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Metyrapone and Trilostane

Mode of action

Metyrapone (metopirone) competitively inhibits 11β-hydroxylation in the adrenal cortex.

  • This results in inhibition of cortisol production. Aldosterone is inhibited to a lesser extent.
  • It can be used as a test of anterior pituitary function.1

Trilostane reversibly inhibits 3 β-hydroxysteroid dehydrogenase and delta 5-4 isomerase in the adrenal cortex.

  • This inhibition of the synthesis of mineralocorticoids and glucocorticoids is useful in Cushing's syndrome and primary hyperaldosteronism.2

Metyrapone: indications for use
  • This is used as a diagnostic aid in the differential diagnosis of ACTH-dependent Cushing's syndrome.1
    • Patient must be an in-patient.
    • Measure 24 hour urinary 17-oxygenic steroid excretion on each of 4 consecutive days.
    • The first 2 days serve as a baseline.
    • On day 3 give 750mg Metyrapone (3 capsules) every four hours giving a total of 6 doses (i.e. 4.5g).
    • Maximum urine steroid excretion may occur on the fourth day.
    Metyrapone leads to a fall in cortisol. Thus ACTH is stimulated and in turn this leads to increased synthesis and release of precursors of cortisol. Therefore an increase in either serum 11-deoxycortisol concentrations or in urinary steroid excretion means there is an increase in ACTH. On the other hand a failure of these values to rise means there is ACTH deficiency or primary adrenal disease.
  • Metyrapone has been found helpful in controlling the symptoms of Cushing's disease. It is also used in other forms of Cushing's syndrome to prepare the patient for surgery.
  • It is used with glucocorticosteroids in the treatment of resistant oedema (due to increased aldosterone secretion) in patients with cirrhosis, nephrosis and congestive heart failure.
  • The Cushing's which occasionally accompanies carcinoma of the bronchus is not usually amenable to surgery and medical therapy may have a role if the patient cannot safely undergo surgery, if surgery fails, or if the tumour recurs.

Research

  • Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis has been well-described in both bipolar and unipolar depression. Hypercortisolaemia may be central to the pathogenesis of depressive symptoms. Recently the addition of metyrapone to imipramine therapy (in treatment-resistant unipolar depression) has been shown to be beneficial.3 Metyrapone blockade has been shown to have therapeutic effects for depressive symptoms and neurocognitive function.4
  • There has also been recent research on the role of cortisol in heart disease. Depression is an independent risk factor for the development of coronary heart disease, and patients with depression have endothelial dysfunction. There are many theories around the cause of this dysfunction, one of which is that it results from abnormal HPA axis function, a feature of depression, resulting in increased exposure to cortisol. Cortisol administration produces endothelial dysfunction in healthy subjects and inhibition of cortisol production by metyrapone improves the endothelial dysfunction seen in depression.5

Trilostane: indications for use
  • This is used to control the symptoms of adrenal cortical hyperfunction in Cushings and primary aldosteronism. However, it appears to be less effective than metyrapone for Cushing's syndrome.
  • Trilostane offers an alternative endocrine treatment in advanced postmenopausal breast cancer. It has a unique mode of action; it is an allosteric modulator of the oestrogen receptor and targets both the oestrogen- and growth factor-dependent pathways through which oestradiol stimulates cell proliferation. In clinical trials, trilostane has been shown to be an effective treatment for breast cancer in patients who have relapsed after receiving treatment with one or more forms of endocrine therapy.6 It may also have a role in the treatment of prostate cancer.
  • It is used to treat resistant oedema due to increased aldosterone secretion in cirrhosis, nephrotic syndrome, and congestive heart failure (with glucocorticoid replacement therapy).

Research

  • A recent study from South Africa showed that trilostane could be given as out-patient therapy (prior to admission for prostaglandin administration) in late medical termination.7 This may be a useful alternative to expensive, often unavailable antiprogestogens.
Dosing

The dosages used are either low, and tailored to cortisol production, or high, in which case corticosteroid replacement therapy is also needed. Therapy is titrated against cortisol level and electrolytes.

  • When medication is the only therapy, a major disadvantage is the need for lifelong therapy.
  • In general, recurrence follows discontinuation of treatment.
  • Metyrapone is a steroidogenesis inhibitor.
  • Metyrapone (and also ketoconazole, mitotane and aminoglutethimide,) are the agents of choice for medical therapy of Cushing's disease.

In general, ketoconazole is the best tolerated of these agents and is effective as monotherapy (an unlicensed indication) in about 70% of patients. Mitotane and metyrapone may be effective as single agents.8

Metyrapone

Contraindications

  • Primary adrenocorticol insufficiency
  • Hypersensitivity to drug, or any of the constituents
  • Pregnancy

Cautions

  • The adrenal cortex should be able to respond to exogenous ACTH before any diagnostic test is performed. Metyrapone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity (panhypopituitarism).
  • If being used as a diagnostic aid, anticonvulsants, anti-depressants and neuroleptics, hormones that affect the hypothalamo-pituitary axis and anti-thyroid agents may influence the results of the test.
  • Long-term treatment may cause hypertension.
  • Patients with liver cirrhosis may show a delayed response due to liver damage delaying the metabolism of cortisol.
  • In hypothyroidism, urinary steroid levels may rise very slowly, or not at all.

Adverse effects

  • This medication causes drowsiness, which may affect the performance of skilled tasks such as driving.
  • Gastrointestinal tract: Occasional: nausea, vomiting. Rare: abdominal pain.
  • Central nervous system: Occasional: dizziness, sedation, headache.
  • Cardiovascular system: Occasional: hypotension.
  • Skin: Rare: allergic skin reactions.
  • Endocrine system: Rare: hypoadrenalism, hirsutism.


Trilostane

Contraindications

  • Pregnancy. The production of progesterone is suppressed by trilostane and so pregnancy may be limited.
  • Not for use in children.

Cautions

  • Pregnancy should be excluded before beginning treatment and non-hormonal contraceptive methods should be used during therapy.
  • Caution should be used in patients with gross hepatic or renal impairment. Response should be monitored when treating adrenal cortical hyperfunction. Regular assays of blood electrolytes and circulating corticosteroids need to be taken and the dose adjusted accordingly.
  • When treating hypercortisolism an initial response may be followed by a relapse, if the hypophyseal/pituitary/adrenal (HPA) axis is still intact and is not suppressed.
  • When administered with thiazide diuretics, the inhibition of aldosterone production caused by Trilostane reduces potassium loss, whilst maintaining the natriuretic effect.

Adverse effects

  • There have been occasional reports of lethargy or drowsiness, but trilostane is unlikely to impair ability.
  • Flushing, tingling in mouth, palatal swelling, rhinorrhoea, sickness, vomiting, diarrhoea, and cramps have been reported commonly. These are generally mild and reversible.
  • More severe signs e.g. bleeding or ulcer, usually occur with concurrent administration of nonsteroidal anti-inflammatory drugs. Skin rashes can occur occasionally but are usually self limiting.
  • Granulocytopenia has been reported (very rarely) in patients whose bone marrow is compromised by disease or chemotherapy. It is reversible on stopping therapy.



Document references
  1. Summary of Product Characteristics - Metopirone® Capsules 250 mg (Metyrapone), Alliance Pharmaceuticals Updated Feb 2005; electronic Medicines Compendium
  2. Summary of Product Characteristics - Modrenal® (Trilostane) Bioenvision Ltd, updated Feb 2005, electronic Medicines Compendium
  3. Rogoz Z, Skuza G, Wojcikowski J, et al; Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression.; Pol J Pharmacol. 2004 Nov-Dec;56(6):849-55. [abstract]
  4. Young AH; Antiglucocoticoid treatments for depression. Aust N Z J Psychiatry. 2006 May;40(5):402-5. [abstract]
  5. Broadley AJ, Korszun A, Abdelaal E, et al; Metyrapone improves endothelial dysfunction in patients with treated depression. J Am Coll Cardiol. 2006 Jul 4;48(1):170-5. Epub 2006 Jun 9. [abstract]
  6. Puddefoot JR, Barker S, Vinson GP; Trilostane in advanced breast cancer. Expert Opin Pharmacother. 2006 Dec;7(17):2413-9. [abstract]
  7. le Roux PA, van der Spuy ZM; Labor induction abortion utilizing trilostane, a 3beta-hydroxysteroid dehydrogenase inhibitor.; Contraception. 2005 May;71(5):343-7. [abstract]
  8. Nieman LK; Medical therapy of Cushing's disease.; Pituitary. 2002;5(2):77-82. [abstract]
Internet and further reading AcknowledgementsEMIS is grateful to Dr Hayley Willacy for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2007.
DocID: 364
Document Version: 2
DocRef: bgp25179
Last Updated: 30 Oct 2007
Review Date: 29 Oct 2008
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