|LETTER TO THE EDITOR
|Year : 2012 | Volume
| Issue : 4 | Page : 670-671
The many lives of mifepristone: Multi-glandular exaptation of an endocrine molecule
Navneet Magon1, Monica Chauhan2, Poonam Goel3, Rupinder K Ruprai4
1 Department of Obstetrics and Gynecology, Air Force Hospital, Kanpur, Uttar Pradesh, India
2 Department of Obstetrics and Gynaecology, NSCB Medical College, Jabalpur, Madhya Pradesh, India
3 Department of Obstetrics and Gynaecology, Government Medical College and Hospital, Sector 32, Chandigarh, India
4 Aster-Gardens Medical Center, Medcare and Aster Hospitals, Dubai, United Arab Emirates
|Date of Web Publication||5-Jul-2012|
Obstetrician, Gynaecologist and Endoscopic Surgeon, Department of Obstetrics and Gynecology, Air Force Hospital, Kanpur, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Magon N, Chauhan M, Goel P, Ruprai RK. The many lives of mifepristone: Multi-glandular exaptation of an endocrine molecule. Indian J Endocr Metab 2012;16:670-1
|How to cite this URL:|
Magon N, Chauhan M, Goel P, Ruprai RK. The many lives of mifepristone: Multi-glandular exaptation of an endocrine molecule. Indian J Endocr Metab [serial online] 2012 [cited 2021 Jan 17];16:670-1. Available from: https://www.ijem.in/text.asp?2012/16/4/670/98048
Teutsch developed RU-486 in 1980 and revolutionized the way medical abortions were performed. Could one have imagined, at that time, that this would go on to be used for treatment of an adrenal disorder, and one day be approved to control hyperglycemia in adults with endogenous Cushing's syndrome? The drug mifepristone has covered a long journey, from the uterus to adrenals.
Mifepristone was 38,486 th compound synthesized by Roussel-Uclaf and code-named RU-486. It was indeed as a part of formal research project for the development of glucocorticoid receptor (GR) antagonists, that in 1980, chemist Georges Teutsch synthesized mifepristone.  It was also discovered to be a progesterone receptor antagonist. In 1981, endocrinologist Etienne-Emile Baulieu arranged testing it for its use for medical abortion in Switzerland by gynecologist Walter Herrmann. It was tested at University of Geneva's Cantonal Hospital, with successful results announced in April 1982. In 1987, following worldwide clinical trials in 20,000 women, of mifepristone with misoprostol for medical abortion, Roussel-Uclaf sought approval in France for their use for medical abortion, which was announced in September 1988. Development and availability of mifepristone was severely restricted initially because of controversy surrounding its ability to function as an "abortion pill." US FDA approval was granted in September 2000. Mifepristone was approved for use in India in 2002.
In addition to being an anti-progestogen, mifepristone is also an anti-glucocorticoid. Mifepristone was the first GR antagonist developed for clinical testing, and it is still the only drug with this property used in humans. It binds to the human GR with an affinity 3-4 times higher than that of dexamethasone and about 18 times higher than that of cortisol.  The anti-glucocorticoid effects of mifepristone are dose dependent, and occur at single doses of 4 mg/ kg and higher, whereas anti-progestin activity is already apparent at much lower doses. 
Endogenous Cushing's syndrome is a serious, debilitating 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 or temporarily control glucocorticoid hypersecretion. All drugs currently used for control of hypercortisolism in this setting, including ketoconazole, aminoglutethimide, metyrapone, and mitotane, decrease adrenal steroid secretion and are frequently associated with significant side effects. A GR antagonist, like mifepristone, was thus purported to be an attractive alternative treatment option.
Problems with long-term treatment with mifepristone in women are the frequent development of endometrial hyperplasia. It has also been associated with low serum potassium levels, a slight increase in serum creatinine levels, or moderate elevation of hepatic enzymes.  It may also be associated with alterations in thyroid homeostasis.
In patients with Cushing's syndrome in whom long-term treatment with mifepristone was, on the whole, well tolerated, improvement of clinical features was impressive. Mifepristone, therefore, was thought to be an interesting treatment option for Cushing's syndrome caused by ectopic ACTH production or adrenocortical carcinoma that cannot be controlled by surgery alone.
Mifepristone received an orphan drug designation by the FDA in 2007 and by European Commission in 2009 also for the treatment of Cushing's syndrome. In Feb 2012, US FDA has approved it to control hyperglycemia in adults with endogenous Cushing's syndrome. This drug has been approved for use in patients with endogenous Cushing's who have type 2 diabetes or glucose intolerance, and are not candidates for surgery or who have not responded to prior surgery. The FDA determined that a Risk Evaluation and Mitigation Strategy was not necessary for mifepristone to 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.
There are revolutionary changes going on in the usage of endocrine molecules. Recently, one more endocrine molecule, oxytocin, has undergone extensive repurposing.  Now, repurposing of mifepristone for use in Cushing's seems like a natural sequence in doing justice to the original research project as a part of which it manufactured, i.e. GR antagonists. This multi-glandular exaptation of an endocrine molecule should pave way for more research not only on this drug, but also on many more molecules, which can mitigate many other diseases. This also proves that the scope of for drug targeting on already available molecules is immense. It brings in a lot of hope for alleviating human suffering. Since our understanding of human physiology is limited, and is growing by leaps and bounds every day, all endocrine molecules must be considered a potential candidate for drug research and therapeutics in humans.
| References|| |
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|2.||Sartor O, Cutler GB Jr. Mifepristone: Treatment of Cushing's syndrome. Clin Obstet Gynecol 1996;39:506-10. |
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|4.||Spitz IM. Progesterone antagonists and progesterone receptor modulators: An overview. Steroids 2003;68:981-93. |
|5.||Magon N, Kalra S. The orgasmic history of oxytocin: Love, lust, and labor. Indian J Endocrinol Metab 2011;15:156-61. |