B3
The Use of Antiprogestins in the Reproductive Cycle

LYNNETTE KAYE NIEMAN, M.D.

Senior Investigator, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda

Progesterone is required for the development of the endometrium in preparation for pregnancy. It is also required for maintenance of pregnancy until the luteal-placental shift in steroidogenesis occurs about midway through the first trimester. During pregnancy, progesterone promotes a quiescent uterine myometrium and a closed cervical os. Because progesterone is essential to these functions, in theory, blockade of its action would result in infertility or abortion. Steroid antagonists of progesterone have been developed that block progesterone action at the receptor level. This paper introduces the use of antiprogestins to alter the reproductive cycle of women, and reviews the published literature regarding such use in the follicular phase of the menstrual cycle. Although a number of such compounds exist, only RU 486 has been studied for these properties in clinical trials. Although those data constitute the bulk of what is reviewed here, it should be kept in mind that other antiprogestins might not produce the same results.

USE OF ANTIPROGESTINS IN THE REPRODUCTIVE CYCLE
Basic Concepts and Assumptions

Apart from its effects on the endometrium, progesterone exerts important activity on the breast, cervix, lipids, pituitary-hypothalamic unit, and brain. It follows, then, that an antiprogestin would block or alter these effects. Progesterone participates in the differentiation of mammary tissue and in the preparation for lactation. It inhibits estro-



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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda B3 The Use of Antiprogestins in the Reproductive Cycle LYNNETTE KAYE NIEMAN, M.D. Senior Investigator, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda Progesterone is required for the development of the endometrium in preparation for pregnancy. It is also required for maintenance of pregnancy until the luteal-placental shift in steroidogenesis occurs about midway through the first trimester. During pregnancy, progesterone promotes a quiescent uterine myometrium and a closed cervical os. Because progesterone is essential to these functions, in theory, blockade of its action would result in infertility or abortion. Steroid antagonists of progesterone have been developed that block progesterone action at the receptor level. This paper introduces the use of antiprogestins to alter the reproductive cycle of women, and reviews the published literature regarding such use in the follicular phase of the menstrual cycle. Although a number of such compounds exist, only RU 486 has been studied for these properties in clinical trials. Although those data constitute the bulk of what is reviewed here, it should be kept in mind that other antiprogestins might not produce the same results. USE OF ANTIPROGESTINS IN THE REPRODUCTIVE CYCLE Basic Concepts and Assumptions Apart from its effects on the endometrium, progesterone exerts important activity on the breast, cervix, lipids, pituitary-hypothalamic unit, and brain. It follows, then, that an antiprogestin would block or alter these effects. Progesterone participates in the differentiation of mammary tissue and in the preparation for lactation. It inhibits estro-

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda gen-induced increases in a cellular, elastic cervical mucus, and induces a cellular, viscous, scanty mucus that is hostile to sperm. Although the impact of endogenous progesterone on circulating lipids is probably small, synthetic progestins, especially those with androgenic properties, antagonize the enhancement of high-density lipoprotein (HDL) cholesterol levels caused by estrogen. Progesterone is important in the feedback regulation of the gonadotropins, especially luteinizing hormone (LH). Although 1-2 mg of progesterone is secreted daily in the follicular phase, its impact is most clear during the luteal phase, when secretion rates rise to 25 mg/day, and circulating levels may reach 10 mg/ml. At this time, progesterone decreases LH pulse frequency and amplitude. Progesterone may have other central actions: at high doses in lower animals it acts as an anesthetic, and speculation regarding its role in the mood changes of pregnancy and in the premenstrual syndrome are long-standing, but unconfirmed. Given the importance of progesterone to female reproductive competence, the availability of progesterone antagonists was hailed as providing new venues for exploration of progesterone action and for treatment of progesterone-dependent conditions. Much of this speculation was based on the assumption that progesterone antagonists would simply reverse or inhibit progesterone actions. This assumption has not always been proven to be correct. Thus, a number of assessment issues must be addressed in the design and interpretation of studies to evaluate progesterone antagonists. Assessment Issues in Evaluating Antiprogestins First, a dose and route of administration must be chosen to maximize the desired effect. RU 486 has glucocorticoid, androgen, and progesterone antagonist properties and little, if any, agonist activity. It does not react with the mineralocorticoid or estrogen receptor (Baulieu, 1989). Only an oral preparation is available for human administration. RU 486 has a prolonged half-life of about 20 hours when given in this way, probably because of extensive binding to plasma proteins (Kawai et al., 1987). Although antiglucocorticoid effects are seen at single doses of >3 mg/kg, antiprogestational activity is seen at smaller doses, in part allowing for the exploitation of antiprogestin properties without clinical compromise of glucocorticoid status. Second, the physiologic status of the subject must be considered. The effects of an antiprogestin may differ dramatically in the absence or presence of progesterone or estrogen. Thus, stage of the menstrual cycle, anovulation, and pregnancy might all show differing effects. Also, end points must be chosen to measure efficacy, to evaluate potential

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda actions on other parts of the reproductive axis, and to assess toxicity and unexpected effects. Evaluation of cervical mucus, endometrial histology or proteins, follicular diameter, body temperature, and plasma concentrations of RU 486, estrogen, progesterone, and gonadotropins may all be useful. Finally, evaluation of the mechanism(s) by which RU 486 affects reproduction should include evaluation of antiglucocorticoid effects. These include antagonism of cortisol action at target tissues, RU 486-induced increases in corticotropin-releasing hormone and opiates, and non-receptor-mediated drug reactions and potential toxicity. Potential Uses of Antiprogestins Given the known actions of progesterone on the reproductive tract, many potential uses of an antiprogesterone exist. RU 486 has been tested as a physiologic probe of progesterone action, as a contraceptive, as an abortifacient, and as an agent to promote cervical ripening and induce labor. The effects of RU 486 in pregnancy are reviewed elsewhere in this report (Bygdeman, Appendix B5; Ulmann and Silvestre, Appendix B6). Antiprogestins have shown promise in the treatment of endometriosis and leiomyomas, also reviewed elsewhere in this report (Yen, Appendix B8). These compounds may be useful in induction of lactation and may have intriguing effects on polycystic ovary syndrome, although such potential actions have not been formally evaluated. The treatment regimens used to test the potential of RU 486 as a contraceptive agent are logical extensions of the dose-response effects at various times in the menstrual cycle. RU 486 might be given during one portion of the cycle, either the follicular phase or the luteal phase; either chronically (daily), intermittently, or in a timed fashion, such as on a specific day of the cycle; or after intercourse. Follicular Phase Administration of RU 486 The effects of RU 486 in the follicular phase depend on the dose and the progress of folliculogenesis at the time of administration. Except for a minimal decrease in serum estradiol levels, RU 486 had little effect on folliculogenesis, timing of ovulation, or duration of the menstrual cycle when given during the first three days of the cycle (Stuenkel et al., 1990). When given during the midfollicular phase at single doses of 10 or 100 mg, LH and follicle-stimulating hormone (FSH) levels decreased in proportion to the plasma estradiol levels at the time the dose was given (Permezel et al., 1989). Thus, the ability of RU 486 to reduce gonadotropins seems dependent on prior exposure to estrogen.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Mid- to late-follicular administration of RU 486 at daily doses of 100 mg or 3 mg/kg for three to seven days inhibits both folliculogenesis and ovulation as judged by estradiol production, follicular growth by ultrasound, and the absence of a midcycle LH surge. Follicular recruitment is reinitiated after discontinuation of the agent, and ovulation occurs about 14 days later (Liu et al., 1987; Shoupe et al., 1987). This effect is dose dependent: lower doses (25 mg on days 1-14 or 50 mg/day on days 7-10) allow continued follicular growth, accompanied by lower than normal daily increments in serum estrogen and a delay in the LH surge until after discontinuation of the agent (Luukkainen et al., 1988; Swahn et al., 1988). At the lowest doses tested, 1 mg/day, started when the dominant follicle was 14-16 mm, the follicular phase is prolonged by 1-11 days; the LH surge is delayed, but occurs in most women (Batista et al., 1992b). These effects on the timing of the LH surge may reflect central antagonism of progesterone action, since the small preovulatory rise in progesterone may be the ultimate trigger of ovulation. This concept is supported by the observation that follicular phase administration of RU 486 reduces LH amplitude (Permezel et al., 1989; Shoupe et al., 1990), whereas progesterone administration increases it (Permezel et al., 1989). RU 486 can inhibit LH secretion from cultured rat pituicytes (Wolf et al., 1989), which suggests a pituitary rather than a hypothalamic site of action. The ability of RU 486, at doses of 25 mg or more, to inhibit ovulation suggests that this may be an effective contraceptive strategy. The degree of suppression of steroidogenesis is critical in this approach. Severe suppression of estrogen secretion would be undesirable because of deleterious effects on libido, bones, and lipids. Conversely, normal unopposed levels of estrogen might lead to endometrial hyperplasia. One strategy uses a dose of RU 486 that should allow adequate estrogen secretion to be maintained while inhibiting ovulation. Endometrial differentiation and shedding are induced monthly by periodic short-term administration of a progestin. This approach has been tested in women who are not at risk for pregnancy by using a combined regimen of RU 486, 25 mg/day, from days 1-14 of the menstrual cycle, followed by norethisterone, 5 mg/day, during days 15 to 24. In that study, follicular phase estradiol levels were blunted, and ovulation was inhibited in most women, but normal cyclic bleeding was maintained (Kekkonen et al., 1990). Ovulation occurred in two of eight women during norethisterone treatment. There are no data regarding additional effects of this regimen on cervical mucus or endometrial histology that might contribute to a contraceptive effect apart from inhibition of ovulation. The contraceptive efficacy in women of follicular phase administration has not been tested directly.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda Other Strategies for Administration of RU 486 During the Menstrual Cycle The effect of progesterone on endometrial tissue is most apparent in the luteal phase. Deficiency of progesterone during the luteal phase is thought to result in infertility or spontaneous abortion. Thus, it was logical that the effects of RU 486 in nonpregnant women were first investigated in the luteal phase (Herrmann et al., 1982). Administration of the agent after luteal phase day 3 at doses of 25 mg (or greater) causes endometrial shedding. At doses higher than 5 mg/kg, luteolysis occurs concurrently with menses; the timing of the cycle is reset so that the next follicular phase begins (Nieman et al., 1988). At lower doses, luteolysis is not achieved consistently with endometrial shedding, and another bleeding episode is commonly observed within two weeks when estrogen and progesterone levels fall to the follicular phase range. Presumably, this second bleeding reflects regrowth of the endometrium under the influence of continued corpus luteum function and subsequent shedding as luteolysis occurs. The differential effects of RU 486 on the endometrium and corpus luteum must be weighed when considering its use as a contraceptive in the luteal phase of the menstrual cycle. Daily administration of an antiprogestin throughout the cycle might impede endometrial maturation without suppressing ovulation or steroidogenesis, and thus offer another contraceptive strategy (Batista et al., 1991, 1992a). Alternatively, administration of RU 486 to inhibit ovulation or prevent implantation may represent an effective strategy for post-coital contraception (Glasier et al., 1992; Webb et al., 1992). The contraceptive potential of daily, post-coital, and luteal phase administration of RU 486 is reviewed elsewhere in this report (Baird, Appendix B4). TOXICITY Side effects have been noted in chronic studies using 200 mg/day of RU 486 for the treatment of meningioma. One study reported fatigue and symptoms consistent with adrenal insufficiency beginning in the second week of drug administration (Lamberts et al., 1992), but another group using a similar regimen noted only fatigue without symptoms of adrenal insufficiency (Grunberg et al., 1993). At this dose, previously cycling women became amenorrheic; three of five women developed metrorrhagia, and one of these women had endometrial hyperplasia. Five patients developed a transient maculopapular rash. At a daily dose of 100 mg of RU 486, one of six women treated for endometriosis reported anorexia, nausea, and fatigue after two weeks. The symptoms resolved within two weeks without treatment (Kettel et al., 1991).

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda No other adverse side effects have been reported in any study using RU 486 at a daily dose of less than 10 mg/kg for more than seven days, or at single doses of up to 25 mg/kg. The range of doses used in contraceptive studies are well within these limits. Since few published studies have examined the effects of chronic administration of antiprogestins for more than one week, definitive information regarding adverse reactions of long-term administration is lacking. QUESTIONS FOR FUTURE RESEARCH A variety of questions remain unanswered concerning follicular phase administration of RU 486. What is the mechanism of estradiol inhibition? Does RU 486 have direct effects on the granulosa cells, or are its actions mediated primarily through suppression of gonadotropins? Related to this issue is whether LH pulsatility is normal and whether LH and FSH bioactivities are affected by exposure to RU 486 and other antiprogestins. How is follicular development affected by antiprogestins? Estradiol concentrations have been used to reflect follicular development. However, assessment of follicular diameter by ultrasound measurement has been used in relatively few studies. A corollary to this is the question of whether ova within developing follicles are normal. If ovulation occurs during RU 486 administration, are ova fertilizable, and would subsequent embryos develop normally? Is follicular phase administration of RU 486 for contraception practical? A number of questions, both social and biologic, pertain. The amount of estrogen produced must be adequate to maintain bone mass, normal lipid profiles, and sexual function. However, if this estrogen level is achieved, some women are likely to develop endometrial hyperplasia because progesterone levels may not be sufficient to transform adequately the endometrium. Thus, some plan for exogenous progestin exposure would need to be built into the schedule, perhaps on a monthly basis, as has been tested. Alternatively, for women in whom long intervals without menses would be acceptable, perhaps progestin could be given at longer intervals. However, this is likely to provoke fears of pregnancy. The short-term (one to three cycles) effects of antiprogestins may change when they are administered for longer times; thus, long-term studies are needed of any regimen. Other dose schedules might also be considered. Finally, the bulk of data on follicular phase administration derive from studies with RU 486. Other antiprogestin compounds will need to be tested, because those compounds may have different properties.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE B3.1 Effects of RU 486 on Follicular Phase Parameters References Amount Days FP LH FD E2 P4 Toxicity Stuenkel et al.(1990) 3 mg/kg 1–3 NE nl LHS and pulses NE dec NE 1/7 HA Permezelet al.(1990) 10 or 100 mg 6, 10 NE LH dec NE NE NE NE Swahn et al. (1988) 50 mg 7–10 21 NE NE dec NE None Kekkonan et al.(1990) 25a mg 1–14 NE 2/6 ovulated <10 dec dec NE Luukkainen et al.(1988) 25 mg 1–14 21 NE NE dec NE None Liu et al. (1987) 3 mg/kg Late FPb 29 nl LHS and FSH levels NE dec NE None Shoupe et al.(1987) 100 mg 10–17 28 nl LHS NE dec NE None Batista et al.(1992) 1 mg Late FPc 16 nl LHS inc NE NE None NOTE: Days = day(s) of follicular phase on which RU 486 was given; FP = follicular phase length in days; FD = follicular diameter in mm; E2 = estradiol levels; P4 = progesterone levels; NE = not examined; LHS = LH surge; dec = decreased; inc = increased; nl = normal; HA = headache. a Norethindrone given on days 15–24. b RU 486 given at FD 15–20 for 3 days. c RU 486 given at FD 14–16 for 5 days.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda SUMMARY RU 486 and other progestin antagonists represent a novel and promising approach to contraception. Further work needs to be done to define optimal schedules of administration that would be convenient and effective. Finally, large-scale contraceptive trials remain to be done to establish with certainty the utility of any of the regimens discussed. REFERENCES Batista, M.C., Bristow, T.L., Mathews, J., et al. Daily administration of the progesterone antagonist RU 486 prevents implantation in the cycling guinea pig. American Journal of Obstetrics and Gynecology 165:82–86, 1991. Batista, M.C., Cartledge, T.P., Zellmer, A.W., et al. Delayed endometrial maturation induced by daily administration of the antiprogestin RU 486: A potential new contraceptive strategy. American Journal of Obstetrics and Gynecology 167:60–65, 1992a. Batista, M.C., Cartledge, T.P., Zellmer, A.W., et al. Evidence for a critical role of progesterone in the regulation of the midcycle gonadotropin surge and ovulation. Journal of Clinical Endocrinology and Metabolism 74:565–570, 1992b. Baulieu, E.E. RU 486 as an antiprogesterone steroid: From receptor to contragestion and beyond. Journal of the American Medical Association 262:1808–1814, 1989. Glasier, A., Thong, K.J., Dewar, M., et al. Mifepristone (RU 486) compared with high-dose estrogen and progestogen for emergency post-coital contraception. New England Journal of Medicine 327:1041–1044, 1992. Grunberg, S.M., Weiss, M.H., Spitz, I.M., et al. Long-term treatment with the oral antiprogestational agent mifepristone (RU 486). In Adjuvant Therapy of Cancer. Vol. 7. Salmon, S. E., ed. Philadelphia: J.B. Lippincott, 1993. Herrmann, W., Wyss, R., Riondel, A., et al. The effects of an anti-progesterone steroid on women: Interruption of the menstrual cycle and of early pregnancy. Comptes Rendus de l'Académie des Sciences (Paris) 294:933–938, 1982. Kawai, S., Nieman, L.K., Brandon, D.D., et al. Pharmacokinetic properties of the antiglucocorticoid and antiprogesterone steroid RU 486 in man. Journal of Pharmacology and Experimental Therapeutics 241:401–406, 1987. Kekkonen, R., Alfthan, M., Haukkamaa, M., et al. Interference with ovulation by sequential treatment with the antiprogesterone RU 486 and synthetic progestin. Fertility and Sterility 53:747–750, 1990. Kettel, L.M., Murphy, A.A., Mortola, J.F., et al. Endocrine responses to long-term administration of the antiprogesterone RU 486 in patients with pelvic endometriosis. Fertility and Sterility 56:402–407, 1991. Lamberts, S.W., Tanghe, H.L., Avezaat, C.J., et al. Mifepristone (RU 486) treatment of meningiomas. Journal of Neurology, Neurosurgery and Psychiatry 55:486–490, 1992. Liu, J.H., Garzo, G., Morris, S., et al. Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU 486. Journal of Clinical Endocrinology and Metabolism 65:1135–1140, 1987. Luukkainen, T., Heikinheimo, O., Haukkamaa, M., et al. Inhibition of folliculogenesis and ovulation by the antiprogesterone RU 486. Fertility and Sterility 49:961–963, 1988. Nieman, L.K., and Loriaux, D.L. The use of anti-progesterones as a medical IUD. Baillieres Clinical Obstetrics and Gynaecology 2:609–616, 1988. Permezel, J.M., Lenton, E.A., Roberts, I., et al. Acute effects of progesterone and the

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda antiprogestin RU 486 on gonadotropin secretion in the follicular phase of the menstrual cycle. Journal of Clinical Endocrinology and Metabolism 68:960–965, 1989. Shoupe, D., Mishell, D.J., Page, M.A., et al. Effects of the antiprogesterone RU 486 in normal women. II. Administration in the late follicular phase. American Journal of Obstetrics and Gynecology 157:1421–1426, 1987. Shoupe, D., Mishell, D.J., Fossum, G., et al. Antiprogestin treatment decreases midluteal luteinizing hormone pulse amplitude and primarily exerts a pituitary inhibition. American Journal of Obstetrics and Gynecology 163:1982–1985, 1990. Stuenkel, C.A., Garzo, V.G., Morris, S., et al. Effects of the antiprogesterone RU 486 in the early follicular phase of the menstrual cycle. Fertility and Sterility 53:642–646, 1990. Swahn, M.L., Johannisson, E., Daniore, F., et al. The effect of RU 486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium. Human Reproduction 3:915–921, 1988. Webb, A.M.C., Russell, J., and Elstein, M. Comparison of Yuzpe regimen, danazol, and mifepristone (RU 486) in oral post-coital contraception. British Medical Journal 305:927–931, 1992. Wolf, J.P., Danforth, D.R., Ulmann, A., et al. Contraceptive potential of RU 486 by ovulation inhibition: II. Suppression of pituitary gonadotropin secretion in vitro. Contraception 40:185–193, 1989.