Pituitary and Hypothalamic Hormones

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Pituitary and Hypothalamic Hormones

• DR.FAROOQ ALAM
• M.B.B.S-M.Phil

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Introduction

• Most pituitary and hypothalamic hormone are
  trophic hormones. This and other factors limit
  their use as drugs.
• Exceptions growth hormone and gonadotropins

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Growth HormoneGH or Somatotropin

• Chemistry a single chain polypeptide.
• Significant differences in amino acid sequence
  between humans and other species prevent use of
  non-human hormone

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Growth Hormone

• Physiological actions
• Mechanism GH receptor stimulation activates an
  intracellular tyrosine kinase, JAK2(Janus kinase2
  is a human protein that has been implicated in
  singling by members of the type 2 cytokines),
  resulting in phosphorylation of proteins and gene
  regulation.

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• Growth almost all body tissues stimulated to
  grow
• ? synthesis of chondroitin and collagen
• ? skeletal growth
• ? soft tissue growth
• Nitrogen metabolism increased nitrogen
  retention, amino acid transport into tissues, and
  incorporation into protein. Urinary retention of
  nitrogen, potassium, phosphate

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Growth Hormone

• Physiological actions
• Carbohydrate and lipid metabolism GH appears to
  promote use of lipids as energy source instead of
  carbohydrates
• GH has a diabetogenic effect in diabetics
• Conserves muscle at the expense of fat during
  stress
• Insulin-like growth factor (IGF, somatomedins)
  peptides produced by liver and other tissues in
  response to GH appear to mediate many GH
  effects. rhIGF-1 (mecasermin, Increlix) now
  available for treatment of growth failure in
  GH-resistant patients

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Growth hormone pathology

• Hypersecretion Þ
• Gigantism in children
• Acromegaly in adults
• progressive enlargement of head, face, hands,
  feet, thorax heat intolerance, sweating,
  fatigue, lethargy
• Deficiency Þ
• Postnatal growth retardation
• Congenital
• Acquired
• Adult GH deficiency
• Adult-onset pituitary/hypothalamic disease,
  surgery, radiation therapy, or trauma

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Growth Hormone

• Clinical applications one of the few pituitary
  hormones with long-term therapeutic utility.
  Recombinant human growth hormone (rh-GH) is used
  clinically. There are two forms, somatotropin
  and somatrem.
• Hypopituitary dwarfism in children with
  insufficient GH secretion, GH will generally
  produce an increased growth rate over several
  years. Recently, FDA approved use in children
  with idiopathic, non-GH-deficient short stature.

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Growth Hormone

• Clinical applications
• Treatment of AIDS associated wasting
• Treatment of adult onset growth hormone
  deficiency
• Turners syndrome(a genetic defect in woemen in
  which there is only one X chromosome)
• Anti-aging supplements OTC(Over the counter)
  supplements which suggest they contain hGH.
  Contain amino acids that are supposed to release
  GH.

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Growth Hormone

• Problems associated with therapy possibility of
  intracranial hypertension and visual changes
  exist, so fundoscopic exams needed.
• Also possibility of type 2 diabetes and
  respiratory difficulties in patients with obesity
  or sleep apnea due to Prader-Willi syndrome.
• Possible contamination of human-derived GH with
  Creutzfeldt-Jakob virus.

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Growth Hormone

• Acromegaly hypersecretion of GH may result in
  acromegaly.
• Octreotide (Sandostatin) or other somatostatin
  analogs are most commonly used to decrease GH
  secretion.
• Dopamine agonists such as bromocryptine will
  inhibit GH secretion from some GH secreting
  tumors.
• Pegvisomant (Somavert), a GH receptor
  antagonist, is now available to treat acromegaly
  in patients who have not responded to other
  treatment. Pegvisomant prevents GH stimulation
  of IGF(Insulin like growth factor).

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Gonadotropins

• Luteinizing hormone (LH, interstitial cell
  stimulating hormone)
• Chemistry glycoprotein hormone with 2 peptide
  chains.
• Physiological actions
• Mechanism of action Specific G protein-coupled
  receptors, activation of adenylate cyclase(Gs)
• Ovary promotes ovulation and luteinization of
  ovarian follicles stimulates synthesis and
  secretion of estrogen and progesterone from
  corpus luteum.
• Testis stimulate interstitial (leydig) cells to
  secrete androgens(Testosterone)

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Figure 56-4. The hypothalamic-pituitary-gonadol
axis A single hypothalamic releasing factor,
gonadotropin-releasing hormone (GnRH), controls
the synthesis and release of both gonadotropins
(LH and FSH) in males and females. Gonadal
steroid hormones (androgens, estrogens, and
progesterone) cause feedback inhibition at the
level of the pituitary and the hypothalamus. The
pre-ovulatory surge of estrogen also can exert a
stimulatory effect at the level of the pituitary
and the hypothalamus. Inhibin, a polypeptide
hormone produced by the gonads, specifically
inhibits FSH production by the pituitary.
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Gonadotropins

• Luteinizing hormone
• Clinical application
• Infertility menotropins (a mixture of urinary
  LH and FSH) and chorionic gonadotropin have been
  used to induce ovulation. Recombinant human LH
  lutropin alpha (Luveris) is now available.
• Hyperstimulation of ovary may occur
• May also increase fertility in men
• Kits available to predict time of ovulation by
  measuring urinary LH

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Gonadotropins

• Follicle stimulating hormone (FSH)
• Chemistry glycoprotein with 2 peptide chains.
  Agents available are recombinant human FSH,
  follitropin (Gonal-F and Follistim), and urinary
  human FSH, urofollitropin
• Physiological actions of FSH
• Mechanism activates Gs
• Ovary promote follicular development

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• Testis FSH stimulates production of
  androgen-binding globulin
• maintains high testosterone levels in the
  seminiferous tubules required for spermatogenesis
• stimulate testicular growth
• Clinical application promote Induce ovulation
  for treatment of infertility

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Adverse effects

• Ovarian stimulation
• Multiple births
• Ovarian hyper-stimulation syndrome (OHSS)
• Increase in vascular permeability Þ rapid fluid
  accumulation in the peritoneal cavity, thorax,
  pericardium
• Monitor patient closely during and after
  treatment, when symptoms may peak
• If ovaries become abnormally enlarged during
  gonadotropin treatment, hCG is not
  administered

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Gonadotropins Diagnostic uses

• Leydig cell failure - stimulation test with CG
• No testosterone response indicates primary
  failure
• Normal testosterone response indicates secondary
  or tertiary disease

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Prolactin - PRL

• Chemistry single chain polypeptide hormone
• Physiological actions
• Binds to a specific receptor, similar to GHR
• Primary target mammary gland
• development during pregnancy
• induces milk protein synthesis
• initiates and maintains lactation
• Lactation causes growth and development of
  breasts, and increased synthesis of milk proteins
• Decreases release or effectiveness of
  gonadotropins

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Hypersecretion hyperprolactinemia may cause
galactorrhea, amenorrhea and infertility.
hypoprolactinemia extremely rare. Not used
clinically Bromocriptine, pergolide (Permax),
and cabergoline (Dostinex) are useful in
suppressing PRL secreting tumors. Secretion
inhibited by dopamine
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Hyperprolactinemia

• Inhibits pulsatile GnRH secretion
• Þ hypogonadism
• Female luteal phase is shortened Þ
• anovulation, oligomonorrhea, amenorrhea
• Male testosterone synthesis ß
• spermatogenesis ß
• Treatment of hyperprolactinemia
• Transphenoidal microsurgery Microadenoma
  s - 85 long term remission
• Macroadenomas - outcome less satisfactory

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Dopamine agonists for GH or prolactin
hypersecretion

• Given orally
• Adverse effects
• nausea, vomiting, dizziness, postural
  hypotension
• Start at reduced doses to minimize adverse
  effects
• Paradoxical inhibitory effect on GH secretion
• Somatroph adenomas express receptor
  characteristics of lactotrophs
• Most useful for GH hypersecretion when prolactin
  secretion also is elevated
• Cabergoline is more effective than bromocriptine
• Normalizes IGF-I in 35 of patients

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Thyrotropin (TSH)

• Chemistry glycoprotein with 2 polypeptide
  chains. Thyrotropin alpha, human recombinant
  TSH, is used clinically.
• Physiological actions Receptor stimulation
  activates Gs which increases function of thyroid
  gland
• Increases uptake of iodine by thyroid, synthesis
  and release of hormone, and growth of gland.

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Thyrotropin (TSH)

• Clinical application
• Increases uptake of radioactive iodine. Used as
  a diagnostic tool for serum thyroglobulin testing
  or whole body scanning in the follow-up of
  patients with thyroid cancer.

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Corticotropin(Adrenal cortex trophic hormone,
ACTH)

• Chemistry natural hormone is a single chain
  polypeptide of 39 amino acids. A synthetic form
  containing amino acids 1-24 is available.
• Physiological actions stimulates adrenal cortex
  to synthesize and secrete cortisol,
  corticosterone, and aldosterone (slightly).
  Prevents atrophy of adrenal cortex.
• Mechanism receptor interaction results in
  activation of adenylate cyclase and synthesis of
  cAMP. cAMP activates enzymes involved in steroid
  synthesis.

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AdrenoCorticotropin hormone, ACTH)

• Clinical use
• Diagnosis of adrenal insufficiency
• Treatment of infantile spasms (epilepsy)

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Hypothalamic Hormones

• Peptides synthesized in hypothalamus and
  transported to the anterior pituitary via portal
  circulation
• Gonadotropin releasing hormone and analogs
  drugs available include Gonadorelin (natural
  hormone) and
• Long-acting analogs histrelin (Suprelin),
  leuprolide (Leupron), gosrelin (Zoladex),
  triptoreline (Trelstar), and nafareline
  (Synarel).
• Gonadorelin is used for induction of ovulation.
• Long acting analogs are used for treatment of
  PMS(post menopausal symptoms), endometriosis,
  prostate cancer, and central precocious(Well
  before time) puberty. Experimental use as male
  contraceptive.

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Hypothalamic Hormones

• Gonadotropin releasing hormone (GnRH or LHRH)
  antagonists ganirelix (Antagon) and cetrorelix
  (Cetrotide)
• Used to inhibit premature endogenous LH(FSH)
  surges during treatment with exogenous
  menotropins for induction of ovulation.
• Also abarelix (Plenaxis) a GnRH receptor
  antagonist used to treat advanced prostate
  cancer. Danger of life-threatening allergic
  reactions in 4 of patients.
• Also used for cryptorchidism(Testis fail to
  descend in scrotum), hypogonadism, and delayed
  puberty

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GnRH Adverse effects

• Long acting agonists induce symptoms of
  hypogonadism, including detrimental effects on
  bone mineralization and lipids

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GnRH Diagnostic uses

• Secondary vs. tertiary hypogonadism
• Stimulation tests- 100 µg infused i.v. over a
  period of 15 seconds
• Plasma LH and FSH measured at 0, 30, 60, and 90
  minutes
• LH should increase 1.3 to 2.6 µg/L
• FSH response is less marked
• Long-standing hypothalamic disease and GnRH
  deficiency may cause lack of LH responsiveness in
  the absence of pituitary disease requires
  prolonged or intermittent stimulation for a valid
  assessment

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Somatostatin (somatotropin release-inhibiting
factor, SRIF)

• Secreted by hypothalamic anterior region and by d
  cells of the pancreatic islets
• Secretion ? by GH, IGF-I, thyroid hormones
• Synthetic analogue Octreotide
• Properties
• More potent at inhibiting GH secretion than
  native SRIF
• Less potent at inhibiting insulin secretion
• Increased half-life 1.7 hours (SRIF 1 to 3
  minutes)
• Resistant to enzymatic degradation- D-Phe, D-Trp
• Rebound hypersecretion lower than for SRIF
• Sustained-release form recently approved for use

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Somatostatin and octeriotide

• Actions
• Inhibits GH secretion but not its synthesis
• Inhibits basal and TRH-stimulated TSH secretion
• Inhibits secretion of GI peptide hormones
• insulin, glucagon, VIP, gastrin, and others
• Mechanism of action
• Gi protein-coupled receptors
• Reduces cAMP production and Ca2

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Clinical uses

• Acromegaly
• For excess GH secretion by somatrope adenomas
  that remains or recurs after irradiation or
  surgery
• Does not induce hyperglycemia
• Carcinoid tumors
• Intestinal tumors, may secrete physiologically
  active substances (5-HT, prostaglandins, etc.)
• Pancreatic cell tumors (VIPomas)
• diarrhea, achlorhydria

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Adverse effects

• Reduction of bile production, gallbladder
  contractility
• ? biliary sludge and/or gallstones
• GI disturbances
• Pain, nausea, diarrhea

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Hypothalamic Hormones

• Somatostatin(somatotropin Release-Inhibiting
  Hormone,SRIF) an analog, octreotide acetate
  (Sandostatin) used to treat acromegaly,
  carcinoid, and VIP secreting tumors. Long acting
  form now available (once per month).
• Growth hormone releasing hormone Semorelin
  (Geref), a synthetic form of GHRH, has been
  approved for treatment of GH deficiency. Will
  only work in patients with functioning pituitary.

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Vasopressinarginine vasopressin (AVP)
antidiuretic hormone (ADH)

• Clinical preparations
• synthetic arginine vasopressin (human form)
• desmopressin (1-deamino-8-D-arginine
  vasopressin, DDAVP), synthetic analog with
  longer duration of action and selective
  activity for renal effects

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Vasopressin secretion

• Stimulated by
• Increasing extracellular fluid osmolality
• Falling blood pressure
• Decreased extracellular fluid volume without
  change in osmolality (as in hemorrhage)
• The renin-angiotensin II system

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Vasopressin secretion

• Other stimulatory factors
• acetylcholine cholecystokinin prostaglandins
• histamine neuropeptide Y
• dopamine substance P
• glutamine VIP
• Inhibitory factors
• stress atrial natriuretic factor (ANF)
• pain GABA
• hypoxia opioid peptides nausea

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AVP secretion Pharmacological agents

• Stimulators
• nicotine
• epinephrine
• vincristine (antimitotic)
• cyclophosphamide (antineoplastic agent)
• morphine (at high doses)
• tricyclic antidepressants
• imipramine
• lithium
• Stimulates secretion but inhibits renal response

• Inhibitors
• ethanol
• glucocorticoids
• phenytoin
• morphine (at low doses)
• butorphanol, oxilorphan (K agonists)
• antipsychotics
• tricyclic phenothiazines
• chlorpromazine
• butyrophenones haloperidol

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Vasopressin Clinical uses

• Treatment of central Diabetes Insipidus
• reduced water permeability and polyuria
• Causes of DI
• AVP deficiency
• Central neurogenic pituitary D.I.
• May be congenital or acquired
• Impaired renal response to AVP
• nephrogenic D.I.

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Vasopressin Clinical uses

• Replacement therapy for central DI
• Use desmopressin
• V2 effects much greater than V1 effects
• 10 µg once or twice a day using aqueous
  solution as metered nasal spray
• or
• 1 to 2 µg once or twice a day s.c.

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Vasopressin Clinical uses

• G.I. Applications
• Based on V1-mediated contraction of GI smooth
  muscle for post-operative ileus and to dispel
  intestinal gas before abdominal imaging
• Based on V1-mediated contraction of vascular
  smooth muscle for emergency treatment of
  bleeding esophageal varices (varicose veins) and
  for acute hemorrhagic gastritis
• DDAVP is not appropriate for these uses.

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Vasopressin Clinical uses

• Diagnostic To differentiate central and
  nephrogenic D.I.
• Challenge with 1 µg desmopressin s.c., i.m., or
  i.v. following water deprivation
• One hour after treatment, urine osmolality
  should increase gt 50 if cause is AVP deficiency

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Vasopressin Adverse effects

• Primarily a result of unwanted V1 effects
• constriction of blood vessels
• coronary vessels
• stimulation of GI muscle
• Cross-reaction with the oxytocin receptor
• stimulation of uterine muscle
• Adverse effects rare
• V2-mediated effects at lower doses than
  V1-mediated effects

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Syndrome of Inappropriate ADH Secretion (SIADH)

• Impaired water excretion in the presence of
  hyponatremia and hypoosmolality
• Hypotonicity may produce lethargy, anorexia,
  nausea and vomiting, muscle cramps may
  eventually lead to coma, convulsions, and death
• From inappropriately high secretion of AVP/ADH
• Ectopic malignant neoplasms
• CNS trauma and infections
• Endocrine disease
• Drug interaction

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Syndrome of Inappropriate ADH Secretion (SIADH)

• Treatment
• water restriction
• i.v. hypertonic saline
• loop diuretics such as furosemide
• demeclocycline, 1 to 2 g/day orally
• reduces renal sensitivity to AVP
• nephrotoxic monitor renal function

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Oxytocin

• Differs from AVP in only two amino acids
• Synthetic oxytocin is used clinically
• By hypothalamic oxytocinergic neurons
• In response to neural stimulation
• Parturition (distention of the cervix and
  vagina)
• Suckling
• Stimulated by plasma hypertonicity, hemorrhage

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Action and mechanism of action

• Specific G protein-coupled receptors
• ? frequency and force of uterine smooth muscle
  contraction during parturition
• ? contraction of mammary myoepithelial cells and
  milk ejection
• Half-life 5 to 12 minutes

• OT receptor binding
• ß
• phospholipase C
• ß
• IP3, Ca2
• ß
• contraction of uterine smooth muscle and mammary
  myoepithelial cells

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Oxytocin Clinical uses

• Induction of term labor drug of choice
• Infused as dilute solution at 10 mU/mL
• Begin at a rate of 1 mU/minute
• Increase gradually to 4 mU/minute
• Maintain for 1 hour before increasing rate
• Monitor uterine activity, fetal heart rate
• Adverse effects
• Uterine rupture
• Trauma or death to the infant
• Risks minimized by conservative protocol

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Oxytocin Clinical uses

• Control of postpartum bleeding
• Administered to maintain uterine tone
• For increasing milk ejection
• Administered as a nasal spray
• 2 to 3 minutes before breast-feeding
• Oxytocin challenge test
• For uteroplacental insufficiency
• OT infused at 0.5 mU/minute initially
• Rate increased until uterine contractions
• (once every 3 - 4 minutes)
• Fetal heart rate used as a measure of distress
• Indicates whether placental reserve is sufficient
  for continuation of a high-risk pregnancy