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CHAPTER 1 IN VITOD J-lKi'lLIZAnCN AND EMBRYO TRANSFER AND SOCIAL CONCERNS The scientific advances that today permit clinicians and veterinarians to use such procedures as drug therapy, laser surgery, artificial insemination, in vitro fertilization, and embryo transfer to combat human infertility or improve the productive capabilities of valuable animals are the results of the work of generations of investigators. Sometimes these achievements came about because of research aimed at resolving specific problems related to human infertility or toward enabling livestock owners to improve the return on their investments. More often, however, scientific advances result from the inquiries of scientists investigating fundamental biological processes in the absence of specific applications. Thus, the work of investigators in areas such as physiology, morphology, endocrinology, molecular biology, developmental biology, and biochemistry have contributed to improvements in the treatment of infertility and to progress in assisted conception in humans and other animals. Just as the findings of scientists pursuing answers to basic sci questions often contribute in unexpected ways, the work of those pushing the frontiers of medically assisted conception has applications beyond the limited number of couples with infertility problems who can benefit directly. There are expectations that, in the future, the work being done to improve the practice of in vitro fertilization and embryo transfer (IWET) will enable practitioners to identify genetic defects in embryos without damaging them, and to quickly determine the sex of embryos so that those with sex-linked genetic diseases can be identified at a very early stage. The stress of abortion later in a pregnancy could be avoided. This chapter briefly outlines some major areas to which advances in research in basic reproductive biology and IVFET would make large contributions. Infertility Infertility is defined in many ways. Most often the word is used to denote the inability of a woman to conceive after some months (12 to 24) of intercourse without contraception, or the inability to carry a pregnancy to term. According to a summary by the National Center for Health Statistics (NCHS), some 8.2 percent of women of childbearing age (4.4 million) suffered from "impaired fecundity*1 in 1982âthe latest data available. This category includes over 800,000 women who said that it was impossible for them to have a baby because of accidents or other unexplained reasons. Also included are 2.9 million women defined as - 15 -
"subfecund" who said that it was physically difficult for then to conceive or deliver a baby, and 650,000 sexually active women who reported that they did not use contraception and did not become pregnant within 36 months. Defining as infertile couples those who were continuously married, had not used contraception, and had not conceived during the preceding 12 months, NCHS reported that 2.3 million women were infertile in 1982. This represents a decline from 11 percent of women in 1965 to 8 percent in 1982. However, problems of infertility are not diminishing for all sections of the population. The overall decline masks an increase in infertility among women under 30 years of age, and an increase from approximately 700,000 to nearly one million infertile couples with no children (National Center for Health Statistics, 1985). Although these figures give a rough approximation of the fecundity of women in 1982, they do not indicate the number of men and women who want a child and are experiencing difficulty conceiving. More than half of the over 4.2 million women who have been surgically sterilized for non-contraceptive reasons, and half of the 4.4 million who have impaired fecundity, say they would like to beorme pregnant (Fuchs and Perreault, 1986). The magnitude of the problem of human infertility is further reflected in data on medical care for infertility. Although not all infertile individuals seek treatment, by one estimate $1 billion was spent in 1980 on medical services for infertility treatment (Office of Technology Assessment, 1988b). In 1982, 1 million women between the ages of 15 and 44 who were or had been married reported at least one infertility visit during the past year (Fuchs and Perreault, 1986). A similar estimate is produced by a survey of primary care and reproductive care specialists in 1987 which indicated that they treated approximately 1.2 million patients for infertility (Office of Technology Assessment 1988a). Infertility is not confined to problems experienced by women. By one estimate, about half of infertility problems are due in whole or in part to problems of the male (Fuchs and Perreault, 1986). Indeed, over 80 percent of the women seeking artificial insemination did so because of the infertility of their male partner, and approximately 65,000 children were conceived by artificial insemination during a 12-month period in 1986-1987 (Office of Technology Assessment, 1988a). Although the emotional toll of infertility cannot be appreciated from these data, in recent years the ocnnunications mndia have begun to portray some of the distress of childlessness, and groups such as Resolve, begun in 1973, have responded to the emotional support needed by childless couples. Equally telling are the lengths to which individuals will go in attempting to conceive. The many months spent undergoing diagnostic procedures can be followed by additional efforts of drug therapy, surgery, and finally the physical, financial, and psychological stress of IVFET. - 16 -
TVFET is a possible solution to infertility for only a snail number of couples. By one estimate, as ouch as 10 to 15 percent of infertile couples who could not be successfully treated by other means could be offered hope through IVFET or by a related technology, gamete intrafallopian transfer (GUT) (Office of Technology Assessment, 1988b). Indications for use of IVFET are quite specific and include tubal ri1n«vne that has not responded to other therapies, endcmetriosis, oligospermia, cervical mucus abnormalities and unexplained infertility. Indications for GIFT are more limited because it can only be used when fallopian tubes are normal. As knowledge expands, assisted conception of all sorts is expected to become applicable to a wider range of indications. IVFET can be applied regardless of whether fallopian tubes are present, therefore it is possible that IVFET will haormo a major therapy relative to the large number of individuals with infertility problems (Jones, 1989). However, research that advances the practice of IVFET will at the same time promote understanding of human reproduction and has the potential of advancing other forms of infertility treatment as well as providing better methods of contraception. As noted by a recent comprehensive study of infertility, "Even as infertility treatments become more sophisticated and complex, basic knowledge of the male and female reproductive process remains lacking. Further research stands as a prerequisite in order for dramatic improvements in infertility treatment to occur41 (Office of Technology Assessment, 1988b). Treatments for Infertility Infertility can be treated in a variety of ways, including ensuring that the infertile couple know how to pinpoint the time of ovulation, eliminating causes of infertility such as infectious diseases or endometriosis, evaluating sperm seminal fluid, using fertility drugs to induce ovulation, performing surgical repair procedures in the male or female, and employing artificial insemination. Before assisted reproduction technologies are attempted a standard evaluation is oondi.rterl which includes hormonal evaluation, endometrial biopsy, hysterosalpingogram, diagnostic laparoscopy. Alternate therapy such as microsurgical corrections of tubal disease or endonetriosis might be attempted. At least two nonooital reproductive technologies have been introduced in the last ten years. The major technologies are in vitro fertilization and embryo transfer (IVFET) and gamete intrafallopian transfer (GIFT). These technologies for establishing a pregnancy are reviewed in detail in a variety of recent publications (Office of Technology Assessment, 1988b; Seine], 1988). To facilitate the understanding of the research agenda proposed in this report, a brief review of the steps utilized during IVFET, GIFT and some other methods of assisted conception follows. - 17 -
In Vitro Fertilization and Etabryo Transfer TVFET can be used to ovenxme infertility caused by numerous conditions including tubal «*i »»»»f endcmetriosis and oligospermia. A first step in IVFET is to prepare the woman for removal of eggs (oocytes). Two methods are used to aoocnplish this. Sometimes oocytes can be obtained during a natural cycle of a woman by determining the of the marked increase in the luteinizing hormone level in the blood, which precedes ovulation by about 1 1/2 days. Using a natural cycle, however, frequent blood samples must be analyzed to exactly pinpoint the increase in this hormone level. Only one mature egg is usually obtained by this method. Alternatively, follicular growth and maturation, which leads to ovulation, can be induced by the use of various fertility drugs such as human mennpausal gcnadotrophin. The subsequent development of ovarian follicles can be monitored by ultrasound and by measuring blood estrogen levels. By this method, which is most commonly used today, more than one oocyte is stimulated to develop and can be obtained for fertilization. Just before the timed ovulation would occur, oocytes are removed from the ovary either laparoscopy or by needle aspiration guided by ultrasonography. The eggs, with their adherent nurse cells, are placed in a petri dish so that their state of maturation can be assessed using the state of dispersion of the attached cells as a marker. Fertilization of the mature egg is accomplished by incubation for approximately 24 hours in the petri dish with washed sperm that have been treated to ensure capacitation. Fertilization is defined by the visible presence of two pronuclei in the newly formed zygote. The first cleavage of the zygote occurs approximately 1 1/2 days after insemination. A catheter is used to transfer the dividing embryo into the lumen of the uterus at somewhere between the 2- and 16-cell stage. To supplement the natural luteal phase, hormones such as progesterone are sometimes administered after transfer of the embryo, (or embryos if more than one oocyte has been fertilized) to the uterus. Pregnancy is established when the developing embryo implants itself into the wall of the uterus. Implantation can be documented by a measured increase in blood levels of human chorionic gcnadotrophin. Sonet imes, a greater number of mature eggs are harvested than can usefully be implanted. Increasingly, these excess eggs are fertilized and preserved by cryopreservaticn for subsequent use. - 18 -
Gamete Intrafallcpian Transfer In 1985, Asch et ad. (1985) reported on gamete intrafallcpian transfer (GIFT) as a new treatment for infertility. In 1987, the Lancet noted that GUT had been readily accepted in to clinical practice (Lancet, 1987). GIFT involves the transfer of eggs and sperm into patent fallopian tubes so that fertilization may take place in vivo. Follicular growth of oocytes and retrieval are performed in a manner similar to that used for IVFET. Semen is collected and placed in a catheter with the eggs, which are then transferred to the fallopian tubes. In 1987, GIFT was achieving a higher success rate than IVFET. Although this might have been due to the better conditions of in vivo fertilization compared to in vitro, it may also have been due to patient selection. GIFT requires that at least one fallopian tube be patent and that a sufficient number of normal sperm can be obtained (Lancet, 1987). By 1987 there was a report of successful use of GIFT with donated oocytes (Craft et al. 1987). Gift can be used when infertility is caused by such factors as endonetriosis, premature ovarian failure, oligospermia, and unexplained infertility (Office of Technology Assessment, 1988b). Donated Gametes or Concept! Sometimes the donation of spermatozoa, eggs, or in some cases fertilized zygotes, are necessary. Excess eggs collected from one female donor patient undergoing IVFET can be fertilized and implanted in a recipient uterus which has been synchronized with the donor's cycle. Artificial insemination using donor spermatozoa is a cannon technique. The results of one survey indicate that each year about 30,000 babies are born from artificial insemination using donor spermatoza (Office of Technology Assessment, 1988a). Two less frequently used methods of treatment for infertility that also involve the manipulation of eggs or embryos are tubal ovum transfer and embryo lavage and transfer. Egg stimulation and harvesting are undertaken as in IVFET and GIFT. The egg is then reinserted below fallopian tube blockage or other damage and fertilization takes place in vivo (Office of Technology Assessment, 1988b). In embryo lavage and transfer fertilized eggs are flushed out and removed by a spprial catheter. They are then transferred to a recipient whose cycle has been synchronized to be ready for the introduced egg. This technique is becoming less frequently used, partly because of fears about transmission of virus and the risk of retained embryos resulting in pregnancy in the donor. - 19 -
Contraception Advances in the basic science that would improve the clinical practice of assisted conception, such as improved understanding of the Mechanics of egg implantation, would be likely, at the same tine, to help in the search for better contxaoeptive technologies. Contraceptive methods range from rhythm methods, the contraceptive sponge, birth control pills, and intrauterine devices to surgical sterilization and barrier methods, including condoms, spermicides, cervical caps, and diaphragms. More than half of American women aged 15 to 44 years used some form of contraception, at a cost of $2.4 billion in 1982 (Fuchs and Perreault, 1986). Despite this widespread use of contraception, there remain unresolved problems of safety, efficacy, and acceptability for each type of contraceptive. The search for improved forms of contraception is spurred not only by the desire of individuals for control over their reproductive lives, but also by the social costs of unwanted pregnancies and the pressures of fast-growing populations in countries whose economies are unable to provide an adequate standard of living for their present population. countries have several options of how to cut their rate of population growth, according to a study by the Office of Technology Assessment (1988c), but the only solution that is both morally tenable and feasible is to lower fertility rates. Contraceptive use is by far the most important means of attaining that goal. Agriculture In 1890, Walter Heape wrote the first paper on transfer of a fertilized egg, stating, "In this preliminary note I wish merely to record an experiment by which it is shown that it is possible to make use of the uterus of one variety of rabbit as a medium for the growth and complete fetal development of fertilized ova of another variety of rabbit." (Heape cited in Adams, 1982). It was not until 1932 that a successful transfer in a larger animal, a goat, was reported. Only after the second World War was the potential for application of the techniques for livestock improvement and production realized (Adams, 1982). In 1981, it was reported in Science that a "multimillion dollar industry centered on recovery, in vitro culture, and transfer of bovine embryos has evolved over the last decade.1* This fast growing activity had developed in less than a decade into a $20 million a year industry (Seidel, 1981). By 1985, assisted conception was the norm in dairy cows, with 70 percent fertilized by artificial insemination; 100,000 embryo transfers were performed in the United States in 1984, and 200,000 worldwide, of which 25 percent were with frozen embryos. Artificial insemination resulted in genetic - 20 -
improvement in dairy cattle to an extent that milk production per cow doubled in 30 years (First, Critser, and Pobl, 1985). The major vise of embryo transfer technology in the food-producing industry is to increase the rate of reproduction of valuable cows. The techniques of superovulation, recovery of embryos, storage in vitro, and transfer to a recipient cow enable some cows to be the egg donors for 50 calves in a year. IVFET can also be used to enable infertile but genetically sound cows to reproduce. The new technologies make the export of cattle breeding stock more economical because it is cheaper to transport embryos (frozen or unfrozen) than mature animals. Moreover, the resulting calves have isnunity to local pathogens (received via the foster mother's colostrum), which imported animals lack (Seidel 1981). In 1988 the possibility arose of further improvements in the reproductive efficiency of food-producing animals; the Granada Corporation claimed that techniques for cloning animals were nearing commercial application (Schneider, 1988). The development of procedures for the control of reproduction in domestic animals has come from universities, nonprofit research institutions, and commercial organizations. Growth of commercial interest has been recent and rapid. In 1986, more than 115 ccomercial companies and 100 veterinary practices offered embryo transfer services. Some of these commercial organizations also contribute to the research effort by establishing research laboratories (Dresser and leibo, 1986). The adoption of the new reproductive technologies to enhance the production of food-producing animals has potential for lowering the cost of food and for increasing the speed with which animals genetically suited to difficult climates can be created. The impact of artificial insemination on the productivity of cows has already been seen. There is reason to expect that further advances in reproductive technologies could improve production of other food animals. Biodiversity Advances in reproductive technologies are potentially important in sustaining biodiversity by improving the reproductive efficiency of endangered species. The new reproductive technologies are being studied by zoo researchers interested in conservation of species. These researchers see IVFET and artificial insemination as a way of improving the reproductive processes of endangered species. Breeding of animals is a new role for zoos, which have in the past regarded themselves mainly as a place to display animals. However, as zoos henme the last repository for some endangered species, and as genetic diversity is lost because of inbreeding, maintaining diversity has henntie an important goal. Thus, the development of reproductive technologies that can be used for endangered exotic species takes on a new urgency as it is increasingly realized that captive breeding programs can prevent extinction (Dresser, 1988). - 21 -
Primates for Itoseaixft The ongoing battle between wildlife preservationists and scientists who use primates for research purposes is a final illustration of the far reaching implications of developments in reproductive technologies. The U.S. Fish and Wildlife service has been asked to put chimpanzees on the endangered species list. Some of those making this request believe that the use of chimpanzees in bionedical research is one cause of their endangennent. This assertion is disputed by officials at the National Institutes of Health. If the chimpanzee is declared endangered, new prohibitions on capture, transport, and use of this species will be imposed. The question remains whether, with such restrictions, the 950 chimpanzees in government facilities at the present tii«*g are enough to meet the needs of biomedical reaeaich, especially in light of their important role in AIDS research (Science, 1988). It is here that the potential of new reproductive technologies might play a role. With a limited number of available animals it will become increasingly important to maximize the reproductive capabilities of the 350 chimpanzees that have been set aside for breeding in government facilities. - 22 -
KEFIKENCES Adams, Cyril E. 1982. Mammalian Egg Transfer. Boca Raton, Florida: CSC Press, Inc. Asch, R.H. et al. 1985. Gamete intra-fallopian transfer (GUT): A new treatanent for infertility. International Journal of Fertility. 30: 41-45. Biggers, John D. 1988. Human Generation: Fact, Foible and Fable. Plenary Lecture to the American Association for the Advancement of Science. Boston, Mass. February 2. Braude, Peter. 1988. Gene Expression in Early Embryonic Development Paper Presented at the Institute of Medicine, Board on Agriculture, Workshop on the Basic Science Foundations of Medically Assisted Conception, Irvine, California, August. Craft, Ian. et al. 1987. Successful Births After Ovum Donation. Letter. lancet. April 18. p. 916-917. Dresser, Betsy L. 1988. Biodiversity. E.O. Wilson ed. Cryobiology, Errbryo Transfer and Artificial Insemination in Ex Situ Animal Conservation Programs. Washington, D.C.: National Academy Press. Dresser, Betsy L. and Leibo, S.P. 1986. Technologies to Maintain Animal Genrplasm in Domestic and Wild Species. In Evaluation of Technologies to Maintain Biological Diversity. Vol.1, Contract Papers, Part B. Animal Technologies. Washington, D.C.: Office of Technology Assessment. First, N.L., Critser, E.S., and Robl, J.M. 1985. Bovine Embryo: Deve- lopment, Cloning, Sexing and Transfer of Genes for Hmunology of Reproduction and Contraception, P. Talwas, ed. Elsevier, 1985 Fuchs, Victor, R. and Perreault, Leslie. 1986. Expenditures for Repro- duction-Related Health Care. Journal of the American Medical Association, Vol. 225, No. 1, Jan 3, pp 76-81. Jones, Howard E. Jr., 1989. Howard and Georgeanna Jones, Institute for Reproductive Medicine. Personal Conmunication. February 23. Lancet. 1987. Clinical Status of IVF, GIFT and Related Techniques. Lancet. October 26, pp. 945-947. - 23 -
National Center for Health Statistics. 1985. Fecundity and Infertility in the United States, 1965-82. Advancedata, No. 104. Feb. 11, Washington, D.C.: U.S. Department of Health and Human Services, Public Health Service. Office of Technology Assessment. 1988a. Artificial Insemination Practice in the United States. OTA BA BP 48. August. Washington, D.C.: Office of Technology Office of Technology Assessment. 1988b. infertility: Medical and Social Choices. OTA BA 358. May. Washington, D.C.: Office of Technology Assessment. Office of Technology Assessment. 1988c. World Population and Fertility Planning Technologies: The Next 20 Years. Summary. OTA HR 158. February. Washington, D.C.: Office of Technology Assessment. Schneider, Keith. 1988. Better Farm Animals Duplicated by Cloning. New York Times, Section D, Page 1, Feb 16. Seibel, Machelle M. 1988. A New Era in Reproductive Technology. In Vitro Fertilization, Gamete Intrafallopian Transfer, and Donated Gametes and Embryos. New England Journal of Medicine. 318(130): 828-834. Seidel, George E., Jr. 1981. Superovulation and Embryo Transfer in Cattle. Science. 211 (4479): 251-357. Science. 1988. Chimps and Itoaeaixh; Endangered? News and Concent. Science 241: 777-778. - 24 -
