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The future of contraceptive technology
TccSno/o~ in Soci&y, Vol. 9. pp. 283-288 (1987) Printed in the USA. All rights reserved.
Copyright
0
0160-719X187 $3.00 + .OO 1987 Pergamon Journlls Ltd
The Future of Contraceptive Technology EZof D. B. Jokamron
Knowledge and core technology for the reg&tion of human fertility are today such that the development of new contraceptive methods ir driven by people’s needs, rather than by auazlab~etechnologies. Despite the rapid increasein knowledge, few new contmcept&es wti? have made a major impact on the market by the year 2OOO.Au&b&y in the US and Japan will be limited by /iabi(itier and vested interest groups. In countries with a government-planned economy, the auaiXzbz@ywill be governed by cost andpoiitzica considerations. On/y in Europe WZZthere be a free choice and a market economy for contmceptibes. The newcomers wi/l be long-acting subcutaneous implants, such as NORPLANP; intravaginal n’ngsfor deiiuety of steroid hotmones or as a base for bani& contraceptiver with prophyti for sexualy transmitted direarer; intrauterine devices re/eas&zgsteroid hormones; ovulatzon inhibition by gonadotrophin-releasing hormone; menses induction based on progesterone-receptor blockage; and maybe a hormonal contraceptive for men based on Inhibin. ABSiTACT.
Contraceptive methods of today are the results of technical breakthroughs during the 1950s and 1960s. Advances in steroid chemistry made possible the development of orally active esuogens and gestagens to mimic the anovulatory effect of the luteal phase of the menstrual cycle and early pregnancy. The result was the first contraceptive pill in 1958.’ This development was largely technology-driven, even though it was supported and pushed by Margaret Sanger, a well-known female activist, who regarded an effective contraceptive method unrelated to coitus and completely in the hands of the female as an important tool for women to overcome male dominance. The thirty-year life of the Pill has been dominated by important - but, in the historical perspective, minor - dose reductions and changes in steroid combinations. The changes have been due mostly to side effects. The 1970s and 1980s have been further devoted to epidemiological studies on the general health aspects of the Pill. The findings have been both positive and negative, but, in general, the side-effects have been reduced by lowering the dosage.2 The first modern intrauterine devices (IUDs) were made possible by the development of plastic material with memory and tissue tolerance.3 Many different models were developed, but the next real step forward came in a combination of copper wire with a plastic T-platform, developed by The Population Council.4 A native of Sweden, E/of D. B. Jobansson bojds an M.D. I;om Uppsa.kaUniversity, and is Executive V&e President and Member of the Board of Pharmacti AB. He isa member of the Governing Board of the Swedz2 Medico/ Society, and a Past Preszdent of the Swedz3 Obstetnk and Gynecological Society.
284
E/ofD. B. Johansson
Several improved plastic platforms were developed with improved copper application to assure optimal coverage of the uterine cavity with copper ions, the vehicle for its high efficacy. The drawbacks of the copper IUDs-increased menstrual blood loss, lower abdominal pain, and increased risk of upper genital tract infections in young women-appear to have been solved by the use of the plastic platform for the local delivery of a very active progestin, levonotgestrel.5 This development will be a major contraceptive method of the future. The levonorgestrel intrauterine device is easily placed in the uterine cavity by any gynecologist or midwife. This IUD delivers a continuous low dosage of levonorgestrel that makes the cervical mucus impenetrable by sperm. It also makes the endometrium almost atrophic, thereby reducing the menstrual flow, and, in many women, the menstrual bleedings go undetected. Ovulation is unaffected, except during the first months of use. This IUD offers excellent protection from pregnancy, and reduces blood loss and menstrual pain. The current model in clinical studies will last for at least five years. The contraceptive based on low-dose progestin medication, such as pills for daily intake or injections of medroxyprogesterone acetate (Depo-Provera@) every third month has gained limited popularity. Depo-Provera@ is highly effective and free from serious side-effects, but disrupts the monthly bleeding pattern.’ DepoProvera@ has been the focus of activist organizations, who have blackmailed the compound, and charged that it can be given to women against their will, which certainly is easier with an injection than with a daily pill. This opposition, based on no sound medical ground, has blocked registration for the contraceptive use of Depo-Provera@ in the United States, its country of origin, and severely limited its use in Europe and in the developing countries. The barrier contraceptives have profited the least from the advance of technologies. Certainly, the condoms are thinner, stronger, and more appealing than in the 1950s, mainly due to the impact of Japanese manufacturers. Barrier methods for females have developed slowly and only a few new designs, based on the same well-known principles- a barrier and a sperm immobilizerhave reached the market. Who Determines the Market for Contraceptives? Customer’s choice or “fashion” will be driven by women in the industrialized countries, who live in a market economy. The choices available to women, however, are many times limited by current medical opinions and also by legal abnormalities, as in the US, where very few contraceptive alternatives are likely to be available if the rules for product liabilities are not changed. In the developing world, the availability of contraceptives is decided on by family planning organizations and medical boards, who are concerned with the cost of the drug or device, but never so far have taken into account the total cost to the user, such as cost of increased menstrual blood loss, frequent visits to family planning clinics, the burden of failure pregnancies, etc. The epidemic spread of sexually transmitted diseases, such as chlamydia and her-
The Future of Contraceptive Technology
285
pes, has been a strong argument for barrier methods. The fear of AIDS, however, has recently changed the sex habits of many people in the Western world, and has also been a strong reason for the increased use of condoms. These trends in use confirm the author’s belief that beneficial health effects will be very important, both for the choice of methods by users and for the choices of projects by those who develop new contraceptive methods. Core Technologies for Contraceptive DeveZopment Molecular biology, a revolution in assay technology, protein separation, and purification and other tools in biological research have expanded knowledge about the female reproductive system much further than knowledge about the same control mechanism in males. Lately, however, things have also started to look better also for the male. The emphasis on basic research on male reproduction that started during the late 1970s is now producing interesting and important results. The mysteries of Inhibin have been unveiled and are likely to answer several questions about the regulation of spermatogenesis. ’ Inhibin inhibits the release of FSH that is necessary for spermatogenesis. Thus, it appears to be possible to block sperm production without blocking the production of testosterone. Recombinant DNA technology will be very important for the further development of the control mechanisms in both men and women that the research on Inhibin can lead to. Enough quantities are needed to establish sensitive assay techniques to allow scientists all over the world to study the biology of Inhibin. Inhibin is a complex protein, difficult to produce with current technologies. It consists of four subunits that can be combined in several ways to different I&bins, but also to Activin, a hormone that stimulates FSH release, which has the directly opposite effect of Inhibin. It is too early to say if Inhibin will be developed into a widely used contraceptive for men. Inhibin is difficult to administer, and it is unlikely that it will be generally used. A more likely circumstance would be that the research on Inhibin will point to other therapeutic possibilities to down-regulate sperm production in men and ovulation in women. The development of the currently available methods has been mainly technology driven, and this is still the situation for the entire panorama of present development efforts. The project list of the special Program for Human Reproduction (HRP) within the World Health Organization from the early 1970s looked like a frontal attack on all possible parts of the female reproductive tract that could be influenced by available technologies. This was an approach that was natural to most scientists in the field. In recent years, the program has modified its strategies to better suit the perceived needs of couples in the developing world, The International Committee for Contraception Research (ICCR) of The Population Council has concentrated its efforts on low-cost and long-acting contraceptive methods, such as intrauterine devices, subdermal implants (e.g., NORPLANTO), and intravaginal ring delivery systems.
286
LiYofD.B. Johaansson
Development within the pharmaceutical industry has mainly been concentrated in European companies, which have perfected the oral pill, moved into IUDs, and, only recently, begun work in new areas, such as menses induction and intravaginal rings. As the customers in the industrialized world are the only ones who have choices, and the pharmaceutical industries have moved very slowly into new areas-for good reasons, the .oral contraceptives have been a profitable business, while, particularly in the United States, all areas outside the oral contraceptives have been plagued with high liability risks and uncertain markets. In a situation like this, it is quite likely that companies without previous presence in the field can come in and be able to command a good part of the market, provided that they can develop and produce products that the customers like.
The Contraceptive Panorama in the Year 2000 What will be available for the customer in the private sector market in the year 2000? Due to special circumstances, that market can be subdivided into four different sectors with poor communication among them. In the United States, due to fears of liabilities, oral contraceptives, condoms, a selection of female barrier methods, female sterilization, vasectomies, and NORPLANT@ will be available. The vested interest of the lawyers working with medical liabilities is such that it is unlikely that the US will curtail the product liability risk, as many European countries have, or adopt the no-fault insurance system like Sweden and other countries have done. The legal system in the US will certainly limit the availability of a choice of contraceptives in the US (as well as of other products, such as vaccines). In Europe, thanks to the European Common Market with its standardized registration rules (now coming into effect), a large variety of methods will be available, which will enable the user to choose a method that best suits his or her reproductive situation and social circumstances. In the year 2000, oral contraceptive pills and the copper IUDs will still be around, but their share of the market will be considerably smaller than it is today. Which are the newcomers? For hormonal contraceptives in the female, there will be a variety of subcutaneous implants like NORPLANT@ with a variety of numbers of implants and different steroid hormones used. Several models of intravaginal rings which release steroids will also be available, but the ring platform will mainly be used for barrier contraceptives with spermicides that-better and more effectively than today - will also provide a prophylaxis against sexually transmitted diseases. Products that prove effective against AIDS will be particularly popular. The IUD market will be dominated by IUDs that release steroid hormones and have a very high contraceptive efficacy combined with a reduction in blood loss. Several models and competing brands, using the same principle, will be available on the European market. These products will be based on the levenorgestrel IUD, developed by The Population Council together with European companies. Depend-
The Fatwe of Contruceptive Technology
287
ing on their market skill, the original product may be the market leader in this segment. Totally new types of contraceptives that will fulfill particular needs in specialized situations will be available, such as: Menses inducers, like the progestin receptor blocker developed by Roussel Uclaf, will have widespread use. These products will be used in some countries as early abortion methods, in combination with some very sensitive diagnostic tests for pregnancy, that will give an answer even before the expected menstrual bleeding. Contraceptive methods during lactation that have been specially developed for the physiological situation of lactation will be available. They will be of two types, one based on low-dose progestins and the other on the ability of releasing hormones for lutenizing hormone to strengthen the blockage of the ovarian function. Methods for the pre-menopausal female that will provide her with both supplementary estrogen and bleeding control, making it possible for women to coast through the often traumatic climacteric years with no symptoms. For males, the condom and vasectomy will still be the major possibilities, but, in some countries, hormonal methods based on Inhibin regulation that will block spermatogenesis will be available. InJapan, the availability of contraceptive methods will still be highly limited, due to the powerful lobbying from gynecologists trying to protect their profitable abortion business. Methods based on new principles like those described above for the European market, however, will be available in Japan shortly before the year ZOO& but they will not have been able to penetrate the market in the same way that they will have done in Europe. In most developing countries, dominated by a centralized public sector supply of contraceptives, few methods will be available. The newcomers will be subcutaneous implants and steroid-medicated IUDs. All other methods will be regarded as too expensive for the purchasing organization and will, for this reason, have small impact. In some developing countries with functioning private sector markets, the availability of products will be similar to that in Europe, but with a few years’ delay in availability. In summary, the contraceptive methods available in the year 2000 will depend on the functions of social and political forces much more than breakthroughs in biology of reproduction or basic science or technology. People in Europe will have the largest and widest choices of methods, while availability in the US. and Japan will be limited by various pressure groups and vested interests, as will be the availability of contraceptive methods in most developing countries.
Notes 1. G. Pincus, J. Rock, C. R. Garcia, E. Rice-Wray, M. Paniagua and I. Rodriguez, “Fertility Control with Oral Medications,” American Joumd of Obstetrics and Gynecofogy 75, (1958). pp. 1333-1346.
288
E.lof D. B. Johansson
2. E. D. B. Johansson, ‘Estrogen-Progcstogcn Combination: Past Experience and Future Development.” in E. Diczfahrsy and A. Diszfahq, cds., Reseanh on the Reguhion of Human Fertility, Vol. II (1983). pp. 637-648. 3. J. Lippes, “Contraception with Intrauterine Plastic Loops,” Amekan /our& of Obstehics and Gynecoiogy 93 (1965). pp. 1024-1030. Ametican /out& of Obstetticr and Gjweco/ogy 112 (1972), pp. 4. H. J. Tatum. “Intrauterine Contraception,” 1001-1023. 5. T. Luukkaincn and C. G. N&on, “Sustained Intrauterine Rcleasc of d-Norgcstrcl,” Contraception 18 (1978). pp. 451-458. 6. I. S. Fraser and E. We&erg, “A Comprehensive Review of Injectable Contraception with Special Emphasis on l(1981). Special Supplement, pp. l-19. Depot Mcdroxyprogcstcrone Acetate,” Medic~Joum~ofAustrah 7. N. Ling. Ying Shao-Yao, N. Ucno, F. Esch. L. Dcnoroy and R. Guikmin, “Isolation and Partial Charactcrization of a M 32000 Protein with Inhibin Activity from Porcine FoIIicular Fluid.” Proceedings of the Nat&& Academy of Science (1985), Vol. 82, pp. 7217-7221.
Copyright
0
0160-719X187 $3.00 + .OO 1987 Pergamon Journlls Ltd
The Future of Contraceptive Technology EZof D. B. Jokamron
Knowledge and core technology for the reg&tion of human fertility are today such that the development of new contraceptive methods ir driven by people’s needs, rather than by auazlab~etechnologies. Despite the rapid increasein knowledge, few new contmcept&es wti? have made a major impact on the market by the year 2OOO.Au&b&y in the US and Japan will be limited by /iabi(itier and vested interest groups. In countries with a government-planned economy, the auaiXzbz@ywill be governed by cost andpoiitzica considerations. On/y in Europe WZZthere be a free choice and a market economy for contmceptibes. The newcomers wi/l be long-acting subcutaneous implants, such as NORPLANP; intravaginal n’ngsfor deiiuety of steroid hotmones or as a base for bani& contraceptiver with prophyti for sexualy transmitted direarer; intrauterine devices re/eas&zgsteroid hormones; ovulatzon inhibition by gonadotrophin-releasing hormone; menses induction based on progesterone-receptor blockage; and maybe a hormonal contraceptive for men based on Inhibin. ABSiTACT.
Contraceptive methods of today are the results of technical breakthroughs during the 1950s and 1960s. Advances in steroid chemistry made possible the development of orally active esuogens and gestagens to mimic the anovulatory effect of the luteal phase of the menstrual cycle and early pregnancy. The result was the first contraceptive pill in 1958.’ This development was largely technology-driven, even though it was supported and pushed by Margaret Sanger, a well-known female activist, who regarded an effective contraceptive method unrelated to coitus and completely in the hands of the female as an important tool for women to overcome male dominance. The thirty-year life of the Pill has been dominated by important - but, in the historical perspective, minor - dose reductions and changes in steroid combinations. The changes have been due mostly to side effects. The 1970s and 1980s have been further devoted to epidemiological studies on the general health aspects of the Pill. The findings have been both positive and negative, but, in general, the side-effects have been reduced by lowering the dosage.2 The first modern intrauterine devices (IUDs) were made possible by the development of plastic material with memory and tissue tolerance.3 Many different models were developed, but the next real step forward came in a combination of copper wire with a plastic T-platform, developed by The Population Council.4 A native of Sweden, E/of D. B. Jobansson bojds an M.D. I;om Uppsa.kaUniversity, and is Executive V&e President and Member of the Board of Pharmacti AB. He isa member of the Governing Board of the Swedz2 Medico/ Society, and a Past Preszdent of the Swedz3 Obstetnk and Gynecological Society.
284
E/ofD. B. Johansson
Several improved plastic platforms were developed with improved copper application to assure optimal coverage of the uterine cavity with copper ions, the vehicle for its high efficacy. The drawbacks of the copper IUDs-increased menstrual blood loss, lower abdominal pain, and increased risk of upper genital tract infections in young women-appear to have been solved by the use of the plastic platform for the local delivery of a very active progestin, levonotgestrel.5 This development will be a major contraceptive method of the future. The levonorgestrel intrauterine device is easily placed in the uterine cavity by any gynecologist or midwife. This IUD delivers a continuous low dosage of levonorgestrel that makes the cervical mucus impenetrable by sperm. It also makes the endometrium almost atrophic, thereby reducing the menstrual flow, and, in many women, the menstrual bleedings go undetected. Ovulation is unaffected, except during the first months of use. This IUD offers excellent protection from pregnancy, and reduces blood loss and menstrual pain. The current model in clinical studies will last for at least five years. The contraceptive based on low-dose progestin medication, such as pills for daily intake or injections of medroxyprogesterone acetate (Depo-Provera@) every third month has gained limited popularity. Depo-Provera@ is highly effective and free from serious side-effects, but disrupts the monthly bleeding pattern.’ DepoProvera@ has been the focus of activist organizations, who have blackmailed the compound, and charged that it can be given to women against their will, which certainly is easier with an injection than with a daily pill. This opposition, based on no sound medical ground, has blocked registration for the contraceptive use of Depo-Provera@ in the United States, its country of origin, and severely limited its use in Europe and in the developing countries. The barrier contraceptives have profited the least from the advance of technologies. Certainly, the condoms are thinner, stronger, and more appealing than in the 1950s, mainly due to the impact of Japanese manufacturers. Barrier methods for females have developed slowly and only a few new designs, based on the same well-known principles- a barrier and a sperm immobilizerhave reached the market. Who Determines the Market for Contraceptives? Customer’s choice or “fashion” will be driven by women in the industrialized countries, who live in a market economy. The choices available to women, however, are many times limited by current medical opinions and also by legal abnormalities, as in the US, where very few contraceptive alternatives are likely to be available if the rules for product liabilities are not changed. In the developing world, the availability of contraceptives is decided on by family planning organizations and medical boards, who are concerned with the cost of the drug or device, but never so far have taken into account the total cost to the user, such as cost of increased menstrual blood loss, frequent visits to family planning clinics, the burden of failure pregnancies, etc. The epidemic spread of sexually transmitted diseases, such as chlamydia and her-
The Future of Contraceptive Technology
285
pes, has been a strong argument for barrier methods. The fear of AIDS, however, has recently changed the sex habits of many people in the Western world, and has also been a strong reason for the increased use of condoms. These trends in use confirm the author’s belief that beneficial health effects will be very important, both for the choice of methods by users and for the choices of projects by those who develop new contraceptive methods. Core Technologies for Contraceptive DeveZopment Molecular biology, a revolution in assay technology, protein separation, and purification and other tools in biological research have expanded knowledge about the female reproductive system much further than knowledge about the same control mechanism in males. Lately, however, things have also started to look better also for the male. The emphasis on basic research on male reproduction that started during the late 1970s is now producing interesting and important results. The mysteries of Inhibin have been unveiled and are likely to answer several questions about the regulation of spermatogenesis. ’ Inhibin inhibits the release of FSH that is necessary for spermatogenesis. Thus, it appears to be possible to block sperm production without blocking the production of testosterone. Recombinant DNA technology will be very important for the further development of the control mechanisms in both men and women that the research on Inhibin can lead to. Enough quantities are needed to establish sensitive assay techniques to allow scientists all over the world to study the biology of Inhibin. Inhibin is a complex protein, difficult to produce with current technologies. It consists of four subunits that can be combined in several ways to different I&bins, but also to Activin, a hormone that stimulates FSH release, which has the directly opposite effect of Inhibin. It is too early to say if Inhibin will be developed into a widely used contraceptive for men. Inhibin is difficult to administer, and it is unlikely that it will be generally used. A more likely circumstance would be that the research on Inhibin will point to other therapeutic possibilities to down-regulate sperm production in men and ovulation in women. The development of the currently available methods has been mainly technology driven, and this is still the situation for the entire panorama of present development efforts. The project list of the special Program for Human Reproduction (HRP) within the World Health Organization from the early 1970s looked like a frontal attack on all possible parts of the female reproductive tract that could be influenced by available technologies. This was an approach that was natural to most scientists in the field. In recent years, the program has modified its strategies to better suit the perceived needs of couples in the developing world, The International Committee for Contraception Research (ICCR) of The Population Council has concentrated its efforts on low-cost and long-acting contraceptive methods, such as intrauterine devices, subdermal implants (e.g., NORPLANTO), and intravaginal ring delivery systems.
286
LiYofD.B. Johaansson
Development within the pharmaceutical industry has mainly been concentrated in European companies, which have perfected the oral pill, moved into IUDs, and, only recently, begun work in new areas, such as menses induction and intravaginal rings. As the customers in the industrialized world are the only ones who have choices, and the pharmaceutical industries have moved very slowly into new areas-for good reasons, the .oral contraceptives have been a profitable business, while, particularly in the United States, all areas outside the oral contraceptives have been plagued with high liability risks and uncertain markets. In a situation like this, it is quite likely that companies without previous presence in the field can come in and be able to command a good part of the market, provided that they can develop and produce products that the customers like.
The Contraceptive Panorama in the Year 2000 What will be available for the customer in the private sector market in the year 2000? Due to special circumstances, that market can be subdivided into four different sectors with poor communication among them. In the United States, due to fears of liabilities, oral contraceptives, condoms, a selection of female barrier methods, female sterilization, vasectomies, and NORPLANT@ will be available. The vested interest of the lawyers working with medical liabilities is such that it is unlikely that the US will curtail the product liability risk, as many European countries have, or adopt the no-fault insurance system like Sweden and other countries have done. The legal system in the US will certainly limit the availability of a choice of contraceptives in the US (as well as of other products, such as vaccines). In Europe, thanks to the European Common Market with its standardized registration rules (now coming into effect), a large variety of methods will be available, which will enable the user to choose a method that best suits his or her reproductive situation and social circumstances. In the year 2000, oral contraceptive pills and the copper IUDs will still be around, but their share of the market will be considerably smaller than it is today. Which are the newcomers? For hormonal contraceptives in the female, there will be a variety of subcutaneous implants like NORPLANT@ with a variety of numbers of implants and different steroid hormones used. Several models of intravaginal rings which release steroids will also be available, but the ring platform will mainly be used for barrier contraceptives with spermicides that-better and more effectively than today - will also provide a prophylaxis against sexually transmitted diseases. Products that prove effective against AIDS will be particularly popular. The IUD market will be dominated by IUDs that release steroid hormones and have a very high contraceptive efficacy combined with a reduction in blood loss. Several models and competing brands, using the same principle, will be available on the European market. These products will be based on the levenorgestrel IUD, developed by The Population Council together with European companies. Depend-
The Fatwe of Contruceptive Technology
287
ing on their market skill, the original product may be the market leader in this segment. Totally new types of contraceptives that will fulfill particular needs in specialized situations will be available, such as: Menses inducers, like the progestin receptor blocker developed by Roussel Uclaf, will have widespread use. These products will be used in some countries as early abortion methods, in combination with some very sensitive diagnostic tests for pregnancy, that will give an answer even before the expected menstrual bleeding. Contraceptive methods during lactation that have been specially developed for the physiological situation of lactation will be available. They will be of two types, one based on low-dose progestins and the other on the ability of releasing hormones for lutenizing hormone to strengthen the blockage of the ovarian function. Methods for the pre-menopausal female that will provide her with both supplementary estrogen and bleeding control, making it possible for women to coast through the often traumatic climacteric years with no symptoms. For males, the condom and vasectomy will still be the major possibilities, but, in some countries, hormonal methods based on Inhibin regulation that will block spermatogenesis will be available. InJapan, the availability of contraceptive methods will still be highly limited, due to the powerful lobbying from gynecologists trying to protect their profitable abortion business. Methods based on new principles like those described above for the European market, however, will be available in Japan shortly before the year ZOO& but they will not have been able to penetrate the market in the same way that they will have done in Europe. In most developing countries, dominated by a centralized public sector supply of contraceptives, few methods will be available. The newcomers will be subcutaneous implants and steroid-medicated IUDs. All other methods will be regarded as too expensive for the purchasing organization and will, for this reason, have small impact. In some developing countries with functioning private sector markets, the availability of products will be similar to that in Europe, but with a few years’ delay in availability. In summary, the contraceptive methods available in the year 2000 will depend on the functions of social and political forces much more than breakthroughs in biology of reproduction or basic science or technology. People in Europe will have the largest and widest choices of methods, while availability in the US. and Japan will be limited by various pressure groups and vested interests, as will be the availability of contraceptive methods in most developing countries.
Notes 1. G. Pincus, J. Rock, C. R. Garcia, E. Rice-Wray, M. Paniagua and I. Rodriguez, “Fertility Control with Oral Medications,” American Joumd of Obstetrics and Gynecofogy 75, (1958). pp. 1333-1346.
288
E.lof D. B. Johansson
2. E. D. B. Johansson, ‘Estrogen-Progcstogcn Combination: Past Experience and Future Development.” in E. Diczfahrsy and A. Diszfahq, cds., Reseanh on the Reguhion of Human Fertility, Vol. II (1983). pp. 637-648. 3. J. Lippes, “Contraception with Intrauterine Plastic Loops,” Amekan /our& of Obstehics and Gynecoiogy 93 (1965). pp. 1024-1030. Ametican /out& of Obstetticr and Gjweco/ogy 112 (1972), pp. 4. H. J. Tatum. “Intrauterine Contraception,” 1001-1023. 5. T. Luukkaincn and C. G. N&on, “Sustained Intrauterine Rcleasc of d-Norgcstrcl,” Contraception 18 (1978). pp. 451-458. 6. I. S. Fraser and E. We&erg, “A Comprehensive Review of Injectable Contraception with Special Emphasis on l(1981). Special Supplement, pp. l-19. Depot Mcdroxyprogcstcrone Acetate,” Medic~Joum~ofAustrah 7. N. Ling. Ying Shao-Yao, N. Ucno, F. Esch. L. Dcnoroy and R. Guikmin, “Isolation and Partial Charactcrization of a M 32000 Protein with Inhibin Activity from Porcine FoIIicular Fluid.” Proceedings of the Nat&& Academy of Science (1985), Vol. 82, pp. 7217-7221.