Cushing Sendromu ve Depresif Hastalıklarda Metiraponun Yeni Perspektifleri

Öz

Metirapon, 11-deoksikortizolün kortizole dönüşümünü katalize eden 11-β hidroksilaz enzimini inhibe eder. Metirapon ayrıca 11β-HSD1'i de inhibe eder ve 11β-HSD2 tarafından kortizolün inaktivasyonunu takiben plazma kortizon: kortizol oranında bir artışa neden olur. Bu derleme, metiraponun etki mekanizmalarına ve tedavi olarak kullanımına odaklanmaktadır. Yayınlanmış literatürler PubMed, SciFinder, ScienceDirect, Wiley Online Library, Google Scholar ve Web of Science gibi bilimsel veri tabanlarından Temmuz 2024'e kadar toplanmıştır. Metirapon, Cushing sendromunun tedavisinde yararlı bir tedavi seçeneğidir. Cushing sendromunun tedavisinde metiraponun etkinliği ve güvenliğine ilişkin kanıtlar, klinik uygulamada altmış yılı aşkın süredir kullanılmasının yanı sıra metiraponun hızlı bir etki başlangıcına sahip olduğunu, etkili olduğunu ve genellikle iyi tolere edildiğini gösteren çalışmaların sonuçlarından elde edilmektedir. Metiraponun depresyon tedavisinde kullanımına ilişkin olumlu kanıtlar bulunmaktadır. Ancak metiraponun antidepresan etkisinin kesin mekanizması açık değildir. Olası mekanizmalar arasında glukokortikoid reseptörleri upregülasyonu, ön beyindeki 5HT1A duyarlılığının değiştirilmesi, mineralokortikoid reseptörleri aktivasyonu veya steroid yolundaki diğer hormonlar tarafından indüklenen bir antidepresan etki yer almaktadır. Metiraponun iyi tasarlanmış randomize klinik çalışmalar kullanılarak farmakokinetik, derinlemesine moleküler mekanizmalar ve güvenlik profili üzerine daha fazla araştırma yapılması önerilmektedir.

Anahtar Kelimeler

• Aldosteron
• Cushing Sendromu
• Kortizol
• Metirapon

New Perspectives of Metyrapone in Cushing's Syndrome and Depressive Disorders

Öz

Metyrapone inhibits the enzyme 11-β hydroxylase, which catalyses the conversion of 11-deoxycortisol to cortisol. Metyrapone also inhibits 11β-HSD1 and causes an increase in the plasma cortisone: cortisol ratio following inactivation of cortisol by 11β-HSD2. This review focuses on the mechanisms of action of metyrapone and its use as a treatment. Published literature was collected until July 2024 from scientific databases including PubMed, SciFinder, ScienceDirect, Wiley Online Library, Google Scholar and Web of Science. Metyrapone is a useful treatment option in the treatment of Cushing's syndrome. Evidence for the efficacy and safety of metyrapone in the treatment of Cushing's syndrome comes from more than sixty years of use in clinical practice, as well as from the results of studies showing that metyrapone has a rapid onset of action, is effective and is generally well tolerated. There is positive evidence for the use of metyrapone in the treatment of depression. However, the exact mechanism of the antidepressant effect of metyrapone is not clear. Possible mechanisms include upregulation of glucocorticoid receptors, alteration of 5HT1A sensitivity in the forebrain, activation of mineralocorticoid receptors or an antidepressant effect induced by other hormones in the steroid pathway. Further research into the pharmacokinetics, in-depth molecular mechanisms and safety profile of metyrapone using well-designed randomised clinical trials is recommended.

Anahtar Kelimeler

• Aldosterone
• Cortisol
• Cushing
• Metyrapone

Kaynakça

1. Al-Salama, Z. T. (2021). Metyrapone in Cushing’s syndrome: a profile of its use. Drugs & Therapy Perspectives, 37(9), 393-406.
2. Braun, L. T., & Reincke, M. (2020). What is the role of medical therapy in adrenal-dependent Cushing's syndrome? Best practice & research Clinical endocrinology & metabolism, 34(3), 101376.
3. Castinetti, F. (2023). Pharmacological treatment of Cushing's syndrome. Archives of Medical Research, 102908.
4. Daniel, E., & Newell-Price, J. D. (2015). Therapy of endocrine disease: steroidogenesis enzyme inhibitors in Cushing's syndrome. European Journal of Endocrinology, 172(6), R263-R280.
5. Rogóz, Z., Skuza, G., Wójcikowski, J., & Daniel, W. A. (2003). Effects of combined treatment with imipramine and metyrapone in the forced swimming test in rats. Behavioral and pharmacokinetic studies. Polish journal of pharmacology, 55(6), 993–999.
6. Fleseriu, M., Auchus, R., Bancos, I., Ben-Shlomo, A., Bertherat, J., Biermasz, N. R., Boguszewski, C. L., Bronstein, M. D., Buchfelder, M., Carmichael, J. D., Casanueva, F. F., Castinetti, F., Chanson, P., Findling, J., Gadelha, M., Geer, E. B., Giustina, A., Grossman, A., Gurnell, M., Ho, K., … & Biller, B. M. K. (2021). Consensus on diagnosis and management of Cushing's disease: a guideline update. The lancet. Diabetes & endocrinology, 9(12), 847–875.
7. Hakami, O. A., Ahmed, S., & Karavitaki, N. (2021). Epidemiology and mortality of Cushing’s syndrome. Best practice & research Clinical endocrinology & metabolism, 35(1), 101521.
8. Healy, D. G., Harkin, A., Cryan, J. F., Kelly, J. P., & Leonard, B. E. (1999). Metyrapone displays antidepressant-like properties in preclinical paradigms. Psychopharmacology, 145, 303-308.

9. Igaz, P., Tombol, Z., Szabo, P., Liko, I., & Racz, K. (2008). Steroid biosynthesis inhibitors in the therapy of hypercortisolism: theory and practice. Current Medicinal Chemistry, 15(26), 2734-2747. Jeffcoate, W., Silverstone, J., Edwards, C., & Besser, G. (1979). Psychiatric manifestations of Cushing's syndrome: response to lowering of plasma cortisol. QJM: An International Journal of Medicine, 48(3), 465-472.
10. Johnson, D. A., Grant, E. J., Ingram, C. D., & Gartside, S. E. (2007). Glucocorticoid receptor antagonists hasten and augment neurochemical responses to a selective serotonin reuptake inhibitor antidepressant. Biological psychiatry, 62(11), 1228-1235.
11. Lacroix, A., Feelders, R. A., Stratakis, C. A., & Nieman, L. K. (2015). Cushing's syndrome. The lancet, 386(9996), 913-927.
12. Levin, J., Zumoff, B., & Fukushima, D. K. (1978). Extraadrenal effects of metyrapone in man. The Journal of Clinical Endocrinology & Metabolism, 47(4), 845-849.
13. Nieman, L. K., Biller, B. M., Findling, J. W., Murad, M. H., Newell-Price, J., Savage, M. O., & Tabarin, A. (2015). Treatment of Cushing's syndrome: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 100(8), 2807-2831.
14. Pivonello, R., Ferrigno, R., De Martino, M. C., Simeoli, C., Di Paola, N., Pivonello, C., Barba, L., Negri, M., De Angelis, C., & Colao, A. (2020). Medical treatment of Cushing's disease: an overview of the current and recent clinical trials. Frontiers in Endocrinology, 11, 648.
15. Raven, P., O'Dwyer, A.-M., Taylor, N., & Checkley, S. (1996). The relationship between the effects of metyrapone treatment on depressed mood and urinary steroid profiles. Psychoneuroendocrinology, 21(3), 277-286.
16. Rigel, D. F., Fu, F., Beil, M., Hu, C.-W., Liang, G., & Jeng, A. Y. (2010). Pharmacodynamic and pharmacokinetic characterization of the aldosterone synthase inhibitor FAD286 in two rodent models of hyperaldosteronism: comparison with the 11β-hydroxylase inhibitor metyrapone. Journal of Pharmacology and Experimental Therapeutics, 334(1), 232-243.
17. Sampath-Kumar, R., Yu, M., Khalil, M., & Yang, K. (1997). Metyrapone is a competitive inhibitor of 11β-hydroxysteroid dehydrogenase type 1 reductase. The Journal of steroid biochemistry and molecular biology, 62(2-3), 195-199.
18. Schöneshöfer, M., Schefzig, B., & Arabin, S. (1980). Short-term kinetics of serum adrenal steroids and plasma ACTH after a single dose of metyrapone in man. Journal of Endocrinological Investigation, 3, 229-236.
19. Simões Corrêa Galendi, J., Correa Neto, A. N. S., Demetres, M., Boguszewski, C. L., & Nogueira, V. D. S. N. (2021). Effectiveness of medical treatment of cushing’s disease: a systematic review and meta-analysis. Frontiers in Endocrinology, 12, 732240.