Pituitary hormones

The hormones of the anterior pituitary are under the control of hypothalamic hormones. The pituitary secretes hormones from the anterior and posterior lobes.

1. Anterior pituitary hormones: 6 major hormones are secreted by the anterior pituitary - FSH, LH, TSH, ACTH, GH and prolactin. TSH, FSH and LH are glycoproteins. Placental HCG is structurally similar to TSH, FSH and LH. ACTH, MSH, beta lipotropin and beta endorphin are derived from the same precursor molecule pro-opiomelanocortin. For this reason ACTH has properties similar to MSH and can lead to hyperpigmentation in Addison’s disease when ACTH is elevated.

   1. Growth hormone: It is synthesized by the somatotrophs in the anterior pituitary. Somatotrophs are the most abundant cell population in the adult pituitary gland. GH is secreted in a pulsatile fashion. Secretion is increased during sleep, hypoglycemia, by ghrelin, at puberty, arginine, exercise, stress, trauma, etc. Secretion is decreased in old age, obesity, glucagon etc.

      Regulation of GH secretion: GHRH or GH releasing hormone of the hypothalamus increases GH secretion by activating a G protein coupled receptor resulting in increased cAMP, IP3 and Ca++. GH secretion is inhibited by hypothalamic hormone somatostatin that activates Gi protein to cause a decrease in cAMP. GH secretion shows three negative feedback mechanisms. GHRH inhibits its own secretion. Somatomedins or Insulin-like Growth Factor I (IGF-I) inhibits GH secretion by a negative loop at both hypothalamic and pituitary levels. Both GH and somatomedins stimulate somatostatin secretion, which then inhibits GH secretion. Estrogens, androgens and ghrelin stimulate GH release.

      GH actions: GH acts both directly through its own receptors and indirectly through the induced production of IGF-I. GH receptors are present in many tissues including fat, lymphocytes, liver, muscle, heart, kidney, brain and pancreas. Activation of receptor-associated Janus kinase (JAK)-2 is the critical step in initiating GH signaling. Phosphorylated residues on GHR and JAK2 form docking sites for different signaling molecules including signal transducers and activators of transcription (STATs). STATs then translocate to the nucleus where they bind to DNA and activate gene transcription. Cytokine-inducible suppressors of cytokine signaling (SOCS) suppress GH signaling by inhibiting JAK2 activity and competing with STAT.

      GH stimulates synthesis of a peptide IGF-I in the liver and many other target tissues. Following the binding of the IGF-I molecule, its receptor undergoes a conformational change which activates tyrosine kinase, leading to auto-phosphorylation of tyrosine. The activated receptor phosphorylates IRS-2, which in turn activates the RAS activating protein SOS. This complex activates the MAPK or MAP kinase pathway leading to the stimulation of cell growth.

      GH stimulates lipolysis and promotes insulin resistance. It increases blood glucose levels. GH stimulates protein synthesis both directly and mediated through IGF-I, insulin or lipid intermediates. IGF 1 is responsible for growth promoting action of GH. It leads to increased organ and muscle size, increased linear growth and increased anabolic activity.

   2. Prolactin: It is synthesized by lactotrophs in the anterior pituitary. Prolactin is also produced in smaller amounts by other tissues such as the brain and pregnant uterus. Production is increased in pregnancy and lactation.

      Regulation of prolactin secretion: Prolactin secretion is inhibited by dopamine while it is stimulated by TRH or thyrotropin releasing hormone, estrogen , suckling, dopamine antagonists (antipsychotics), stress, and sleep. Prolactin inhibits its own secretion by stimulating the release of dopamine. Dopamine agonists like bromocriptine inhibit prolactin secretion.

      Prolactin actions: Prolactin receptor is a type-I cytokine receptor that signals predominantly via the JAK2-STAT5 signaling pathway similar to growth hormone receptor. During pregnancy the mammary gland undergoes extensive ductal side-branching and alveolar budding evolving to a milk-secreting gland. Prolactin contributes to both proliferation and differentiation of mammary tissue. Prolactin stimulates the production and secretion of milk. Prolactin levels are high during pregnancy but lactation is inhibited by high levels of estrogen and progesterone. Prolactin inhibits ovulation by inhibiting the release of GnRH or gonadotrophin from the hypothalamus. Prolactin has other effects like proliferation of pancreatic beta cells, T cell activation and tumorigenesis.

2. Posterior pituitary hormones: Antidiuretic hormone or ADH, also called vasopressin, and oxytocin are synthesized in the hypothalamus and secreted by nerve terminals in the posterior pituitary gland.

   1. ADH, antidiuretic hormone or vasopressin or arginine vasopressin:** It is mainly produced by magnocellular neurons within the supraoptic nucleus of the hypothalamus. It has dual functions of osmotic and cardiovascular homeostasis.

      Regulation of ADH secretion: Release of ADH is stimulated by hyperosmolarity of the plasma which activates osmoreceptors in the hypothalamus. ADH is also secreted in times of hypovolemia or volume contraction. Cardiovascular effect is coordinated by inputs from the baroreceptors travelling via the vagus nerve to the CNS and relaying to the paraventricular and supraoptic nuclei of the hypothalamus. Angiotensin II, pain, nausea, hypoglycemia, nicotine and opiates stimulate ADH secretion. It is inhibited by hypo-osmolarity of the plasma, ethanol, alpha-adrenergic agonists, atrial natriuretic peptide and hypervolemic states.

      Actions: The actions of vasopressin (ADH) are mediated by stimulation of tissue-specific G-protein-coupled receptors (GPCR) which are classified into V1 vascular , V2 renal , V3 pituitary and P2 purinergic receptors. Vasopressin’s signal is transmitted through both Gs and Gq, leading to increased levels of cAMP and IP3 and Ca++ respectively. Gq also activates the transcription factor nuclear factor-κB.

      V1 are found in high density on vascular smooth muscle and cause vasoconstriction by an increase in intracellular calcium. Platelets also express V1, which upon stimulation induces an increase in intracellular calcium, facilitating thrombosis. V1 receptors are also found in the kidney, where they occur in high density on medullary interstitial cells, vasa recta and epithelial cells of the collecting duct. Vasopressin acts on medullary vasculature through V1 to reduce blood flow to the inner medulla without affecting blood flow to outer medulla. Additionally, vasopressin selectively contracts efferent arterioles acting through V1 receptor thus increasing GFR.

Antidiuretic effect of vasopressin occurs via activation of the V2 receptor located at the basolateral membrane of the late distal tubule and collecting ducts. V2 activates Gs protein leading to rise in intracellular cAMP. The increased intracellular cAMP in the kidney in turn triggers fusion of aquaporin-2-bearing vesicles with the luminal plasma membrane of the principal cells, increasing water reabsorption.

1. Oxytocin: It is produced mainly by the paraventricular nucleus of the hypothalamus. Similar to ADH, it is released by nerve terminals into the posterior pituitary upon stimulation.

   Regulation of oxytocin secretion: Suckling, sight, smell or sound of the infant, dilation of the cervix are all excitatory stimuli for oxytocin release. Opioids inhibit oxytocin release.

   Actions of oxytocin: The oxytocin receptor is widely distributed and is present not only on the myoepithelial cells surrounding the mammary ducts and uterine myometrium but also in the olfactory processing regions of the brain, limbic system and brainstem. Oxytocin receptors act through Gq leading to rise in intracellular Ca++. Oxytocin leads to milk ejection in lactating mothers by stimulating myoepithelial cells around the alveoli of the mammary glands. This is called “milk letdown” as the milk already produced and stored under the action of prolactin is ejected by contraction caused by oxytocin. Oxytocin also causes contraction of uterine smooth muscle and may play a role in the initiation of labor. Oxytocin receptors are present in both the myometrium and parietal decidua of pregnant women. Oxytocin binding in decidua could mediate the stimulation of prostaglandin synthesis that would enhance the oxytocin-induced contractions of the myometrium. It has been postulated that oxytocin is involved in a wide array of social behaviors like maternal bonding, social decision-making and processing of social stimuli and social memory.