BL2 Biochemistry of Hypothalamic & Pituitary Hormones

• Hypothalamus

  • Integrates functions that maintain chemical and temperature homeostasis
  • Functions with the limbic system
  • Controls the release of hormones from the anterior and posterior pituitary
• Hypothalamic neuropeptides

  Hypothalamic releasing factors
• Releasing factors

  Neurosecretions synthesized in the hypothalamus and released through the hypothalamic pituitary portal circulation<|>Have their effect on the secretion of pituitary tropic hormones

  
• Hypothalamic neuropeptides


  • Produced by supraoptic and paraventricular nuclei of the hypothalamus
  • Neurohormones = ADH & Oxytoxin
  • Precursors are long polypeptides
  • Synthesised in hypothalamus
  • Cleaved into the active molecule and then transported to the posterior pituitary and stored
  • Released to bloodstream by exocytosis

  
• Antidiuretic hormone (ADH)


  Also called vasopressin<|>Arginine vasopressin – lysine vasopressin
• Functions of ADH

  • Prevents diuresis
  • Reduces urine output
  • Acts on distal convoluted tubules producing reabsorption of water
• Mechanism of action of ADH

  1. Binds membrane receptor and activates adenylate cyclase – cAMP mediated signalling

  2. Proteins of microtubules and microfilaments are phosphorylated
• Regulation of ADH secretion

  ↓ osmolality (haemodilution) suppresses ADH secretion<|>↑ osmality (dehydration or haemoconcentration) stimulates ADH secretion
• Aquaporins


  Responsible for the reabsorption of water from kidney tubules under the effect of ADH<|>Eight different types of isoforms located at different sites along PCT, HL and CD
• Nephrogenic diabetes insipidus


  Low levels of expression of aquaporins<|>Mutant proteins also result in defective water reabsorption
• Deficiency of ADH

  • Diabetes insipidus – excretion of large volumes of dilute urine
  • Hypernatremia and hypertonic contraction of extracellular fluid volume (very rare)
• Excess secretion of ADH

  • Due to ectopic production of ADH by malignant tumors – SIADH (Syndrome of inappropriate secretion of ADH)
  • Hyponatremia, Euvolaemia, hypotonic expansion of extracellular volume
  • Water intoxication (headache, confusion, anorexia, nausea, vomiting, coma and convulsions
  • Impaired urinary dilutions
• Oxytocin


  'to stimulate birth'<|>Acts on estrogen primed uterus<|>Pitocin – synthetic derivative used to induce labor<|>Has effects on mammary gland<|>Suckling generates neurogenic reflex, which stimulates the production of oxytocin<|>It causes contraction of the myoepithelial cells expelling the milk into milk ducts from the acini
• Hypothalamic releasing factors

  • The secretion of hormones by adenohypophysis or anterior pituitary is under the control of peptides secreted by hypothalamus
  • Several peptides have effects on anterior pituitary, either stimulant (releasing factors), or inhibitory
  • The secretion of hypothalamic peptides are also under the feedback control of anterior pituitary tropic hormones (short loop feedback) as well as the target gland hormones (long loop feedback)
• Major hypothalamic releasing factors

  • Thyrotopin releasing hormone (TRH) - Tripeptide - Induces secretion of TSH and PRL, Neuromodulator
  • Gonadotropin releasing hormone (GnRH) - Decapeptide (Active part) - Releases LH and FSH, induces spermatogenesis, ovulation and testosterone
  • Growth hormone releasing hormone (GHRH) - 37-44 amino acid - Stimulates growth hormone secretion
  • Corticotropin releasing factor (CRF) - 41 amino acids - Release of ACTH, inhibited by cortisol
  • Somatostatin, Growth hormone inhibitory factor - 14 amino acids - Inhibits secretion of GH and TSH, inhibits gut hormones, pancreatic and gastric secretion
  • Prolactin inhibitory factor (PIF) - Dopamine - Inhibits PRL release
• Hormones of Anterior Pituitary

  • The anterior pituitary hormones are tropic in nature
  • Stimulates the secretion of hormones from target organs
  • Secretions of all these hormones are under the control of hypothalamic releasing or inhibitory factors

  
• Anterior Pituitary Hormones

  • Follicle Stimulating hormone (FSH)
  • Leutinizing hormone (LH)
  • Adrenocorticotrophic hormone (ACTH)
  • Thyroid Stimulating hormone (TSH)
  • Melanocyte Stimulating hormone (MSH)
  • Prolactin (PRL)
  • Endorphins (E)
  • Growth Hormone (GH)

  
• Follicle Stimulating Hormone (FSH)


  Gonatropin secreted by gonadotrophes of anterior pituitary gland<|>Secreted under the effect of gonadotropin releasing hormone (GnRH)<|>Regulates the development, growth, pubertal maturation, and reproductive process of the body<|>Stimulates the growth of ovarian follicles in females and spermatogenesis (Sertoli cells) in males

  
• Raised levels of FSH

  • Primary gonadal failure
  • Ovarian or testicular agenesis
  • Castration
  • Klinefelter's syndrome
  • Alcoholism
  • Menopause
  • Orchitis
  • Gonadotropin secreting pituitary tumors
• Decreased levels of FSH

  • Anterior pituitary hypofunction
  • Hypothalamic disorders
  • Pregnancy
  • Anorexia nervosa
  • Polycystic ovary disease
  • Haemochromatosis
  • Sickle cell anaemia
  • Hyperprolactinaemia
• Luteinizing Hormone (LH)

  Gonatropin secreted by gonadotrophes of anterior pituitary gland<|>Secreted under the effect of gonadotropin releasing hormone (GnRH)<|>Puberty does not set in until the pulsatile secretion of LHRH is started by hypothalamus<|>Testosterone in males (secreted by Leydig interstitial cells) and progesterone in females (secreted by corpus luteum) are increased under the influence of LH<|>Ovulation occurs as a result of positive feedback effect of oestrogen producing the preovulatory LH surge
• Raised LH

  • Primary gonadal dysfunction
  • Polycystic ovary syndrome
  • Postmenopausal women
  • Pituitary adenoma

  
• Decreased LH


  • Pituitary hypothalamic impairment
  • Kallman's syndrome with anosmia
  • Anorexia nervosa
  • Severe illness
• Gonadotropin production

  Under feedback control by the sex hormones<|>In postmenopausal women FSH and LH levels are high due to the lack of this feedback control
• Factors that increase ACTH

  • Pain, cold exposure, acute hypoglycaemia, trauma, depression and surgery
• Mechanism of action of ACTH

  1. ACTH binds to specific receptors on the adrenal gland, then activates adenylate cyclase and so, cAMP level is raised

  2. ACTH induces adrenocortical steroidogenesis through the melanocortin-2 receptor

  3. Steroid hormones inturn cause feedback inhibition of HPA
• Cosyntropin stimulation test (Rapid ACTH) test


  With rapid administration of ACTH blood cortisol level is raised<|>In adrenal insufficiency, adrenal gland cannot be stimulated by the ACTH administration, so
• ACTH


  Adrenocorticotropic hormone, released from pituitary in a pulsatile manner with definite diurnal rhythm, secretion highest in the early morning and minimum at midnight
• ACTH pattern of secretion

  Reflected in cortisol also
• Factors that increase ACTH

  • Pain
  • Cold exposure
  • Acute hypoglycaemia
  • Trauma
  • Depression
  • Surgery
• ACTH action

  1. Binds to specific receptors on the adrenal gland

  2. Activates adenylate cyclase

  3. Raises cAMP level

  4. Induces adrenocortical steroidogenesis through the melanocortin-2 receptor
• Cosyntropin stimulation test (Rapid ACTH) test


  With rapid administration of ACTH, blood cortisol level is raised<|>In adrenal insufficiency, adrenal gland cannot be stimulated by the ACTH administration, so subnormal or low response of cortisol occurs
• Dexamethasone Suppression Test


  An analog of cortisol<|>Suppresses ACTH hormone and cortisol production in normal subjects<|>Does not suppress ACTH hormone and cortisol production in patients with Cushing's syndrome
• ACTH secreting tumors of pituitary


  Cause Cushing's disease
• Deficiency of ACTH secretion


  May occur as a part of panhypopituitarism
• TSH

  Thyroid stimulating hormone, increases the secretion of thyroid hormones by stimulating all the steps of production of synthesis of thyroxine<|>Acts through cAMP by binding with a receptor on thyroid cell surface
• Regulation of TSH

  1. Stimulated by TRH

  2. Inhibited by PIF

  3. Also controlled by the level of thyroid hormones
• High levels of TSH

  • Primary hypothyroidism
  • Lack of feedback control
  • Hashimoto's thyroiditis
  • Ectopic secretion by tumors (lung, breast)
  • Thyroid hormone resistance
• Decreased levels of TSH

  • Primary hyperthyroidism
  • Secondary hypothyroidism (pituitary origin)
  • Tertiary hypothyroidism (hypothalamic)
  • Subclinical hyperthyroidism (toxic multinodular goitre, exogenous thyroid hormone administration, autonomous thyroid hormone secretion)
  • Euthyroid sick syndrome
• Melanocyte Stimulating Hormones (MSH)


  Small peptides derived from the precursor prohormone proopiomelanocortin (POMC), which also gives rise to ACTH<|>There are three MSH molecules: α-MSH, β-MSH, and γ-MSH<|>cAMP mediated hormone action<|>Involved in the production of melanin pigment and in the neural regulation of feeding and anti-inflammation