Drugs and the Treatment of Pituitary Disease

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Drugs and the Treatment of Pituitary Disease

• Joe Collier

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Aims

• The session will describe
• how drugs can modify pituitary function,
• how drugs can be used to treat patients with
  abnormal circulating blood levels of
• prolactin, growth hormone, testosterone,
  oestrogen and vasopressin.
• Key pharmacodynamic and pharmacokinetic
  properties of the drugs will be reviewed, as will
  the main unwanted effects

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• At the end of the session you should be able to
  describe
• how drugs are used to treat patients with
  abnormal circulating blood levels of prolactin,
  growth hormone, testosterone, oestrogen and
  vasopressin.
• the actions of dopamine agonists
  (bromocriptine), growth hormone and its analogue
  (somatropin) gonadorelin analogues (goserelin),
  somatostatin analogues (octreotide), oestrogen
  receptor antagonists (clomiphene) and
  carbamazepine and the vasopressin analogues
  desmopressin, explaining, where possible, the
  pharmacokinetics of these drugs.
• briefly their interactions and unwanted effects
  and the principles of their use.

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Effects of circulating prolactin

• Prolactin is a 198 amino acid single chain
  polypeptide released from the anterior pituitary.
  
• normal (physiological) properties initiation and
  maintenance of lactation (effects on breast
  tissue balanced by oestrogen)
• pathophysiological effects (as in
  hyperprolactinaemia)
• infertility (amenorrhoea, anovulatory cycles or
  sperm motility problems, reduced semen volume)
• lack of libido
• galactorrhoea
• gynaecomastia

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Control of Prolactin Release

• Primarily through an inhibitory (braking) system
  whereby dopamine released by the hypothalamus
  inhibits prolactin release from the anterior
  pituitary.
• There is also probably a prolactin releasing
  factor released by the hypothalamus which
  promotes prolactin release from the anterior
  pituitary.

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Causes of hyperprolactinaemia

• Anything that reduces dopamine inhibition
• (hypothalamic disease)
• (stalk section)
• inhibitors of dopamine production or release
• methyl dopa
• reserpine
• inhibitors of dopamine receptors
• antipsychotics (haloperidol, chlorpromazine etc)
• metoclopramide
• (pituitary tumour)

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Reducing Prolactin Levels

• Stop dopamine antagonist
• Give dopamine agonist such as bromocriptine (used
  for inhibiting lactation in women not wishing to
  breast feed). Unwanted effects are dose-dependent
  eg nausea, vomiting, hypotension, stroke,
  confusion, dyskinetic movements.
• Give stilboestrol to potentiate the negative
  oestrogen effect (post partum). The drug must be
  started straight after birth. The risks include
  increased thromboembolism and uterine bleeding.

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Pituitary Growth hormone (GH)

• 191 amino acid single chain polypeptide
  synthetic derivative known as somatropin.
• Control. GH release is regulated by hypothalamic
  
• Growth Hormone-Releasing Factor (GHRF synthetic
  derivative known as sermorelin)
• Growth Hormone-Release-Inhibiting Factor (GHRIF
  or somatostatin synthetic derivative known as
  octreotide)
• Dopamine which inhibits release

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Treating GH Deficiency

• This uses somatropin, produced by recombinant DNA
  technology, with the same amino acid sequence as
  naturally occurring GH, is given by subcutaneous
  or im injection.
• Uses
• Children somatropin is given to those with
  pituitary insufficiency and reduced growth
• In adults somatropin is given to those with
  Turner syndrome and (sometimes) those with GH-
  deficiency syndromes (lassitude, muscle weakness,
  heart failure, diminished bone density). The
  place of GH in adult deficiency syndromes is not
  yet established.

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Drug treatment of excess growth hormone secretion

• Bromocriptine (orally up to four times daily,
  which acts as a dopamine receptor stimulant and
  so inhibits GH release. Doses higher than used in
  suppression of lactation and unwanted effects
  more pronounced tolerance to these develops
  with repeated exposure.

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Drug treatment of excess growth hormone secretion

• Octreotide. This is a synthetic somatostatin
  given by im or subcutaneous injection three times
  daily (reserved for those in whom surgery or
  bromocriptine are unsuccessful or inappropriate).
  A new depot formulation of octreotide for im
  injection (Sandostatin LAR) needs to be given
  only monthly.

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Treatment of low levels of testosterone

• Secondary to hypothalamic disease
• GnRH (gonadorelin) subcutaneuosly in pulsed doses
  
• Secondary to pituitary disease
• Human chorionic gonadotrophin (this has LH
  activity).
• Primary testicular failure testosterone
• oral capsules (twice daily, unpredictable),
• im injections (every three weeks),
• subdermal implants (every 4-6 months)
• skin patches (predicatable, once daily).

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Treatment to lower testosterone

• Give synthetic GnRH (gonadorelin) such as
  goserelin as a subcutaneous injection once
  monthly. This initially stimulates LH release
  from the pituitary, then after 2-3weeks,
  inhibits LH release due to receptor
  desensitisation. NB The initial LH release gives
  a testosterone burst (flare) which might need to
  be blocked by a testosterone receptor antagonist
  such as flutamide.

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Oestrogen

• Physiological control. Oestrogen is synthesised
  in the ovary in response to follicular
  stimulating hormone (FSH) and luteinising
  hormone(LH) released from the anterior pituitary.
  These are synthesised in response to hypothalamic
  Gonadotrophin-Releasing Hormone (GnRH
  gonadorelin). Circulating oestrogen levels
  inhibit gonadorelin release.

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Oestrogen

• Raising the levels of LH and FSH so stimulating
  ovulation
• Give a central oestrogen receptor blocker such as
  the stilboestrol analogue clomiphene (taken
  orally for 5 days).Lowering the levels of
  oestrogens (as for example in endometriosis or
  breast cancer). Give a synthetic gonadorelin such
  as goserelin.

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Vasopressin (anti diuretic hormone ADH)

• A nonapeptide synthesised in the hypothalamus and
  subsequently secreted from the posterior
  pituitary in response to increased blood osmotic
  pressure.
• Pharmacological properties of vasopressin
• increases permeability of the collecting ducts to
  water so causing water retention (reabsorption).
• vasoconstriction (arteries, arterioles
  venules).
• increases gut motility. Note that its effects on
  vessels and tubule are about equal.

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Diabetes insipidus treatment

• Desmopressin (desamino-8-D-arginine vasopressin -
  ADH activityvasoconstrictor activity 30001)
• Desmopressin is destroyed in the gut and has a
  half-life of 75min. Give as nasal instillation,
  spray or subcutaneous injection 2-3 times daily.
• Additional approaches Chlorpropamide (increases
  renal sensitivity to ADH), carbamazepine
  (potentiates release of ADH from pituitary)
  bendrofluazide (paradoxically effects renal
  tubules to cause water retention).