Response to tribute IVF: Past and future

Transcription

1 RBMOnline - Vol 6. No Reproductive BioMedicine Online; on web 20 December 2002 Response to tribute IVF: Past and future Howard Jones is a Professor Emeritus of Obstetrics and Gynecology at Eastern Virginia Medical School, and Chairman of the Board (honorary) of the Jones Institute for Reproductive Medicine. He also holds the rank of Professor Emeritus at the Johns Hopkins University School of Medicine where, between 1967 and 1976, he served as Professor of Gynecology and Obstetrics, acting chairman of that department, and Secretary General of the University s Program for International Education. Born 30 December 1910 in Baltimore, Maryland, Professor Jones attended Amherst College, where he received his BA degree in 1931, and Johns Hopkins, where he received his MD qualification in He was awarded honorary degrees by the University of Cordoba, Old Dominion University, Amherst College, University of Madrid, and Medical College of Hampton Roads. He is the recipient of the Medal of the College of France and the Distinguished Service Award of the American Professor Howard Jones College of Obstetrics and Gynecology, and has been made an honorary member of over 20 foreign scientific societies, including the Fellowship ad eundem of the Royal College of Obstetricians and Gynecologists. Professor Jones and his wife, Dr Georgeanna Jones, moved to Norfolk, Virginia in That year two doctors in England were responsible for the world s first baby born after in-vitro fertilization. The Joneses were given the challenge to create a similar programme in Norfolk. Out of that challenge grew the now world-renowned Jones Institute for Reproductive Medicine at Eastern Virginia Medical School. Professor Jones continues to hold key positions in the development of ethical standards for reproductive technologies. He is a past Chairman of the American Fertility Society Ethics Committee on Reproductive Technology. He and his wife were the only American gynaecologists invited by the Vatican to participate on a panel to advise the Pope concerning assisted reproduction. Scientists from as far away as Europe, Africa, Australia, Asia, and South American have travelled to Norfolk to study under the two doctors. Howard W Jones, Jr Professor Emeritus, Eastern Virginia Medical School, Norfolk, Virginia, USA Professor Emeritus, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence: Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, Virginia 23507, USA; Tel: ; Fax: ; joneshw@evms.edu Abstract The introduction of IVF into the New World had its roots in Robert Edwards six-week fellowship at Johns Hopkins in 1965, when he and I made a systematic attempt to fertilize human oocytes in vitro. While fertilization was not claimed in the publication of the work done in 1965, a retrospective examination of published photos indicate that human fertilization was obtained at that time. Edwards and Steptoe achieved a term birth with IVF in 1978, and this stimulated the establishment of an IVF clinic in Norfolk, Virginia. Using ovarian stimulation in 1981, the first delivery in the New World took place. This led to a series of studies on the influence of ovarian stimulation on the normal menstrual cycle and resulted in the finding that with ovarian stimulation there are three response patterns: high, normal and low. It was shown that an LH surge does not occur in ovarian stimulation. This latter observation led to the discovery of the LH surge inhibiting factor. The Norfolk programme became involved in the societal impact of IVF through an invitation to the Vatican, the Ethical Committee of the American Fertility Society (later the American Society for Reproductive Medicine), a lawsuit for libel against the local newspaper, and other activities. Keywords: infertility, IVF, IVF and society, ovarian stimulation On the occasion of this symposium, I have been immodest enough to assume that the assignment to speak about the past was meant to refer to the very immediate past and specifically to the past of the first successful IVF programme in the New World. To do so, of course, is to pass over the work of many unnamed investigators on whose shoulders we stand, and specifically to pass over the work of Schenk, who before 1880 in Vienna attempted to fertilize rabbit eggs extracorporally (Schenk, 1880); to pass over the many early studies with the newly isolated and identified internal secretions, such as those of Roy Hertz and his associates, who, as early as 1934, were amazed by the response of immature rabbit ovaries to the injection of pituitary substances (Hertz and Hisaw, 1934); to pass over the work of Pincus and Enzmann (1934), who mixed spermatozoa and eggs in a rabbit s Fallopian tube to achieve fertilization in vivo; to pass over the efforts of John Rock, who, during the mid-1940s, attempted to fertilize human eggs in vitro before the time had come for this process to be successful (Menken 375

2 376 Figure 1. Dr Victor McKusick, Director of the Division of Medical Genetics in 1964 and instrumental in arranging for a fellowship for Bob Edwards at Hopkins. and Rock, 1948); to pass over the pioneering work of Chang (Chang, 1959), who in 1959 proved that mammalian fertilization in vitro was not only possible, but that eggs so fertilized could give rise to mammalian young; and even to pass over the seminal work of Edwards and Steptoe (Steptoe and Edwards, 1978), without whose vision to pursue the biological underpinnings of IVF the time might still not be here to have IVF as a clinical reality. And so, with this explanation, let us turn to the past as we have chosen to define it. In talking about the past in the New World, it is necessary to turn to the Old World, which, after all, is the source of our cultural heritage. About the time John F Kennedy was assassinated in Dallas, Texas in November 1963, I received a telephone call from Dr Victor McKusick (Figure 1), then Director of the Division of Medical Genetics in the Department of Medicine at Johns Hopkins and later the Sir William Osler Professor and Chairman of the Department of Medicine at that institution. He said that he was acquainted with a young scientist whose work he greatly respected. He was an expert in the genetics of mice but had recently become interested in human oocyte maturation and fertilization in vitro following the publication of the work of Chang four years before, and he was interested in obtaining some human eggs to complete his oocyte maturation programme carried out in UK with the help of Dr Molly Rose of the Edgware and District General Hospital, London. He wished for more oocytes to complete this programme and begin to attempt fertilization in vitro. Victor inquired if it might be possible to give him some eggs if he were to come to Hopkins on a fellowship. I asked what his name was and he said he was Dr Robert Edwards. Arrangements were made, and Bob came to Hopkins during the summer of 1964, when attempts were made to fertilize in vitro eggs that we gave him from slices of ovary taken during various operative procedures, especially from wedge resections of the ovary for polycystic ovarian syndrome (PCOS). Bob s notion at that time was that the problem of IVF could be solved if the spermatozoa could be capacitated; in order to capacitate the spermatozoa, it was thought desirable to put some part of the female generative tract into the culture medium, because, after all, it was in the female generative tract that the spermatozoa were physiologically capacitated. During the course of the summer, therefore, cultures were done with spermatozoa and eggs, with washed spermatozoa, with pieces of cervical mucus, with pieces of endometrium, with scrapings of the Fallopian tube; eggs and spermatozoa were placed in the rabbit Fallopian tube as Pincus and Enzmann had done, and indeed spermatozoa and eggs were placed in the Fallopian tube in the cynomologous monkey. This was reported in the gray journal in 1966 (Edwards et al., 1966; Figure 2). No fertilization was claimed but, in retrospect looking at some of the photographs published in that journal, it is indeed likely that human fertilization was achieved at the Johns Hopkins Hospital during the summer of 1964 (Figure 3). The reason it was not claimed was because Bob felt that for absolute proof the sperm tail needed to be seen in the cytoplasm and such was not identified; but clearly pronuclei were there, and nowadays we accept pronuclei as proof positive of fertilization. Bob returned to Cambridge, where he teamed up with Patrick Steptoe a couple of years later, and, of course, you know the rest of the story. The programme in Norfolk got started also by virtue of a second telephone call. When Louise Brown was born, the Norfolk newspaper was anxious to get a local quote about this monumental event, and a reporter telephoned Dr Mason Andrews (Figure 4), then Chairman of the Department of Obstetrics and Gynecology at the Eastern Virginia Medical School. Dr Andrews gave her suitable quotes, but in closing he said it just happened that today there had moved into town a couple who knew Bob Edwards and knew something about the procedure and the reporter may want to call them. She did indeed call us and came out and interviewed us in our new home while we were sitting on packing boxes and while the movers were moving the rest of the furniture into the house. Toward the end of the interview, the reporter had asked as she was leaving whether IVF could be carried out in Norfolk. This seemed like a flip question, and I gave her a flip answer. I said of course, and she said, What would it take? I said oh, it would take some money. The next day in reporting about the interview, at the end of the article, the reporter indicated that the doctor said all it takes is money. As a result of this article in the paper, we had a telephone call from a patient who had been sent to Baltimore by Dr Mason Andrews to see Dr Georgeanna about an infertility problem. The trip was rewarded by a birth of a young girl whose name is Georgia. This couple telephoned us and said that they did not know that we were coming to Norfolk, that they were glad to welcome us to the city. They also said that they noted by the newspaper report that we needed some money and they had called to inquire how much money we would like to have. As a result of this unusual enquiry, a second meeting was held with this anonymous

3 couple and with Dr and Mrs Andrews, the Joneses, and with Mr Henry Clay Hofheimer, the then President of the Foundation for the Eastern Virginia Medical School. At that meeting, a programme of IVF was planned for Norfolk. Weeks later, during the course of our planning, I had a telephone call from Mr Glen Mitchell, the then Director of the Norfolk General Hospital where the laparoscopic aspirations were planned. Mr Mitchell said that he had been thinking, and it occurred to him that in order for our IVF programme to go ahead, we needed from the Health Department of the State of Virginia a Certificate of Need, that is a piece of paper saying that it was OK to introduce a new programme. The Certificate of Need project was introduced to prevent duplication of services in nearby hospitals and thereby save expense. Mr Mitchell explained that as there was no other programme it would not be necessary for us to appear at the hearing, that he could take care of it by what was called the administrative route. However, the agenda of the meeting was routinely published, and at the administrative hearing a large number of protestors appeared and objected to the granting of the Certificate of Need for this IVF project. As a result of that hearing, the application for a certificate was denied, but the hearing officer indicated that it would be entirely possible to apply for a Certificate of Need through the routine channel of a public hearing. This was done, and a hearing was held on Halloween Day of The hearing began at 2 o clock and lasted until about 8 o clock at night. The right-to-lifers, who were the people who objected to this effort, brought people in from out of town to testify. We, of course, did the same thing, and among those who testified were Dr Roy Parker, the then President of the American College of Obstetrics and Gynecology, and several religious leaders and civic leaders from Norfolk and the State of Virginia; the result was that after that hearing and several subsequent hearings, a Certificate of Need was granted in February 1980 (Figure 5). All this occurred during the presidency of Mr Jimmy Carter. I mention this in order to give you some notion of the time line. Figure 2. The header of the paper detailing the work of Edwards and his associate at Hopkins. After the hearings had been held and before a decision had been made, an event occurred that caused us considerable anxiety. Through the good offices of Dr William Andrews, the brother of Dr Mason Andrews, arrangements were made for Mr Patrick Steptoe to visit Norfolk to tell us about his experience and to give us available advice. We were concerned about what effect this might have on the process underway for the granting of the Certificate of Need. However, the arrangements for this trip had been made some months before, and we thought we would go ahead with the meeting in spite of our concerns. Mr Steptoe proved extremely helpful and gave us the then conventional wisdom, which was to use the natural cycle, to inseminate as quickly as possible, to do our transfer not before the 8-cell stage and to do the transfer at night. As it turned out, none of these choice titbits proved to be exactly correct, illustrating the insecure underpinnings of the process as it then existed (Figure 6). Prior to the initiation of the programme and while we were planning, we would take every opportunity at laparotomy for other conditions to aspirate promising follicles and gain experience handling the follicular fluid to look for the egg. Thus, after the granting of the Certificate of Need, we started in 1980 using the natural cycle. Various experiences ensued. Using the natural cycle required us to guess when the patient would ovulate from determining the LH surge by the 4-h method, which had been devised by Dr George Wright of the Department of Physiology and, as a result, we often predicted that the patient would ovulate at night. This required laparoscopy during the early morning hours. On one occasion, we had predicted that the patient would ovulate around 4 o clock in the morning and therefore we scheduled laparoscopy for 1 o clock that morning. However, this occurred during the greatest snowstorm that ever occurred in Norfolk, before or since. Indeed, there were 3 feet of snow in the end. The result of all this was that the team, and indeed the patient, were delayed in getting to the hospital and it was not until about 5 o clock that we were able to do the 377

4 Figure 3. Micrographs demonstrating fertilization of the human oocyte in vitro. This figure is one example of the existence of nuclei in an inseminated human oocyte and shows one typical pronucleus, and a smaller one with only a small section in focus. Sperm tails were not observed in this or other living inseminated eggs, nor after fixation, although this may have been due to the use of acetic-acid base fixatives. Reprinted from the American Journal of Obstetrics and Gynaecology (Edwards et al., 1966), with permission from Elsevier. Figure 4. Dr Mason Andrews, Chairman of the Department of Obstetrics and Gynecology at the Eastern Virginia Medical School in Norfolk, VA at the beginning of the IVF programme. 378 laparoscopy. As you can imagine, we were anxious because we were afraid the patient might have ovulated, and, indeed, when we got in with the laparoscope, we discovered a stoma in the ovary and a collapsed follicle, all confirming our worst fears. We could not, of course, see the egg, but we had the notion that if we irrigated with salt solution around the ovary and then aspirated the cul-de-sac we might be able to identify the egg. Accordingly, we introduced a 5 mm cannula, suprapubically, to aspirate the cul-de-sac, irrigated with salt solution around the ovary, aspirated the cul-de-sac, and lo and behold, a freshly ovulated human egg was identified. This was probably the first time anyone had ever seen a freshly ovulated human egg, and I think very few of them have been observed since, if any. It became apparent that because of the huge expansion of the cumulus that the diameter of the needle we were using would be insufficient to allow the entire cumulus and egg to transit the needle without shearing off some of the cumulus. At that time, we thought that it was desirable to keep the cumulus on until the egg was fertilized, and so arrangements were made to have a needle four times the cross-sectioned area of a previous needle by using no. 12 calibre tubing and so was born what we call the Blizzard needle. Following this, our per cent of aspiration of oocytes greatly increased during that first year, but even with the help of the Blizzard needle, we had 41 aspirations with only 13 transfers and no pregnancies. In spite of our failure, we were rather inundated by patients seeking care but decided in this first year that we would confine our activities to patients who had had bilateral salpingectomies so that we would be quite certain that the procedure we carried out was indeed responsible for the pregnancy. Our early failures led us to raise the question of whether Fallopian tubes were necessary for pregnancy over and above the function of providing transportation for the oocyte and for the spermatozoa. The fact that we ultimately succeeded with patients without tubes, as did others, indicates that this thought, like many others that we had, was not consistent with physiology. During the Christmas holidays at the end of 1980, Georgeanna, my wife, insisted that it was ridiculous to continue with the natural cycle. She had had considerable experience with the induction of ovulation in anovulatory women with gonadotrophins and with pregnancies and she felt that the difficulties encountered using this with normal menstruating women in England could be overcome. As of December 1980, in Oldham there had been 77 transfers from stimulated cycles with three pregnancies, all of which terminated without delivery. In Melbourne in 1980, there had been 48 transfers following stimulation, all with Clomid, with three pregnancies, all of which ended in miscarriage with no term deliveries. When we began, therefore, in 1981 with ovarian stimulation, there had been no term deliveries anywhere in the world in normal menstruating woman with stimulation combined with IVF (Lopata, 1980). Nevertheless, beginning in 1981 it was decided that we would use Pergonal in normal menstruating women to induce more than the single egg during the menstrual cycle in order to enhance the pregnancy rate. The stimulation was very gentle compared with modern techniques and, to cut a long story short, on our 13th try we were successful (Figure 7).

5 of the fact that there were three response types: the high responder; the low responder; and the intermediate responder, or normal responder, in which category most patients fell (Garcia et al., 1983). Figure 5. The local newspaper reports on the Halloween Day hearing. All this occurred while Ronald Reagan was President of the United States. During our second series in 1982, we had five pregnancies from 19 transferred, all of which went to term. Interestingly enough, there were no miscarriages, even of so-called chemical pregnancies, at least we didn t recognize any, and the 26% pregnancy rate of that series was statistically no different from the SART(Society for Assisted Reproductive Technology) registry pregnancy rate as late as 1996 (Jones et al., 1982). With the use of ovarian stimulation, it soon became apparent that there were some alterations that were inconsistent with our understanding of normal menstrual physiology. Following the lead of Edwards and Steptoe, who had taught us the importance of studying basic physiological processes, a series of studies were initiated to explain these discrepancies. It was recognized that all patients did not respond in the same way to the same stimulatory dose. This led to the verbalization It was further recognized that in spite of the fact that in the late follicular phase, oestradiol concentrations reached to and above the trigger point for the initiation of an LH surge as observed in the normal cycle, in the stimulated cycle the spontaneous LH surge did not occur (Ferraretti et al., 1983). In order to substitute for that, human chorionic gonadotrophin (HCG) was routinely used. The question was why the triggering level of oestradiol did not work in the stimulated cycle. In collaboration with Dr Channing of the University of Maryland, an old friend from Baltimore days, the follicular fluid, which we had routinely saved and frozen, was examined for the possible presence of large doses of inhibin for which Dr Channing had a biological test, these being the days before the availability of radioimmunoassay. In 1983, a study was published in which it was demonstrated that in the follicles from a stimulated cycle, compared with those from a normal cycle, there were very greatly increased amounts of a substance that behaved biologically as inhibin in the biological inhibin assay (Channing et al., 1984). As it turned out, this substance proved to be what was later called the LH surge inhibiting factor, and these early observations led to the isolation and identification of this factor many years later by Dr Douglas Danforth, who at the time of the investigation was a young investigator in Dr Gary Hodgen s laboratory in Norfolk. In addition, it became clear that the quality of the oocyte in terms of its ability to be fertilized and to support pregnancy was very much related to the oestradiol pattern of the follicular phase (Jones et al., 1983). These correlations were published in 1983, and the follicular fluid from this study was also examined by Dr Channing, who was able to demonstrate a decline in oocyte maturation inhibitor (OMI) in relation to the maturation of the oocyte at aspiration. These data were published in 1983, and as they were reviewed for the purposes of this symposium, it seems that there is still an opportunity to examine OMI in relation to oocyte quality. This whole subject seems to me to be ripe for re-visitation (Channing et al., 1983). Later on, there were many other physiological studies, such as the first description of the evaluation of ovarian reserve by 3rd Figure 6. The Virginian-Pilot reports on Patrick Steptoe s visit to Norfolk. 379

6 Figure 7. The chart on the stimulation of Judy Carr, the first mother in North America who conceived after IVF. Note the limited number of ampoules of Pergonal that were used. She had a total of seven ampoules. 380 day hormone determinations, but we are here concerned only with those in the beginning (Muasher et al., 1988). With the biological studies just recorded, there were certain serendipitous activities that were thrust upon us. The Norfolk General Hospital engaged a newspaper clipping service to keep track of publicity associated with the early IVF efforts, and among the data collected were editorials across the country related to the IVF effort in Norfolk. There were over 100 of these editorials collected, all of them favouring what was going on, with one exception. The exception was the editorial content of the Norfolk newspaper the Virginian Pilot- Ledger Star. The editorial policy of this Norfolk newspaper was consistently opposed to the effort, and in addition they published on the Op-Ed page many Letters to the Editor, which questioned what we were about. One of these editorials caught the eye of Mr Robert Nusbaum, a local attorney, who happened to be a friend of Dr Mason Andrews. He called upon us and said that he thought that it was unlikely that the editorial policy of the local newspaper would change unless some legal action was taken to prevent it. He furthermore said that the editorial that he had in his hand might furnish a means to accomplish this goal. He pointed out that the editorial contained all the legal points necessary for libel. The editorial had said that we would not allow an abnormal child to be born because we had required that the patients have an amniocentesis and an elective termination if any abnormality were found. Mr Nusbaum knew that this was not so. It mentioned that those doctors at the hospital would so act. There were only five doctors to which this could apply, Dr Mason Andrews, Dr Anibal Acosta, Dr Jairo Garcia, Dr Georgeanna Jones and Dr Howard Jones. Mr Nusbaum recommended that a libel suit be entered by one of these doctors and that it should be the one who would seem to be the less cantankerous. Dr Georgeanna Jones was elected by the others to be this person and she entered suit against the newspaper and, as it turned out, against the Associated Press. After many hours spent at procedures that we had never heard of, such as discovery and depositions and the like, we were called upon by two of the leading citizens of Norfolk and asked if we would allow them to attempt to be intermediaries to settle this dispute, which had become the talk of the town. This indeed was carried out and, to cut a very long story short, we received a public apology and a substantial sum of money, which paid for our research for the next couple of years. This turned out to be much easier than writing a grant request to the National Institutes of Health. Out of the clear blue sky in 1983, Dr Georgeanna and I each received an identical letter in the same mail from Rio de Janeiro. The letter was on the letterhead of the Pontifical Academy of Science, an institution I knew nothing about, and it inquired if we would be prepared to come to the Vatican if we received an invitation to discuss IVF in the Vatican Garden in November of I was quite unsure as to whether this was a legitimate invitation from a legitimate organization, and I thought the whole thing might be a hoax. The letter was signed by Dr Carlos Chagas, Professor of Pathology at the University of Rio de Janeiro. It turned out to be legitimate. We accepted the invitation and spent 5 days in the Vatican discussing IVF. The purpose of the meeting was to inform the Holy Father about IVF so that a decision could be made about the licitness of this procedure. The role of the gynaecologists, who were Dr Georgeanna Jones, myself and Dr René Frydman from Paris, was to explain exactly what we were doing, to be quizzed by the moral theologians, and then to produce a document recording the deliberations of the 12-man group that had been assembled for this purpose. On the last day of the procedure, Professor Chagas polled the members of the group and the nine non-medical moral theologians voted 8:1 to consider the procedure, which we had described as licit. There was one dissenter, Monsigneur Carlos Cafferra, who in the end prevailed. He said that IVF was illicit because it was outside the bonds of conjugal marriage. Conjugal marriage was defined by Carlos Cafferra as sexual intercourse. The publication of the Vatican, Donum Vitae (Congregation of the Doctrine of the Faith, 1987), said that IVF was illicit. As a result of this experience, Dr Georgeanna Jones wrote an open

7 letter to the Vatican, in which she called into the question the definition of conjugal love as consisting of sexual intercourse alone. She made the point that if this was the true basis of marriage then a rethinking of the Vatican definition of marriage was in order (Jones, 1987). This letter came to the attention of Dr Giuseppe Benagiano, Professor and Chairman of the Department of Obstetrics and Gynecology at the University of Rome. He made a trip to Norfolk, during which a second conference was planned, with the hope of finally persuading the Vatican. This conference was held and the proceedings published under the title The Evolution of the Meaning of Sexual Intercourse in the Human (Benagiano, 1996). However, to this date, no further statement has been made by the Vatican to alter the opinion originally expressed in Donum Vitae. On the plane back from Rome, it occurred to me that IVF was being carried out in the States without any consideration to the weighty problems that had been raised in the five-day discussion within the Vatican. I, therefore, wrote to Dr Charles Hammond, who at that time was President of the American Fertility Society, suggesting to him that it might be appropriate if an organization such as the American Fertility Society provided ethical guidelines to the various programmes that were then involved in IVF. This resulted in the American Fertility Society asking me to form a committee to make recommendations, and, to cut a long story short, the Ethics Committee s report first appeared in 1986 and was subsequently revised in 1990 and 1994, after which that original ad hoc Ethics Committee was dissolved and a permanent Ethics Committee established (The Ethics Committee of The American Fertility Society, 1986, 1994, 1999). There were several other serendipitous events, which time does not allow us to cover. The original assignment was to discuss IVF, past and future. However, the time spent on describing the past has been so extensive that it seems inappropriate to spend more time giving one person s opinion of the future. After all, this entire meeting is devoted to the future, and I think I shall let the meeting speak for the future of our discipline. References Benagiano G, Di Renzo GC, Cosmi EV 1996 The Evolution of the Meaning of Sexual Intercourse in the Human. International Institute for the Study of Man, Firenze, Italy. Chang MC 1959 Fertilization of rabbit ova in vitro. Nature 184, 466. Channing CP, Liu CQ, Jones GS 1983 Decline of follicular oocyte maturation inhibitor coincident with naturatin and achievement of fertilizability of oocytes recovered at midcycle of gonadotropin-treated women. Proceedings of the National Academy of Sciences of the USA 80, Channing CP, Tanabe K, Jones GS 1984 Inhibin activity of preovulatory follicles of gonadotropin-treated and untreated women. Fertility and Sterility 42, Congregation for the Doctrine of the Faith 1987 Instruction on respect for human life in its origin and on the dignity of procreation. Rome, Italy, February 22, 1987, the Feast of the Chair of St. Peter, the Apostle. Edwards RG, Donohue RP, Baramki TA, Jones HW Jr 1966 Preliminary attempts to fertilize human oocytes matured in vitro. American Journal of Obstetrics and Gynecology 96, Ferraretti AP, Garcia JE, Acosta AA 1983 Serum luteinizing hormone during ovulation induction with human menopausal gonadotropin for in vitro fertilization in normally menstruating women. Fertility and Sterility 40, Garcia JE, Jones GS, Acosta AA 1983 Human menopausal gonadotropin/human chorionic gonadotropin follicular maturation for oocyte aspiration: Phase I, Fertility and Sterility 39, Hertz R, Hisaw FL 1934 Effects of follicle-stimulating and luteinizing pituitary extracts on the ovaries of the infantile and juvenile rabbit. American Journal of Physiology 108, 1. Jones GS 1987 Reply to the Vatican Instruction on Respect for Human Life in its Origin and on the Dignity of Procreation. Fertility News 21, 4 5. Jones HW Jr, Acosta A, Andrews et al The importance of the follicular phase to success and failure in in vitro fertilization. Fertility and Sterility 40, Jones HW Jr, Jones GS, Andrews MC et al The program for in vitro fertilization at Norfolk. Fertility and Sterility 38, Lopata A 1980 Successes and failures in human in vitro fertilization. Nature 288, Menken I, Rock J 1948 In vitro fertlization and cleavage of human ovarian eggs. American Journal of Obstetrics and Gynecology 55, 440. Muasher SJ, Oehninger S, Simonetti S et al The value of basal and/or stimulated gonadotropin levels in prediction of stimulation response and in vitro fertilization outcome. Fertility and Sterility 50, Pincus G, Enzmann EV 1934 Can mammalian eggs undergo normal development in vitro? Proceedings of the National Academy of Sciences of the USA 20, Schenk SL 1880 Das Saugethierei kunstlich befrunchtet ausserhalb des Mutterthieres. Mittheilungen aus dem Embryologischen Institut der Wien IX Band. Steptoe PC, Edwards RG 1978 Birth after the reimplantation of a human embryo. Lancet 2, 366. The Ethics Committee of The American Fertility Society 1986 Ethical Considerations of the New Reproductive Technologies. Fertility and Sterility 46 (suppl. 1), pp The Ethics Committee of The American Fertility Society 1994 Ethical Considerations of the New Reproductive Technologies. Fertility and Sterility 53 (suppl. 2), pp The Ethics Committee of The American Fertility Society 1999 Ethical Considerations of Assisted Reproductive Technologies. Fertility and Sterility 62 (suppl. 1), pp Paper based on contribution presented at the Serono Symposium Toward Optimizing ART: a Tribute to Howard and Georgeanna Jones in Williamsburg, VA, USA, April Received 30 August 2002; refereed 18 September 2002; accepted 6 December