpal tunnel syndrome Glucose intolerance Proximal myopathy Cardiac failure (and also ischemia) B MSH, B Lipotropin Function of B lipotrophin is unsettled but it may be for mobilisation of fats MSH is important for skin pigmentation It increases synthesis of melanin It is under the control of hypothalamus via MIF ACTH can also cause skin pigmentation Pituitary Hyperfunction Acromegaly Cushing’s Syndrome (Nelson’s syndrome – tumors secreting ACTH) Hyperprolactenemia Tumors secreting other anterior pituitary hormones are rare Pituitary Insufficiency It is usually caused by tumors of anterior pituitary and suprasellar cysts Pituitary infarction can also lead to pituitary insufficiency (Sheehan’s syndrome, hemorrhagic fevers) Clinical Features It is characterised by ◦ ◦ ◦ ◦ ◦ Growth inhibition Hypothyroidism Hypogonadism Inability to cope with stress Pallor Other Anterior Pituitary Hormones Regulate the function of peripheral glands i) TSH – thyroid gland ii) ACTH – adrenal cortex iii) Gonadotropins – Gonads These will be covered in subsequent lectures Thank You