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Latin America’s contributions to contraceptive development *
Editor's corner FERTILITY AND STERILITY Copyright
C>
1993 The American Fertility Society
Vol. 60, No.2, August 1993
Printed on acid-free paper in U. S . A.
Latin America's contributions to contraceptive development*
Elsimar M. Coutinho, M.D.t
Faculdade de Medicina Maternidade Climerio de Oliveira, Universidade Federal da Bahia, Centro de Pesquisas Clinicas em Reproducao H umana, Organizacao M undial de Saude, Salvador, Bahia, Brazil
Received April 20, 1993. * Presented at the 14th World Congress on Fertility and Sterility, Caracas, Venezuela, November 22 to 27, 1992. (The keynote address in its entirety is available from the author upon request.) t Reprint requests: Elsimar M. Coutinho, M.D., Faculdade de Medicina, Maternidade Clime rio de Oliverira, Universidade Federal da Bahia, Rua do Limoeiro number 1, Salvador, Bahia, Brazil. The opinions and commentary expressed in Editor's Corner articles are solely those of the author. Its publication does not imply endorsement by the Editor or The American Fertility Society. Vol. 60, No.2, August 1993
The first milestone in contraceptive development was reached in October 1951 by the Mexican chemist, Miramontes, who, at the time of his discovery, was preparing his bachelor's thesis at the Syntex Laboratories under the supervision of two other chemists, Rosenkranz from Cuba and the Austrian Djerassi. The importance of the synthesis of 19-nor-17 a ethinyl-T, known generically as norethisterone or norethindrone (NET) cannot be over emphasized. Although Miramontes is named as the drug's inventor in the patent listed in the National Inventor's Hall of Fame in Akron, Ohio, NET, which was to become one of the most widely used progestins in oral contraceptive (OC) pills, became known as Djerassi's (or Syntex's) compound. Djerassi et al. (1) reported the details of Miramontes' discovery at the April 1952 meeting of the American Chemical Society. Norethindrone and its prodrug Norethynodrel, in combination with ethinyl E2 (EE 2), were used in the very early studies that led to the development of the first commercial OC pill. These studies were conducted mostly in Puerto Rico, where collaboration of Latin American doctors was indispensable for the success of pilot studies and clinical trials. The first publication describing these clinical studies in the international medical literature, which may be considered the second milestone in contraceptive development, includes inevitably as co-authors to Pincus and Rock, Garcia, Rice-Wray, Paniagua, and Rodriguez (2). As in many other instances, recognition for this first study is deservedly cast on Pincus and Rock for their leadership. Nevertheless, the role played by those who actually carried out the clinical trials in Puerto Rico and who were in fact the doctors who observed for the first time in history the effects and side effects of OCs, reporting it back to the leaders, are undeservedly forgotten. A flurry of activity followed the reports from Puerto Rico and during the following decade investigators in Latin America engaged with missionary zeal, determination and gusto in contraceptive development. Studies concentrated in Mexico, Peru, Chile, and Brazil, countries in which rapid population growth was already taking its toll on the continent's fragile social and economic structure, and the demand for effective contraception was becoming evident. Argentina and Uruguay, countries that had the best scientific basis to do the job, did not experience the explosive population growth being imposed on those other countries and, in fact, remain to the present the only countries in Latin America that have a stable population. The next milestone in OC development was probably the introduction in 1966 of estrogen (E)-free OC by Martinez-Manautou and Coutinho
Editor 's corner
227
his collaborators Giner-Velasquez, Cortes-Gallegos, Aznar, Rojas, Gutierrez-Najar, and Rudel. In a series of studies conducted by the Mexican investigator and his Latin American colleagues, the concept of luteal supplementation as an effective alternative for contraception became well established (3). Today, this mode of fertility control has the preference of millions of women. That same year we published the first detailed report of the longacting, contraceptive effect of medroxyprogesterone acetate (MPA, Depo Provera; Upjohn Company, Kalamazoo, MI), based on work done in Brazil (4). Approved recently by the United States Food and Drug Administration, it will certainly become one of the most successful entries in the armamentarium of fertility control, almost 30 years after the publication of our report. Another first to come from the laboratories of Brazil was the proposal to use MPA with a longacting E as a monthly contraceptive (5). This concept seems to have also survived the test of time because, under the seal of approval of the World Health Organization (WHO), this combination monthly injectable, at precisely the same dose levels we proposed, will soon be introduced worldwide with the name of Cyclofem by a manufacturer to be designated and licensed by the WHO, as one of the most cost-effective and acceptable contraceptives. The subsequent development of Depo-Provera for its various uses in contraception and other areas of gynecology took place mostly in Latin America. In this connection, the work of the group led by Zanartu in Chile deserves special mention (6). The second most important long-acting injectable contraceptive, NET enanthate, was also introduced by two Peruvians, Kesseru and Larranaga (7). Our work in Brazil in the prolific 1960s made available to the Brazilian public an OC that contained as its active ingredient norgestrel, a novel compound obtained by total synthesis that, like NET, was to become one of the stars in the field. The first commercial preparation of the now wellknown and widely used steroid was introduced in Brazil after the dose finding tests, acceptability and effectiveness trials, that I conducted in Bahia with de Souza in the early 1960s. The description of this new contraceptive pill was published in the journal "Revista de Ginecologia e d'Obstetricia" in 1966 (8), a Brazilian medical journal that had obviously limited circulation but that served the purpose of fulfilling a prerequisite by Brazilian authorities to allow registration of the product in Brazil. An instant commercial success, Anfertil (Fon228
Coutinho Editor's corner
toura-Wyeth, Sao Paulo, Brazil) as the first norgestrel-containing pill registered in Brazil, was introduced in the United States market with even greater success 2 years later as Ovral (Wyeth, Philadelphia, PA). D-I norgestrel and later levonorgestrel became one of our most cherished compounds because we found very early during the development of Anfertil that women missing as many as eight pills of a monthly supply failed to get pregnant. Aware of criticism already reaching the lay press that side effects associated with high doses of both components of OCs, we hastened to investigate the possibility of reducing the dose by either providing half a tablet daily or one tablet every other day. To our delight, both approaches worked out fine. The half tablet was undoubtedly one of the precursors of the low-dose OCs of today but the every other day pill, which was as effective, failed to impress the pharmaceutical industry's executives and never reached the market (9). Either approach would reduce the amount of levonorgestrel and EE2 ingested over a period of 21 days to half, as compared to Ovral, bringing the dose down to that offered in the current, modern generation minipills and corresponding to 125 /lg of levonorgestrel and 25 /lg of EE2 daily. This was proposed before Ovral was introduced in the United States market 25 years ago. We also explored the use of norgestrel in an E-free tablet and as an injectable suspension for monthly administration (10). The first product is now being introduced, 20 years after it was first proposed, but the injectable remains unavailable. The early dose-finding studies with norgestrel that led to the selection of six capsules in the development of Norplant were also carried out in our laboratories in Brazil (11). Regarding implant contraception, the Latin American contribution is indeed outstanding because of our participation from the very beginning and throughout its development. Horacio Croxatto from Chile, working at the Population Council in New York, conducted with Sheldon Segal the very early laboratory studies that showed the possibility of using capsules made of Silastic tubing to introduce contraceptive steroids subcutaneously in animals. The first clinical trials in women were carried out simultaneously in Chile by the Chilean group headed by Croxatto (12) and in Brazil by our group and published in 1969 (13). The Latin American investigators, with a long series of studies, developed several alternative implants that had the potential to become widely used. The multicenter clinical trial that led to the selection of norgestrel as Fertility and Sterility
the drug of choice for further development by the Population Council's International Committee for Contraceptive Research (ICCR), which was conducted in Brazil, Chile, Dominican Republic, Jamaica, and two centers in Scandinavia, had an unmistakable Latin flavor (14). The late 1970s saw more inventiveness and toil from Latinos working now with more continuous support from both the Population Council (New York) and WHO Special Programme (Geneva). In addition, the Ford Foundation (New York) and the Rockefeller Foundation (New York) provided core support to several of our centers. Mora et al. (15) proposed the use of R-2323 as a weekly contraceptive, whereas Coutinho (16) offered a vaginal pill. Incursions in the unexplored realm of male contraception also began in this decade. The Argentinean leader in male reproductive physiology, Roberto Mancini, opened the pathway in the search for sperm-specific antigens that could serve as the basis for immunological control of fertility. As early as 1973, Coutinho and Melo (17) published their paper on male contraception induced by R-2323 and T implants. Inhibition of spermatogenesis by MPA and T enanthate was thoroughly investigated. Clinical trials conducted by Melo and Coutinho (18) and Alvarez-Sanchez et al. (19) on this approach were published in the 1970s. Although a male contraceptive remains elusive, it was not for lack of initiative from macho countries that we have not succeeded. The first clinical trials outside of China with gossypol, the Chinese discovery that may become the first commercial male contraceptive pill, were carried out in Brazil (20). But it was not only in pills, injectables, and implants that the Latinos came up with good ideas. The most significant step in making the intrauterine device the effective and modern contraceptive that will certainly be used by millions of women for many years to come was the proposal by the Chilean, Jaime Zipper, to use copper wire as an adjunct to the device (21). Introduction of copper was indeed revolutionary because it transformed a low efficacy method tainted with the label of abortifacient into a highly effective contraceptive that became easily accepted even in predominantly Catholic Latin American countries. Although I have cited Latinos from Anibal to Zipper in this modest attempt to contribute to the history of contraception, I have to apologize to the many others who, without being the first in print, contributed to improve the new as well as the old methods in the various areas of contraception. Vol. 60, No.2, August 1993
Most ofthose, like myself, who have had the opportunity to contribute decisively to contraceptive development are, nevertheless, disappointed to see this contribution ignored in the pertinent literature. Citations such as those I have mentioned rarely, if ever, appear among the relevant lists of references. With the exception of Martinez-Manatou's paper on E-free contraception, none of the other firsts were included among the 50 most cited papers in Fertility and Sterility (22). The disappointment that comes from not being recognized for scientific achievement is bad for science because recognition is the only real compensation for dedicated work and the frustration of seeing it ignored can do only harm and benefits none. REFERENCES 1. Djerassi C, Miramontes LE, Rosenkranz G, Sondheimer F. Steroids. LIV. Synthesis of 19-nor 17 alpha ethinyl testosterone and 19-nor-17 alpha methyltestosterone. J Am Chern Soc 1954;4092-6. 2. Pincus G, Rock J, Garcia CR, Rice-Wray E, Paniagua M, Rodriguez J. Fertility control with oral medication. Am J Obstet Gynecol 1958;75:1333-9. 3. Martinez-Manautou J, Giner-Velasquez J, Cortes-Gallegos V, Aznar R, Rojas B, Gutierrez-Najar A, et al. Daily progestogen for contraception: a Clinical Study. Br Med J 1967;3:370-4. 4. Coutinho EM, de Souza JC, Csapo AI. Reversible sterility induced by medroxyprogesterone injections. Fertil Steril 1966;17:261-6. 5. Coutinho EM, de Souza JC. Conception control by monthly injections of medroxyprogesterone suspension and long acting estrogen. J Reprod FertiI1967;15:209-14. 6. Zanartu J. Long term contraceptive effects of injectable progestogens: inhibition and re-establishment of fertility. Int J Fertil 1968;13:415-9. 7. Kesseru E, Larranaga A, Hurtado H, Scharff HJ. Fertility control with norethindrone enanthate, a long-acting parenteral progestogen. Acta Eur FertiI1973;4:203-10. 8. Coutinho EM, de Souza JC. Controle da fertilidade com urn novo progestinico obtido por sintese total. Rev Gin D'Obstet 1966;118:374-9. 9. Coutinho EM, de Souza JC. The every other day pill. J Reprod FertiI1968;16:137-9. 10. Souza JC, Coutinho EM. Control of fertility by monthly injections of a mixture of Norgestrel and a long acting estrogen. Contraception 1972;5:395-9. 11. Coutinho EM. Clinical experience with implant contraception. Contraception 1978;18:411-27. 12. Croxatto H, Diaz S, Vera R, Etchart M, Atria P. Fertility control in women with a progestogen released in microquantities from subcutaneous capsules. Am J Obstet Gynecol 1969;105:1135-8. 13. Tatum HJ, Coutinho EM, Adeodato Filho J, Sant'Anna ARS. Acceptability of long term contraceptive steroid administration by subcutaneous silastic capsules. Am J Obstet Gynecol 1969;105:1139-43. 14. Coutinho EM, Silva AR, Mattos CER, Diaz S, Croxatto HB, Coutinho Editor's corner
229
15.
16.
17.
18.
Alvarez-Sanchez F, et al. Contraception with long acting subdermal implants. I. An effective and acceptable modality in international clinical trials. Contraception 1978;18:31533. Mora G, Faundes A, Pastore U. Clinical evaluation of an oral progestin contraceptive, R-2323, 5 mg, administered at weekly intervals. Contraception 1984;10:145-57. Coutinho EM, Coutinho EJ, Reboucas Goncalves MT, Barbosa IC. Ovulation suppression in women following vaginal administration of oral contraceptive tablets. Fertil Steril 1982;38:380-1. Coutinho EM, Melo JF. Successful inhibition of spermatogenesis in man without loss of libido. A potential new approach to male contraception. Contraception 1973;8:20717. Melo J, Coutinho EM. Inhibition of spermatogenesis in
230
Coutinho Editor's corner
men with monthly injections of medroxyprogesterone acetate and testosterone enanthate. Contraception 1977;15: 627-34. 19. Alvarez-Sanchez F, Faundes A, Brache V, and Leon P. Attainment and maintenance of azoospermia with combined monthly injections of depot medroxyprogesterone acetate and testosterone enanthate. Contraception 1977;15:635-42. 20. Coutinho EM, Melo JF, Barbosa IC, Segal S. Antispermatogenic action of gossypol in men. Fertil Steril 1984;42:42430. 21. Zipper J, Tatum HJ, Medel M, Rivera M, Pastene L. Metallic copper as an intrauterine contraceptive adjunct to the T device. Am J Obstet Gynecol 1969;105:1274-8. 22. Key JD, Kempers RD. Citation classics: most cited articles from Fertility and Sterility. Fertil Steril1987;47:910-5.
Fertility and Sterility
C>
1993 The American Fertility Society
Vol. 60, No.2, August 1993
Printed on acid-free paper in U. S . A.
Latin America's contributions to contraceptive development*
Elsimar M. Coutinho, M.D.t
Faculdade de Medicina Maternidade Climerio de Oliveira, Universidade Federal da Bahia, Centro de Pesquisas Clinicas em Reproducao H umana, Organizacao M undial de Saude, Salvador, Bahia, Brazil
Received April 20, 1993. * Presented at the 14th World Congress on Fertility and Sterility, Caracas, Venezuela, November 22 to 27, 1992. (The keynote address in its entirety is available from the author upon request.) t Reprint requests: Elsimar M. Coutinho, M.D., Faculdade de Medicina, Maternidade Clime rio de Oliverira, Universidade Federal da Bahia, Rua do Limoeiro number 1, Salvador, Bahia, Brazil. The opinions and commentary expressed in Editor's Corner articles are solely those of the author. Its publication does not imply endorsement by the Editor or The American Fertility Society. Vol. 60, No.2, August 1993
The first milestone in contraceptive development was reached in October 1951 by the Mexican chemist, Miramontes, who, at the time of his discovery, was preparing his bachelor's thesis at the Syntex Laboratories under the supervision of two other chemists, Rosenkranz from Cuba and the Austrian Djerassi. The importance of the synthesis of 19-nor-17 a ethinyl-T, known generically as norethisterone or norethindrone (NET) cannot be over emphasized. Although Miramontes is named as the drug's inventor in the patent listed in the National Inventor's Hall of Fame in Akron, Ohio, NET, which was to become one of the most widely used progestins in oral contraceptive (OC) pills, became known as Djerassi's (or Syntex's) compound. Djerassi et al. (1) reported the details of Miramontes' discovery at the April 1952 meeting of the American Chemical Society. Norethindrone and its prodrug Norethynodrel, in combination with ethinyl E2 (EE 2), were used in the very early studies that led to the development of the first commercial OC pill. These studies were conducted mostly in Puerto Rico, where collaboration of Latin American doctors was indispensable for the success of pilot studies and clinical trials. The first publication describing these clinical studies in the international medical literature, which may be considered the second milestone in contraceptive development, includes inevitably as co-authors to Pincus and Rock, Garcia, Rice-Wray, Paniagua, and Rodriguez (2). As in many other instances, recognition for this first study is deservedly cast on Pincus and Rock for their leadership. Nevertheless, the role played by those who actually carried out the clinical trials in Puerto Rico and who were in fact the doctors who observed for the first time in history the effects and side effects of OCs, reporting it back to the leaders, are undeservedly forgotten. A flurry of activity followed the reports from Puerto Rico and during the following decade investigators in Latin America engaged with missionary zeal, determination and gusto in contraceptive development. Studies concentrated in Mexico, Peru, Chile, and Brazil, countries in which rapid population growth was already taking its toll on the continent's fragile social and economic structure, and the demand for effective contraception was becoming evident. Argentina and Uruguay, countries that had the best scientific basis to do the job, did not experience the explosive population growth being imposed on those other countries and, in fact, remain to the present the only countries in Latin America that have a stable population. The next milestone in OC development was probably the introduction in 1966 of estrogen (E)-free OC by Martinez-Manautou and Coutinho
Editor 's corner
227
his collaborators Giner-Velasquez, Cortes-Gallegos, Aznar, Rojas, Gutierrez-Najar, and Rudel. In a series of studies conducted by the Mexican investigator and his Latin American colleagues, the concept of luteal supplementation as an effective alternative for contraception became well established (3). Today, this mode of fertility control has the preference of millions of women. That same year we published the first detailed report of the longacting, contraceptive effect of medroxyprogesterone acetate (MPA, Depo Provera; Upjohn Company, Kalamazoo, MI), based on work done in Brazil (4). Approved recently by the United States Food and Drug Administration, it will certainly become one of the most successful entries in the armamentarium of fertility control, almost 30 years after the publication of our report. Another first to come from the laboratories of Brazil was the proposal to use MPA with a longacting E as a monthly contraceptive (5). This concept seems to have also survived the test of time because, under the seal of approval of the World Health Organization (WHO), this combination monthly injectable, at precisely the same dose levels we proposed, will soon be introduced worldwide with the name of Cyclofem by a manufacturer to be designated and licensed by the WHO, as one of the most cost-effective and acceptable contraceptives. The subsequent development of Depo-Provera for its various uses in contraception and other areas of gynecology took place mostly in Latin America. In this connection, the work of the group led by Zanartu in Chile deserves special mention (6). The second most important long-acting injectable contraceptive, NET enanthate, was also introduced by two Peruvians, Kesseru and Larranaga (7). Our work in Brazil in the prolific 1960s made available to the Brazilian public an OC that contained as its active ingredient norgestrel, a novel compound obtained by total synthesis that, like NET, was to become one of the stars in the field. The first commercial preparation of the now wellknown and widely used steroid was introduced in Brazil after the dose finding tests, acceptability and effectiveness trials, that I conducted in Bahia with de Souza in the early 1960s. The description of this new contraceptive pill was published in the journal "Revista de Ginecologia e d'Obstetricia" in 1966 (8), a Brazilian medical journal that had obviously limited circulation but that served the purpose of fulfilling a prerequisite by Brazilian authorities to allow registration of the product in Brazil. An instant commercial success, Anfertil (Fon228
Coutinho Editor's corner
toura-Wyeth, Sao Paulo, Brazil) as the first norgestrel-containing pill registered in Brazil, was introduced in the United States market with even greater success 2 years later as Ovral (Wyeth, Philadelphia, PA). D-I norgestrel and later levonorgestrel became one of our most cherished compounds because we found very early during the development of Anfertil that women missing as many as eight pills of a monthly supply failed to get pregnant. Aware of criticism already reaching the lay press that side effects associated with high doses of both components of OCs, we hastened to investigate the possibility of reducing the dose by either providing half a tablet daily or one tablet every other day. To our delight, both approaches worked out fine. The half tablet was undoubtedly one of the precursors of the low-dose OCs of today but the every other day pill, which was as effective, failed to impress the pharmaceutical industry's executives and never reached the market (9). Either approach would reduce the amount of levonorgestrel and EE2 ingested over a period of 21 days to half, as compared to Ovral, bringing the dose down to that offered in the current, modern generation minipills and corresponding to 125 /lg of levonorgestrel and 25 /lg of EE2 daily. This was proposed before Ovral was introduced in the United States market 25 years ago. We also explored the use of norgestrel in an E-free tablet and as an injectable suspension for monthly administration (10). The first product is now being introduced, 20 years after it was first proposed, but the injectable remains unavailable. The early dose-finding studies with norgestrel that led to the selection of six capsules in the development of Norplant were also carried out in our laboratories in Brazil (11). Regarding implant contraception, the Latin American contribution is indeed outstanding because of our participation from the very beginning and throughout its development. Horacio Croxatto from Chile, working at the Population Council in New York, conducted with Sheldon Segal the very early laboratory studies that showed the possibility of using capsules made of Silastic tubing to introduce contraceptive steroids subcutaneously in animals. The first clinical trials in women were carried out simultaneously in Chile by the Chilean group headed by Croxatto (12) and in Brazil by our group and published in 1969 (13). The Latin American investigators, with a long series of studies, developed several alternative implants that had the potential to become widely used. The multicenter clinical trial that led to the selection of norgestrel as Fertility and Sterility
the drug of choice for further development by the Population Council's International Committee for Contraceptive Research (ICCR), which was conducted in Brazil, Chile, Dominican Republic, Jamaica, and two centers in Scandinavia, had an unmistakable Latin flavor (14). The late 1970s saw more inventiveness and toil from Latinos working now with more continuous support from both the Population Council (New York) and WHO Special Programme (Geneva). In addition, the Ford Foundation (New York) and the Rockefeller Foundation (New York) provided core support to several of our centers. Mora et al. (15) proposed the use of R-2323 as a weekly contraceptive, whereas Coutinho (16) offered a vaginal pill. Incursions in the unexplored realm of male contraception also began in this decade. The Argentinean leader in male reproductive physiology, Roberto Mancini, opened the pathway in the search for sperm-specific antigens that could serve as the basis for immunological control of fertility. As early as 1973, Coutinho and Melo (17) published their paper on male contraception induced by R-2323 and T implants. Inhibition of spermatogenesis by MPA and T enanthate was thoroughly investigated. Clinical trials conducted by Melo and Coutinho (18) and Alvarez-Sanchez et al. (19) on this approach were published in the 1970s. Although a male contraceptive remains elusive, it was not for lack of initiative from macho countries that we have not succeeded. The first clinical trials outside of China with gossypol, the Chinese discovery that may become the first commercial male contraceptive pill, were carried out in Brazil (20). But it was not only in pills, injectables, and implants that the Latinos came up with good ideas. The most significant step in making the intrauterine device the effective and modern contraceptive that will certainly be used by millions of women for many years to come was the proposal by the Chilean, Jaime Zipper, to use copper wire as an adjunct to the device (21). Introduction of copper was indeed revolutionary because it transformed a low efficacy method tainted with the label of abortifacient into a highly effective contraceptive that became easily accepted even in predominantly Catholic Latin American countries. Although I have cited Latinos from Anibal to Zipper in this modest attempt to contribute to the history of contraception, I have to apologize to the many others who, without being the first in print, contributed to improve the new as well as the old methods in the various areas of contraception. Vol. 60, No.2, August 1993
Most ofthose, like myself, who have had the opportunity to contribute decisively to contraceptive development are, nevertheless, disappointed to see this contribution ignored in the pertinent literature. Citations such as those I have mentioned rarely, if ever, appear among the relevant lists of references. With the exception of Martinez-Manatou's paper on E-free contraception, none of the other firsts were included among the 50 most cited papers in Fertility and Sterility (22). The disappointment that comes from not being recognized for scientific achievement is bad for science because recognition is the only real compensation for dedicated work and the frustration of seeing it ignored can do only harm and benefits none. REFERENCES 1. Djerassi C, Miramontes LE, Rosenkranz G, Sondheimer F. Steroids. LIV. Synthesis of 19-nor 17 alpha ethinyl testosterone and 19-nor-17 alpha methyltestosterone. J Am Chern Soc 1954;4092-6. 2. Pincus G, Rock J, Garcia CR, Rice-Wray E, Paniagua M, Rodriguez J. Fertility control with oral medication. Am J Obstet Gynecol 1958;75:1333-9. 3. Martinez-Manautou J, Giner-Velasquez J, Cortes-Gallegos V, Aznar R, Rojas B, Gutierrez-Najar A, et al. Daily progestogen for contraception: a Clinical Study. Br Med J 1967;3:370-4. 4. Coutinho EM, de Souza JC, Csapo AI. Reversible sterility induced by medroxyprogesterone injections. Fertil Steril 1966;17:261-6. 5. Coutinho EM, de Souza JC. Conception control by monthly injections of medroxyprogesterone suspension and long acting estrogen. J Reprod FertiI1967;15:209-14. 6. Zanartu J. Long term contraceptive effects of injectable progestogens: inhibition and re-establishment of fertility. Int J Fertil 1968;13:415-9. 7. Kesseru E, Larranaga A, Hurtado H, Scharff HJ. Fertility control with norethindrone enanthate, a long-acting parenteral progestogen. Acta Eur FertiI1973;4:203-10. 8. Coutinho EM, de Souza JC. Controle da fertilidade com urn novo progestinico obtido por sintese total. Rev Gin D'Obstet 1966;118:374-9. 9. Coutinho EM, de Souza JC. The every other day pill. J Reprod FertiI1968;16:137-9. 10. Souza JC, Coutinho EM. Control of fertility by monthly injections of a mixture of Norgestrel and a long acting estrogen. Contraception 1972;5:395-9. 11. Coutinho EM. Clinical experience with implant contraception. Contraception 1978;18:411-27. 12. Croxatto H, Diaz S, Vera R, Etchart M, Atria P. Fertility control in women with a progestogen released in microquantities from subcutaneous capsules. Am J Obstet Gynecol 1969;105:1135-8. 13. Tatum HJ, Coutinho EM, Adeodato Filho J, Sant'Anna ARS. Acceptability of long term contraceptive steroid administration by subcutaneous silastic capsules. Am J Obstet Gynecol 1969;105:1139-43. 14. Coutinho EM, Silva AR, Mattos CER, Diaz S, Croxatto HB, Coutinho Editor's corner
229
15.
16.
17.
18.
Alvarez-Sanchez F, et al. Contraception with long acting subdermal implants. I. An effective and acceptable modality in international clinical trials. Contraception 1978;18:31533. Mora G, Faundes A, Pastore U. Clinical evaluation of an oral progestin contraceptive, R-2323, 5 mg, administered at weekly intervals. Contraception 1984;10:145-57. Coutinho EM, Coutinho EJ, Reboucas Goncalves MT, Barbosa IC. Ovulation suppression in women following vaginal administration of oral contraceptive tablets. Fertil Steril 1982;38:380-1. Coutinho EM, Melo JF. Successful inhibition of spermatogenesis in man without loss of libido. A potential new approach to male contraception. Contraception 1973;8:20717. Melo J, Coutinho EM. Inhibition of spermatogenesis in
230
Coutinho Editor's corner
men with monthly injections of medroxyprogesterone acetate and testosterone enanthate. Contraception 1977;15: 627-34. 19. Alvarez-Sanchez F, Faundes A, Brache V, and Leon P. Attainment and maintenance of azoospermia with combined monthly injections of depot medroxyprogesterone acetate and testosterone enanthate. Contraception 1977;15:635-42. 20. Coutinho EM, Melo JF, Barbosa IC, Segal S. Antispermatogenic action of gossypol in men. Fertil Steril 1984;42:42430. 21. Zipper J, Tatum HJ, Medel M, Rivera M, Pastene L. Metallic copper as an intrauterine contraceptive adjunct to the T device. Am J Obstet Gynecol 1969;105:1274-8. 22. Key JD, Kempers RD. Citation classics: most cited articles from Fertility and Sterility. Fertil Steril1987;47:910-5.
Fertility and Sterility