Pituitary Hormones

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Pituitary Hormones

• The pituitary is composed of the adenohyophysis
  (glandular or epithelial) and the
  neurohypophysis.
• Adenohypophysis, pars distalis, pars anterior
  derives from an inward invagination of oral
  ectoderm of the primitive mouth known as Rathkes
  pouch.
• Neurohypophysis, pars nervosa, posterior
  pituitary is the neural component which comes
  from neural ectoderm of the floor of the midbrain.

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Pituitary Hormones

• An infundibular process develops as a
  diverticulum of the floor of the diencephalon and
  increases in size due to neuroepithelial cell
  proliferation. Nerve fibers grow into the
  infundibulum from hypothalamic nuclei. These
  neuroepithelial cells differentiate into
  pituicytes.
• Cells of the anterior wall of Rathkes pouch
  proliferate to give rise to the anterior
  pituitary. Continued proliferation of these
  cells leads to reduction of the lumen of Rathkes
  pouch to a residual cleft and separation of cells
  of the posterior and anterior pituitary.

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Pituitary Hormones

• Cells adjacent to the infundibulum may
  proliferate to give rise to a pars intermedia,
  but not all species have a P.I. Or it regresses
  with age as in the human.
• Dorsal extensions of the anterior pituitary
  surround the infundibular stalk to make the pars
  tuberalis.
• Definitive pituitary in many species consists of
  the pars distalis, pars intermedia, pars
  tuberalis and the pars nervosa.

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Vascularization Innervation

• Pituitary gland receives its blood supply from
  the superior and inferior hypophyseal arteries.
  Anterior and posterior branches of the superior
  hypophyseal artery penetrate the hypophyseal
  stalk and hypothalamus.
• Pars nervosa receives a separate blood supply
  from the inferior hypophyseal artery. P.I. Is
  relatively avascular.

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Vascularization Innervation

• Except for neurovascular elements there is no
  evidence that neurons innervate or directly
  influence cells in the pars distalis.
• Pars nervosa is composed of axonal endings of
  neurons whose perikarya are located in
  hypothalamic nuclei, and in mammmals in the PVN
  and the SON.

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Cytology

• Cells of the pituitary are referred to as
  acidophils, basophils, or chromophobes.
• Cells of the pars distalis have differentiated
  into somatotrophs, lactotrophs, corticotrophs,,
  thryotrophs, and gondadotrophs.
• Extent to which a cell expresses acidophilia,
  basophilia, or chromophobia depends upon granular
  content of a cell. Except for sparse pituicytes,
  the pars nervosa contains only neuronal axonal
  endings.

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Cytology

• Nongranular, nonsecretory cells in the PA, PI,
  and PN are glial cells, stellate cells of
  follicular cells and separate one pituitary cell
  from contacting another. These cells may
  modulate pituitary hormone secretion in response
  to regulatory cues.
• Although each pituitary hormone is localized to a
  particular cell type, most gonadotrophs contain
  LH and FSH. But, subpopulations of gonadotrophs
  contain only 1 gonadotropin which may account for
  nonparallel release of FSH and LH to certain
  stimuli.

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Cytology

• Hormones of the pituitary can also be classified
  into 4 groups based upon structure similarity and
  origin. GH and Prl posses numerous similar
  sequences and are related to placental lactogen.
• TSH, FSH, LH are glycoproteins that share the a
  subunit and are related to hCG. a-melanotropin
  and ACTH contain a sequence of amino acids in
  common.

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Growth Hormone(somatotropin)

• GH is polypeptide of 191 a.a. made by
  somatotrophs and contains two disulfide bonds.
  It is very similar to Prl and is identical in 161
  a.a.
• GH is made as a prohormone and is cleaved to GH
  by proteolysis.
• GH circulates in the plasma bound to one or more
  binding proteins. Circulating levels of GH
  decrease 2-3 wks after birth and reach basal
  levels characteristic of adulthood.

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Growth Hormone

• GH remains constant during accelerated growth in
  early childhood but there is an increase during
  the maximal growth period around puberty.
• In all mammals studied so far, spontaneous
  episodes of GH occur several times over a 24 h
  period and most during the first 90 minutes of
  nocturnal sleep.
• GHRH from the hypothalamus and somatostatin
  control GH secretion.

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Growth Hormone

• GH is anabolic and enhances amino acid
  incorporation into muscle protein and stimulates
  collagen deposition and produces a concomitant
  decrease in blood urea nitrogen and amino acid
  levels.
• Effects of GH are mediated by somatomedins
  (IGFs) released from the liver in response to
  GH. They stimulate cellular growth in a number
  of organs and tissues.

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Growth Hormone

• Absence of GH leads to short stature and xs leads
  to acromegaly. Short stature may result from
  lack of GH or lack of response by the liver to GH
  (Laron dwarfism).
• Acromegalic effects of GH result from direct
  effects of GH on target tissues as well as
  effects through IGFs. Proliferation of
  connective tissue and interstitial fluid results
  in thickening of the skin and an increase in
  subcutaneous tissues.

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Growth Hormone

• Acromegalics may display increased BMR and
  lipolytic actions of GH combined with
  anti-insulin actions on other tissues, may result
  in hyperglycemia as a symptom of developing
  diabetes milletus.
• In young animals the epiphyses of long bones are
  separated from the shaft of bones by an
  epiphyseal cartilaginous plate. Chodrogenesis is
  accelerated by GH which results in widening of
  the epiphyseal plates as more chondroitin sulfate
  is made and released by chondrocytes. This is
  also used as a bioassay for GH.

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Prolactin

• Prl is a single chain polypeptide 23 kDa with 3
  disulfide bonds. Structural variants of Prl
  arise from differential splicing and CHO moieties
  vary among species.
• Serum Prl increases at puberty but only modestly
  compared to the rise in FSH/LH. E2 stimulates
  Prl secretion. Prl increases during pregnancy
  and reaches maximal values at parturition.

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Prolactin

• Production and secretion of Prl by lactotrophs is
  stimulated by E2. E2 increases mitotic activity
  and cell number of pituitary lactotrophs.
• Prl levels decrease by 3 wks in mothers that do
  not nurse. Concentrations of Prl in amniotic
  fluid exceed that found in serum.
• Mammotrophic action of Prl requires participation
  of E2, P4, insulin, glucocorticoids and GH. In
  ovx rabbits given E2 and P4 to induce
  lobuloalveolar growth, Prl was able to induce
  milk production.

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Prolactin

• Prl is luteotrophic in some mammals and may act
  in concert with LH and FSH on the CL to stimulate
  P4 biosynthesis and secretion.
• Prl has profound effects on the growth,
  differentiation and function of hair, sebaceous
  glands, and brood patch feathers.
• In pigeons and doves Prl controls the production
  of so-called crop sac milk. Epithelium of the
  walls of the crop thicken and cells accumulate
  lipid and begin to degenerate and form crop milk.

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Prolactin

• Hypophysectomy of adult rats causes loss of
  testicular LH receptors but inhibition of LH or
  FSH secretion form pituitary is not associated
  with a loss of LH receptors but inhibition of Prl
  is associated with loss of testicular LH
  receptors.
• Prl is secreted episodically and has a hlf life
  of 15 20 min in blood. There is also a
  nocturnal surge of Prl associated with sleep.

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Prolactin

• Most potent stimulus for Prl secretion is nursing
  mediated by cutaneous sensations arising from the
  breast and nipple in the female, not in the male.
• Secretion of Prl is under tonic inhibition by
  Prl-inhibiting factor (dopamine), however, Prl
  secretion in birds is under stimulatory control.
• Mammary alveolar cells have Prl receptors in the
  plasmalemma.

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Glycoprotein Hormones

• TSH, LH, and FSH contain covalently bound CHO
  moieties at one or more positions.
• Each is composed of an a subunit and a b subunit.
  The a subunits of the three glycoproteins within
  a species are identical and the b subunit is
  structurally distinct.

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Glycoprotein Hormones

• The a subunit is composed of 92 96 amino acids
  and is very similar among species, the b subunits
  are composed of 110-111 residues (FSH), 112-118
  residues (TSHs), 117-121 residues (LHs) or 145
  reisdues (hCG).
• The a and b subunits are independently
  synthesized, and each subunit has a separate mRNA
  species. Peptide component of the glycoproteins
  is synthesized first under genetic control and
  glycosylation is a post-ribosomal event that
  occurs in the Golgi.

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Glycoprotein Hormones

• CHO moities of the a subunit are needed for
  biological function. Specific removal of these
  without affecting the structure causes an
  uncoupling of the receptor-AC system in target
  cells.
• Removal of 70 75 of the CHO in gondaotropins
  leads to derivatives that bind to receptors but
  cannot stimulate AC. Deglycosylated
  gonadotropins can anatagonize action of the
  hormones.

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Glycoprotein Hormones

• It is suggested that the a subunit endows the b
  subunit with a confirmation necessary to bind to
  the receptor and the a subunit is necessary for
  AC activity.
• Hormonal specificity is conferred by the b
  subunit.

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Thyrotropin Stimulating Hormone

• TSH is synthesized within basophilic thyrotrophs
  of the pars distalis and its structure is known
  for many species.
• The number of secretory granules present in the
  thyrotrophs is decreased in animals treated with
  T4.
• TSHs most important role is the control of
  thyroid gland function. In amphibians it is
  responsible for metamorphosis and in mammals it
  is important for thermogenesis.

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Luteinizing Hormone

• Hypophysectomy leads to atrophy of the gonads and
  extracts of the pituitary causes a recurdesence
  of the gonads.
• Originally, two pituitary fractions possessing
  gonadotropic activity were obtained, one
  stimulated follicular growth of ovaries and
  increased spermatogenesis in the testes. This
  was referred to as follicle stimulating hormone
  (FSH).

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LH

• The other fraction stimulated CL formation and
  ovulation in the female and stimulated
  testosterone secretion and the 2o sex
  characteristics in males. This was termed LH.
• LH stimulates testosterone synthesis by Leydig
  cells of the testes but FSH must induce LH
  receptors first.

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LH

• LH indirectly stimulates spermatogenesis by
  increasing testosterone levels.
• In the female, LH causes ovulation and is
  necessary for initial development of the CL.

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Follicle Stimulating Hormone

• FSH is responsible for the early development of
  the ovarian follicle and the initial steps of
  spermatid maturation.
• In the male, FSH increases LH receptors on the
  Leydig cells and synthesizes androgen binding
  protein (ABP) from the Sertoli cells.
• FSH interacts with granulosa cells of developing
  follicles and its actions are mediated by cAMP.

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Pro-opiomelanocortin (POMC)

• bLPH was first discovered in the pars distalis
  but it wasnt realized that it is a component of
  an even larger precursor molecule known as POMC.
• Within POMC is the amino acid sequence of ACTH
  and other hormonal peptides.
• POMC precursor in the pituitary is cleaved to a
  16 kDa peptide and proopiocortin.
• Proopiocortin is immediately cleaved to ACTH (39
  residues) and bLPH (91 residues). This occurs in
  the PA and the PI.

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POMC

• Within the molecule of bLPH is the amino acid
  sequence of bMSH.
• The c-terminal 61 93 amino acids of bLPH is
  referred to as b-endorphin and is cleaved very
  fast in the intermediate lobe and slowly in the
  AP.
• bLPH is in turn cleaved to gLPH.

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POMC

• Met-enkephalin is cleaved from bLPH as well.
• In the pars distalis enzymes within the
  corticotrophs split ACTH from the precursor
  protein. In the PI, enzymes release aMSH and
  corticotropin like peptide (CLIP).
• Remaining components of POMC protein are released
  with ACTH or aMSH during vesicular exocytosis.
• ACTH and aMSH have similar sequences and each
  stimulates target tissues of the other hormone,
  melanocytes, and adrenals.

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ACTH

• In most mammals steroidal tissues surrounds the
  adrenal medulla to form the adrenal cortex.
• Hypox results in atrophy of the adrenal cortex.
  Pituitary extracts will restore the steroidogenic
  tissue.
• ACTH is synthesized within basophils of the pars
  distalis and are often chromophobic.
• ACTH is a single linear chain of 39 amino acids
  and structural differences are found in species
  in residues 24 33. The biological activity of
  ACTH resides in the invariant 1 24 sequence of
  the hormone.

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ACTH

• ACTH stimulates steroid biosynthesis within the
  adrenal and cortisol and corticosterone are the
  major glucocorticoids produced in response to
  ACTH.
• Excessive secretion of ACTH leads to Cushings
  disease characterized by excess cortisol and
  alterations of glucose metabolism.
• Absence of ACTH secretion results in Addisons
  disease characterized by decreased cortisol
  secretion.

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ACTH

• In primary Addisons disease and in Cushings
  syndrome of 2o origin where ACTH is secreted in
  excessive amounts, hyperpigmentation can occur
  because a heptapeptide of ACTH is an active
  sequence of aMSH.
• ACTH is also localized to certain neurons in the
  brain and may function as a neuropeptide in
  processes related to memory and learning.

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Melanocyte Stimulating Hormone

• a-MSH is a 13 amino acid protein made by the pars
  intermedia. Pituitary gland of the adult human
  lacks a PI and there is an absence of aMSH in the
  pituitary and plasma.
• aMSH is present in the pituitary of other
  vertebrates and plays a role in skin color.