Cortisol Regulation and Endogenous Hypercortisolism

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The hypothalamic-pituitary-adrenal (HPA) axis integrates physical, physiological, and psychosocial influences in order to adapt effectively to internal and external factors1

Normal HPA axis functioning includes feedback mechanisms2,3

  1. Hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland
  2. Pituitary gland subsequently secretes adrenocorticotropic hormone (ACTH), resulting in the activation of the adrenal glands
  3. Adrenal glands respond by releasing cortisol into the bloodstream
  4. Hypothalamus and pituitary can reduce the amount of CRH and ACTH, respectively, when there is an adequate amount of cortisol (negative feedback)

HPA axis

Cortisol secretion follows a diurnal rhythm

In healthy, day-working people, cortisol is at its highest level between 6 AM and 8 AM—tapering off during the day and reaching its trough toward midnight.4 This cyclic trough at night is necessary to restore and maintain homeostasis and to avoid development of pathologic conditions.4

Hormone dysregulation outside of the control of normal HPA axis function disrupts feedback influences and can result in hypercortisolism, otherwise known as Cushing syndrome2

ACTH dependent

Pituitary adenoma (Cushing Disease)

  • Secretion of ACTH by a pituitary tumor stimulates the adrenal glands to secrete excess cortisol

 

Ectopic tumor

  • Secretion of ACTH from an ectopic tumor stimulates the adrenal glands to secrete cortisol

 

Neither pituitary nor ectopic tumors require stimulation by CRH and are usually not sensitive to negative feedback. This leads to unchecked ACTH secretion, high cortisol levels, and loss of diurnal rhythm.

ACTH independent

Adrenal adenoma

  • Autonomous cortisol secretion independent of ACTH stimulation
  • Autonomous cortisol secretion from an adrenal adenoma will reduce ACTH levels

 


References:

  1. Herman JP, McKlveen JM, Ghosal S, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6(2):603-621.
  2. Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012;25(2):199-208.
  3. Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 2006;8(4):383-395.
  4. Chung S, Son GH, Kim K. Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. Biochim Biophys Acta. 2011;1812(5):581-591.

Important Safety Information IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING ON TERMINATION OF PREGNANCY.

BOXED WARNING: TERMINATION OF PREGNANCY

Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone and glucocorticoid (GR-II) receptors, respectively. The antiprogestational effects will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with Korlym and prevented during treatment and for one month after stopping treatment by the use of a nonhormonal medically acceptable method of contraception unless the patient has had a surgical sterilization, in which case no additional contraception is needed. Pregnancy must also be excluded if treatment is interrupted for more than 14 days in females of reproductive potential.

DOSAGE AND ADMINISTRATION

Administer once daily orally with a meal. The recommended starting dose is 300 mg once daily. Renal impairment: Do not exceed 600 mg once daily. Mild-to-moderate hepatic impairment: Do not exceed 600 mg once daily. Do not use in severe hepatic impairment. Based on clinical response and tolerability, the dose may be increased in 300-mg increments to a maximum of 1200 mg once daily. Do not exceed 20 mg/kg per day.

Concomitant use of Korlym with a strong CYP3A inhibitor resulted in a 38% increase in mean plasma concentration of mifepristone. For patients already being treated with a strong CYP3A inhibitor, start with a Korlym dose of 300 mg per day and titrate to a maximum of 600 mg per day if clinically indicated. When a strong CYP3A inhibitor is administered to patients already receiving Korlym, adjust the dose as follows: For patients receiving a daily dose of 600 mg, reduce the daily dose to 300 mg. Titrate to a maximum of 600 mg per day if clinically indicated. For patients receiving a daily dose of either 900 mg or 1200 mg, reduce the daily dose to 600 mg.

CONTRAINDICATIONS

Pregnancy; use of simvastatin or lovastatin and CYP3A substrates with narrow therapeutic range; concurrent long-term corticosteroid use; women with history of unexplained vaginal bleeding; women with endometrial hyperplasia with atypia or endometrial carcinoma.

WARNINGS AND PRECAUTIONS

Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency.

Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment.

Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if the patient also has a hemorrhagic disorder or is on anticoagulant therapy.

QT interval prolongation: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval.

Use of strong CYP3A inhibitors: Concomitant use increases mifepristone plasma levels. Adjust Korlym dose as described in Dosage and Administration. Use only when necessary and do not exceed a Korlym dose of 600 mg.

ADVERSE REACTIONS

Most common adverse reactions in Cushing’s syndrome (≥20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.

DRUG INTERACTIONS

Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with Korlym.

CYP3A inhibitors: Caution should be used when Korlym is used with strong CYP3A inhibitors. Adjust Korlym dose as described in Dosage and Administration. Use only when necessary, and do not exceed a Korlym dose of 600 mg.

CYP3A inducers: Do not use Korlym with CYP3A inducers.

Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with Korlym.

Drugs metabolized by CYP2B6: Use of Korlym should be done with caution with bupropion and efavirenz.

Hormonal contraceptives: Do not use with Korlym.

USE IN SPECIFIC POPULATIONS

Nursing mothers: Discontinue drug or discontinue nursing.

Please see accompanying full Prescribing Information and Medication Guide.

INDICATIONS AND USAGE

Korlym® (mifepristone) is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery.

Important Limitations of Use

Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing’s syndrome.