0013-7227/90/1275-2043$02.00/0 Endocrinology Copyright © 1990 by The Endocrine Society

Vol. 127, No. 5 Printed in U.S.A.

Editorial: RU486 and the Early Nineties Over 50,000 women in France have chosen RU486/PG over surgery for abortion. Trials in Great Britain have obtained satisfactory results up to 63 days of amenorrhea (10). The evidence for the safety and efficacy of this method is compelling.

I. The Reproductive Issue Since the first publication (1), the story of RU4861 has been dominated by the abortion issue.2 The talent of the Roussel-Uclaf chemists and pharmacologists, the work on steroid receptors and antihormones, the progress in understanding progesterone action in the human menstrual cycle and pregnancy, and the concern for insufficient available fertility control methods have merged to produce the first efficient, acceptable nonsurgical method of "contragestion" (short for contra-gestation, as contraception for contra-conception) (2-4). A short interruption of progesterone activity seems sufficient to stop early pregnancy (5) and the luteal phase of a nonfertile cycle. Therefore, only a brief period of toxicology studies in animals was required before testing clinically the antiprogesterone activity of RU486. Whereas the success rate for a single dose of 600 mg RU486 alone (6, 7) is 80% in pregnancies of less than 42 days of amenorrhea, this percentage decreases significantly in longer pregnancies. However, in conjunction with RU486, a small dose of prostaglandin (PG) (8), given 36-48 h later (9-11), would raise the efficiency rate to equal to or greater than 96% up to 49 days of amenorrhea (12). Three percent failures are due to incomplete abortions and/or bleeding, indicating instrumental intervention. In 1%, RU486 exerts no effect. There may be a genetic reason since, for instance, RU486 does not act as an antiprogesterone in chicks. The progesterone receptor does not bind RU486 in this species, apparently for a single amino acid difference in the steroid binding domain (Garcia, T., at Roussel-Uclaf, and H. Gronemeyer at INSERM U184, Strasbourg, in preparation).

What's next with voluntary pregnancy interruption (VPI)?

Received August 3,1990. The author of this editorial, Etienne-Emile Baulieu, is a physicianscientist at the INSERM Laboratories in the Bicetre Hospital in southern Paris. He received the Lasker Prize in 1989 for his work on steroid hormones and the development of RU486 and was elected at the National Academy of Science as a foreign Associate in 1990. This article has been written with the collaboration of Thanh-Van Ngoc Nguyen, second year medical student of the University of California, San Francisco; Interuniversitary exchange program (MICEFA) with Universite Paris XI. 1 Full number in Roussel-Uclaf list of products: 36,486. Generic name: mifepristone. Formula: ll/3-(4-dimethyl-amino phenyl)-17/3-hydroxy-17a-(prop-l-ynyl)-estra-4,9-dien-3-one. 2 This text refers only to the clinical aspects of RU486. In the nineties, there also will be more research to elucidate cellular, molecular, and physiological mechanisms of action of antisteroids.

Although 96% is a high rate of efficiency, it may still be possible to improve the method. RU486 doses lower than 600 mg (e.g. 200 mg) may yield the same results in the combined treatment, but may necessitate discomfortably higher doses of PG. The search for an active PG that would cause less uterine cramps should have high priority. Furthermore, an oral PG would render the process of VPI less intimidating to patients; presently injections and vaginal pessaries are used. If a PG derivative could exert a delayed effect and could be administered at the same time as RU486, then one less visit would be required. In France, all VPIs done with RU486/PG respect the obligations of the law, which was originally conceived for instrumental techniques: consultation at a registered center, medical supervision during administration of RU486 and PG, and a follow-up visit. In fact, provided that medical surveillance is established, the RU486/PG treatment should not necessarily be performed in a medical center, and thus the privacy of a woman would be better ensured. However, medical supervision will remain necessary for detection of ectopic pregnancy (not cured by RU486) and for prevention and treatment of complications such as hemorrhagies, incomplete evacuation, and cardiovascular effects of PG. In addition, the French abortion law imposes a delay of reflection of 1 week. To make this delay period optional would be desirable medically (earlier = easier evacuation, less pain and bleeding) and psychologically (given that the woman has clearly made up her mind). In all other European countries (except Ireland), although different laws regulating abortion exist, RU486 should become available to women in the next few years. The registration process is starting currently in Great Britain and soon in Holland and the Scandinavian countries. In the United States, there is no law preventing the use of RU486, but it is important to consider several


The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 12:15 For personal use only. No other uses without permission. . All rights reserved.



points. First, the current climate of uncertainty over the legal status of abortion has discouraged the big drug companies, including Hoescht-Roussel Product Incorporated, from even applying for licensing RU486. However, recent events have suggested that soon a radical change will appear in the official standpoint of the American policy makers in this matter, thanks to the determination of pro-choice women and planned parenthood organizations. Women should not remain prisoners of the feminine physiology when science can help to liberate them from biological constraints. Second, and probably more important, product liability concerns and the prospect of expensive litigation have deterred companies from any involvement in fertility control research in the United States (and consequently in the rest of the world). An urgent change in the legal practice is needed for the survival of reproductive medicine as well as many other therapeutic innovations. A third difficulty is the lack of PG for pregnancy interruption in the United States; this problem must be resolved together with RU486 registration. Globally, the situation in the United States is critical, not only to American women, but also to women of developing countries because American financial support is needed by the world Health Organization (WHO) and by other important groups involved in trying to solve population problems. In the developing countries, although each has a different situation, all share one common problem: the deficit in medical manpower and health system. Surgery for appendicitis in any country of the developing world involves more risk than in the United States or in France. With RU486, we shall see misuses and accidents. However, compared to the present tragic situation of 150,000 deaths yearly in addition to grave infections, countless cervical and uterine traumatisms and perforations, a nonsurgical method cannot be but progress toward solving a major health problem. It has to be combined with the education of physicians and medical personnel as well as women (to consult early). I do not agree with those who are preventing the introduction of RU486 into the developing world and believe that research such as that conducted by WHO and the Program for Appropriate Technology in Health is of extreme value. Abortion has been a fact of humanity for centuries. In the next generation, the inefficiency of contraceptive methods, which unfortunately will remain in spite of scientific progress, should be backed up by a safe and dignified means to interrupt early pregnancies. Contraception Besides the successful clinical use of RU486 for early abortion, this compound appears, from experimental studies in animals, to inhibit follicle maturation, ovula-

Endo • 1990 Vol 127 • No 5

tion, and egg implantation. Much work has been done on interruption of the cycle at midluteal phase (1, 13, 14) with 50-200 mg RU486/ day X 2-4 times. However, this method leads often to changing the time of the next ovulation even in the absence of fertilization and thus would be extremely unreliable. The use of RU486 late in the cycle, specifically on the last 2 days, 100-400 mg/day X 2 times, induces earlier menses in the nonpregnant women with no change in the next cycle (14, 15). A woman with a regular sex life has 20% chance of becoming pregnant if unprotected. This contraceptive method has a 20% failure rate (16, 17). Thus, the overall 4% (20% X 20%) failure rate of late luteal contraception leads to one pregnancy in 2 yr. This result is insufficient. It may be improved with the addition of a small dose of PG or anti-GnRH; however trials have not been conducted. Periovulatory, and more precisely 2-3 days after the LH peak, administration of RU486 at very low dose does not modify the luteal function and LH output. It provokes endometrium alteration (18, 19) which may then prevent implantation (midcycle). Although this method works postovulatorily, it fits the definition of contraception by most societies of obstetrics and gynecology. Finally, conventional contraception by prevention of fertilization could be obtained with RU486 since, administered during the follicular phase, it delays and eventually suppresses ovulation (20, 21). A succession of RU486-progestin-RU486 has been proposed to ensure an ovulation and cyclic menses (22). However, even if this appealing estrogen-free contraception proves to have high efficacy, it probably will not be available in the near future. The problem lies in finding a drug company that would be willing to spend money on safety testing and development of a new contraceptive pill while several already exist. The fact remains that RU486 may offer new methods of contraception in the near future.

II. Other Uses of RU486 as an Antiprogestin During pregnancy, RU486 can facilitate endouterine maneuvers that require opening and softening of the cervix. These maneuvers include pregnancy interruptions due to mother or fetus pathological states. Late in pregnancy, placental production of progesterone increases to a much higher level than that present during early pregnancy, and part of it may reach directly the uterine tissues (in contrast to progesterone of luteal origin). At delivery time, when the aim is to deliver a healthy child, RU486 may trigger labor in cases of undue delay. Experiments in monkeys have indicated its effectiveness (23). Incidentally the antiprogesterone effect of RU486

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 12:15 For personal use only. No other uses without permission. . All rights reserved.


also facilitates early milk secretion. Beyond pregnancy management, RU486 may have a role in the treatment of endometriosis and breast cancer. Roussel-Uclaf clinical coordinators, Andre Ulmann and Louise Silvestre, are currently establishing multicenter programs to conduct appropriate studies. Trials are also performed in progesterone receptor-containing neurological tumors (e.g. meningiomas). The depressing effect of RU486 on LH and FSH output (13, 14), including after menopause (24), may be of therapeutical importance. In any case, for long-term administration of RU486, evaluation of the safety of the drug will be necessary, particularly with reference to the glucocorticosteroid system. III. Uses of RU486 as an Antiglucocorticosteroid Originally, RU486 was found to be an anticorticosteroid (25) and indeed it binds with high affinity to the glucocorticosteroid receptor. The counteraction of RU486 on the negative feed-back activity of corticosteroids provokes an increase of ACTH, endorphin, and cortisol in human (26, 27). Thus, large doses of RU486 are needed to overcome this reaction in order to obtain a state of hypocorticism. Four categories of use may be envisaged: 1) Exploration of the hypothalamus-pituitary-adrenals (HPA) system, thus providing a new way to test this important axis implied in stressful conditions, immunological reactions, etc. 2) Therapeutical intervention on the functioning of the HPA regulation in some states of depression, immunological abnormalities, stressful conditions. Much work will be necessary to establish useful therapeutical protocols. 3) Intervention on cortisol excess independent of the central nervous system-pituitary regulatory mechanism, as in inoperable adrenal cancers or ACTH-producing ectopic tumors. These rare cases have clearly demonstrated the antiglucocorticosteroid effect of RU486. Surgical removal of a tumor has occasionally become possible with this treatment. 4) Local administration of RU486, permitting a circumscribed antiglucocorticosteroid effect without interference with the HPA system. This could be the case for treating glaucoma or favoring/accelerating the healing of wounds or burns. IV. Projections Other antiprogestins and antiglucocorticosteroids, possibly better than RU486, will appear in the near future. However, considering the time and money necessary for developing new compounds, it is advisable to continue further studies with RU486, treating it as a representative of a new class of useful drugs. Besides being used in


human fertility control, RU486 may help the treatment of several serious conditions. Despite the controversy surrounding this compound, further research needs to be done not only for medical and humanitarian reasons, but also for the preservation of scientific integrity. Etienne-Emile Baulieu

References 1. Herrmann W, Wyss R, Riondel A, Philibert D, Teutsch G, Sakiz E, Baulieu EE 1982 Effet d'un steroide anti-progesterone chez la femme: interruption du cycle menstruel et de la grossesse au debut. C R Acad Sci [III] 294:933 2. Baulieu EE 1985 RU486: an antiprogesterone steroid with contragestive activity in women. In: Baulieu EE, Segal SJ (eds) The Antiprogestin Steroid RU486 and Human Fertility Control. Plenum Press, New York, p 1 3. Baulieu EE 1989 Contragestion and other clinical applications of RU486, an antiprogesterone at the receptor. Science 245:1351 4. Baulieu EE 1989 RU486 as an antiprogesterone steroid. From receptor to contragestion and beyond. JAMA 262:1808 5. Csapo AI, Erdos T 1976 The critical control of progesterone levels and pregnancy by anti-progesterone. Am J Obstet Gynecol 126:598 6. Ulmann A 1987 Uses of RU486 for contragestion: an update. Contraception 36:27 7. Couzinet B, Le Strat N, Ulmann A, Baulieu EE, Schaison G 1986 Termination of early pregnancy by the progesterone antagonist RU486 (mifepristone). N Engl J Med 315:1565 8. Bergstrom S, Diczfaluzy E, Borell U, Karim S, Samuelsson B, Uvnas B, Wiqvist N, Bygdeman M 1972 Prostaglandins in fertility control. Science 175:1280 9. Bygdeman M, Swahn ML 1985 Progesterone receptor blockage: effect on uterine contractility and early pregnancy. Contraception 32:45 10. Rodger MW, Baird DT 1987 Induction of therapeutic abortion in early pregnancy with Mifepristone in combination with prostaglandin pessary. Lancet 2:1415 11. Dubois C, Ulmann A, Aubeny E, Elia D, Jourdan MC, Van Den Bosch MC, Leton M, Baulieu EE 1988 Contragestion par le RU486: interet de l'association a un derive prostaglandine. C R Acad Sci [III] 306:57 12. Silvestre L, Dubois C, Renault M, Rezvani Y, Baulieu EE, Ulmann A 1990 Voluntary interruption of pregnancy with mifepristone (RU486) and a prostaglandin analogue. N Engl J Med 322:645 13. Schaison G, George M, Lestrat N, Reinberg M, Baulieu EE 1985 Effects of the antiprogesterone steroid RU486 during mid-luteal phase in normal women. J Clin Endocrinol Metab 61:484 14. Garzo VG, Liu J, Ulmann A, Baulieu EE, Yen SSC 1988 Effects of an antiprogesterone (RU486) on the hypothalamic-hypophysealovarian-endometrial axis during the luteal phase of the menstrual cycle. J Clin Endocrinol Metab 66:508 15. Croxatto HB, Salvatierra AM, Romero C, Spitz IM 1987 Late luteal phase administration of RU486 for three successive cycles does not disrupt bleeding patterns or ovulation. J Clin Endocrinol Metab 65:1272 16. Lahteenmaki P, Rapeli T, Kaariainen M, Alfthan H, Ylikorkala O 1988 Late postcoital treatment against pregnancy with antiprogesterone RU486. Fertil Steril 50:36 17. Dubois C, Ulmann A, Baulieu EE 1988 Contragestion with late luteal administration of RU486 (Mifepristone). Fertil Steril 50:593 18. Li TC, Dockery P, Thomas P, Rogers AW, Lenton EA, Cooke ID 1988 The effect of progesterone receptor blockade in the luteal phase of normal fertile women. Fertil Steril 50:732 19. Swahn ML, Johannisson E, Daniore V, de la Torre B, Bygdeman M 1988 The effect of RU486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium. Hum Reprod 3:915 20. Liu JH, Yen SCC 1983 Induction of midcycle gonadotropin surge

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 12:15 For personal use only. No other uses without permission. . All rights reserved.



by ovarian steroids in women: a critical evaluation. J Clin Endocrinol Metab 57:797 21. Collins RL, Hodgen GD 1986 Blockade of the spontaneous midcycle gonadotropin surge in monkeys by RU486: a progesterone antagonist or agonist. J Clin Endocrinol Metab 63:1270 22. Croxatto HB, Salvatierra AM, Cyclic use of antigestagens for fertility control. Runnebaum B, Kiesel L (eds) Proceeding of the III International Symposium on Contraception. Heidelberg, West Germany, 1990, Parthenon Publishing, in press 23. Wolf JP, Sinosich M, Anderson TL, Ulmann A, Baulieu EE, Hodgen GD 1989 Progesterone antagonist (RU486) for cervical dilation, labor induction, and delivery in monkeys: effectiveness in combination with oxytocin. Am J Obstet Gynecol 160:45

Endo • 1990 Vol 127 • No 5

24. Gravanis A, Schaison G, George M, De Brux J, Satyaswaroop PG, Baulieu EE, Robel P 1985 Endometrial and pituitary responses to the steroidal antiprogestin RU486 in postmenopausal women. J Clin Endocrinol Metab 60:151 25. Philibert D, Deraedt R, Teutsch G, RU486 a potent antiglucocorticoid in vivo. Program of the 8th International Congress of Pharmacology, Tokyo, Japan, 1981, p 1463 (Abstract) 26. Gaillard RC, Riondel A, Herrman W, Muller AF, Baulieu EE 1984 RU486: a steroid with antiglucocorticosteroid activity that only disinhibits the human pituitary-adrenal system at a specific time of day. Proc Natl Acad Sci USA 81:3879 27. Bertagna X, Bertagna C, Luton JP, Husson JM, Girard F 1984 The new steroid analog RU486 inhibits glucocorticoid action in man. J Clin Endocrinol Metab 59:25

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 12:15 For personal use only. No other uses without permission. . All rights reserved.

RU486 and the early nineties.

0013-7227/90/1275-2043$02.00/0 Endocrinology Copyright © 1990 by The Endocrine Society Vol. 127, No. 5 Printed in U.S.A. Editorial: RU486 and the Ea...
492KB Sizes 0 Downloads 0 Views