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C=PIER 1 IN Vet ~:L:[Z~ON AND EME~O MANS' AND SOCCAL OONCE3~ lee scientific Alvarez that today permit clinicians arm veteri~~ariar~ o 11~ SUM pi as dmg therapy, laser surgery, artificial initiation, in vitro fertilization, arm embryo transfer to cx~t human infertility or improve the primitive capabilities of valuable animals are the results of the work of generations of investigators. Sometimes Muse achievements came ~ because of r~ a; at resolving Specific Prague; ream ~ human inferLili~r or Card enabling livened atoners to improve the reman on their invesbrents. Ire often, hover, sci~cific add rat frmn ~ inquiries of scientists investigating fatal biological per ~ a=== In Me he of Specific applications. mus, ~ work of investigators areas such as physiology, morphology, endocrinology, molecular biology, develcpmental biology, and biochemistry have contributed to improvements in the treatment of infertility and to progress in assisted conception in humans and other animals. Just ~.c the findings of scientists Ruin answers totic science questions often oc~ntribute in ~t~ ways, the work of t:h~ pushing the frontiers; of musically ~~=is~ corrosion has applications beyond the limited Her of maples with infertility problerrE; do can benefit directly. mere are e ~ tations that, in the future, the work being done to improve the practice of in vitro fertilization and embryo transfer (IVFET) 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. me stress of abortion later in a pregnancy could be avoided. this chapter briefly airlines sad major areas ~ which adders research In Chic reproductive biology and IVAN wand make large contributions. Infertility Infertility Is defined in mark ways. most often the word is 11~ to denote the inability of a An to chive after scare months (12 to 24) of inters without contraception, or the inability to carry a pregnancy to term. Am)rdi~ to a Try by the National Center for Health Statistics (Nat;), sane 8.2 Perot of An of dhildbearir~ age (4.4 million) suffered fan "impaired f~n~dity" In 1982- the latest delta available. -this category include curer 800, 000 An who said Cat it was impassible for them to have a baby because of accidents or our unexplained reasons. Also ir~cl~d are 2.9 million wan defined as

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"subfecund" who said that it was physically difficult for them to conceive or deliver a baby, and 650,000 sexually active women who reported that they did nct use contraception and did not hQfnme pregnant within 36 months. Defining as infertile couples those who were continucusly married, had not used contraception, and had not conceived during the pry 12 months, ICE; Dory that 2.3 million warren were infertile ~ 1982. This represents a Kline fraa 11 percent of an In 1965 to 8 percent In 1982. Hoer, primly of infertility are not diminish for all sections of the probation. me overall decline masks an Case In infertility ardors women urger 30 year:; of age, arm an insane face a~r~x~nat=ly 700,000 to nearly me million infertile cables with no children (National Cents for Health Statistics, 1985~. Alth - ah these figures give a rough approximation of the feamdity of an ~ 1982, they do not indicate the mob of men and women who want a child and are experiencir~ difficulty conceiving. Mbre than half of ye aver 4.2 million wan who have been surgically sterilizer] for r~on-contrac~ptive reasons, and half of the 4.4 million who have impaired fecundity, say they would like to become pregnant (Fuchs and Perreault, 1986~. The magnitude of the problem of human infertility is further reflected ~ data on ceding care for infertility. Although not all infertile individuals seek treatment, by one estimate $1 billion was spent in 1980 on medical serving for infertility treatment (Office of Technology Assessment, 1988b). In 1982, 1 ~ llion 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 prc~uced by a survey of primary care and reprc~uctive care specialists in 1987 whit indicated that they treated approximately 1.2 mi11ion 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 wan seeking artificial sedition did so because of the infertility of their male partner, arm approxi~ly 65,000 children were conceived by artificial insertion during a 12-~nth period ~ 1986-1987 (Office of Technology Ant, 1988a). Although the emotions toll of infertility carrot be appreciated Luau these data, in recent years the communications Iota have begun to portray saw of the distress of childlessness, arx] groups such as Twelve, begun ~ 1973, have r~r~ed ~ the emotional suborn newer by child couples. Equally telling are we laths to With individuals will go in attesting to conceive. The many ads Spent ur~ergoing diagr=;tic pa ~ rue can be followed by additional efforts of dn ~ therapy, surgery, and finally the physical, financial, and psychological stress of IVFET. - 16 -

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IVEEr ~ a Ex~;sible solution to infertility for only a Snow of copies. py one estimate, as ~ as 10 ~ 15 percent of infertile copies who cold not be stressfully treated by other owns Scold be offer Acre throw IV=r or by a related technology, gamete ~ntrafallqpian tea nsfer (Gate) (Office of T ~ nology As ~ s ~ nt, 1988b). Indications for Face of [VFET are quite specific and include tube Ice that has not responded to other t ~ ins, endometriosis, oligFEperm~a, oervir~l mucus abnormalities and unexplained infertility. Indications for GIFT are more limited becalms= it can only be used when fallopian Ethic are normal. As knowledge expands, ~-C=isbed conception of all sorts ~ Item to became applicable to a wider parse of indications. Iv~r can be applied r~ar~-~= of whether fallopian tubes are present, therefore it is possible that Iv~r will fine a major therapy relative to the lard nuder of individuals with infertility prowls (Jorge, 1989~. Ever, Heat that a*var~es the practice of IV=r will at the same time promote under starship of human rep ~ :ioa1 and has the potential of advancing cipher forms of infertility treatment as well as providing better meth 0= 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 occur" (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 surging repair procedures in the male or female, and emptying artificial ir~oination. Before Hiss Suction t~rK>logies are att~ a seaward Suction is cord which includes hormonal evaluation, ~ometrial biopsy, hyst~alpingcgram, diagnostic Apart. Alternate therapy sub as micro Logical corrections of tube d ~ ase or endometriosis might be attempted. At least two noncoital reproductive technologies have been intrc~uced In the last ten years. The major technologies are in vitro fertilization and embryo transfer (IVFET) and gamete intrafallqpian transfer (GIFT). mese technologies for establishing a pregnancy are reviewed In detail in a variety of recent publications (Office of Technology Assessment, 1988b; Seibel, 1988). TO facilitate the ~3i~ of the reward agenda pried in this report, a brief review of He sips Citizen curing IVETT, Giver and sane other Lathes of assisted conception foliate.

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In Vitro Fertilization and Embryo Transfer [VFET can be used to overcome infertility caused by numerous conditions including tubal disease, endometrios ~ and olig ~ ia. A first step in IVFET is to prepare the woman for removal of eggs (oocybes) Two methods are And to accomplish this. Sometimes oocybes can be obtained during a natural cycle of a woman by determining the time of the marked increase In the Ju~inizir~ harn~ne level in the blood, which precedes ovulation by abaft 1 l/2 days. Using a natural cycle, hover, frequent blood samples nest be analyzed to exactly pinpoirrt the ir~:e in this honoree fired. Curly one mature egg is usually Staid by this method. Alternatively, fo1li~lar go ~ h are mat ration, which leads to ovulation, can be induced by the use of various fertility drugs such as human mencpau=~1 ganadakrephin. 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 ooc~ Is stimulated to develpE? arm can be hairy for fertilization. Just before the timed ovulation ~d char, Locates am Caved fen the ovary either la~r~ or by rile aspiration guided bar ultrasorx~ra~hy. me eggs, with their adherent reverse cells, are places in a petri dish so that their state of maturation can be as ~ s ~ using the state of dispersion of the attached Otis as a marker. Fertilization of the mature egg is accomplished by incubation for approximately 24 hours the petri dish with washed sperm that have been treater to ensure capacitation. Fertilization is defined by the visible presence of two pronuclei in the newly formed zygote. m e 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 lutes phase, hormones such as progesterone are sometimes administered after transfer of the embryo, (or embryos if Are Can one oocyte has been fertilized) to the uterus. Ear is established Hen the developing embryo implants itself irrto the wall of the uterus. Implantation can be documented by a measure impose In blood levels of human dhorion~c gonadotrophin. Sc~netimes, a greater ~ of mature eggs are hat than can usefully be implanted. ~ reasingly, these ego=== ~ gs are fertilized art preserved by cryc preservation for subsequent use. - 18

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Ganete l~trafall~ian Transfer In 1985, Ash et al. (1985) reported on gamete int~fall~pian transfer (G]P'1') as a new treatment for infertility. In 1987, he At Aced that Girl had bed readily aged In to clinic practice (text, 1987). GIIT involves the transfer of eggs and Sperm into patent fallopian he so that fertilization may take place in viva. Folliallar Growth of Axles and retrieval are performed In a mare similar to that ~~ for IV=r. grin Is c~llec~d and placed In a catheter with the 6~, which are then transferred to the fallopian tubes. In 1987, GIFT was achieving a higher sub= rate than IVEET. Al~cha~h this might have bun due to the better conditions of In viva fertilization, ~ r ~ to In vitro, it may also have been due to patient selection. G1P '11 requires that at 1-ass ane fallopian tube be patent and that a sufficient number of normal sperm can be obtained (Lancet, 1987~. By 1987 there was a report of ~Kx~=fu use of GIFT ~ th donated oocytes (Craft et al. 1987~. Gift can be used when infertility is caused by such factors as endometrios~s, premature Ovarian failure, oligospermia, and unexplained infertility (Office of Technology Assessment, 1988b). Donated Gametes or Conoepti Sometimes the donation of spermatozoa, eggs, or in some Rae=== fertilized zygotes, are necessary. Excess eggs collected from one female donor patient undergoing IVFET can be fertilized and implant ~ in a recipient uterus which has been synchronized with the donor's cycle. Artificial insemination using donor spermatozoa is a common 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 leas frequently TYPO methods of treatment for infertility that also involve the manipulation of eggs or embryos are tubal ovum transfer and embryo ravage and transfer. Egg stimulation and harvesting are undertaken as in [VFET and GIFT. The egg is then reins orbed below fallopian tube blockage or cipher damage and fertilization takes place in viva (Office of Technology Assessment, 1988b). In embryo lav age and transfer fertilized eggs are flushed out and removed by a special catheter. m ey are then transferred to a recipient whose cycle has been synchronized to be reedy for the introduced egg. This technique is gig 1~= fray USA, partly because of fears abaft transmission of virus arm be risk of Cocaine embryos rating In pr~nar~y In the Torpor. 19

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~ntra~ion h3v~s ~ Me basic science ~t ~d improve the clinics practice of ~.mcis~ corrosion, sum as improve<] ur~sb~i~ of ~ Panics of ~ implantation, ~161 be likely, at the same time, to help in Me sears for bear c~rac~ive ~nologics. Contraceptive reshows range from rhythm mess, the oontra~ive sense, birth control pills, arm intrauterine device to surgical sterilization arx] barrier ~:hods, incises I;, ~rmici~C, cervical cam, and cliaphra~n~. Mare than half of Africa Karen aged 15 44 year; use saw form of Oration, at a ~ of $2.4 bionics 1982 (Fuchs arx] ~rreault, 1986~. Indite this widespread use of oc)ntrac~ption, there ~ma~n unsolved prnblmE; of safety, efficacy, and a~bility for each type of Curative. ~ seat for improved form of contraception ~ Purred net only }fly the desire of ir~ivi*uals for Iron over their r~pr~uctive live;, but also by the social cats of unwanted pregnancies art the pr ~ of fast-growing populations in countries whose Amiss 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 forcible Is to lower fertility rates. Contraceptive use Is by far the most important weans of attaining that goal. Agriculture In 1890, Walter Hoe wrote the first paper on transfer of a fertilized egg, stating, "In this preli~ note I with merely to ~rd an experiment by which it is The n that it is possible to ~ ke BURP of the uterus of one variety of rabbit as a medium for the growth and obsolete fetal development of fertilized ova of another variety of rabbit." (Heape cited in Adams, 1982~. It was not until 1932 that a su-~-n-==cful 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 end production realized (Adams, 1982~. In1981, it was reared ~ Science that a '~timillion collar icy centered on ~very, in vitro An are, and trar~;fer of bovine curios has evolved aver the last diode." This fast groins activity had developed in lo than a decade into a $20 million a year iffy (Seidel, 1981). By 1985, a.c-=isted Option was the rearm in dairy axes, with 70 percent fertilized by artificial Action; 100,000 embryo transfers vow performed In the United Staff In 1984, and 200,000worldwide, of Airs 25 parent were with frozen Embryos. Artificial insertion resulted In genetic - 20 -

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invest in dairy cattle to an extent bat milk production, per on dall31ed in 30 years (First, Critter, arm R~1, 1985~. Ibe major once of embryo transfer technology in the f~-pr~ir~ industry is to increase rate of Orion of valuable cons. the nines of ~ regulation, 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. [VFET can also be used to enable infertile but genetically sound cows to reproduce. The new technologies.make the export of cattle breeding stock more econom~1 because it is cheaper to transport embryos (frozen or unfrozen) than mature animals. Mbreover, the resulting calves have inanity to local paths; (received via We fir n~ther's ool~trurn), With imported animals lack (Seidel 1981~. In 1988 We poss~ili~ se of further inverts In the reproductive efficierx~y of focxi-pr~cing anions; We Granada Corporation chains that Anises for cloning animals were n~rir~ commercial abdication (Schneider, 1988~. me devel~nt of pro for the control of reproduction In d~ic animus has core fmn universities, nonprofit relearn ~ institutions,- art Dial organizations. Arch of commercial intent has been Ant ~ rapid. In 1986, Are than 115 cx~rcial Denies art 100 veterinary practicer offers embryo transfer services. Scare of these Hernial organizations also oontri ~ e to the ~ an ~ effort by establi ~ research laboratories (Dresser and Leibo, 1986~. The ado pLion of the new reprc~uctive 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 climatic 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 animal s. Biodiversi~y Advances in reproductive technologies are potentially important in sustaining biodiversity by improving the reproductive efficiency of endangered species. The new reproductive technologies are being storied 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 z006 become the last repository for some endangered species, and as genetic diversity is lost begat of inbreeding, maintaining diversity has borage an important goal. Thus, the development of reproductive technologies that can be used for endangered exotic Species tales on a new urgency as it is irx~asingly realized that captive breeding prc~rans can prevent extinction (lesser, 1988).

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Primate for Rearm me armoire battle between life preservationists arm scientists who use primates for Irk purism is a final illustration of the far reaching implications of develc~nts in reproductive teleologies. me U.S. Fish are Wildlife service has been at to put Inn; on me er~a~ered Species list. Scare of muse making this retest1 isle that the t~=- of ~inp~z~ in biar~ir=1 r~r~ is ore c- of their er~anger~nt. Is assertion is did by officials at the National Institutes of Health. If the ~i~nzee is declare dangers, new prohibitions ~ cadre, transport, are use of this specie will be it. me question mains whether, with such restrictions, the 950 ~i~nz~- in gcnrer~rent facilities at the present time are etch to Nat the reds of bianedim=l r~, espy tally in light of their important role in AIDS Heard (Science, 1988~. It is here that the Essential of new repr~uc:tive teleologies might play a role. With a limited mmiber of available animals it will become ir~ingly important to maximize the repr~x3uctive capabilities of the 350 ~anzees that have been set aside for breeding in go~rer~nt facilities. 22 -

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~RENOF~ Adams, Cyril E. 1982. Mammalian Egg Transfer. Boca Raton, Florida: CRC Passe ~ Arch, R.H. et al. 1985. Gamete intra-fallopian transfer (GIFT): A new treatment for infertility. International Jcurnal 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 -& fence. RnRton, Mass. February 2. Braude, Peter. 1988. Gene Expression in Folly Embryonic Development Paper Presented at the Institute of Medicine, Board on Agriculture, Works p on the Chic Science Formations of Medically Assist Conception, Irvine, =1 ifornia, it. craft, Ian. et al. 1987. Sulfur Births After Ovum Donation. fetter. beret. April 18. p. 916-917. lesser, Betsy L. 1988. Biodiversity. E.O. Wilson ed. C:rycbiola3y, Embryo Transfer and Artificial Pagination In Ex Situ Arrival Conservation tram. Wash;~t=, D.C.: National Scaler mess. Dresser, Betsy L. and Leibo, S.P. 1986. Technologies to Maintain Animal Germplasm in Domestic and Win ~ Species. In Evaluation of Technologies to Maintain Biological Diversity. Vol.l, Contract Papers, Part B. Animal Technologies. Washington, D.C.: Office of Technology Assessment. First, N.L., Critser, E.S., and Rcbl, J.M. 1985. Bovine Embryo: Deve- lop meet, Cloning/ Sexing and Transfer of Genes for Immunology of P~ction art Oo~aception, P. balsas, ed. Elsevier, 1985 Fuchs, Victor, R. arm Per~ault, T-clie. 1986. E~iturm; for Pepr~ ~tion-Rela~ Health Am. Journal of the American MA Asscx~iation, Vol. 225, No. 1, Jan 3, EN 76-81. Jones, HE E. Jr., 1989. Ed arx] Georgeanra Jones, Institute for P~pr~uctive medicine. Person Fornication. February 23. fit. 1987. Clinical Slates of IVF, GIN and Related Piques. Imp. (itch 26, Ed. 945~947.

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National Center for Health Statistic;. ,985. F~xtity arm Infertility In the Unity Stab, 1965-82. data, No. 104. Fib. 11, Wait, D.C.: U.S. fib of Health arm Stan Serbia, Public Health Savior. Office of Technology Ass_~t. l98sa. Artificial ~eminatioa~ Practice In the Uhited States. Ctm BA BP 48. August. Walton, D.C.: Office of Technology Ass~nh. Office of l~ol~y Ass_~t. 1988b. Infertility: C0i~. ad BA 358. May. Shit, D.C.: As~t. Dimes ~ did Office of Ideology Office of ]~logy ~C~=rner~t. 1988c. World Predation art Fertility P1~ Technologies: ~ N~t 20 Years. Summary. ~ Et 158. February. Wait, D.C.: Office of Penology Aunt. Sc~ider, Keith. 1988. Better Form Anli~s Duplicate by Cloning. New York Times, Action D, Page 1, Fib 16. Libel, Madhelle M. 1988. A New Era In Preductive Technology. In Vitro Fertilization, Gamed Intrnfall~ian Transfer, and Donald Gaelic arm Embryos. New E=1arx] Journal of Medicine. 318~130~: 828-834. Seidel, George E., Jr. 1981. ~rovulation arm Embryo Transfer in Cattle. Scienoe. 211 (4479): 251-357. Science. 1988. aliens arm ~rd~: Science 241: 777-778 . 24 Erx3angE~d? New art dent.