• Overview: thyrotropin-releasing hormone,TRH
  • Tripeptide
  • Location: hypothalamus (and other brain regions)
  • TRH ® portal venous system ® pituitary stimulation ®thyroid-stimulating hormone (TSH, thyrotropic) production ®thyroid-stimulation and release ® thyroxine (T4) & triiodothyronine
  • TRH stimulation of thyrotropin:
    • blocked by thyroxine
    • enhanced by thyroxine deficiency

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• Chemistry/pharmacokinetics: TRH
  • Glu-His-Pro-NH₂
  • IV administration
  • plasma half-life: 4-5 minutes

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• Pharmacodynamics:TRH
  • Hyperthyroidism: serum thyrotropin level reduced
  • Primary hypothyroidism:
    • thyrotropin levels: high
    • enhanced thyrotropin response to TRH
  • Secondary (pituitary) hypothyroidism:
    • thyrotropin serum levels: low (by sensitive TSH assay) or "inappropriately normal"
    • TSH often does not increase after TRH
  • Tertiary (hypothalamic) hypothyroidism:
    • serum thyrotropin levels: normal or low
    • thyrotropin response to TRH: normal or attenuated
  • TRH infusion:
    • ­ increased prolactin released by the pituitary
    • no effect on growth hormone or ACTH
    •  Pituitary tumors:
      • some pituitary tumors:
        1.  release growth hormone in response to TRH (acromegaly)
        2.  release ACTH in response to TRH (Cushing's disease)
        3.  failure to release prolactin (prolactinoma).

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Thyroid-Stimulating Hormone (Thyrotropin, TSH)

• Overview:thyrotropin, TSH
  • Anterior pituitary hormone
  • Thyroid function regulation -- stimulation of thyroxine & triiodothyronine production and release

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• Chemistry:thyrotropin, TSH
  • consists of two peptides (a and b) with associated carbohydrate side chains
  • Therapeutic thyrotropin:
    • source -- bovine anterior pituitaries
    • homology between bovine & human peptides: 70% (a) & 90% (b).
    • TSH-b subunit provides thyroid specificity since TSH-a subunit is nearly identical to a subunit of FSH, LH, hCG.

• Pharmacokinetics:thyrotropin, TSH
  • Route of Administration:
    • intramuscular
    • subcutaneous
  • half-life: one-hour
  • renal degradation
• Pharmacodynamics:thyrotropin, TSH
  • Thyrotropin ® ­ thyroid cell adenylyl cyclase activation ® ­ increased cyclic AMP production® ­ increased iodine uptake ® ­increased thyroid hormone production

• Clinical Use:thyrotropin, TSH
  • Diagnostic/therapeutic:
    • possible diagnostic use in a metastatic thyroid carcinoma
    • bovine TSH: top toxic for therapeutic stimulation of radioactive iodine for treatment of metastatic thyroid carcinoma

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 Corticotropin-Releasing Hormone (CRH)

• Overview:corticotropin-releasing hormone,CRH
  • hypothalamic hormone;
  • stimulates ACTH & b-endorphins pituitary release.
• Chemistry:corticotropin-releasing hormone, CRH
  • Human CRH: 41-amino acid peptide

• Pharmacokinetics:corticotropin-releasing hormone, CRH
  • Route of Administration: IV
  • serum half-life (first phase): approximately nine minutes
  • widely metabolized; < 1% excreted unchanged in the urine
• Pharmacodynamics:corticotropin-releasing hormone, CRH
  • Diagnostic use only:
    • Cushing's syndrome -- distinguishing between Cushing's disease and ectopic ACTH secretion-- limited usefulness;

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Adrenocorticotropin (corticotropin, ACTH, ACTH_1-24 )

• Overview:ACTH
  • peptide hormone;
  • synthesis site: anterior pituitary
  • Major endocrine function: stimulation of cortisol synthesis & release from adrenal cortices
  • Synthetic corticotropin-derivative use clinically to assess adrenocortical status
    •  reduced adrenocortical response to corticotropin administration® adrenocortical insufficiency

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• Chemistry:ACTH
  • single 39-amino acid peptide
    • amino acids 1-24: required for full biological activity
    • amino acids 25-39: species specificity
  • Synthetic, human ACTH_1-24: cosyntropin
  • Amino terminal sequence (1-13): identical to melanocyte-stimulating hormone (a-MSH)
    •  with excess ACTH pituitary secretion hyperpigmentation due to a-MSH activity due to ACTH

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• Pharmacokinetics:ACTH
  • Porcine & synthetic corticotropin: well absorbed following intramuscular administration
  • Corticotropin: no oral administration due to GI proteolysis
  • half-life: < 20 minutes
  • Tissue concentration: in liver & kidney

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• Pharmacodynamics: ACTH
  • ACTH stimulates adrenal cortex to produce glucocorticoid, mineralocorticoid, & androgen.
  • ACTH increases cholesteryl esters activity ( cholesterol ® pregnenolone step: rate-limiting in steroid hormone production)
  • ACTH promotes adrenal hypertrophy & hyperplasia
  • corticotropin may cause increased in skin pigmentation

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• Clinical Use:ACTH
  • ACTH adrenal stimulation: inadequate response in adrenal-insufficiency
  • Cosyntropin may be used rule out adrenal-insufficiency
    • following cosyntropin, plasma cortisol should exceed 18 ug/dL
      •  subnormal response: ® primary or secondary adrenocortical insufficiency
      •  Primary adrenocortical insufficiency: increased endogenous plasma ACTH levels
      •  Secondary adrenocortical insufficiency: decreased endogenous plasma ACTH levels
  • Differentiation of "late-onset" (non-classic) congenital adrenal hyperplasia from states of ovarian hyperandrogenism
    •  21-hydroxylase deficiency: ACTH stimulation ® incremental increase in plasma 17-hydroxyprogesterone (substrate for the deficient enzyme)
    •  11-hydroxylase deficiency: ACTH stimulation ®increase 11-deoxycortisol
    •  3-b-hydroxy-D 5 steroid dehydrogenase deficiency: ACTH stimulation® increase in 17-hydroxypregnenolone
  • Therapeutics: corticotropin -- no advantage over direct glucocorticoid administration

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