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Development of the oral contraceptives
Development of the oral contraceptives M.
C. CHANG,
Shrewsbury,
PH.D.,
Sc.D.
Massachusetts
DLIRINCTHESECONDWORLDWAR, lwasworkingin the laboratory of Sir John Hammond and Dr. Arthur Walton at Cambridge University on methods of preservation of mammalian sperm and other problems concerning the improvement of fertility in domestic animals. In 1945, I came to the Worcester Foundation for Experimental Biology, which had just recently been established by Drs. Hudson Hoagland and Gregory Pincus. My assignments were the perfusion of cow ovaries, induction of superovulation, the recovery of eggs, their fertilization in vitro, and subsequent transfer to another cow for the production of genetically superior calves. In 1946, I was invited to give a paper on the fertilizing capacity of rabbit spermatozoa at a Conference on Fertility under the auspices of the National Committee of Maternal Health in New York, New York, where I met Dr. Robert L. Dickinson who, because of his concern about the large population in China, encouraged me to work on contraception. When the “population explosion” made headlines in newspapers at the end of the Second World War, Dr. Pincus, other scientists, and myself often discussed various possible methods for contraception but we did not plan a specific research program. After Pincus made contact with Mrs. Margaret Sanger and Mrs. S. McCormick, we started to think about some promising and novel methods for contraception. Certainly, development of an oral contraceptive was one of the possibilities. It was already known in 1937 to 1939 that progesterone could inhibit ovulation,1-3 and the possibility of inhibition of fertilization during the luteal phase by administration of progesterone4-6 was reported in 1947 to 1949. One of the most attractive and promising approaches to development of an oral contraceptive was to investigate the effects of progesterone and the newly synthesized progestational compounds on reproduction by various routes of administration. The experimental procedures were simple and straightforward and they were left completely to me, but I was more interested in the possibility of inhibiting fertilization and the effect on fertility by deposition of From
the Worcester
Foundation
OOOZ-937&-S/78/02132-0217$00.30/O@
for Experimental
1978 l-be C. V. Mosby
Biology. Co.
progesterone into the vagina. Female rabbits were treated with progesterone or related compounds by injection, feeding, or deposition into the vagina. They were mated and the ovulation spots, the number of sperm in the female tract, the number of unfertilized and fertilized eggs, and the number of implantation sites were recorded. The very first experiment was started on April 25, 1951, by me with assistance later on from Dr. A. T. Gregoire (at present, working for the Food and Drug Administration). The results of this experiment were not to my satisfaction because the effects on sperm transport and fertilization were not clear, but it was shown that high doses of progesterone and other newly synthesized compounds inhibited ovulation. The first paper’was published in 1953, in honor of Professor A. Lipschutz of Chile. I always liked to do comparative studies so the second series of experiments was conducted on rats by me and my Ph.D. student Dr. Slechta (at present, the Dean of Boston University) and the results were published in 1954.* From this experiment a simple procedure was established for investigations on fertility control and more promising and effective compounds were found. Based on our animal studies, Pincuss gave a paper at the Fifth lnternational Conference on Planned Parenthood on October 28, 1955, in Tokyo and stated the possibility of using progestational compounds for oral contraception. This again caught the headlines in the world press. Because so many compounds had to be tested for their effects on reproduction as well as endocrinologic reactions, the third series of experiments on rabbits, rats, and mice was conducted by us, including the late Dr. M. X. Zarrow and Dr. E. S. E. Hafez (at present, a professor at Wayne State University), Ms. Anne Merrill (then chief assistant to Pincus), and many other research assistants; this paper was published in 1956.‘O Pincus’ good connections with pharmaceutical companies in this country and abroad gave us the opportunity to test hundreds of the newest synthesized progestational compounds during this period and we found that two 19-norsteroid compounds, norethynodrel” (product of G. D. Searle 8~ Co., Chicago, Illinois) and norethindrone’* (product of Syntex Laboratories, Inc., Palo Alto, California), were most effective for the pre217
218
September Am. J. Obstrr.
Chang
vention of pregnancy in animals by oral administration. The late Dr. Pincus not only was interested in scientific discovery but also wanted to put our findings into practice, When we found out that these two compounds very effectively prevented pregnancy in laboratory animals, he immediately discussed with Dr. John Rock, who was interested in progestational reactions for a long time, the possibility of testing these two compounds in women. As a result, extensive tests were carried out by Dr. Rock, Dr. Garcia (now a professor at the University of Pennsylvania), and a group of medical doctors in Puerto Rico. Thus, the animal studyi and and pubthe first clinical study14 were summarized lished in the same issue of Science in 1956. Extensive clinical investigation of these compounds in human subjects in Puerto Rico and Haiti led to the introduction of estrogen into the progestational compounds for the prevention of breakthrough bleeding but the estrogen-progestogen combination proved to be more effective for contraception.15-I* Thus, by the time of the Sixth International Conference on Planned Parenthood, in New Delhi, February, 1959, the oral contraceptive was well established, and Pincus, Rock, Garcia, E. T. Tyler, and V. A. Drill each gave a good account concerning the effectiveness of the oral contraceptives. Pincus had a private interview with Prime Minister Nehru and was very pleased. A final report on the control of conception by hormonal steroids was summarized by Pincus.lY However, I was not happy with pill ingestion every month for 22 days. After the oral contraceptive pill was on the market, I did some studies on the effects of various compounds administered to animals soon after mating for the prevention of pregnancy. We found out that high doses of norethynodrel, an ingredient of the oral contraceptive, and any compounds with estrogenic activity could prevent pregnancy when administered soon after mating. In fact, this was known in 1926, and Dr. Morris of Yale University”’ has used estrogenic compounds as “morning-after” pills for many years. Moreover, we have found that an A-norsteroid (H24 1)
REFERENCES
1. Makepeace, A. W., Weinstein, G. L., and Friedman, M. H.: Am. J. Physiol. 119: 512, 1937. 2. Dempsey, E. W.: Am. J. Physiol. 120: 126, 1937. 3. Astwood, E. B., and Fevold, H. L.: Am. J. Physiol. 127: 192, 1939. 4. Murphree, J. L., Warwick, E. J., Casida, L. E., and McShan, W. H.: Endocrinology 41: 308, 1947. 5. Boyarsky, L. H., Baylis, H., Cysida, L. E., and Meyer, R. K.: Endocrinology 41: 312, 1947. 6. Austin, C. R.: J. Endocrinol. 6: 63, 1949.
15, 1978 Gynecol.
that has estrogenic activity is more effective when administered orally soon after mating.*l This finding was not exploited by the medical profession in Western countries but was used as a ‘morning-after” pill in the People’s Republic of China in t975.** As an academic scientist, I was not satisfied with the interpretation held by Pincus and other workers that the mechanism of action of the pill was solely due to the prevention of ovulation, because there was.only indirect evidence from a few cases of laparatomy in women. Moreover, if they were so effective, they must disturb other reproductive processes. Further studies have shown that the oral contraceptives not only inhibit ovulation but also inhibit fertilization (due to the disturbance of sperm capacitation and speed-up of egg transport) and prevent implantation and embryonic development (due to the endometrial development being out of phase with the developing embryo}. Thus, at the Eighth International Conference on Planned Parenthood held in Chile, in 1967, I gave a good account on the physiologic mechanism responsible For the effectiveness of oral contraceptives.‘” Because of the complexity of modern society and scientific research in recent years, an important discovery cannot be achieved by one person. Many people contributed their talent and labor, but I can only mention a few in the early development of the oral contraceptives. The development of oral contraceptives was described in two reports to the National Science Foundation (NSF-C535 NSF-C667). These reports contained a list of 10 important innovations, giving details of their dates of conception to the times when they were put into practice. The shortest interval between conception and actual realization of a particular innovation was six years and the longest was 32 years, with an average of 19 years. Oral contraceptives took only nine years, from 1951 to 1960, which was mainly due to the organizational ability and enterprising spirit of the late Gregory Pincus, to whom we are all grateful for various reasons.
7. Pincus, G., and Chang, M. C.: Acta Physiol. Lat. Am. 3: 177, 1953.
8. Slechta, R. F., Chang, M. C., and Pincus, G.: Eertil. Steril. 5: 282,
1954.
9. Pincus, G.: Proceedings of the Fifth International ference on Planned Parenthood, October 24-29, Tokyo, Japan. 1955, p. 175. 10. Pincus, G., Chang, M. C., Zarrow, M, X., HaFeqE. and Merrill, A: Endocrinology !I% 695, 1956. 11. Colton, F. B.: United States Fat. 2,691,028 to G. D. & co., I954.
Con1955, S. E., Sear%
Volume Number
132 2
12. Djerassi, C.: United States Pat. 2,744,122 to Syntex Laboratories, 1956. 13. Pincus, G., Chang, M. C., Hafez, E. S. E., Zarrow, M. X., and Merrill, A.: Science 144: 890, 1956. 14. Rock, J., Pincus, G., and Garcia, C. R.: Science 124: 891, 1956. 15. Garcia, C. R., Pincus, G., and Rock, J.: AM. J. OBSTET. GYNECOL. 75: 82, 1958. J., Garcia, C. R., Rice-Wray, E., 16. Pincus, G., Rock, Paniaqua, M., and Rodriquez, I.: AM. J. OBSTET. GYNECOL. 75: 1333, 1958. 17. Pincus, G., Garcia, C. R., Rock, J., Paniaqua, M., Pendleton, A., Iaraque, F., Nicolas, R., Borno, R., and Pean, V.: Science 130: 81, 1959.
Development of oral contraceptives
219
18. Pincus, G., Rock, J., Chang, M. C., and Garcia, C. R.: Fed. Proc. 18: 1051, 1959. Pincus, G.: Science 153: 493, 1966. :X: Morris, J. M., and van Wagenen, G.: AM. J. OBSTET. GYNECOL. 115: 101, 1973. 21. Chang, M. C., and Yanagimachi, R.: Fertil. Steril. 16: 28 1, 1965. 22. Ku, C. P., Chu, M. K., Chiang, H. C., Chao, S. H., Pang, T. W., and Tsou, K.: Sci. Sin. 18: 262, 1975. 23. Chang, M. C.: Proceedings of the Eighth International Conference on Planned Parenthood, April 9-15, 1967, Santiago, Chile. 1967, p. 386.
C. CHANG,
Shrewsbury,
PH.D.,
Sc.D.
Massachusetts
DLIRINCTHESECONDWORLDWAR, lwasworkingin the laboratory of Sir John Hammond and Dr. Arthur Walton at Cambridge University on methods of preservation of mammalian sperm and other problems concerning the improvement of fertility in domestic animals. In 1945, I came to the Worcester Foundation for Experimental Biology, which had just recently been established by Drs. Hudson Hoagland and Gregory Pincus. My assignments were the perfusion of cow ovaries, induction of superovulation, the recovery of eggs, their fertilization in vitro, and subsequent transfer to another cow for the production of genetically superior calves. In 1946, I was invited to give a paper on the fertilizing capacity of rabbit spermatozoa at a Conference on Fertility under the auspices of the National Committee of Maternal Health in New York, New York, where I met Dr. Robert L. Dickinson who, because of his concern about the large population in China, encouraged me to work on contraception. When the “population explosion” made headlines in newspapers at the end of the Second World War, Dr. Pincus, other scientists, and myself often discussed various possible methods for contraception but we did not plan a specific research program. After Pincus made contact with Mrs. Margaret Sanger and Mrs. S. McCormick, we started to think about some promising and novel methods for contraception. Certainly, development of an oral contraceptive was one of the possibilities. It was already known in 1937 to 1939 that progesterone could inhibit ovulation,1-3 and the possibility of inhibition of fertilization during the luteal phase by administration of progesterone4-6 was reported in 1947 to 1949. One of the most attractive and promising approaches to development of an oral contraceptive was to investigate the effects of progesterone and the newly synthesized progestational compounds on reproduction by various routes of administration. The experimental procedures were simple and straightforward and they were left completely to me, but I was more interested in the possibility of inhibiting fertilization and the effect on fertility by deposition of From
the Worcester
Foundation
OOOZ-937&-S/78/02132-0217$00.30/O@
for Experimental
1978 l-be C. V. Mosby
Biology. Co.
progesterone into the vagina. Female rabbits were treated with progesterone or related compounds by injection, feeding, or deposition into the vagina. They were mated and the ovulation spots, the number of sperm in the female tract, the number of unfertilized and fertilized eggs, and the number of implantation sites were recorded. The very first experiment was started on April 25, 1951, by me with assistance later on from Dr. A. T. Gregoire (at present, working for the Food and Drug Administration). The results of this experiment were not to my satisfaction because the effects on sperm transport and fertilization were not clear, but it was shown that high doses of progesterone and other newly synthesized compounds inhibited ovulation. The first paper’was published in 1953, in honor of Professor A. Lipschutz of Chile. I always liked to do comparative studies so the second series of experiments was conducted on rats by me and my Ph.D. student Dr. Slechta (at present, the Dean of Boston University) and the results were published in 1954.* From this experiment a simple procedure was established for investigations on fertility control and more promising and effective compounds were found. Based on our animal studies, Pincuss gave a paper at the Fifth lnternational Conference on Planned Parenthood on October 28, 1955, in Tokyo and stated the possibility of using progestational compounds for oral contraception. This again caught the headlines in the world press. Because so many compounds had to be tested for their effects on reproduction as well as endocrinologic reactions, the third series of experiments on rabbits, rats, and mice was conducted by us, including the late Dr. M. X. Zarrow and Dr. E. S. E. Hafez (at present, a professor at Wayne State University), Ms. Anne Merrill (then chief assistant to Pincus), and many other research assistants; this paper was published in 1956.‘O Pincus’ good connections with pharmaceutical companies in this country and abroad gave us the opportunity to test hundreds of the newest synthesized progestational compounds during this period and we found that two 19-norsteroid compounds, norethynodrel” (product of G. D. Searle 8~ Co., Chicago, Illinois) and norethindrone’* (product of Syntex Laboratories, Inc., Palo Alto, California), were most effective for the pre217
218
September Am. J. Obstrr.
Chang
vention of pregnancy in animals by oral administration. The late Dr. Pincus not only was interested in scientific discovery but also wanted to put our findings into practice, When we found out that these two compounds very effectively prevented pregnancy in laboratory animals, he immediately discussed with Dr. John Rock, who was interested in progestational reactions for a long time, the possibility of testing these two compounds in women. As a result, extensive tests were carried out by Dr. Rock, Dr. Garcia (now a professor at the University of Pennsylvania), and a group of medical doctors in Puerto Rico. Thus, the animal studyi and and pubthe first clinical study14 were summarized lished in the same issue of Science in 1956. Extensive clinical investigation of these compounds in human subjects in Puerto Rico and Haiti led to the introduction of estrogen into the progestational compounds for the prevention of breakthrough bleeding but the estrogen-progestogen combination proved to be more effective for contraception.15-I* Thus, by the time of the Sixth International Conference on Planned Parenthood, in New Delhi, February, 1959, the oral contraceptive was well established, and Pincus, Rock, Garcia, E. T. Tyler, and V. A. Drill each gave a good account concerning the effectiveness of the oral contraceptives. Pincus had a private interview with Prime Minister Nehru and was very pleased. A final report on the control of conception by hormonal steroids was summarized by Pincus.lY However, I was not happy with pill ingestion every month for 22 days. After the oral contraceptive pill was on the market, I did some studies on the effects of various compounds administered to animals soon after mating for the prevention of pregnancy. We found out that high doses of norethynodrel, an ingredient of the oral contraceptive, and any compounds with estrogenic activity could prevent pregnancy when administered soon after mating. In fact, this was known in 1926, and Dr. Morris of Yale University”’ has used estrogenic compounds as “morning-after” pills for many years. Moreover, we have found that an A-norsteroid (H24 1)
REFERENCES
1. Makepeace, A. W., Weinstein, G. L., and Friedman, M. H.: Am. J. Physiol. 119: 512, 1937. 2. Dempsey, E. W.: Am. J. Physiol. 120: 126, 1937. 3. Astwood, E. B., and Fevold, H. L.: Am. J. Physiol. 127: 192, 1939. 4. Murphree, J. L., Warwick, E. J., Casida, L. E., and McShan, W. H.: Endocrinology 41: 308, 1947. 5. Boyarsky, L. H., Baylis, H., Cysida, L. E., and Meyer, R. K.: Endocrinology 41: 312, 1947. 6. Austin, C. R.: J. Endocrinol. 6: 63, 1949.
15, 1978 Gynecol.
that has estrogenic activity is more effective when administered orally soon after mating.*l This finding was not exploited by the medical profession in Western countries but was used as a ‘morning-after” pill in the People’s Republic of China in t975.** As an academic scientist, I was not satisfied with the interpretation held by Pincus and other workers that the mechanism of action of the pill was solely due to the prevention of ovulation, because there was.only indirect evidence from a few cases of laparatomy in women. Moreover, if they were so effective, they must disturb other reproductive processes. Further studies have shown that the oral contraceptives not only inhibit ovulation but also inhibit fertilization (due to the disturbance of sperm capacitation and speed-up of egg transport) and prevent implantation and embryonic development (due to the endometrial development being out of phase with the developing embryo}. Thus, at the Eighth International Conference on Planned Parenthood held in Chile, in 1967, I gave a good account on the physiologic mechanism responsible For the effectiveness of oral contraceptives.‘” Because of the complexity of modern society and scientific research in recent years, an important discovery cannot be achieved by one person. Many people contributed their talent and labor, but I can only mention a few in the early development of the oral contraceptives. The development of oral contraceptives was described in two reports to the National Science Foundation (NSF-C535 NSF-C667). These reports contained a list of 10 important innovations, giving details of their dates of conception to the times when they were put into practice. The shortest interval between conception and actual realization of a particular innovation was six years and the longest was 32 years, with an average of 19 years. Oral contraceptives took only nine years, from 1951 to 1960, which was mainly due to the organizational ability and enterprising spirit of the late Gregory Pincus, to whom we are all grateful for various reasons.
7. Pincus, G., and Chang, M. C.: Acta Physiol. Lat. Am. 3: 177, 1953.
8. Slechta, R. F., Chang, M. C., and Pincus, G.: Eertil. Steril. 5: 282,
1954.
9. Pincus, G.: Proceedings of the Fifth International ference on Planned Parenthood, October 24-29, Tokyo, Japan. 1955, p. 175. 10. Pincus, G., Chang, M. C., Zarrow, M, X., HaFeqE. and Merrill, A: Endocrinology !I% 695, 1956. 11. Colton, F. B.: United States Fat. 2,691,028 to G. D. & co., I954.
Con1955, S. E., Sear%
Volume Number
132 2
12. Djerassi, C.: United States Pat. 2,744,122 to Syntex Laboratories, 1956. 13. Pincus, G., Chang, M. C., Hafez, E. S. E., Zarrow, M. X., and Merrill, A.: Science 144: 890, 1956. 14. Rock, J., Pincus, G., and Garcia, C. R.: Science 124: 891, 1956. 15. Garcia, C. R., Pincus, G., and Rock, J.: AM. J. OBSTET. GYNECOL. 75: 82, 1958. J., Garcia, C. R., Rice-Wray, E., 16. Pincus, G., Rock, Paniaqua, M., and Rodriquez, I.: AM. J. OBSTET. GYNECOL. 75: 1333, 1958. 17. Pincus, G., Garcia, C. R., Rock, J., Paniaqua, M., Pendleton, A., Iaraque, F., Nicolas, R., Borno, R., and Pean, V.: Science 130: 81, 1959.
Development of oral contraceptives
219
18. Pincus, G., Rock, J., Chang, M. C., and Garcia, C. R.: Fed. Proc. 18: 1051, 1959. Pincus, G.: Science 153: 493, 1966. :X: Morris, J. M., and van Wagenen, G.: AM. J. OBSTET. GYNECOL. 115: 101, 1973. 21. Chang, M. C., and Yanagimachi, R.: Fertil. Steril. 16: 28 1, 1965. 22. Ku, C. P., Chu, M. K., Chiang, H. C., Chao, S. H., Pang, T. W., and Tsou, K.: Sci. Sin. 18: 262, 1975. 23. Chang, M. C.: Proceedings of the Eighth International Conference on Planned Parenthood, April 9-15, 1967, Santiago, Chile. 1967, p. 386.