Medical Pharmacology Chapter 28:  Physiology and Pharmacology: Adrenocorticosteroids / Adrenocortical Antagonists

Adrenocortical Hyperfunction

• Congenital adrenal hyperplasia

  • "Hyperplastic adrenals and poorly developed ovaries, uterine tubes and uterus in a female child with congenital adrenal hyperplasia"; KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

  • Caused by cortisol synthetic defects

    • Autosomal recessive mutations

  • Most common adrenal disorder of childhood and infancy

  • Late-onset adrenal hyperplasia cause:

    • 5%-25% of hirsuitism and oligomenorrhea cases in women

    • Pregnancy at risk for congenital adrenal hyperplasia:

      • Dexamethasone administration to the mother is protective.

  • Most common deficiency:

    •  Decrease or lack of cytochrome P450c21 (21ß hydroxylase) activity {95% frequency) which results in:

      • Cortisol synthesis reduction

      • Compensatory increase of ACTH release

    • Other deficiencies:

      • P450c18, P450c17_a , P450c11_ß, 3ß- hydroxysteroid dehydrogenase

    • Increased compensatory ACTH can result in normal cortisol levels if sufficient P450c21 activity is present; however the gland will:

      • Become hyperplastic

      • Produce excessive precursors such as 17-hydroxyprogesterone -- diverted to androgen pathways-- leading to virilization.

      • Diagnosis:

        • Excessive 17-hydroxyprogesterone is metabolized in the liver to pregnanetriol, detected in large amounts in the urine.

        • Most reliable detection: increased plasma 17-hydroxyprogesterone to ACTH stimulation

    • Physiological consequences:

      • Female:

        • Adrenal virilization associated with:

          1. Ambiguous external genitalia (female pseudohermaphroditism)

          2. Enlargement of the clitoris

          3. Partial/complete labial fusion

          4. Urogenital sinus (possible)

      • Male: enlarged genitalia

      • Postnatal period:

        • Female virilization

        • Isosexual prococity in the male

        • Excessive androgen levels:

          • Accelerated growth

          • Early epiphyseal closure; growth stops --truncal development continues-- (short child with well-developed trunk.

      • 11-hydroxylation defects:

        •  Excessive desoxycorticosterone production: hypertension

      • 17-hydroxylation defects:

        •  Adrenal and gonadal defects increased 11-desoxycorticosterone levels-- mineralocorticoid excess signs/symptoms:

          1. Hypertension

          2. Hypokalemia

    • Infant with congenital adrenal hyperplasia:  Presenting Symptoms

      • Treatment

        •  If acute adrenal crisis:

          1. IV cortisol

          2. Mineralocorticoid

          3. Electrolyte solutions

        • After stabilization:

          • Hydrocortisone (Cortef, Solu-Cortef)-- adjusted as required

          • Alternative: prednisone (Deltasone)

          • Mineralocorticoids may be required (fludrocortisone (Florinef))

1. Goldfien, A.,Adrenocorticosteroids and Adrenocortical Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 635-650.

2. Williams, G. H and Dluhy, R. G. , Diseases of the Adrenal Cortex, 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 2035-2056