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Chapter 16 Chemical Control of Fertility
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Metabolic Diseases and Endocrine Function
Editor: Denis M. Bailey, Sterling-Winthrop Research Institute Rensselaer, New York 12144 Chapter 16. Chemical Control of Fertility Malcolm R. Bell, Robert G. Christiansen and H. Philip Schane, Jr. Sterling-Winthrop Research Institute, Rensselaer, New York 12144 Introduction - The results of a survey1 of married women aged 15-44 for the 1973-1976 period indicated the following major contraceptive choices: "pill" ( 2 2 % ) , sterilization (19%, female and male), condom (7%), intrauterine device (IUD) (6%), rhythm (3%), foam ( 3 % ) , diaphragm (3%). Major trends are the increasing use of sterilization and a somewhat decreasing reliance on the "pill". Approximately 600,000 male and 600,000 female sterilizations are performed annually in the U. S. With compliance, the "pill" is an excellent method of family planning with a failure rate of 1 pregnancy or less per 100 women-years. A beneficial effect to undernourished women is a decrease in menstrual blood loss. Compliance can be a problem and missed medications can result in pregnancy. Although the IUD is not as effective as the "pill", compliance is not a problem if the IUD is properly inserted and remains in place. Associated with the use of the unmedicated IUD is a significant increase in menstrual blood The incorporation of Cu or a progestin in these devices has increased their effectiveness.4 , 5 Menstrual blood loss seen with the unmedicated IUD is reduced with Progestasert@, an IUD whose effectiveness approaches that of the Elective abortion as a method of family planning is increasing as a result of the availability of safe and legal abortion services.6 There is one elective abortion in the U.S. (1.3 million in 1977) for every three live births. Since the introduction of the "pill" in 1960, the major advances from a medicinal chemical point of view have been the introduction of prostaglandins (PG's) as abortifacients and the medicated IUD's. Neither has yet had the impact of the "pill" but progress has been reported in the development of PG's and IUD's with improved properties. Most of the recent research with sex hormones deals with previously reported compounds. An important finding in the area of luteinizing-hormone-releasing hormone (LH-RH) analogs is that both agonists and antagonists are potential antifertility agents. There are no reports evaluating this class of drugs as human antifertility agents. The immunological approach to fertilit trol has been re~iewed.~A review of many approaches is available. con-
8
Steroids - Two recent re~iews~,~'summarize the adverse reactions from use of the "pill". The "paper pill", a square of edible cellulose impregnated with the steroids, is advantageous with respect to packaging, transportation, acceptability and storage. The conventional and the "paper pill", each containing 1 5 0 pg of levonorgestrel and 30 pg of ethynylestradiol (EE), were equally effective in suppressing ovu1ation.l' The EE content of the "pill" was lowered to 30 ug without loss of contraceptive Copyright @ 1979 by Academic Press, Inc. All rights of reproduction in any form resaNed. ISBN 0-12-040514-8
Chap. 16
Control of Fertility Bell, Christiansen, Schane
169
efficacy.12 In a modified sequential oral contraceptive dosage schedule, 50 pg of EE administered for 7 days followed by 50 pg of EE and 1 mg of lynestrenol for 15 days resulted in complete inhibition of 0vu1ation.l~ A useful alternative to the pill especially in women in whom estrogen is contraindicated, is Depo-Provera' (medroxypfogesterone acetatpi which when given i.m. every 3 months is an effective contraceptive. This progestin in large continuous doses induced an increased incidence of mammary cancer in beagle dogs, an effect not reported in other animals or women.15 The drug is not available in the U.S.16 Danazol (1) has been reported to be an oral contraceptive in the rhesus monkeyl7z8 and in women.19 In rats, this substance was a pituC E C H itary gonadotropin inhibitor which neither exhib3 ited estrogenic nor progestational activity but did have weak impeded androgen-like activity.2o Administration of estrogens, either 5 mg of EE or 50 mg of diethylstilbestrol p.0. for 5 days beginning within 3 days of coitus in midcycle, is effective in preventing pregnancy in women. Nausea and vomiting are common side effects. Diethylstilbestrol caused an increased incidence of vaginal adenosis and adenocarcinoma of the vagina and cervix in female offspring of women treated during the first trimester with this drug for other reasons.21 In China, the estrogen anordrin (2) is taken immediately after coitus for prevention o f pregnancy.22 When EE and dl-norgestrel were administered in combination to 608 women shortly after coitus, one pregnancy occurred nu nu OCOC,H,
J
U -
I -
rather than the 12-30 pregnancies expected.23 The antiprogestin R-2323 (norgestrienone, 2) had low contraceptive efficacy in w 0 m e n . ~ 4 , ~It ~ was suggested that the antifertility effects of RMI 12,936 (5) resulted from its antiprogestational activity as well as inhibition of progesterone (P) biosynthesis.26 The abortifacient activity of the cyanohydrin diacetate 5 in the rat may be the result of its transformation to estrogens in the ovary.27 ORF 9326 (6) terminated pregnancy in rats when administered P.O. on days 9-12 of gestation.28 At the effective dose, the compound lacked estrogenic, androgenic, and progestational activities. The spiroether 7
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was an estrogen antagonist in mice and ewes but was not estrogenic in rats. When administered to normally cycling rhesus monkeys, it increased the viscosity of the cervical mucus, a possible antiestrogenic effect, and prevented pregnancy.29
-
Steroidogenesis Inhibitors Aminoglutethimide (8), which blocks the conversion of cholesterol to P, terminated pregnancy in rats3’ but not in baboons.31 The 5,lO-seco steroids 9 irreversibly blockedA5-3-ketoisomerase from testosteroni in vitro and caused a decrease in the weight of male sex accessory organs of the rat, an effect which could be the result of inhibition of androgen biosynthesis.3L Azastene (10)was a competitive inhibitor of P biosynthesis in vitro and disrupted pregnancy in both the rat33 and rhesus monkey.34 This agent blocked human chorionic gonadotropin-induced prolongation of corpus luteum function and lacked hormonal activity.35 Trilostane also a competitive inhibitor of 38R /COCH3
e.
0
JfJp NH2
H
-8
(s),
R=O,
..
‘H
R’=-CH2C =C-CH2 or CH=C=CHCH2
hydroxysteroid dehydrogenase, was more effective in blocking adrenal steroidogenesis than in disrupting pregnancy in the rat36 and rhesus mon-
CH3 CH3
‘SR R=-C H -p-NH2 6 4 10 11 12 13 key.37 Pregnancy in the monkey was terminated at a time when the ovaries are required for the continuation of pregnancy as well as when the placenta is capable of maintaining pregnancy in the absence of the ovaries. The estrogen synthetase blocker 12 inhibited mating, ovulation, and implantation in rats.38 Of a series of aromatase inhibitors, j.3- was the most active in vitro.39 ‘0
Prostaglandins - PGF c1 is available on a limited basis in the U.S. for the termination of seconi trimester pregnancy by the intraamniotic route. PGE2 has been approved in the U.S. for the same indication as an intravaginal s u p p o ~ i t o r y . The ~ ~ primary action of the PG’s in humans is believed to be a direct stimulatory effect on myometrial smooth m ~ s c l e . ~ l - 4 ~ The decreases in serum P and estradiol levels are considered a consequence and not a cause of the disruption of pregnancy. It should be remembered that pregnancy termination by luteolysis is only possible during early gestation since the corpus luteum is not required for maintenance of pregnancy after 6 or 7 weeks of estation, the time at which the luteoplacental shift takes p l a ~ e . ~When ~ , administered ~ ~ in the mid-luteal phase
Chap. 16
Control of Fertility Bell, Christiansen, Schane
171
PGFZa is not luteol tic in normal cycling women but is luteolytic in rats and other The results of an international multicenter study were interpreted to indicate that intraamniotic saline and PGF2, (25 mg repeated in 6 hours) are safe and effective for termination of second trimester pregnan~y,~'and that PGF2clis significantly more effective than saline in the termination of pregnancy within 48 hours. Another interpretation of these results pointed out the hazards of PGFZa and intraamniotic saline and advised that, up to the sixteenth week dilatation and evacuation is the most advantageous available method. 51 An advantage of dilatation and evacuation i s the low incidence of incomplete abortion compared with intraamniotic PGF or saline.51 In second trimester pregnancy a single intraamniotic injec&on of 2.5 mg of 15(S)-methyl PGFZ, methyl ester was slight1 more effective than 5 0 mg of PGF2, in inducing abortion within 48 hours.5T About one half of the abortions were incomplete with both drugs. In another multicenter study, a 92% abortion rate, 50% of which were incomplete, was achieved within 30 hours after repeated intravaginal administration of 15(S)-methyl PGFZa methyl ester during the second trimester.53 Vomiting and diarrhea were significantly more common with the PG analog, but the mean incidence of diarrhea and vomiting ranged from 2 to 6 episodes per patient in both s t u d i e ~ . ~ ~ 9 ~ 3 and second First trimester pregnancy was terminated with 15(S)-meth 1 PGFZa methyl ester administered as a single intravaginal suppository.34-56 Intravaginal administration of 16,16-dimethyl PGE2 was as effective in terminating first trimester pregnancy as vacuum aspiration but was associated with a much higher incidence of side effects. The incidence of side effects was lower than with 15(S)-methyl PGF2a methyl ester.57 Summaries of the results of clinical evaluation of PG's for pregnancy termination have been published. 58959
specie^.^'
Sulprostone (CP-34,089, ZK 57,671, SHB 286, 14) was 10-30X active than PGE2 as an antifertility agent in laboratory studies to or less active than PGE in laboratory tests considered to be tive of side effects.60 A3ministration of this agent i.v., i.m. 0
0
CONHS02CH3
HO
more but equal predicor by the
14 -
OH
e
HO'
2
15 -
~
6H
transcervical intrauterine route terminated first and second trimester HO pregnancies in women.61-64 A decrease in the incidence of side effects com.:\MM CHc 0 2 3 pared with other PG's was reported, a particularly significant result since the i.m. route could be advantageous HO' HO CH3 in the developing countries.65 A similar favorable separation of activi16 ties has been reported in the monkey for ONO-802 (15) .66 This PG terminated early regnancy in women when given by the transcervical intrauterine route6Por by pessary.68 In the latter study, complete abortion occurred in 54 of 63 women; nausea and
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vomiting were reported by one patient. Encouraging results have also been obtained in studies with 16,16-dimethyl PGE2 p-benzaldehyde semicarbazone ester for termination of first and second trimester pregnancies and with the dihomo PG derivative 16 for termination of abnormal intrauterine pregnancies.59 LH-RH Antagonists - Des-Glylo-[Trp2,Leu3,D-A1a6]LH-RH ethyl amide (EA) inhibited ovulation in rats after a single s . ~ .dose of 1.5 mg/rat on the day of r o e s t r ~ s . ~ ID-Phe2 ~ Pro3,D-Trp6 or D-Phe'1LH-W were active at 750 p5.'99 70 Ac- [Pro ,D-Phe2,D-Trp3,D-Trp6]LH-RH and [D-
Chap. 16
Control of Fertility Bell, Christiansen, Schane __ 173
dotro in receptor concentrations in the gonads of both male and female rats.fjo-82 Ovulation inhibition in women was achieved by treatment with [D-Ser(t-Bu)']LH-RH EA (HOE 766) S.C. daily for 22-30 days at a dose of 5 p g commencing within 3 days of the beginning of menstruation.83 Premature luteolysis in women resulted from administration of des-GlylO-LHRH EA S.C. for 5 days during the post-ovulatory phase.84 Administration of LH-RH at a dose of 250 ug several times on one day between the second and seventh day following ovulation caused premature luteolysis in women.85 There was evidence of ovulation on laparotomy in 9 of 10 women after pretreatment with EE every 12 hours on days 10 and 11 or days 9-11 followed by one injection of [D-Leu6]LH-RH EA.86 If these results are confirmed, a method could be available for improving the effectiveness of the rhythm method. As in the above study,86 however, it may be necessary to prime the hypothalamic-pituitary-gonadal system by administration of an estrogen prior to the administration of the LH-RH agonist. The observation that cyclo [ (B-Alal) and (6-Aminohexanoyll),D-Ala6) ]LH-RH were more potent agonists than the uncyclized peptides, although only about 1% as potent as LH-RH, supports an "U" shape conformation for LH-RH.87 Structure-activity relationships of LH-RH and its analogs have been reviewed.88 Male Contraception - The most promising approach to male contraception is suppression of spermatogenesis mediated by inhibition of gonadotropin release by the pituitary gland.89-91 Inhibition of spermatogenesis in men by monthly injections of a combination of Depo-Provera and testosterone enanthate (TE) continues to be studied with the objective of developing the optimum dosage schedule,92-94 Danazol (1)plus testosterone nate or TE caused a variable reduction of spermatogenesis in man. TE administered i.m. biweekly also did not result in uniform azoospermia in a year-long study.97 It is not known if azoospermia must be achieved for complete inhibition of fertility or whether oligospermia would be sufThe use of implants containing androgens is not yet practical since the im lant would be too large emphasizing the need for more active The D-homo steroids 1 7 and 18 are considered possible candidates €or use in implants since they are more effective than testosterone in suppressing pituitary gonadotropin secretion and, as a result, have an appropriate balance of peripheral and central activities.99 Antiandrogens such as cyproterone acetate have not been useful as male antifertility agents since libido is reduced at effective contraceptive doses.lOO The effects of prolonged suppression of spermatogenesis need to be studied and it must be established whether fertility returns upon withdrawal of drug. 97s g 8 a-Chlorohydrin(3-chloropropane-l,2-diol) is an example of a compound that interferes with sperm maturation."' Toxic side COOH effects, particularly in the monkey, precluded trials of the compound in man. The antifertility activity of a-chlorohydrin may be the result of an inhibition of glyceraldehyde-3-phosphate de0 'R& hydrogenase in spermatozoa. The 1 7 R=COC2H5,R'=H S(+)-isomer is more active in vitro and in vivo than the R(-)18 R=H, R' =C = CH c1 isomer. In vitro experiments sug19 gest that conversion to the 1-
androgen^.^^
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phosphate is necessary for activity.l02 Some 6-chloro-6-deoxy sugars had a reversible contraceptive action in the male rat and were less toxic than a - c h l ~ r o h y d r i n . ~AF~ ~1312/TS (19)inhibited spermatogenesis in the rat and in the monkey.'04-lo6 Miscellaneous Compounds - Centchroman (20)inhibited pregnancy in rats, mice, do s and monkeys when administered once orally within 24 hours of coitus.1 7 The drug was estrogenic, antiestrogenic and antiprogestational and inhibited ova development in the rat. Coadministration with P and estradiol diproprionate prevented the termination of pregnancy. Centchroman possessed both gonadotropin inhibitory and stimulatory properties in unilaterally ovariectomized rats deR R pending upon the dose. The compound resembles in this respect the structurally related clomiphene ( 2 1 , an antiestrogen and a known ovulation stimulator. Centchroman induced ovu5 H CH30 6 : &' 0 lation in women when administered C ~ H ~ dail log The drug is well-tolera21 C6H5 tedl" and is being studied as a 20 once-a-week contraceptive.'l0 The contraceptive activity was suggested R=CH CH N E ~ ~ R=CH2CH2 2 2 to be a result of an inhibition of implantation and sperm transport. The triazoles 22 and 23, inhibitors of PG metabolism in the rat uterus, placenta, and were completely effective in terminating pregnancy in rats and hamsters when administered S.C. daily during any one of four 5-day periods between days 1 and 12 of pregnancy. These compounds were most effective when administered immediately following implantation; they lacked hormonal or antihormonal activity, and their antifertility effect was not reversed by P.lI2 The closely related 24 given S.C. in
8
Q
7
OR
3 23 n=2,R=CH
-
3
24 n=2,R=C H 2 5 25 -
26 -
combination with PGE2 during esfrus blocked ovulation almost completely in the hamster.l15 PGE2 alone was ineffective and 2 alone was weakly active; 24 also hastened ova transport. Indomethacin, a PG synthetase inhibitor suppressed spontaneous and induced ovulation in rats and rabbits,I l b suppressed gonadotropin-induced ovulation in rhesus monkeysll7 and marmosets,118 but failed t o inhibit spontaneous ovulation in rhesus monkeys.119 Studies with indomethacin as an ovulation inhibitor in women were inconclusive120 and in two small studies in women aspirin was ineffective.121,122 The biphenyl derivative 2 was completely effective inhibiting pregnancy in rats on days 4 and 5 at a dose of 5 mg/kg p.0. 6-Chloromelatonin (26) inhibited ovulation in rats when administered i.v. or p.0. on the day of proestrus and was more effective than melatonin, probably as a result of an increased metabolic stability.124
&
Chap. 16
Control of Fertility
Bell, Christiansen, Schane
175
A review of adrenergic innervation of the mammalian oviduct includes
a summary of drugs that modif
the sympathetic nervous system and affect ovum transport and fertility.P25 Plants are a relatively untapped potential source of new antifertility agents.126 References
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2. 3. 4.
J. F. Hulka.
11,
132,
2.
so.
11.
176 44. 45. 46. 47. 48. 49. 50.
51. 52.
53. 54. 55. 56. 57.
58.
59. 60.
61. 62. 63. 64. 65.
66. 67.
68.
69. 70. 71.
72. 73. 74. 75. 76. 77. 78. 79.
80. 81. 82.
83. 84.
Sect.
Iv -
Metabolic Diseases, Endocrine Function
~
~
Ed. i l
3.1048 (1977). P. F y l l i n g and F. J e r v e . P r o s t a g l a n d i n s , 2, 785 (1977). T. Yashimi, C. A. S t r o t t . J . R. M a r s h a l l and M. B. L i p s e t t . J . Clin. Endocr., 29. 225 (1969). A. I . Csapo, M. 0. Pukkinen. 8. R u t t n e r , J. P. Sauvage and W. G. Wiest, Am. J . O b s t e t . Cynecol., 112, 1061 (1972). P. Kajanoja, T. Ranta and M. Sepp'dlI, P r o s t a g l a n d i n s , 16, 327 (1978). A. K. Hall and J. Robinson, i b i d . . 4. 1013 (1978). Br. Med. J., 1. 1373 (1976). W. Cates, J r . , D. A. Grimes, K. F. Schulu, H. W. Ory and C. W. T y l e r , J r . , O b s t e t . Cynecol., 52, 493 (1978). Am. J. O b s t e t . Cynecol., 129, 601 (1977). M. Bygdeman, P. K. Devi, E. S. Crech, A. A. Haspels, R. Nyberg, V. N. Purandare and P. 4 . Roue, C o n t r a c e p t f o n . l.6, 175 (1977). C. A. B a l l a r d , K. F o r t e and N. H. Lauersen, i b i d . . lJ, 383 (1978). C. Kinra, N. Agarwal. K. T. J a g a n n a t h a and V. Hingorani. i b i d . . 17. 455 (1978). M. W n d e l i n , P r o s t a g l a n d i n s , 16. 1 4 3 (1978). V. Lundstrifm. M. Bygdeman, S. Fotiou. K. Green and K. K i n o s h i t a . C o n t r a c e p t i o n , 2,167 (1977). Popul. Rep. S e r . C., No. 7. S e p t . , 1976. S. S. Ratnam and S. M. M. Karlm. Aust. N . Z . J . O b s t e t . Gyn., 2,4 1 (1978). H. -J. Hess. J. S. Bindra, J. W. C o n s t a n t i n e , W. E l g e r , 0. Loge, E. S c h i l l i n g e r and W. Losert, E x p e r i e n t i a , 33. 1076 (1977). S. M. M. Karin, B. Rao, S. S. Ratnam, R. N. V. P r a s a d , Y . M. Wong and A. I l l a n c h e r a n . C o n t r n c e p t l o n , l6. 377 (1977). M. 0 . Pulkklnen, P r o a t a n g l a n d i n s , l5, 161 (1978). S. M. M. Karin, H. T. Choo. A. L. Lim. K. C. Yeo and S . S. Ratnam, i b i d . , 15,1063 (1978). M. Schmidt-Collwitzer. K. Schmidt-Collwitzer, B. S c h u s s l e r , R. Koch and J . NevinnyS t i c k e l , C e b u r t s h . u. F r a u e n h e i l k . , 37, 1030 (1977). U. K r i s h n a , A. C. C a n g u l l , A. V . Mandlekar and V. N . P u r a n d a r e , P r o s t a g l a n d i n s . l5, 685 (1978). K. Oshlma, K. M a t s u m t o . T. Tsuda, K. S h i b a t a and M. Hayashi, i b i d . , g.473 (1978). S. T a k a g i , H. Sakata. T. Yoshida, S. Nakazawa, K. T. F u j i i , V . Tominaga, 7. Iwasa. T. Nfnagawa. T. Hiroshlma, Y. Tomida, K. I t o h and R. Matsukawa, i b i d . . 14,791 (1977). S. Takagi. H. S a k a t a , T. Yoshida, K. Den, T. K. F u j i i , H. Amemiya and M. Tomita. i b i d . , 15, 913 (1978). J. Humphries, Y. -P. Wan, K. F o l k e r s and C . Y. Bowers. J . Med. Chem., 20, 1674 (1977). J. Humphries. Y. -P. Wan, K. F o l k e r s and C. Y. Bowers, i b i d . . 1, 120 (1978). J. Humphries, T. Wasiak, Y. -P. Wan and K . F o l k e r s , Biochem. Biophys. R e s . Commun., E , 709 (1978). A. S. h t t a . B. J. A. F u r r , M. B. C i l e s , B. V a l c a c c i a and A. L. Walpole, i b i d . , g , 382 (1978). J . S e p r o d l . D. H. Coy, J . A. Vilchez-Martinez, E. Pedroza and A. V. S c h a l l y , J . Med. Chem., 21. 276 (1978). F. A. Momany, i b i d . , 3.6 3 (1978). A. Corbin. S. J a s z c z a k . J . P e l u s o , N. L. S h a n d i l y a and E. S . E. Hafez. C o n t r a c e p t i o n , 18, 105 (1978). D. Conzalez-Barcena, A. J. K a s t i n , D. H. Coy, K. N i c o l i c s and A. V. S c h a l l y , L a n c e t , 11. 997 (1977). A. Corbin, C. W. B e a t t i e , J . Tracy, R. J o n e s , T. J. F o e l l . J . Yardley and R. W. A. Rees, I n t . J. F e r t i l . , 3,81 (1978). A. C o r b i n , C. W. Beattie, R. Rees, J . Yardley. T. J . F o e l l , S . Y. C h a i , H. McGregor. V. Carsky, D. S a r a n t a k l s and W. A. McKinley, F e r t i l . S t e r i l . . 2, 471 (1977). C. P e l l e t i e r . I,. Cusan, C. A u c l a i r , P. A. K e l l y , L. Desy and F. L a b r i e , Endocrinology, 103, 6 4 1 (1978). C. S. K l e d z i k , L. Cusan, C. A u c l a i r . P. A. K e l l y and F. L a b r i e , F e r t i l . S t e r i l . , 2. 348 (1978). G. P e l l e t i e r and L. Desy, Clin. Res., 26, 684A (1977). C. S. K l e d z i k , L. Cusan, C. A u c l a i r , P. A. K e l l y and F. L a b r i e , F e r t i l . S t e r i l . , 29, 560 (1978). S. J. N i l l i u s , C. BergquiSt and L. Wide, C o n t r a c e p t i o n , 2, 537 (1978). T. Koyama, T. Ohkura, T. Kumasaka and M. S a i t o , F e r t i l . S t e r i l . , 30, 549 (1978). J . Robins, F e r t i l . S t e r i l . ,
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~
~
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85. A. Lemay. F. L a b r i e , C. Azadian-Boulanger and J . -P. Raytiand, C . R. Acad. Sc . S e r . D., 28, 527 (1978). 86. J. Z a n a r t u , J . M. R osner, E. Guiloff, A. A. I b a r r a - P o l o , H . D. C r o x a t t o . H . B. E. A g u i l e r a , D . H. Coy and A. V. S c h a l l y , Br. Med. J . . 2. 527 (1975). 87. J. S e p r o d i , D. H. Coy, J. A. Vi l chez-Mart i nez, E . Pedroza. W . - Y . Huang and A. S c h a l l y , J. Med. Chem., 2.993 (1978). 88. J . Sandow, W. Kdriig. R. G e i g e r , R . Uhmann and W. von Rechenberg, Proc . E a s t e r S c i . Univ. Nottingham. 26, 49 (1977). 8 9 . D. M. DeKretser, B u l l . W.H.O.. 56. 353 (1978). 90. J . S e n i o r , Pharm. J . , 341 ( 1 9 7 8 z 91. L. L. Ewing a n d B. R o b a i r e , Annu. Rev. Pharmacol. T o x i c o l . . 18, 167 (1978).
92. 93. 94. 95. 96. 97 98. 99. 100. 101.
Paris. Croxatto, V.
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B a r t s c h and W. -H. Weiske, C o n t r a c e p t i o n . 6 c (1977). F r i c k , 0. B a r t s c h and W. -H. Weiske, i b i d . , 15, 669 (1977). 635 (1977). M v a r e z - S a n c hez. A. Faundes, V. Brache and P . Leon, i b i d . , D. Skoglund and C. A. P a u l s e n . i b i d . , 1. 357 (1973). U l s t e i n , N. Netto, J . Leonard and C. A. P a u l s e n . i b i d . . 12. 437 ( 1 9 7 5 ) . S t e i n b e r g e r and K. C. Smith. F e r t i l . S t e r i l . , 2.1320 ( E 7 7 ) . J. Hammerstein and J. B r o t h e r t o n , I n t . J . Androl. , Suppl. 2 , 659 (1978). F. Neumann, R. C. Ni ckol son, 8. Schenck and H. S t e i n b e c k , i b i d . . 147 (1978). B. Schenck a n d F. Neumann, i b i d . , 1 5 5 (1978). P. D. C. Brown-Woodman, H. Mohri. T. Mohri. D. S u t e r a nd I . C. White, Biochem. J . , 170 2 3 (1978). 102. R. W. F i t z p a t r i c k , H. J a c k s o n and N . A. Di ckins on. C o n t r a c e p t i o n , g. 477 ( 1 9 7 8 ) . 103. W. C. L. Ford and G. M. H. Waites, J . Reprod. F e r t . , 52, 1 5 3 (1978). 1 0 4 . G. Corsi, G. P a l a z z o , C. Germani, P. S. Barcellona a nd E. S i l v e s t r i n i , J . Hed. Chem.. 1 9 , 778 (1976). 105. S. B u r b e r i , B. C a t a n e s e , V. C i o l i , B. S. B a r c e l l o n a and B. S i l v e s t r i n i , Exp. Hol. P a t h o . , 9, 308 (1975). 1 0 6 . F. C o u l s t o n . W. J . Dougherty. R . LeFevre. R. Abraham and B. S i l ~ ~ r s t r i n iI. b i d . . 2 , 3;; (1975). 107. V. P. Kamboj, B. S. S e t t y , H . Chandra, S . K. Roy and A. B. Kar, I n d i a n J . Exp. H i o l . . 15, 1144 ( 1 9 7 7 ). 108. S. Roy, G . L. Kumari, K. Madoiya, V. P r a k a s h and S . Ray. F r r t i l . S t r r i l . , 3. 1108 (1976). 109. H. Chandra, R. C. Srimal, V. P. Kamboj, B. N . Dhawan and N. N . Gupta. I n d i a n 3 . Exp. B i O l . , 2.1 1 7 0 (1977). 1151 (1977). 110. J . S. Munshi, R. K. Nair and P. K. Devi , i b i d . , 111. R. Vaidya. U . J o s h i , P. M e h e r j i , N. Rege, S. B e t r a b e t . L . J o s h i , A. S h e t h a nd P. K . Devi, i b i d . , 2,1 1 7 3 (1977). 1 3 0 (1975). 112. L. J . L e r n e r , G. G a l l i a n i . P. C a r m i n a t i and M. C. Mosca, N a t u r e , 113. L. J . L e r n e r and P. C a r m i n a t i i n "Advances in P r o s t a g l a n d i n and Thromboxane Research". Vol. 2 , 5. Samuelsson and R. P a o l e t t i , Ed., Raven P r e s s , New York, NY, 1976, p 645. 114. L. J . Le r n e r and P. C a r m i n a t i , J . S t e r o i d Biochem., S, 395 (1977). 115. L. J . L e r n e r . C. O l d a n i and A. V i t a l e , P r o s t a g l a n d i n s , 15, 525 (1978). 116. H. R. L i n d n e r , V . Zor, S. Bauminget, A. T s a f r i r i , S . A. Lamprecht, Y. Koch. S. A n t e b i and A. S c h w a r tz i n " P r o s t a g l a n d i n S y n t h e t a s e I n h i b i t o r s " , H. J . Robinson and J . R. Vane, Ed., Raven P r e s s , NY, 1974, p 271. 1 1 7 . E. E . Wallach. A. d e l a Cruz. J. Hunt, K. H. Wright a nd V . C. S t e v e n s , P r o s t a g l a n d i n s . -9 , 645 ( 1 9 7 5 ) . 118. H. Maia, I. Barbosa a n d E. M. Cout i nho, F e r t i l . S t e r i l . , 565 (1978). 119. K. H . Wr ig h t , V. C. S t e v e n s , Y . Hamada and E. E. Wallach. i b i d . , 239 (1978). 120. A. R. Souka, H. Rahman and F. S a l e h , IRCS M e d i c a l S c i e n c e : E n d o c r i n e S e c t i o n , 61 (1978). 1 2 1 . G. Chandhuri and M. G. E l d e r , P r o s t a g l a n d i n s , 11, 727 (1976). 122. F. L . Greenway and R. S. S w e r d l o f f , F e r t i l . S t e r i l . , 30, 364 (1978). 1 2 3 . S. K . Garg, I n d i a n J . Med. Res.. 2,392 (1978). 124. M . E . F la u g h , T. A . C r o w e l l , J. A. Clemans and 8. D. Sawyer, J . Med. Chen., 11. 63 (1979). 1 2 5 . D. M. P a to n , J . H. Widdicombe, D. E. Rheaume and A. J o h n s , Pharmacol. Rev., 2. 67 (1978). 126. D. D. S o e j a r t o , A . S. B i n g e l , M. S l a y t o r and N . R . F a r n s w o r t h , B u l l . W.H.O., 343 (1978).
.,
J . F r i c k . G.
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J. F. R. M. E.
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Section IV
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Editor: Denis M. Bailey, Sterling-Winthrop Research Institute Rensselaer, New York 12144 Chapter 16. Chemical Control of Fertility Malcolm R. Bell, Robert G. Christiansen and H. Philip Schane, Jr. Sterling-Winthrop Research Institute, Rensselaer, New York 12144 Introduction - The results of a survey1 of married women aged 15-44 for the 1973-1976 period indicated the following major contraceptive choices: "pill" ( 2 2 % ) , sterilization (19%, female and male), condom (7%), intrauterine device (IUD) (6%), rhythm (3%), foam ( 3 % ) , diaphragm (3%). Major trends are the increasing use of sterilization and a somewhat decreasing reliance on the "pill". Approximately 600,000 male and 600,000 female sterilizations are performed annually in the U. S. With compliance, the "pill" is an excellent method of family planning with a failure rate of 1 pregnancy or less per 100 women-years. A beneficial effect to undernourished women is a decrease in menstrual blood loss. Compliance can be a problem and missed medications can result in pregnancy. Although the IUD is not as effective as the "pill", compliance is not a problem if the IUD is properly inserted and remains in place. Associated with the use of the unmedicated IUD is a significant increase in menstrual blood The incorporation of Cu or a progestin in these devices has increased their effectiveness.4 , 5 Menstrual blood loss seen with the unmedicated IUD is reduced with Progestasert@, an IUD whose effectiveness approaches that of the Elective abortion as a method of family planning is increasing as a result of the availability of safe and legal abortion services.6 There is one elective abortion in the U.S. (1.3 million in 1977) for every three live births. Since the introduction of the "pill" in 1960, the major advances from a medicinal chemical point of view have been the introduction of prostaglandins (PG's) as abortifacients and the medicated IUD's. Neither has yet had the impact of the "pill" but progress has been reported in the development of PG's and IUD's with improved properties. Most of the recent research with sex hormones deals with previously reported compounds. An important finding in the area of luteinizing-hormone-releasing hormone (LH-RH) analogs is that both agonists and antagonists are potential antifertility agents. There are no reports evaluating this class of drugs as human antifertility agents. The immunological approach to fertilit trol has been re~iewed.~A review of many approaches is available. con-
8
Steroids - Two recent re~iews~,~'summarize the adverse reactions from use of the "pill". The "paper pill", a square of edible cellulose impregnated with the steroids, is advantageous with respect to packaging, transportation, acceptability and storage. The conventional and the "paper pill", each containing 1 5 0 pg of levonorgestrel and 30 pg of ethynylestradiol (EE), were equally effective in suppressing ovu1ation.l' The EE content of the "pill" was lowered to 30 ug without loss of contraceptive Copyright @ 1979 by Academic Press, Inc. All rights of reproduction in any form resaNed. ISBN 0-12-040514-8
Chap. 16
Control of Fertility Bell, Christiansen, Schane
169
efficacy.12 In a modified sequential oral contraceptive dosage schedule, 50 pg of EE administered for 7 days followed by 50 pg of EE and 1 mg of lynestrenol for 15 days resulted in complete inhibition of 0vu1ation.l~ A useful alternative to the pill especially in women in whom estrogen is contraindicated, is Depo-Provera' (medroxypfogesterone acetatpi which when given i.m. every 3 months is an effective contraceptive. This progestin in large continuous doses induced an increased incidence of mammary cancer in beagle dogs, an effect not reported in other animals or women.15 The drug is not available in the U.S.16 Danazol (1) has been reported to be an oral contraceptive in the rhesus monkeyl7z8 and in women.19 In rats, this substance was a pituC E C H itary gonadotropin inhibitor which neither exhib3 ited estrogenic nor progestational activity but did have weak impeded androgen-like activity.2o Administration of estrogens, either 5 mg of EE or 50 mg of diethylstilbestrol p.0. for 5 days beginning within 3 days of coitus in midcycle, is effective in preventing pregnancy in women. Nausea and vomiting are common side effects. Diethylstilbestrol caused an increased incidence of vaginal adenosis and adenocarcinoma of the vagina and cervix in female offspring of women treated during the first trimester with this drug for other reasons.21 In China, the estrogen anordrin (2) is taken immediately after coitus for prevention o f pregnancy.22 When EE and dl-norgestrel were administered in combination to 608 women shortly after coitus, one pregnancy occurred nu nu OCOC,H,
J
U -
I -
rather than the 12-30 pregnancies expected.23 The antiprogestin R-2323 (norgestrienone, 2) had low contraceptive efficacy in w 0 m e n . ~ 4 , ~It ~ was suggested that the antifertility effects of RMI 12,936 (5) resulted from its antiprogestational activity as well as inhibition of progesterone (P) biosynthesis.26 The abortifacient activity of the cyanohydrin diacetate 5 in the rat may be the result of its transformation to estrogens in the ovary.27 ORF 9326 (6) terminated pregnancy in rats when administered P.O. on days 9-12 of gestation.28 At the effective dose, the compound lacked estrogenic, androgenic, and progestational activities. The spiroether 7
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Bailey, Ed.
was an estrogen antagonist in mice and ewes but was not estrogenic in rats. When administered to normally cycling rhesus monkeys, it increased the viscosity of the cervical mucus, a possible antiestrogenic effect, and prevented pregnancy.29
-
Steroidogenesis Inhibitors Aminoglutethimide (8), which blocks the conversion of cholesterol to P, terminated pregnancy in rats3’ but not in baboons.31 The 5,lO-seco steroids 9 irreversibly blockedA5-3-ketoisomerase from testosteroni in vitro and caused a decrease in the weight of male sex accessory organs of the rat, an effect which could be the result of inhibition of androgen biosynthesis.3L Azastene (10)was a competitive inhibitor of P biosynthesis in vitro and disrupted pregnancy in both the rat33 and rhesus monkey.34 This agent blocked human chorionic gonadotropin-induced prolongation of corpus luteum function and lacked hormonal activity.35 Trilostane also a competitive inhibitor of 38R /COCH3
e.
0
JfJp NH2
H
-8
(s),
R=O,
..
‘H
R’=-CH2C =C-CH2 or CH=C=CHCH2
hydroxysteroid dehydrogenase, was more effective in blocking adrenal steroidogenesis than in disrupting pregnancy in the rat36 and rhesus mon-
CH3 CH3
‘SR R=-C H -p-NH2 6 4 10 11 12 13 key.37 Pregnancy in the monkey was terminated at a time when the ovaries are required for the continuation of pregnancy as well as when the placenta is capable of maintaining pregnancy in the absence of the ovaries. The estrogen synthetase blocker 12 inhibited mating, ovulation, and implantation in rats.38 Of a series of aromatase inhibitors, j.3- was the most active in vitro.39 ‘0
Prostaglandins - PGF c1 is available on a limited basis in the U.S. for the termination of seconi trimester pregnancy by the intraamniotic route. PGE2 has been approved in the U.S. for the same indication as an intravaginal s u p p o ~ i t o r y . The ~ ~ primary action of the PG’s in humans is believed to be a direct stimulatory effect on myometrial smooth m ~ s c l e . ~ l - 4 ~ The decreases in serum P and estradiol levels are considered a consequence and not a cause of the disruption of pregnancy. It should be remembered that pregnancy termination by luteolysis is only possible during early gestation since the corpus luteum is not required for maintenance of pregnancy after 6 or 7 weeks of estation, the time at which the luteoplacental shift takes p l a ~ e . ~When ~ , administered ~ ~ in the mid-luteal phase
Chap. 16
Control of Fertility Bell, Christiansen, Schane
171
PGFZa is not luteol tic in normal cycling women but is luteolytic in rats and other The results of an international multicenter study were interpreted to indicate that intraamniotic saline and PGF2, (25 mg repeated in 6 hours) are safe and effective for termination of second trimester pregnan~y,~'and that PGF2clis significantly more effective than saline in the termination of pregnancy within 48 hours. Another interpretation of these results pointed out the hazards of PGFZa and intraamniotic saline and advised that, up to the sixteenth week dilatation and evacuation is the most advantageous available method. 51 An advantage of dilatation and evacuation i s the low incidence of incomplete abortion compared with intraamniotic PGF or saline.51 In second trimester pregnancy a single intraamniotic injec&on of 2.5 mg of 15(S)-methyl PGFZ, methyl ester was slight1 more effective than 5 0 mg of PGF2, in inducing abortion within 48 hours.5T About one half of the abortions were incomplete with both drugs. In another multicenter study, a 92% abortion rate, 50% of which were incomplete, was achieved within 30 hours after repeated intravaginal administration of 15(S)-methyl PGFZa methyl ester during the second trimester.53 Vomiting and diarrhea were significantly more common with the PG analog, but the mean incidence of diarrhea and vomiting ranged from 2 to 6 episodes per patient in both s t u d i e ~ . ~ ~ 9 ~ 3 and second First trimester pregnancy was terminated with 15(S)-meth 1 PGFZa methyl ester administered as a single intravaginal suppository.34-56 Intravaginal administration of 16,16-dimethyl PGE2 was as effective in terminating first trimester pregnancy as vacuum aspiration but was associated with a much higher incidence of side effects. The incidence of side effects was lower than with 15(S)-methyl PGF2a methyl ester.57 Summaries of the results of clinical evaluation of PG's for pregnancy termination have been published. 58959
specie^.^'
Sulprostone (CP-34,089, ZK 57,671, SHB 286, 14) was 10-30X active than PGE2 as an antifertility agent in laboratory studies to or less active than PGE in laboratory tests considered to be tive of side effects.60 A3ministration of this agent i.v., i.m. 0
0
CONHS02CH3
HO
more but equal predicor by the
14 -
OH
e
HO'
2
15 -
~
6H
transcervical intrauterine route terminated first and second trimester HO pregnancies in women.61-64 A decrease in the incidence of side effects com.:\MM CHc 0 2 3 pared with other PG's was reported, a particularly significant result since the i.m. route could be advantageous HO' HO CH3 in the developing countries.65 A similar favorable separation of activi16 ties has been reported in the monkey for ONO-802 (15) .66 This PG terminated early regnancy in women when given by the transcervical intrauterine route6Por by pessary.68 In the latter study, complete abortion occurred in 54 of 63 women; nausea and
~
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Bailey, Ed.
vomiting were reported by one patient. Encouraging results have also been obtained in studies with 16,16-dimethyl PGE2 p-benzaldehyde semicarbazone ester for termination of first and second trimester pregnancies and with the dihomo PG derivative 16 for termination of abnormal intrauterine pregnancies.59 LH-RH Antagonists - Des-Glylo-[Trp2,Leu3,D-A1a6]LH-RH ethyl amide (EA) inhibited ovulation in rats after a single s . ~ .dose of 1.5 mg/rat on the day of r o e s t r ~ s . ~ ID-Phe2 ~ Pro3,D-Trp6 or D-Phe'1LH-W were active at 750 p5.'99 70 Ac- [Pro ,D-Phe2,D-Trp3,D-Trp6]LH-RH and [D-
Chap. 16
Control of Fertility Bell, Christiansen, Schane __ 173
dotro in receptor concentrations in the gonads of both male and female rats.fjo-82 Ovulation inhibition in women was achieved by treatment with [D-Ser(t-Bu)']LH-RH EA (HOE 766) S.C. daily for 22-30 days at a dose of 5 p g commencing within 3 days of the beginning of menstruation.83 Premature luteolysis in women resulted from administration of des-GlylO-LHRH EA S.C. for 5 days during the post-ovulatory phase.84 Administration of LH-RH at a dose of 250 ug several times on one day between the second and seventh day following ovulation caused premature luteolysis in women.85 There was evidence of ovulation on laparotomy in 9 of 10 women after pretreatment with EE every 12 hours on days 10 and 11 or days 9-11 followed by one injection of [D-Leu6]LH-RH EA.86 If these results are confirmed, a method could be available for improving the effectiveness of the rhythm method. As in the above study,86 however, it may be necessary to prime the hypothalamic-pituitary-gonadal system by administration of an estrogen prior to the administration of the LH-RH agonist. The observation that cyclo [ (B-Alal) and (6-Aminohexanoyll),D-Ala6) ]LH-RH were more potent agonists than the uncyclized peptides, although only about 1% as potent as LH-RH, supports an "U" shape conformation for LH-RH.87 Structure-activity relationships of LH-RH and its analogs have been reviewed.88 Male Contraception - The most promising approach to male contraception is suppression of spermatogenesis mediated by inhibition of gonadotropin release by the pituitary gland.89-91 Inhibition of spermatogenesis in men by monthly injections of a combination of Depo-Provera and testosterone enanthate (TE) continues to be studied with the objective of developing the optimum dosage schedule,92-94 Danazol (1)plus testosterone nate or TE caused a variable reduction of spermatogenesis in man. TE administered i.m. biweekly also did not result in uniform azoospermia in a year-long study.97 It is not known if azoospermia must be achieved for complete inhibition of fertility or whether oligospermia would be sufThe use of implants containing androgens is not yet practical since the im lant would be too large emphasizing the need for more active The D-homo steroids 1 7 and 18 are considered possible candidates €or use in implants since they are more effective than testosterone in suppressing pituitary gonadotropin secretion and, as a result, have an appropriate balance of peripheral and central activities.99 Antiandrogens such as cyproterone acetate have not been useful as male antifertility agents since libido is reduced at effective contraceptive doses.lOO The effects of prolonged suppression of spermatogenesis need to be studied and it must be established whether fertility returns upon withdrawal of drug. 97s g 8 a-Chlorohydrin(3-chloropropane-l,2-diol) is an example of a compound that interferes with sperm maturation."' Toxic side COOH effects, particularly in the monkey, precluded trials of the compound in man. The antifertility activity of a-chlorohydrin may be the result of an inhibition of glyceraldehyde-3-phosphate de0 'R& hydrogenase in spermatozoa. The 1 7 R=COC2H5,R'=H S(+)-isomer is more active in vitro and in vivo than the R(-)18 R=H, R' =C = CH c1 isomer. In vitro experiments sug19 gest that conversion to the 1-
androgen^.^^
Sect. IV - Metabolic Diseases, Endocrine Function
174 -
Bailey, Ed.
phosphate is necessary for activity.l02 Some 6-chloro-6-deoxy sugars had a reversible contraceptive action in the male rat and were less toxic than a - c h l ~ r o h y d r i n . ~AF~ ~1312/TS (19)inhibited spermatogenesis in the rat and in the monkey.'04-lo6 Miscellaneous Compounds - Centchroman (20)inhibited pregnancy in rats, mice, do s and monkeys when administered once orally within 24 hours of coitus.1 7 The drug was estrogenic, antiestrogenic and antiprogestational and inhibited ova development in the rat. Coadministration with P and estradiol diproprionate prevented the termination of pregnancy. Centchroman possessed both gonadotropin inhibitory and stimulatory properties in unilaterally ovariectomized rats deR R pending upon the dose. The compound resembles in this respect the structurally related clomiphene ( 2 1 , an antiestrogen and a known ovulation stimulator. Centchroman induced ovu5 H CH30 6 : &' 0 lation in women when administered C ~ H ~ dail log The drug is well-tolera21 C6H5 tedl" and is being studied as a 20 once-a-week contraceptive.'l0 The contraceptive activity was suggested R=CH CH N E ~ ~ R=CH2CH2 2 2 to be a result of an inhibition of implantation and sperm transport. The triazoles 22 and 23, inhibitors of PG metabolism in the rat uterus, placenta, and were completely effective in terminating pregnancy in rats and hamsters when administered S.C. daily during any one of four 5-day periods between days 1 and 12 of pregnancy. These compounds were most effective when administered immediately following implantation; they lacked hormonal or antihormonal activity, and their antifertility effect was not reversed by P.lI2 The closely related 24 given S.C. in
8
Q
7
OR
3 23 n=2,R=CH
-
3
24 n=2,R=C H 2 5 25 -
26 -
combination with PGE2 during esfrus blocked ovulation almost completely in the hamster.l15 PGE2 alone was ineffective and 2 alone was weakly active; 24 also hastened ova transport. Indomethacin, a PG synthetase inhibitor suppressed spontaneous and induced ovulation in rats and rabbits,I l b suppressed gonadotropin-induced ovulation in rhesus monkeysll7 and marmosets,118 but failed t o inhibit spontaneous ovulation in rhesus monkeys.119 Studies with indomethacin as an ovulation inhibitor in women were inconclusive120 and in two small studies in women aspirin was ineffective.121,122 The biphenyl derivative 2 was completely effective inhibiting pregnancy in rats on days 4 and 5 at a dose of 5 mg/kg p.0. 6-Chloromelatonin (26) inhibited ovulation in rats when administered i.v. or p.0. on the day of proestrus and was more effective than melatonin, probably as a result of an increased metabolic stability.124
&
Chap. 16
Control of Fertility
Bell, Christiansen, Schane
175
A review of adrenergic innervation of the mammalian oviduct includes
a summary of drugs that modif
the sympathetic nervous system and affect ovum transport and fertility.P25 Plants are a relatively untapped potential source of new antifertility agents.126 References
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2. 3. 4.
J. F. Hulka.
11,
132,
2.
so.
11.
176 44. 45. 46. 47. 48. 49. 50.
51. 52.
53. 54. 55. 56. 57.
58.
59. 60.
61. 62. 63. 64. 65.
66. 67.
68.
69. 70. 71.
72. 73. 74. 75. 76. 77. 78. 79.
80. 81. 82.
83. 84.
Sect.
Iv -
Metabolic Diseases, Endocrine Function
~
~
Ed. i l
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-
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Chap. 16
C o n t r o l of Fertility B e l l , Chrlstiansen, Schane
85. A. Lemay. F. L a b r i e , C. Azadian-Boulanger and J . -P. Raytiand, C . R. Acad. Sc . S e r . D., 28, 527 (1978). 86. J. Z a n a r t u , J . M. R osner, E. Guiloff, A. A. I b a r r a - P o l o , H . D. C r o x a t t o . H . B. E. A g u i l e r a , D . H. Coy and A. V. S c h a l l y , Br. Med. J . . 2. 527 (1975). 87. J. S e p r o d i , D. H. Coy, J. A. Vi l chez-Mart i nez, E . Pedroza. W . - Y . Huang and A. S c h a l l y , J. Med. Chem., 2.993 (1978). 88. J . Sandow, W. Kdriig. R. G e i g e r , R . Uhmann and W. von Rechenberg, Proc . E a s t e r S c i . Univ. Nottingham. 26, 49 (1977). 8 9 . D. M. DeKretser, B u l l . W.H.O.. 56. 353 (1978). 90. J . S e n i o r , Pharm. J . , 341 ( 1 9 7 8 z 91. L. L. Ewing a n d B. R o b a i r e , Annu. Rev. Pharmacol. T o x i c o l . . 18, 167 (1978).
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