FERTILITY AND STERILITY Copyright
©
1991 The American Fertility Society
Vol. 56, No.3, September 1991
Printed on acid-free paper in U.S.A.
Antiprogestins: the political chemistry of RU486
Gary D. Hodgen, Ph.D. Professor and President The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia
Received July 9, 1991. Reprint requests: Gary D. Hodgen, Ph.D., The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia 23510.
394
Hodgen
Editor's corner
Perhaps no word in reproductive medicine today causes as much divisiveness as RU486. This progesterone antagonist (antiprogestin) . . . this antiglucocorticoid . . . this noncompetitive antiestrogen . . . indeed, RU486 manifests all of these biological properties depending on the hormonal milieu into which the compound is introduced. But did you know that >400 antiprogestins have been synthesized with several dozen having preliminary evaluations by at least six pharmaceutical companies. Their differential properties include plasma clearance half-lives as short as 2 to 3 hours versus >20 hours for others. Some are virtually free of antiglucocorticoid activity. Whether their recently recognized capacities to diminish (block) the mitogenic impact of estrogens on certain tissues are universal or quite selective is unknown. RU486 is but one of these antiprogestins, albeit by far the most familiar both to reproductive scientists and the lay public. Since the original article of Herrman et al. 1 in 1982, > 700 research reports and scientific abstracts have appeared revealing the high level of research interest in general antiprogestins. This issue of the journal further inspires our readers: first by the review article on use of RU486 (Mifepristone) alone or in combination with prostaglandins for termination of early pregnancy (Avrech et al., page 385) 2 and second by the preliminary findings of Kettel et al. (page 402) 3 demonstrating the potential utility of RU486 in the treatment of endometriosis. These reports join so many others collectively suggesting that antiprogestins as a group should be studied thoroughly because the list of potential clinical indications includes: (1) abortifacient (with prostaglandin), (2) endometriosis treatment, (3) cervical dilation and myometrial contractility adjunctive to labor and delivery, (4) contraception by blocking ovulation, (5) modulation of premenstrual syndrome, (6) retardation of certain estrogen-dependent neoplasia such as breast and endometrial cancer, (7) modulation of cortisol excess in Cushing's syndrome, (8) evacuation of the failed conceptus in advanced pregnancy after unfortunate intrauterine death, (9) making easier hysteroscopic or other transcervical procedures requiring access to the uterine lumen, and (10) acceleration of breast milk production from the near-term interval to a few weeks thereafter, etc. Before we allow (foster) the misperception that RU486, or any of the other antiprogestins, is a new "wonder drug," let us hasten to point out that the database for the potential clinical indications cited above, and several others, ranges from single study reports on a few subjects either in different animal species or humans (such as Kettel et al., page 402), 3 to a series of progressive small- to medium-sized studies that Fertility and Sterility
deserve cohesive interpretation as preclinical and clinical results (such as multisource evidence of antiprogestins for contraception via ovulation inhibition), or finally, extensive human data demonstrating overall profound evidence of safety and efficacy (such as the abortifacient use ofRU486 reviewed by Avrech et al., page 385). 2 Moreover, caution is in order in part because such varied potential clinical indications reflect the differential biological activities of antiprogestins, as stated in the opening paragraph. Recall, too, that the only available firm database for clinical practice is for RU486 when used as an abortifacient (with prostaglandins) in what is exclusively an acute protocol closely supervised by clinic physicians in France. Responses during longterm exposure to antiprogestins must be assessed carefully with specific attention to possible undesirable side-effects. For example, during the 3-month treatment course employed by Kettel et al. (page 000), 3 there was clear patient benefit with regard to decreased pain from pelvic endometriosis, but cortisol and adrenocorticotropic hormone levels were significantly elevated. Only more extensive investigations will clarify whether these unintended actions of RU486 on the pituitary-adrenal cortical axis are of consequence. We ask: Would antiprogestins lacking antiglucocorticoid activity be superior for chronic diseases? Would antiprogestins expressing more profound noncompetitive antiestrogenic properties be more effective on endometriosis lesions via combined suppression of gonadotropin secretion, resulting in low ovarian estrogen secretion, as well as a direct diminution of residual estrogenic stimulation? 4 The course by which to proceed seems clear enough. Continued careful preclinical and clinical investigations will reveal and, ultimately, elucidate the safe and effective clinical applications for antiprogestins, if any. But wait! There is a problem that precludes the natural evolution of scientific inquiry on antiprogestins. It is the politics of abortion. Federal funding to assist in these endeavors may be hard to come by even for urgent potential indications unrelated to abortion, such as breast cancer treatment. There is ongoing political, economic, and personal intimidation. Certain members of Congress have pressured
Vol. 56, No.3, September 1991
the Food and Drug Administration to insist by import alert that federal customs officers seize even individual prescription quantities of RU486 that might be brought into the United States. Antiabortion groups boldly threaten to boycott the whole spectrum of products marketed by any pharmaceutical company that would pursue development of any antiprogestin product. Individual investigators and their families are harassed in their homes only because they desire to know whether and how antiprogestins may benefit patients presenting with a broad spectrum of medical needs, as listed above. These circumstances rival the nonsense to be recalled in the Scopes Monkey Trial of the 1920s, where logic and reason were challenged by the narrowness of zealotism derived from a singular viewpoint to the exclusion of any other appropriate motives. Now, that issue is abortion. Whatever be our individual perspective-against abortion or prochoice-(and under what circumstances), it is time to recognize that the scientific agenda on antiprogestin research must be seen more broadly by governmental agencies, the pharmaceutical industry, the academic researchers, and most of all, those who lobby and inflame solely on the abortion issue. There are other people in need of this new knowledge on antiprogestins; they shouldn't have to care about the political chemistry of RU486.
REFERENCES 1. Herrman W, Wyss R, Riondel A, Philibert D, Teutsch B, Bak GE, Baulieu EE: Effect d'un steroid antiprogesterone chez Ia femme, interruption du cycle menstruel et de Ia prossesse au debut. C R Acad Sci Paris 294:933, 1982 2. Avrech OM, Golan A, Weinraub Z, Bukovsky I, Caspi E: Mifepristone (RU486) alone or in combination with a prostaglandin analog for termination of early pregnancy: a review. Fertil Steril 56:385, 1991 3. Kettel LM, Murphy AA, Mortola JF, Liu JH, Ulmann A, Yen SSC: Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis. Fertil Steril 56:402, 1991 4. Wolf JP, Hsiu JG, Anderson TL, Ulmann A, Baulieu EE, Hodgen GD: Noncompetitive antiestrogenic effect of RU486 in blocking the estrogen -stimulated luetinizing hormone surge and proliferative action of estradiol on endometrium in castrate monkeys. Fertil Steril 52:1055, 1989
Hodgen Editor's corner
395
©
1991 The American Fertility Society
Vol. 56, No.3, September 1991
Printed on acid-free paper in U.S.A.
Antiprogestins: the political chemistry of RU486
Gary D. Hodgen, Ph.D. Professor and President The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia
Received July 9, 1991. Reprint requests: Gary D. Hodgen, Ph.D., The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia 23510.
394
Hodgen
Editor's corner
Perhaps no word in reproductive medicine today causes as much divisiveness as RU486. This progesterone antagonist (antiprogestin) . . . this antiglucocorticoid . . . this noncompetitive antiestrogen . . . indeed, RU486 manifests all of these biological properties depending on the hormonal milieu into which the compound is introduced. But did you know that >400 antiprogestins have been synthesized with several dozen having preliminary evaluations by at least six pharmaceutical companies. Their differential properties include plasma clearance half-lives as short as 2 to 3 hours versus >20 hours for others. Some are virtually free of antiglucocorticoid activity. Whether their recently recognized capacities to diminish (block) the mitogenic impact of estrogens on certain tissues are universal or quite selective is unknown. RU486 is but one of these antiprogestins, albeit by far the most familiar both to reproductive scientists and the lay public. Since the original article of Herrman et al. 1 in 1982, > 700 research reports and scientific abstracts have appeared revealing the high level of research interest in general antiprogestins. This issue of the journal further inspires our readers: first by the review article on use of RU486 (Mifepristone) alone or in combination with prostaglandins for termination of early pregnancy (Avrech et al., page 385) 2 and second by the preliminary findings of Kettel et al. (page 402) 3 demonstrating the potential utility of RU486 in the treatment of endometriosis. These reports join so many others collectively suggesting that antiprogestins as a group should be studied thoroughly because the list of potential clinical indications includes: (1) abortifacient (with prostaglandin), (2) endometriosis treatment, (3) cervical dilation and myometrial contractility adjunctive to labor and delivery, (4) contraception by blocking ovulation, (5) modulation of premenstrual syndrome, (6) retardation of certain estrogen-dependent neoplasia such as breast and endometrial cancer, (7) modulation of cortisol excess in Cushing's syndrome, (8) evacuation of the failed conceptus in advanced pregnancy after unfortunate intrauterine death, (9) making easier hysteroscopic or other transcervical procedures requiring access to the uterine lumen, and (10) acceleration of breast milk production from the near-term interval to a few weeks thereafter, etc. Before we allow (foster) the misperception that RU486, or any of the other antiprogestins, is a new "wonder drug," let us hasten to point out that the database for the potential clinical indications cited above, and several others, ranges from single study reports on a few subjects either in different animal species or humans (such as Kettel et al., page 402), 3 to a series of progressive small- to medium-sized studies that Fertility and Sterility
deserve cohesive interpretation as preclinical and clinical results (such as multisource evidence of antiprogestins for contraception via ovulation inhibition), or finally, extensive human data demonstrating overall profound evidence of safety and efficacy (such as the abortifacient use ofRU486 reviewed by Avrech et al., page 385). 2 Moreover, caution is in order in part because such varied potential clinical indications reflect the differential biological activities of antiprogestins, as stated in the opening paragraph. Recall, too, that the only available firm database for clinical practice is for RU486 when used as an abortifacient (with prostaglandins) in what is exclusively an acute protocol closely supervised by clinic physicians in France. Responses during longterm exposure to antiprogestins must be assessed carefully with specific attention to possible undesirable side-effects. For example, during the 3-month treatment course employed by Kettel et al. (page 000), 3 there was clear patient benefit with regard to decreased pain from pelvic endometriosis, but cortisol and adrenocorticotropic hormone levels were significantly elevated. Only more extensive investigations will clarify whether these unintended actions of RU486 on the pituitary-adrenal cortical axis are of consequence. We ask: Would antiprogestins lacking antiglucocorticoid activity be superior for chronic diseases? Would antiprogestins expressing more profound noncompetitive antiestrogenic properties be more effective on endometriosis lesions via combined suppression of gonadotropin secretion, resulting in low ovarian estrogen secretion, as well as a direct diminution of residual estrogenic stimulation? 4 The course by which to proceed seems clear enough. Continued careful preclinical and clinical investigations will reveal and, ultimately, elucidate the safe and effective clinical applications for antiprogestins, if any. But wait! There is a problem that precludes the natural evolution of scientific inquiry on antiprogestins. It is the politics of abortion. Federal funding to assist in these endeavors may be hard to come by even for urgent potential indications unrelated to abortion, such as breast cancer treatment. There is ongoing political, economic, and personal intimidation. Certain members of Congress have pressured
Vol. 56, No.3, September 1991
the Food and Drug Administration to insist by import alert that federal customs officers seize even individual prescription quantities of RU486 that might be brought into the United States. Antiabortion groups boldly threaten to boycott the whole spectrum of products marketed by any pharmaceutical company that would pursue development of any antiprogestin product. Individual investigators and their families are harassed in their homes only because they desire to know whether and how antiprogestins may benefit patients presenting with a broad spectrum of medical needs, as listed above. These circumstances rival the nonsense to be recalled in the Scopes Monkey Trial of the 1920s, where logic and reason were challenged by the narrowness of zealotism derived from a singular viewpoint to the exclusion of any other appropriate motives. Now, that issue is abortion. Whatever be our individual perspective-against abortion or prochoice-(and under what circumstances), it is time to recognize that the scientific agenda on antiprogestin research must be seen more broadly by governmental agencies, the pharmaceutical industry, the academic researchers, and most of all, those who lobby and inflame solely on the abortion issue. There are other people in need of this new knowledge on antiprogestins; they shouldn't have to care about the political chemistry of RU486.
REFERENCES 1. Herrman W, Wyss R, Riondel A, Philibert D, Teutsch B, Bak GE, Baulieu EE: Effect d'un steroid antiprogesterone chez Ia femme, interruption du cycle menstruel et de Ia prossesse au debut. C R Acad Sci Paris 294:933, 1982 2. Avrech OM, Golan A, Weinraub Z, Bukovsky I, Caspi E: Mifepristone (RU486) alone or in combination with a prostaglandin analog for termination of early pregnancy: a review. Fertil Steril 56:385, 1991 3. Kettel LM, Murphy AA, Mortola JF, Liu JH, Ulmann A, Yen SSC: Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis. Fertil Steril 56:402, 1991 4. Wolf JP, Hsiu JG, Anderson TL, Ulmann A, Baulieu EE, Hodgen GD: Noncompetitive antiestrogenic effect of RU486 in blocking the estrogen -stimulated luetinizing hormone surge and proliferative action of estradiol on endometrium in castrate monkeys. Fertil Steril 52:1055, 1989
Hodgen Editor's corner
395
