Letters to the Editor C. Gopalakrishnan Nair, Pradeep Jacob, the way medical abortions were performed. Could one Misha Babu, Riju Menon have imagined, at that time, that this would go on to be Department of Surgery, Surgical Endocrinology Division, used for treatment of an adrenal disorder, and one day Amrita School of Medicine, Kochi, Kerala, India be approved to control hyperglycemia in adults with Corresponding author: Dr. C. Gopalakrishnan Nair, endogenous Cushing’s syndrome? The drug mifepristone Department of Surgery, Surgical Endocrinology Division, has covered a long journey, from the uterus to adrenals. Amrita School of Medicine, Kochi, Kerala, India. th E-mail: [email protected]. Mifepristone was 38,486 compound synthesized by Roussel- Uclaf and code-named RU-486. It was indeed as a part of REFERENCES formal research project for the development of glucocorticoid receptor (GR) antagonists, that in 1980, chemist Georges 1. Als C, Gedeon P, Rösler H, Minder C, Netzer P, Laissue JA. Survival [1] analysis of 19 patients with toxic thyroid carcinoma. J Clin Endocrinol Teutsch synthesized mifepristone. It was also discovered to be Metab 2002;87:4122-7. a progesterone receptor antagonist. In 1981, endocrinologist 2. Kraimps JL, Bouin-Pineau MH, Mathonnet M, De Calan L, Etienne-Emile Baulieu arranged testing it for its use for Ronceray J, Visset J, et al. Multicenter study of thyroid nodules in medical abortion in Switzerland by gynecologist Walter patients with Graves’s disease. Br J Surg 2000;87:1111-3. 3. Stocker DJ, Foster SS, Solomon BL, Shriver CD, Burch HB. Thyroid Herrmann. It was tested at University of Geneva’s Cantonal cancer yield in patients with Grave’s disease selected for surgery on Hospital, with successful results announced in April 1982. the basis of cold scintiscan defects. Thyroid 2002;12:305-11. In 1987, following worldwide clinical trials in 20,000 women, 4. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association management guidelines of mifepristone with misoprostol for medical abortion, for patients with thyroid nodules and differentiated thyroid cancer. Roussel-Uclaf sought approval in France for their use for The American Thyroid Association (ATA) Guidelines Taskforce medical abortion, which was announced in September 1988. on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid Development and availability of mifepristone was severely 2009;19:1167-214. 5. Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, restricted initially because of controversy surrounding its et al. Somatic mutations in the thyrotrophic receptor gene cause ability to function as an “abortion pill.” US FDA approval hyper functioning thyroid adenomas. Nature 1993;365:649-51. was granted in September 2000. Mifepristone was approved 6. Krohn K, Führer D, Bayer Y, Eszlinger M, Brauer V, Neumann S, for use in India in 2002. et al. Molecular pathogenesis of euthyroid and toxic multinodular goitre. Endocr Rev 2005;26:504-24. 7. Niepomniszcze H, Suárez H, Pitoia F, Pignatta A, Danilowicz K, In addition to being an anti-progestogen, mifepristone Manavela M, et al. Follicular carcinoma presenting as autonomous is also an anti-glucocorticoid. Mifepristone was the first functioning thyroid nodule and containing an activating mutation of the TSH receptor (T620I) and a mutation of the Ki-RAS (G12C) GR antagonist developed for clinical testing, and it is Genes. Thyroid 2006;16:497-503. still the only drug with this property used in humans. It 8. Chao TC, Lin JD, Jeng LB, Chen MF. Thyroid cancer with concurrent binds to the human GR with an affinity 3–4 times higher hyperthyroidism. Arch Surg 1999;134:130-4. than that of dexamethasone and about 18 times higher [2] Access this article online than that of cortisol. The anti-glucocorticoid effects of mifepristone are dose dependent, and occur at single doses Quick Response Code: Website: of 4 mg/ kg and higher, whereas anti-progestin activity is www.ijem.in already apparent at much lower doses.[3] DOI: Endogenous Cushing’s syndrome is a serious, debilitating 10.4103/2230-8210.98047 multisystem disorder, caused by the overproduction of cortisol by the adrenal glands, which increases blood sugar levels. Caused by ectopic adrenocorticotrophin (ACTH)-producing tumors or adrenocortical carcinoma, surgical resection of the tumor can often only partially The many lives of or temporarily control glucocorticoid hypersecretion. All mifepristone: Multi- drugs currently used for control of hypercortisolism in this setting, including ketoconazole, aminoglutethimide, glandular exaptation of an metyrapone, and mitotane, decrease adrenal steroid secretion and are frequently associated with significant endocrine molecule side effects. A GR antagonist, like mifepristone, was thus purported to be an attractive alternative treatment option. Sir, Teutsch developed RU-486 in 1980 and revolutionized Problems with long-term treatment with mifepristone 670 Indian Journal of Endocrinology and Metabolism / Jul-Aug 2012 / Vol 16 | Issue 4 Letters to the Editor in women are the frequent development of endometrial Sector 32, Chandigarh, India, 3Aster-Gardens Medical Center, hyperplasia. It has also been associated with low serum Medcare and Aster Hospitals, Dubai, UAE potassium levels, a slight increase in serum creatinine levels, Corresponding Author: Dr. Navneet Magon, or moderate elevation of hepatic enzymes.[4] It may also be Obstetrician, Gynaecologist and Endoscopic Surgeon, associated with alterations in thyroid homeostasis. Department of Obstetrics and Gynecology, Air Force Hospital, Kanpur, Uttar Pradesh, India. E-mail: [email protected] In patients with Cushing’s syndrome in whom long- term treatment with mifepristone was, on the whole, well REFERENCES tolerated, improvement of clinical features was impressive. Mifepristone, therefore, was thought to be an interesting 1. Ulmann A, Teutsch G, Philibert D. RU 486. Sci Am 1990;262:42-8. 2. Sartor O, Cutler GB Jr. Mifepristone: Treatment of Cushing’s treatment option for Cushing’s syndrome caused by ectopic syndrome. Clin Obstet Gynecol 1996;39:506-10. ACTH production or adrenocortical carcinoma that cannot 3. Sitruk-Ware R, Spitz IM. Pharmacological properties of mifepristone: be controlled by surgery alone. Toxicology and safety in animal and human studies. Contraception 2003;68:409-20. 4. Spitz IM. Progesterone antagonists and progesterone receptor Mifepristone received an orphan drug designation by the modulators: An overview. Steroids 2003;68:981-93. FDA in 2007 and by European Commission in 2009 also 5. Magon N, Kalra S. The orgasmic history of oxytocin: Love, lust, and for the treatment of Cushing’s syndrome. In Feb 2012, US labor. Indian J Endocrinol Metab 2011;15:156-61. FDA has approved it to control hyperglycemia in adults Access this article online with endogenous Cushing’s syndrome. This drug has been Quick Response Code: approved for use in patients with endogenous Cushing’s Website: who have type 2 diabetes or glucose intolerance, and are not www.ijem.in candidates for surgery or who have not responded to prior surgery. The FDA determined that a Risk Evaluation and DOI: Mitigation Strategy was not necessary for mifepristone to 10.4103/2230-8210.98048 ensure that the benefits outweigh the risks for patients with endogenous Cushing’s syndrome. Since there are no other approved medical therapies for this debilitating form of Cushing’s syndrome, it was thought that very sick patients would suffer if impediments to access were imposed. Hypertriglyceridemia‑ induced acute pancreatitis There are revolutionary changes going on in the usage of endocrine molecules. Recently, one more endocrine treatment with insutin and molecule, oxytocin, has undergone extensive repurposing.[5] Now, repurposing of mifepristone for use in Cushing’s heparin seems like a natural sequence in doing justice to the original research project as a part of which it manufactured, Sir, i.e. GR antagonists. This multi-glandular exaptation of an In response to “Hypertriglyceridemia-induced recurrent endocrine molecule should pave way for more research not acute pancreatitis: A case-based review”, we report a only on this drug, but also on many more molecules, which similar case of familial hypertriglyceridemia-induced acute can mitigate many other diseases. This also proves that the pancreatitis in which we used a slightly different treatment scope of for drug targeting on already available molecules approach. is immense. It brings in a lot of hope for alleviating human suffering. Since our understanding of human physiology A 42-year-old female with history of newly diagnosed is limited, and is growing by leaps and bounds every day, Type V hypertriglyceridemia and diabetes mellitus type 2 all endocrine molecules must be considered a potential presented to our institution with 10/10 mid-epigastric candidate for drug research and therapeutics in humans. abdominal pain with associated non-bloody/non-bilious emesis, and decrease oral intake for the following 3 days. Navneet Magon, Monica Chauhan1, Poonam Goel2, She ran out of her omega-3 fatty acids and fenofibrate the 3 Rupinder K. Ruprai week prior and did not get refills. Department of Obstetrics and Gynecology, Air Force Hospital, 1 Kanpur, Uttar Pradesh, Department of Obstetrics and Gynaecology, On admission, patient was afebrile, heart rate of 120, NSCB Medical College, Jabalpur, Madhya Pradesh, 2Department of Obstetrics and Gynaecology, Government Medical College and blood pressure of 95/76, saturating 97% on room air. Hospital, Her admission labs were significant for blood sugar Indian Journal of Endocrinology and Metabolism / Jul-Aug 2012 / Vol 16 | Issue 4 671 Copyright of Indian Journal of Endocrinology & Metabolism is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use..