Annals of Medicine
`
`ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20
`
`Antiprogesterone RU 486—a Drug for Non-Surgical
`Abortion
`
`Oskari Heikinheimo, Olavi Ylikorkala & Pekka Lähteenmäki
`
`To cite this article: Oskari Heikinheimo, Olavi Ylikorkala & Pekka Lähteenmäki (1990)
`Antiprogesterone RU 486—a Drug for Non-Surgical Abortion, Annals of Medicine, 22:2, 75-84, DOI:
`10.3109/07853899009147247
`To link to this article: https://doi.org/10.3109/07853899009147247
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`Articles
`
`Antiprogesterone RU 486 - a Drug for
`Non=Surgical Abortion
`
`Oskari Heikinheimo', Olavi YIikorkala* and Pekka Lahteenmaki'
`
`RU 486 is the first steroidal antiprogesterone in clinical use. It acts by binding to
`progesterone receptor, thus blocking the effects of progesterone at the uterine level,
`and provoking endometrial necrosis and shedding. RU 486 can, therefore, be used to
`interrupt early human pregnancy. In pregnancies of up to 7-8 weeks duration, the rate
`of complete abortions with RU 486 has ranged from 50 '10 to 90 %. The success rate
`can, however, be augmented up to 95 %-100 YO by combining RU 486 with a low dose
`prostaglandin. RU 486 induced abortion has been well tolerated by women and highly
`acceptable to them. The bleeding starts 2-3 days after RU 486 administration lasting
`for 12-14 days. Possible clinical uses of RU 486 include induction of menstruation,
`late post-coital contraception, induction of labour after intrauterine fetal death, preoper-
`ative cervical ripening and treatment of progesterone receptor positive mammary
`tumours. When administered in the follicular phase of the cycle, RU 486 inhibits follic-
`ular development. In addition, the antiglucocorticoid properties of RU 486 have been
`used in symptomatic treatment of hypercortisolemia of Cushings disease. The phar-
`macokinetics of RU 486 are characterised by high micromolar serum concentrations,
`long half-life of 26-48 hours and substantial metabolism after oral administration. Al-
`though effective and well tolerated, RU 486 has aroused great moral controversy, which
`is currently hampering furter testing and distribution of the drug. So far RU 486 has
`been accepted for termination of pregnancy in France and in the Peoples Republic of
`China, to be used with prostaglandins and under strict medical surveillance.
`Key words: RU 486; mifepristone; endocrine effects; pharmacokinetics; clinical use.
`(Annals of Medicine 22: 75-84, 1990)
`
`Introduction
`
`Estimates of pregnancy terminations in the world vary
`between 50 to 60 million annually, whereas the annual
`increase in population is approximately 90 millions (1).
`Legal abortions are also needed in developed countries
`because accidental pregnancies occur, no matter how
`effective family planning services are. In Finland, where
`contraception is easily available, the annual number of
`abortions exceeds 13 000 (2). Safe, effective, discreet
`and less traumatizing methods of termination of un-
`wanted pregnancy are needed. Since the discovery of
`the indispensable role of progesterone hormone in the
`maintenance of early human pregnancy (3), one of the
`
`~
`
`~~
`
`From the Steroid Research Laboratory, Department of Medi-
`cal Chemistry, University of Helsinki, Finland, and 2 Second
`Department of Obstetrics and Gynaecology, University of Hel-
`sinki, Helsinki, Finland.
`Address and reprint requests: Oskari Heikinheimo, M.D.,
`Steroid Research Laboratory, Department of Medical chemistry,
`University of Helsinki, Siltavuorenpenger 10 A, SF-00170 Hel-
`sinki, Finland.
`Received: Auaust 31. 1989.
`
`main goals in contraceptive research has been direct-
`ed towards antagonising this progesterone action, thus
`terminating early pregnancy by a non-surgical method.
`Specific antagonism of progesterone can be achieved
`in two different ways: by inhibiting synthesis of
`progesterone, or by interfering with the interaction of
`progesterone with its intranuclear receptor protein in
`target cell. Both strategies are being currently tested.
`RU 486 (mifepristone), the first progesterone and
`glucocorticoid antagonist at the receptor level was in-
`troduced in 1981 (4,5). Since then, rapid progress has
`occurred in evaluating clinical applications of RU 486.
`More than 10 000 women have been enrolled in studies
`to evaluate of RU 486-induced termination of early preg-
`nancy (6); several of these have been conducted under
`the supervision of the World Health Organization
`(WHO) and The Population Council.
`
`Development of Antiprogesterone
`
`Purification of progesterone (pro-gestare) from porcine
`corpus luteum, and the understanding of its biologi-
`
`Ann Med 22
`
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`

`

`76
`
`Heikinheimo . Ylikorkala LBhteenmBki
`
`cat importance in the maintenance of pregnancy in rab-
`bits date back to 1930s (7, 8). Conclusive evidence on
`the indispensability of progesterone in the main-
`tenance of early human pregnancy was not, however,
`presented until 1972 (3). Thus, antagonism of progester-
`one might be used for termination of an unwanted early
`human pregnancy. Various approaches have been tried:
`immunization against progesterone,
`inhibition of
`progesterone synthesis and biological antagonism by
`administring prostaglandins (9-1 1). Of these methods,
`only prostaglandin therapy has clinical significance in
`the termination of early pregnancy, but it is complicat-
`ed by a high incidence side effects (11). Inhibition of
`synthesis of progesterone by Epostane, an inhibitor of
`3fl-hydroxy steroid dehydrogenase enzyme system, is
`being currently tested with a successrate of 84 O/O (12).
`In target cells, the effects of agonist steroid hor-
`mones are mediated by intracellular receptor proteins,
`which characteristically bind steroids of their class
`with high affinity and specificity. Steroid hormones
`thus activate their receptors, which further bind to chro-
`matin and regulate gene transcription (13). Studies by
`Teutsch and his co-workers (14) have shown that the
`structure of both progesterone and glucocorticoid
`receptors include a hydrophobic region capable of ac-
`cepting large hydrophobic substituents in the 11p-PO-
`sition of the steroid molecule. This discovery, togeth-
`er with knowledge of the properties of two important
`compounds in steroid biochemistry, tamoxifen and
`norethindrone, led to the introduction of RU 486 (Fig. l),
`the first specific progesterone and glucocorticoid
`receptor antagonist used in clinical work (4, 5).
`
`Endocrine Effecs of RU 486
`
`Mechanism of Action of RU 486 at the Receptor
`Level
`RU 486 binds with high affinity to nearly all mammalian
`progesterone receptors investigated (15, 16). To the hu-
`man progesterone receptor, RU 486 has an affinity more
`than twice as great as progesterone (17). The an-
`tiprogesterone effect of RU 486 is mediated via errone-
`ous binding of activated RU 486-progesterone recep-
`tor complexes to chromatin (18,19). RU 486 has a four
`times greater affinity to the human glucocorticoid
`receptor than DXM, a potent synthetic glucocorticoid
`(17). In contrast to the antiprogesterone action of RU
`486, the antiglucocorticoid action is mediated by main-
`taining the RU 486-glucocorticoid receptor complexes
`in an unactivated state, which are then unable to bind
`to chromatin (20, 21).
`
`Effects on the Hypothalamus-Hypophysis
`Early studies by Herrmann et al. (15) showed that in the
`midluteal phase of the cycle, RU 486 (50 mg x 4d) lo-
`wered the basal levels of gonadotrophins, and this was
`accompanied by falls in the concentrations of serum
`estradiol and progesterone. Further studies in the Iu-
`teal phase have shown that suppression of gonadotropin
`secretion by RU 486 was dose dependent; and that both
`the basal levels, and pulse amplitude of luteinizing hor-
`
`Ann Med 22
`
`CORTISOL
`
`PRCGESTERONE
`
`R U 486
`
`Flgure 1. Molecular structures of progesterone, cortisol and
`RU 486.
`
`mone (LH) secretion were lowered (22). The effect of
`RU 486 on the pulse frequency of gonadotropin secre-
`tion is controversial: Schaison et at. (22) showed that
`the pulse frequency of LH increased, whereas in
`studies by Garzo et at. (23) RU 486 either had no effect,
`or prolonged the frequency of LH secretion depending
`on the stage of the luteal phase. In addition, RU 486
`impaired the pituitary responses of LH to exogenous
`gonadotropin releasing hormone (GnRH) both in vitro
`(24) and in vivo (23). Hence, RU 486 has distinctly differ-
`ent effects on pituitary hormone secretion than proges-
`tins, which reduce LH pulse frequency and augment
`pulse amplitude (25).
`Administration of RU 486 in the late follicular phase
`has been reported to reduce only slightly the basal lev-
`els of gonadotropins, LH pulse amplitude and frequen-
`cy being unaffected. The midcycle LHIFSH-surge was,
`however inhibited by the treatment (26). In humans, the
`RU 486-attenuated midcycle gonadotropin surge is
`most likely caused by the significant reduction of ovar-
`ian estradiol production, and thus lack of positive feed-
`back on the hypophysis and hypothalamus (26, 27).
`
`Effects on the Ovaries
`In addition to induction of uterine bleeding by direct
`action on the endometrium, RU 486 has a dose depen-
`dent luteolytic effect, which is independent of the con-
`comitant gonadotropin levels (22, 28). Thus, after ad-
`ministration of RU 486 in the Meal phase, two distinct
`endocrine responses can be observed: RU 486 induced
`luteolysis with a single period of bleeding resembling
`normal menstruation, accompanied by declining serum
`levels of estradiol and progesterone. When RU 486
`causes only partial luteal regression, the serum levels
`of estradiol and progesterone remain unaffected, and
`after RU 486-induced light uterine bleeding, a second
`bleeding occurs at the time of expected menstruation
`(23, 29).
`In humans administration of RU 486 in the follicular
`phase of the cycle inhibits augmentation of ovarian es-
`tradiol production (26,27,30). Analogously with proges-
`tins, RU 486 lowers the amount of basal and hCG-stimu-
`lated estradiol and progesterone secretion by human
`granulosa cells in vitro (31).
`
`Effects on the Uterus
`RU 486 induces uterine bleeding by direct action on
`the endometrium (Fig. 2). In monkeys, RU 486-induced
`endometrial shedding occurs homogenously and quite
`deeply throughout the uterus (32). In the absence of
`progesterone, RU 486 has a weak progestomimetic ef-
`fect on the human endometrium, but when ad-
`
`Ex. 2007-0003
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`

`

`Antiprogesterone RU 486 - a Drug for Non-Surgical Abortion
`
`77
`
`I
`
`I
`
`Figure 2. Schematic presentation of the principal mechan-
`isms of action of RU 486 at the uterine and ovarian level.
`
`ministered with progesterone, RU 486 behaves as a
`pure angatonist (16).
`Throughout pregnancy a continuous supply of
`progesterone maintain the human uterus in a quiescent
`stage by suppressing prostaglandin (PG) synthesis (33).
`RU 486 stimulates the synthesis of PGs of F,,
`and E,
`series by strornal cells of endometrium and glandular
`cells of decidua in vitro (34,35). In early pregnancy, ex-
`ogenous PGs, when administered 1.5-3 days after
`commencement of RU 486 treatment, greatly stimulate
`the frequency and amplitude of uterine contractions
`(36). The time lag between the start of RU 486 adminis-
`tration and the increased sensitivity of uterus to PGs
`accords well with the delay in the start of uterine bleed-
`ing and the lack of histological changes in endometri-
`um at 1.5 days after intake of RU 486 (23). Thus, these
`studies show that at the endometrial andlor myometrial
`level the primary effects of RU 486 are mediated
`through increased concentrations of PGs.
`
`Effects on the Placenta
`In cell cultures of first and third trimester placentas RU
`486 impairs the synthesis of the placental hormones
`and proteins human chorionic gonadotrophin jhCG),
`human placental lactogen (hPL), progesterone and
`pregnancy-associated plasma protein-A (PAPP-A) (37,
`38). After administration of RU 486, serum levels of
`placental protein 12 (PP12) fell rapidly in patients re-
`quiring termination of pregnancy (39). In vivo, a decline
`in circulating levels of these hormones by RU 486 might
`potentiate the abortifacient properties of RU 486 (37, 38).
`
`Effects on the Pituitary-Adrenal -Axis
`RU 486 increases the pituitary secretion of adrenocor-
`ticotrophic hormone
`(ACTH) and other proopi-
`omelanocortin-derived peptides in a dose dependent
`manner, thereby also increasing the secretion of cor-
`tisol (40, 41). In all species investigated the an-
`tiglucocorticoid effects of RU 486 are seen only after
`high oral doses of RU 486 (42,43). In dogs, high doses
`of RU 486 also increased serum concentrations of al-
`dosterone, but this was associated only with mild nor-
`
`mosmolar hypervolemia (43). Analogous to its partial
`progestomimetic action in humans, RU 486 suppress-
`es the pituitary secretion of ACTH in response to ex-
`ogenous corticotropin releasing hormone (CRH), sug-
`gesting a weak glucocorticoid agonist activity of RU
`486 (16,44). The glucocorticoid agonist effect of RU 486
`life in
`was not, however, sufficient to support
`adrenalectomized monkeys (45).
`
`Antiproliferative Effect on Cancer Cells
`RU 486 is cytotoxic against progesterone receptor posi-
`tive breast cancer cell lines in vitro (46, 47). This prop-
`erty of RU 486 is mediated via a progesterone recep-
`tor and is independent of concomitant estrogen levels
`(48), but the precise mechanism of cytotoxity remain
`unclear. The growth inhibiting property of RU 486 is a
`progestin like effect, although RU 486 does not stimu-
`late the synthesis of progestin induced proteins or in-
`sulin binding sites, indicating pure antiprogesterone
`action (46,47). Thus, as regards breast cancer cells, the
`cytotoxic effects of RU 486 reflect the dual agonist-
`antagonist nature of RU 486. In endometrial cancer
`cells RU 486 shows adistinctly different behaviour, for
`in vitro, RU 486 reverses the progestin induced growth
`inhibition of these cells (49).
`
`Clinical Use of RU 486
`Termination of Unwanted Pregnancy with RU 486
`Since the introduction of RU 486, the main focus of clini-
`cal research has been directed towards terminating un-
`wanted pregnancies by blocking
`the effect of
`progesterone. RU 486 induces decidual necrosis and
`softening of the cervix, which elicit uterine bleeding,
`whereas the trophoplast remains histologically un-
`altered (50). Expulsion of the trophoplast, leading to
`declining serum hCG concentrations, causes subse-
`quent lyteolysis, although RU 486 itself seems to have
`some luteolytic activity (Fig. 2) (22, 28).
`Table 1 summaries the main clinical studies on ter-
`mination of early pregnancy with RU 486. A common
`feature in these studies has been the lack of correla-
`tion between the doses of RU 486 used, and the clini-
`cal outcome. The studies by Haspels (52) and Elia (55)
`suggest that the shorter the duration of the pregnan-
`cy, the better the clinical outcome. In pregnancies
`shorter than seven weeks duration, the gestational
`length did not affect the clinical outcome (56-58,60).
`The reasons why some women fail to respond to RU
`486 therapy are not known. However, uterine bleeding
`and thus complete or incomplete abortion seems to oc-
`cur in almost all women. Classification of pretreatment
`parameters in patients who have had complete or in-
`complete abortions, has shown that the only predic-
`torof successful clinical outcome is a low value of se-
`rum hCG, which has a sensitivity of 93 O/O
`(58). By ac-
`cepting only patients with pretreatment B-hCG values
`below 18000 UII for their study, Couzinet et al. (54)
`reported high success rates of 82-88 YO.
`
`Ann Med22
`
`Ex. 2007-0004
`
`

`

`78
`
`Heikinheimo Ylikorkala Lahteenmaki
`
`Table 1. Pregnancy termination with RU 486.
`
`Investigators
`
`~
`
`~~
`
`Patients’
`
`RU 486
`
`Outcomet
`
`Herrmann et al. (15)
`Kovacs et al. (51)
`
`Imp 6-8 w
`Imps6 w
`
`Haspels (52)
`
`Cameron et al. (53)
`Couzinet et al. (54)
`
`Elia (55)
`
`Shoupe et al. (56)
`
`Mishell et al. (57)
`
`Birgerson and
`Odlind (58)
`
`lmp<8 w
`
`Imp 6-10 w
`lmp<8 w
`lmp<5 417 w +
`p-hCG < 18 000 U/I
`
`lmp<5 w
`Irnp 5-6 w
`lmp>6 w
`Imps7 w
`
`Imps7 w
`
`Imp47 w
`
`200 mg x 4d
`I.
`25 mg bid x 4d
`50 mg bid x4d
`II.
`Ill. 100 mg bid x4d
`I.
`100 mg bid x4d
`II.
`200mgx4d
`200 mg x 4d
`150 mgx4d
`50 mg bid x4d
`I.
`II
`50 mg x Ill x 4d
`111. 400 mg x 2d
`
`Single dose 600 mg
`
`(82 ”0)
`(63 Yo)
`(50 Yo)
`(63 %)
`(75 Yo)
`(83 O h )
`(33 ” 0 )
`(60 O h )
`(82 O h )
`(88 010)
`(85 Yo)
`(89 Yo)
`(75 ”0)
`(58 Yo)
`(72 %)
`(20 ” 0 )
`
`
`
`9/11
`12119
`5/10
`5/8
`911 2
`10112
`319
`12/20
`28134
`23126
`34/49
`931105
`193/257
`41/71
`34147
`50 mg bid x7d
`I.
`115
`II. 100 mg bidx4d
`015
`Ill. 200 mg bidx4d
`25 mg bid x 7d
`(50 Yo)
`15130
`1.
`(73 O h )
`48/66
`50 mg bid x7d
`II.
`(73 Y O )
`35/48
`I.
`10 mg bid x 7d
`(66 %)
`34/52
`II.
`25 mg bid x 7d
`(64 Yo)
`50 mg bid x 7d
`34153
`111.
`44/49 (90 Yo)
`Imps7 w
`Grimes et al. (59)
`Single dose 600 mg
`Ylikorkala et al. (60)
`Imps6 117 w
`Single dose 600 mg
`36150
`(72 %)
`Patients: Criteria for the maximum duration of pregnancy accepted for the study (Irnp = last menstrual period, i.e. duration
`of pregnancy), in addition to verified intrauterine pregnancy.
`t Outcome: Frequency of complete abortions (uterine bleeding subsequent to RU 486; low P-hCG and empty uterine cavity
`by ultra-sonographic or bimanual examination on re-examination). Number of complete abortionslnumber of women treat-
`ed, (percentage of complete abortions).
`
`Patterns of Bleeding Following RU 486 Treafmenf
`After administration of various doses of RU 486 the pat-
`terns of bleeding are remarkably similar: in women with
`complete abortions bleeding starts 2-3 days after the
`start of RU 486 administration and lasts for 12-14 days
`thereafter (56-58). The products of conception are ex-
`pelled approximately one day after the start of bleed-
`ing (58). With the lowest doses of RU 486 tested for
`pregnancy termination, the bleeding starts somewhat
`later (56, 58). When abortion is incomplete, bleeding
`tends to start later and its duration is shorter (56, 58).
`
`Acceptance of RU 486 Treatmenl
`Only two papers describe the subjective acceptance
`of RU 486-induced termination of pregnancy. Bigerson
`O/O of their patients
`and Odlind (61) report that 81 %-88
`were satisfied and willing to repeat the treatment
`should they ever want an abortion again. In another
`study most patients tended to describe their ex-
`periences as “not unpleasant” and “not as bad as I ex-
`pected” (52). Positive comments accord favourably with
`the rates of complete abortions.
`
`Side Effects Associated with RU 486
`The frequency of reported side effects associated with
`RU 486-induced abortion vary considerably between
`studies. Side effects such as mild uterine pain, fatigue,
`
`nausea and vomiting have been reported (51,52, 58),
`but the distiction between these and the usual sym-
`ptoms of early pregnancy and abortion is difficult.
`Weakness has been reported by 22 O/O and 25 %, and
`nausea by 24
`and 47 % of the patients (54, 57).
`A mild fall in blood hemoglobin concentration occurs
`subsequent to RU 486 treatment (58, 62). Heavy uter-
`ine bleeding complicated RU 486 induced abortions in
`18 o/o and 56 O/O of the patients, respectively, in the
`studies by Couzinet et al. (54) and Mishell et al. (57).
`In addition, some authors have reported occasional pa-
`tients suffering from severe bleeding requiring blood
`transfusions (15, 51, 52).
`
`Termination of Pregnancy by Combination of
`RU 486 and Prostaglandins
`In vitro studies have shown that RU 486 induces syn-
`thesis of prostaglandins (PG) in glandular cells of the
`decidua(35). Hence the oxytocic action of RU 486 might
`be potentiated and better success rates achieved by
`administration of additional PGs. In practice, the ad-
`dition of subtherapeutic doses of PGs to RU 486 treat-
`ment increases the frequency of complete abortions
`to between 90 o/o and 100 %; the results of these
`studies are summarized in Table 2.
`The patterns of bleeding, side effects and return of
`menstruation were similar between the “RU 486 only”
`and the “RU 486 + PG” -groups (53). When compared
`
`Ann Med 22
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`

`Antiprogesterone RU 486 - a Drug for Non-Surgical Abortion
`
`79
`
`Table 2. Pregnancy termination with RU 486 combined with prostaglandin analogs.
`
`Investigators
`
`Swahn et al. (63)
`
`Patients’
`
`Imps7 w
`
`Cameron et al. (53)
`
`lrnp<8 w
`
`Rodger and Baird (64)
`
`lrnpc8 w
`
`Ji et al. (65)
`
`Rodger et al. (66)
`
`Imps7 w
`
`lrnpc8 w
`
`I.
`
`II.
`
`I
`
`II.
`
`I.
`
`II.
`
`Ill.
`
`IV.
`
`I.
`
`II.
`
`Ou tcorne t
`
`919
`
`717
`
`(100 Yo)
`
`(100 Yo)
`
`18/19
`
`515
`
`(95 “/a)
`(100 %)
`
`19/20
`
`29/30
`
`27/30
`
`(95 Yo)
`(97 %)
`(90 Yo)
`
`20120
`
`(100 %)
`
`136/160
`
`(87 Yo)
`
`59/60
`
`(98 O h )
`
`RU 486
`25 mg bid x 4d16d + 0.25 rng
`PGE,-analog im.:
`25 mg x IV x 4d + 0.25 rng
`PGE,-analog i.m.
`150 rngx4d+1 mg
`PGE,-vaginal pessarys
`150 rngx4d+2 mg
`PGE,-vaginal pessary
`150 mgx4d+1 rng
`PGE,-vaginal pessaryQ
`single dose 500 mg + 0.5 rng
`PGE,-vaginal pessary
`single dose 400 rng + 0.5 mg
`PGE,-vaginal pessary
`single dose 600 mg + 0.5 mg
`PGE,-vaginal pessary
`single dose 600 mg + 1.0 mg
`PGF,,-vaginal supp.II
`single dose 600 mg + 0.5 mg
`PGE,-vaginal pessarys
`single dose 600 mg + 1.0 mg
`(100 Yo)
`60160
`PGE,-vaginal pessary
`Patients: Criteria for the maximum duration of pregnancy accepted for the study (Imp = last menstrual period, i.e. duration
`of pregnancy), in addition to verified intrauterine pregnancy.
`t Outcome: Frequency of complete abortions (low P-hCG and empty uterine cavity by ultra-sonographic or birnanual exami-
`nation on re-examination). Number of complete abortionslnurnber of women treated, (precentage of complete abortions).
`16-pheno~y-tetranor-PGE~ methyl sylfonylamine (Schering AG, Berlin).
`Q 16, 16-dimethyl-trans-A2-PGE, methylester (Gemeprost).
`II 15-methyl-PGF2,-methyl ester (PG05).
`
`to treatment with high doses of PGs alone, the combi-
`nation therapy of “RU 486 + subtherapeutic PG” were
`equally effective, but with a significantly lower inci-
`dence of gastrointestinal side effects (67). In termina-
`tion of second trimester pregnancies (i.e. 16-18
`weeks), addition of RU 486 into extra-amniotic PG ther-
`apy significantly reduced both the induction to abor-
`tion interval and the total dose of PG needed (68).
`
`Other Possible Uses of RU 486 in
`Gynaecology and Obstetrics
`
`RU 486 in Induction of Menstruation, and in
`Late Postcoital Contraception
`RU 486 induces uterine bleeding by direct action on
`progesterone primed endometrium when administered
`in the mid- or late-luteal phase of the cycle (15,22,28).
`The bleeding starts 2-3 days after starting RU 486 and
`corresponds to regular menstruation both in duration
`and in amount (22). In addition, administration of 100
`m g x 4d of RU 486 during the late luteal phase in three
`consequtive cycles was well tolerated and resulted in
`regular and endocrinologicaily normal cycles (69).
`These results have encouraged the use of RU 486 as
`a late postcoital contraceptive or an inducer of once
`a month menstruations. Preliminary clinical ex-
`perience, however, has been somewhat disappointing:
`van Santen and Haspels (70) reported one pregnancy
`among 62 patients requesting postcoital contraception.
`Lahteenmaki et al. (71) studied the late postcoital use
`
`of RU 486 in 30 women following unprotected inter-
`course around the midcycle. A single dose of 600 mg
`of RU 486 was administered as the time of expected
`menstruation. In 60 YO of these patients pregnancy was
`confirmed by raised serum hCG concentrations; preg-
`nancy continued in 3.3 % of patients despite of RU 486
`treatment. An additional complication was a length-
`ening of the subsequent cycle by four days, which may
`limit regular once a month use of RU 486. Van Santen
`and Haspels (72) studied the use of RU 486 (100 mg x
`4d) as a monthly, late luteal phase contraceptive:
`among the 24 cycles studied three conceptions oc-
`curred, two of which continued despite RU 486 treat-
`ment.
`
`RU 486 in Fetal Death and Extrauterine Pregnancy
`RU 486 has been used in induction of labour in late
`pregnancy after intrauterine fetal death (73). In addition,
`two groups of investigators have speculated on the
`possible use of RU 486 in the extraction of an extra-
`uterine pregnancy. Paris et al. (74) concluded that
`pretreatment with RU 486 facilitates the extraction of
`the fetus by laparoscopy, whereas in a study by
`Keningsberg et al. (754, RU 486 was ineffective in treat-
`ing of residual ectopic trophoplastic tissue.
`
`Follicular Phase Administration of RU 486
`Follicular phase administration of RU 486, commencing
`either a few days before the expected midcycle
`gonadotropin surge (26, 27,76) or from the start of the
`
`Ann Med 22
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`Ex. 2007-0006
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`

`

`80
`
`Heikinheimo Ylikorkala LahteenmBki
`
`cycle (30), interrupts follicle development, delays
`gonadotropin surge and thus prolongs the cycle. This
`effect of RU 486 is most probably mediated via inhibi-
`tion of ovarian estradiol production (26). Luukkainen
`et al. (30) administered 25 mg of RU 486 to healthy women
`for 14 or21 days from the beginning of their cycle. Dur-
`ing the treatment period folliculogenesis was sup-
`pressed, as judged by low serum estradiol levels; after
`treatment was stopped the serum levels of estradiol
`and progesterone rose to levels similar to those in the
`control cycle (Fig. 3). The treatment was well tolerated
`and in combination with progestin it might enable the
`development of a new form of estrogen free oral con-
`traceptive (30).
`
`Preoperative Cervical Ripening with RU 486
`Preoperative treatment with RU 486 for one day before
`termination of a first trimester pregnancy induced sig-
`nificant softening and dilatation of the cervix (77, 78).
`This property of RU 486 enables gradual and atraumatic
`cervical dilatation, thereby reducing the risks of con-
`ventional termination of pregnancy by dilatation and
`curettage.
`
`RU 486 in the Treatment of Breast Cancer
`Studies in vitro have shown that RU 486 is cytotoxic
`ag ai n s t progesterone receptor positive breast cancer
`cell lines (46). In a preliminary clinical study, RU 486
`(100 mg twice aday) was administered to patients with
`metastatic breast cancer resistant to chemotherapy
`and other endocrine therapies (i.e. tamoxifen or proges-
`tins). The treatment with RU 486 was well tolerated,
`55 % of the patients partially responsed to RU 486 ther-
`apy, and the response rate at three months was 18 %.
`The positive clinical response correlated with the
`progesterone receptor content of tumours (79).
`
`RU 486 in Treatment of Hypercortisolemia
`At high oral doses (i.e. 2400 mgld) RU 486 behaves as
`an antiglucocorticoid, judged by increased morning
`values of serum ACTH, other proopiomelanocortin de-
`rived peptides and cortisol, and inhibition of DXM-in-
`duced suppression of ACTH and cortisol secretion in
`normal subjects (40,41). In addition, RU 486 suppress-
`es peripheral glucocorticoid induced vasoconstriction
`in humans (80). Hence RU 486 might be valuable in
`symptomatic treatment of hypercortisolemia of Cushing's
`disease. Nieman et al. (81) reported successful symp-
`tomatic treatment of a patient with Cushing's syn-
`drome: hypercortisolemia induced aberrations in vari-
`ous laboratory parameters, and in clinical and in psy-
`chological status were greatly improved by administra-
`tion of high doses of RU 486.
`
`Pharmacokinetic Studies on RU 486
`
`After the first clinical studies with RU 486 (51) it soon
`became apparent that the clinical outcome was not cor-
`related with the doses of RU 486 administered. Further-
`more, in each study some patients remained refractory
`
`Ann Med 22
`
`1
`
`
`
`PU a06 25mo x l
`
`
`
`8
`
`'
`
`7 45
`
`10
`
`5
`
`Figure 3. Inhibition of folliculogenesis and ovulation by RU
`486. Healthy female volunteers received 25 mg of RU 486 daily
`for 14 days (upper panel) or 21 days (lower panel), the serum
`levels of estradiol, progesterone and RU 486 are shown. The
`control and treatment cycles of both subject are shown. Men-
`strual bleedings are shown as hatched areas.
`
`to RU 486 treatment. Various methods, including direct
`RIA, radioreceptor assays, high performance liquid
`chromatography (HPLC) or RIA preceded by column
`chromatography, have been used to quantitate serum
`concentrations of RU 486 (82-85). Owing to cross
`reacting demethylated metabolites, the direct RIA lacks
`the specificity to measure accurately serum RU 486
`(86). The micromolar serum levels of RU 486 are excep-
`tionally high for a synthetic steroid. Utilising these high
`concentrations, a specific HPLC method was devel-
`oped for the assay of RU 486 and its major metabolites
`in serum (83, 87).
`
`Serum levels
`After oral administration of various single doses, RU 486
`is rapidly absorped, with peak levels reached at approx-
`imately one hour. Thereafter the serum levels of RU 486
`plateau at the micromolar range (i.e. 2.5 Vmolll) for the
`next 24-48 h and can be measured for up to 5-7 days
`(88). Interestingly, within the dose range of 100-
`800 mg either the peak or steady state serum levels of
`RU 486 did not correlate with the dose ingested (Fig.
`4) (84, 87). Saturation of a,-acid glycoprotein (AAG),
`the principal transport protein for RU 486, explains the
`similar concentrations of RU 486 seen in human serum
`following different doses (87,89). At serum concentra-
`tions below 2.5 pmolll, the free fraction of RU 486 is
`only 2.3 %. With increasing concentrations, however,
`the fraction of free RU 486, which is available for ex-
`cretion or tissue distribution, rapidly increases (87). The
`volume of distribution of RU 486 is small, thus the con-
`centrations in myometrium are approximately one third
`of those measured in serum (82,90). Within the doses
`tested for pregnancy termination, however, the concen-
`trations of RU 486 must have been exceedingly high
`to saturate the uterine progesterone receptors.
`The saturation of serum binding capacity and thus
`identical serum levels of RU 486 also occurs after mul-
`tiple dose administration when the daily doses of RU
`486 exceeds 50 mg (91). The individual serum levels of
`RU 486 are similar during the treatment period, but the
`elimination phase pharmacokinetics show considerable
`individual variation (Fig. 5). After multiple dose adminis-
`tration the half life of RU 486 ranges from 26 to 48 hours
`
`Ex. 2007-0007
`
`

`

`Antiprogesterone RU 486 - a Drug for Non-Surgical Abortion
`
`RU 486
`
`monodemQthyIatad metah
`
`didemethylatad metab
`
`0 hydroxylatad metab.
`
`p m o l / l * h
`
`4 5 0
`
`n n
`
`81
`
`0 0
`
`300
`
`\
`\
`\
`\
`0
`
`150
`
`20 days
`5
`15
`10
`1
`Figure 5. The individual (open symbols) and mean (closed cir-
`cles) serum concentrations of RU 486 following oral intake
`of 50 mg twice a day for seven days. Each bar indicates 1 SE.
`The elimination phase half-life, mean (SE), of RU 486 in these
`patients was 40.9 (6.2)h.
`
`100rng 400mg 600mg 800mg
`Figure 4. Total amounts (pmol/l x h) of circulating RU 486, the
`monodemethylated, didemethylated and hydroxylated metabo-
`lites within the first 24h following ingestion of 100 mg-
`800 mg of RU 486 by female volunteers.
`
`(91). The similar serum levels of RU 486 measured fol-
`lowing various doses seems to explain the observation
`that there is no correlation between the regimen of RU
`486 and the clinical outcome (Tables 1,2) when RU 486
`is used for abortion induction.
`In humans RU 486 is excreted via the bile (82): only
`a very small fraction can be detected in urine (82, 85).
`In addition, RU 486 is partly pooled in the enterohepatic
`cycle, which might explain the long half life of RU 486
`(90).
`
`Metabolism of RU 486
`RU 486 is extensively metabolised in humans by two
`step demethylation and by hydroxylation - owing to
`first pass metabolism, bioavailability of the parent RU
`486 is approximately 40 O/O following the dose of 100 mg
`of RU 486 (82, 85). Interestingly, after single dose ad-
`ministration of increasing doses of RU 486 equal lev-
`els of RU 486, but increasing amounts of mono-,
`didemethylated and hydroxylated metabolites, were
`