Bromocriptine in Cushings Disease

The mechanism of action of bromocriptine and its clinical application in the management of Cushing’s disease will be reviewed.

Physiology

The Hypothalamic-Pituitary-Adrenal Axis : Refer to this article to review the effects of hypothalamic-derived dopamine on ACTH-producing corticotrophs.

Mechanism of action

Although approximately 80% of corticotroph adenomas express D2 receptors, they have a relatively low D2 receptor density making, dopaminergic agonists (DAs) a less favorable therapeutic option(1). Bromocriptine and cabergoline reduce cortisol production by binding to D2 receptors present on corticotrophs; however, they are not as effective as SSAs(2).

 

Practice Guide

  • Patients on dopaminergic agonists (Bromocriptine and Cabergoline) exhibit an “escape phenomenon,” which is characterized by up to a third of previously responsive patients experiencing rebound hypercortisolemia(1).
  • Cabergoline is associated with valvular heart disease, especially in patients exposed to doses close to the upper limit of the acceptable dose range(3). Therefore, serial echocardiograms are reasonable in patients who are either on high doses of cabergoline(3) or exposed to a cumulatively high lifetime dose(4).
  • Common side effects of dopaminergic agonists include postural dizziness, nausea, and headaches(5).
  • In contrast to the lower dose range of 0.5 to 2.0mg per week of cabergoline used in prolactinomas(6), a much higher dose range between 2.5 and 5mg per week is required to treat CD(7,8).

Clinical Trial Evidence

The long-term effects of cabergoline therapy in patients with Cushing’s disease were explored in this study(9).

The efficacy of cabergoline in Cushing’s disease was assessed in this open-label, single-arm, retrospective study. A total of 30 patients received oral cabergoline 0.5-1.0mg per week, uptitrated weekly. The primary outcome was defined as either normalization of urinary free cortisol (UFC) levels or >50% reduction in UFC (this occurred in 36.6% of subjects)(9).

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References

  1. Cuevas-Ramos D, Lim DST, Fleseriu M. Update on medical treatment for Cushing’s disease. Clin Diabetes Endocrinol. 2016 Sep 13;2(1):16.
  2. Tateno T, Kato M, Tani Y, Oyama K, Yamada S, Hirata Y. Differential expression of somatostatin and dopamine receptor subtype genes in adrenocorticotropin (ACTH)-secreting pituitary tumors and silent corticotroph adenomas. Endocr J. 2009;56(4):579–84.
  3. Auriemma RS, Pivonello R, Ferreri L, Priscitelli P, Colao A. Cabergoline Use for Pituitary Tumors and Valvular Disorders. Endocrinol Metab Clin North Am. 2015 Mar 1;44(1):89–97.
  4. Stiles CE, Tetteh-Wayoe ET, Bestwick JP, Steeds RP, Drake WM. A Meta-Analysis of the Prevalence of Cardiac Valvulopathy in Patients With Hyperprolactinemia Treated With Cabergoline. J Clin Endocrinol Metab. 2019 Feb 1;104(2):523–38.
  5. Verhelst J, Abs R, Maiter D, van den Bruel A, Vandeweghe M, Velkeniers B, et al. Cabergoline in the Treatment of Hyperprolactinemia: A Study in 455 Patients. J Clin Endocrinol Metab. 1999 Jul 1;84(7):2518–22.
  6. Vroonen L, Jaffrain-Rea ML, Petrossians P, Tamagno G, Chanson P, Vilar L, et al. Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients. Eur J Endocrinol. 2012 Nov;167(5):651–62.
  7. Burman P, Edén-Engström B, Ekman B, Karlsson FA, Schwarcz E, Wahlberg J. Limited value of cabergoline in Cushing’s disease: a prospective study of a 6-week treatment in 20 patients. Eur J Endocrinol. 2016 Jan;174(1):17–24.
  8. Ferriere A, Cortet C, Chanson P, Delemer B, Caron P, Chabre O, et al. Cabergoline for Cushing’s disease: a large retrospective multicenter study. Eur J Endocrinol. 2017 Mar;176(3):305–14.
  9. Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol. 2010 Nov 1;163(5):709–16.
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