Corticotropin-Releasing Hormone (CRH)

• Overview:  corticotropin-releasing hormone,CRH

  • Hypothalamic hormone;

  • Stimulates ACTH and 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:

    • Distinguishing between Cushing's disease and ectopic ACTH secretion  (limited usefulness)

 

Adrenocorticotropin (corticotropin, ACTH, ACTH_1-24 )

• Overview:  ACTH

  • Peptide hormone;

  • Synthesis site: anterior pituitary

  • Major endocrine function: stimulation of cortisol synthesis and release from adrenal cortices

  • Synthetic corticotropin-derivative use clinically to assess adrenocortical status

    • Reduced adrenocortical response to corticotropin administration:  adrenocortical insufficiency

• 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

• Pharmacokinetics:  ACTH

  • Porcine and synthetic corticotropin: well absorbed following intramuscular administration

  • Corticotropin: no oral administration due to GI proteolysis

  • half-life: < 20 minutes

  • Tissue concentration: in liver and kidney

• Pharmacodynamics:  ACTH

  • ACTH stimulates adrenal cortex to produce glucocorticoid, mineralocorticoid, and androgen.

  • ACTH increases cholesteryl esters activity ( cholesterol:  pregnenolone step: rate-limiting in steroid hormone production)

  • ACTH promotes adrenal hypertrophy and hyperplasia

  • Corticotropin may cause increased in skin pigmentation

• Clinical Use:  ACTH

  • ACTH adrenal stimulation: inadequate response in adrenal-insufficiency

  • Cosyntropin may be used rule out adrenal-insufficiency

  • 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:  increased 11-deoxycortisol

    •  3-β-hydroxy-D 5 steroid dehydrogenase deficiency: ACTH stimulation:  increase in 17-hydroxypregnenolone

  • Therapeutics: corticotropin:  no advantage over direct glucocorticoid administration

Primary Reference: Fitzgerald, P.A. and Klonoff, D.C. Hypothalamic and Pituitary Hormones, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 603-618.

Primary Reference: Biller, Beverly M. K. and Daniels, Gilbert, H. Neuroendocrine Regulation and Diseases of the Anterior Pituitary and Hypothalamus, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1972-1998