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The World Health Research

- and Training Center in Human Reproduction at the Karolinska Institute

E S S Ä Marc Bygdeman Essäist

The World Health Research and Training Center in Human Reproduction at the Karolinska Institute Marc Bygdeman, Professor em. Institutionen fÜr Kvinnor och Barns hälsa Introduction Research in human redroduction has a long tradition at the Karolinska Institute. A pioneer in the field was Axel Westman who became professor of Obstetrics and gynekology at KI in 1972. He was one of the first scientists who integrated Obstetrics and Gynecology with the new science endocrinology and together with collaborators described important findings regarding the functional relationship between the hypothalamus, pituitary and ovary. Axel Westman created an endocrine laboratory, the Reproduction Endocrinology Research Unit, at the Karolinska Hospital where impressive research was performed. An example of the research which attended world wide attention was the study published 1958 by C. Gemzell, E. Diczfalusy and K-G. Tillinger, on the successful use of a partially purified follicle stimulating hormone preparation from human pituitaries in stimulating ovarian function and ovulation in amenorrhoic women. The treatment is in principal the same as the one used to-day for stimulation of ovarian function and for in vitro fertilization. Establishment of WHO research programme In the 1960-ies the population issue started to be a major concern and the World Health Assembly requested the World Health Organization (WHO) to develop a comprehensive programme including i.a. studies on medical aspects of sterility and fertility control methods. The Swedish Government had planned to initiate an international research council, Agency

for Contraceptive Research and Development but changed to instead support an intergovernmental approach. With support from Sweden and Ford foundation WHO initiated in November 1971 The Expanded Programme of Research, Development and Research Training in Human Reproduction. Professor Egon Diczfalusy had been deeply involved in the planning of the Programme and the Reproduction Endocrinology Research Unit at KI headed by professor Egon Diczfalusy became a WHO Research and Training Centre. The major objectives of the Programme were: a/ improve the quality and expand the quantity of multidisciplinary research in priority areas b/ conduct collaborative clinical studies of fertility regulating agents on a global basis c/ organize multicentred research teams for collaborative research and development d/ improve communication and collaboration among scientists e/ increase the number of scientists engaged in the field thereby increasing the understanding of the human reproductive process leading to the development of a variety of safe, acceptable and effective methods for the regulation of human fertility. The programme was based in four major research centres, each providing a critical mass in terms of disciplines, number of scientists and facilities for research and development, and research training. The centres approved by WHO were beside Stockholm, Moscow, New Dehli and three centers in South America together(Buenos Aires, Montevideo and Santiago). A unique characteristic for the Programme

was the setting-up of a global network of clinical research centres for collaborative trials of new fertility regulating methods. The research performed was decided by multinational, multidisciplinary Task Forces who regularly met at the head office in Geneva. The orientation of the Special Programme encompasses a broad spectrum of activities, such as research on and the development of new and improved methods of fertility regulation, extensive studies on the safety and efficacy of existing and newly developed methods, research on the diagnosis, treatment and prevention of infertility, studies on the behavioural and social determinants of fertility regulation and health service research. An equally important component of the Programme was the support and further development of the necessary national and internationally resources for research, the provision of research training, quality control and standardization of laboratory procedures, or the provision of standardized reagents. The WHO centre at Karolinska Institutet In 1972 the centre in Stockholm was expanded to include beside the Reproduction Endocrinology Research Unit, the Department of Obstetrics and Gynecology and the Department of Medical Chemistry. During more recent years, the activities of the centre have been more clinically oriented and although the Department of Medical Chemistry is no longer part of the Centre, the Centre collaborates closely with different units of the Karolinska Institute. At the start, the Director of the Centre was professor Egon Diczfalusy who together with Professors Sune Bergstrรถm, Ulf Borell and Bengt Samuelsson decided the activities of the Centre. In 1986 professor Egon Diczfalusy retired and has been followed as Acting director

by assistant professor Sten Cekan, professor Marc Bygdeman and to-day professor Kristina Gemzell Danielsson. The object of the Research and Training Centre in Stockholm was to initiate and/or participate in collaborative research and development efforts, to provide research training, to organize conferences, symposia and seminars, to serve as a regional documentation center, and to advice WHO on matters related to research and research training in human reproduction. Thus began a long and valuable collaboration between the Programme and the Karolinska Institute and Hospitals. Research training was initially an important aspect of the activities of the Centre. During the years 1972 to 1985, approximately 180 scientists from 44 countries were trained at the Centre. In addition, the Centre arranged a number of courses for foreign scientists and clinicians in, for example, scientific methodology, assay techniques and abortion technology. The training programme gave us working at the Centre an unique possibility to be acquainted with scientists all over the world. As mentioned previously the research initiated, performed and financially supported by WHO is decided upon by Task Forces with different research areas e.g. evaluation of current and new hormonal and intra-uterine contraceptive methods, male contraceptive methods, safety of contraception, abortion methods and prevention, evaluation and treatment of infertility. The research includes both basic research and clinical evaluation of the actual procedure. An apprehension of the magnitude of the Programme was given in a summary of the activities up to 1986. At that time the Programme had conducted more than 180 multicentred clinical trials involving approximately 185.000 subjects in 150 centres in 53 countries. Several members of the Stockholm Cen-

tre have been deeply involved in this work as members of the Steering committees of different Task Forces, scientific technical advisory groups, site visiting teams etc. An important strength of the Stockholm Centre has been the knowledge and expertise in the development of new assay techniques. It has allowed the Centre to perform a number of basic and phase I clinical studies which have been the starting point of a number of more extended tests of new fertility-regulating compounds. The development of reliable radioimmunoassay methods for the measurement of ovarian steroids and fertilityregulating compounds was of outmost importance for studying their effect on e.g. ovarian function, degree of absorption, resulting plasma levels, and duration of action. In the area of prostaglandins it was a prerequisite for the development of different routes of administration, doses to be used and treatment interval. Measurement of anti-hCG antibodies is an other example. The capacity to do such analyses was one of the prerequisites for doing the phase II study on the contraceptive efficacy of the treatment. Clinical research activities A large number of scientist have been working at the Stockholm Centre during the years and it is not possible for me to summarize all their research activities. Instead I will give some examples to illustrate the research activities. Development of new methods for termination of pregnancy has been an area of research and development since the start of the centre. The work by the Programme on prostaglandins clearly defined which compounds to be used, how to use it and when. Initially multicentre trials monitored from Stockholm including some 15.000 patients world wide provided the largest

data base on these novel compounds and facilitated the availability of several prostaglandin analogues for clinical use. More recently our Centre has in collaboration with the Prostaglandin Task Force and the Task Force for Postovulatory methods continued the work which has resulted in the development of the use of the oral prostaglandin analogue Misoprostol for abortion. In collaboration with the WHO centre in Szeged, the first dose-finding study on the abortifacient effect of the antiprogestin Mifepriston during early pregnancy was performed in 1983. The outcome of the study was rather disappointing, since the frequency of complete abortion was 60-70%. The efficacy problem was solved by studies in Stockholm which showed that treatment with Mifepriston activated the uterus, increased the sensitivity of the myometrium to prostaglandin and that a combined treatment increased the frequency of complete abortion to 95% and above. The combination of Mifepriston and a prostaglandin analogue is now used as a medical alternative to vacuum aspiration for termination of early pregnancy in a large number of countries world wide. Further studies in Stockholm and elsewhere have shown that the treatment can be managed by the woman herself at home. In Sweden more than 70% of the abortions are performed with this procedure. Studies on the effects of gestagen on pituitary and ovarian function and on endometrial development and function were initiated during the early 1970s in Stockholm and the Centre was for many years much involved in the development of vaginal rings for contraceptive purposes. The development of a ring is an important step forward in contraceptive technology. It represents a long-acting contraceptive that is completely under the control of the user. The work by the Programme created

a knowledge which has been of importance for the development of the vaginal ring now available on the market. Since the establishment of the Task Force on Long-Acting Systemic Agents for Fertility Control 1973, the Stockholm Centre has been involved in the development of long-acting injectables. Initially, the work was concentrated on the effect of possible compounds such as medroxyprogesterone acetate on ovarian function and endometrial development and function, and later the degree and rate of absorption, duration of action and the effect of different combinations of gestagen and estrogen. This has resulted in two once-amonth injectables being introduced on the market. These are Cyclofem, which is a combination of 25 mg of medroxyprogesterone acetate and 5 mg estradiol cyprionate, and Mesigyna, a combination of 50 mg norethisterone enanthate and 5 mg of estradiol valerate. The Stockholm Centre has participated in a large number of multicentre studies arranged by different Task Forces. One example is the studies on abortion methods mentioned previously, an other is “The standardized investigation of the infertile couplesâ€?. In Stockholm, some 650 infertile couples were thoroughly investigated. The study not only provided important data on the causes of infertility world-wide, but also within each participating country. A study like this also has the important spin-off effect that it gives the guidelines about how a medically correct evaluation of an infertile couple should be performed, which is of importance for the participating centre but also for the country involved. Already in 1974, The Programme had initiated research to develop an antifertility vaccine and in 1988 the Programme successfully completed a phase I clinical trial with a vaccine against the β-subunit of hCG. The Stockholm Centre was not involved in this initial work but our Cen-

tre and the one in Uppsala were chosen when a phase II trial on the contraceptive efficacy of the vaccine was planned because we had both the knowledge to do the necessary measurements of anti-hCG titers and extensive experience of clinical studies. Unfortunately, the preparation caused strong local reactions which stopped the study. The vaccine has been reformulated but further development been stopped due to lack of financial support to WHO. As mentioned previously, the Stockholm Centre played a very important part in the development of medical methods for termination of early pregnancy, e.g. treatment with antiprogesterone. However, progesterone also plays an important role in ovulation and is responsible for the development of the endometrium during the secretory phase of the menstrual cycle which is a prerequisite for implantation. In collaboration with the Task Force on Postovulatory Methods for Fertility Regulation the Stockholm Centre has performed a number of studies to clarify in detail the effect of antiprogestin on ovulation and on the endometrium. These studies showed that Mifepriston if given in the late proliferative phase ovulation was delayed and if given just after ovulation the maturation of the endometrium was inhibited. In Stockholm the first study on the contraceptive effect of regular use of Mifepriston has been performed. Twenty-one women received 200 mg mifepriston once monthly immediately after ovulation for up to 12 months as their only contraceptive method. The study showed that the treatment was highly effective in preventing pregnancy. An other possibility is to give a low daily dose of Mifepristone which will effectively inhibit ovulation and shown by the Centre in Edinborough also to be an effective contraceptive method. Since treatment with antiprogestin most likely will not cause tromboembolic complications and do not increase the risk for breast

cancer it would be an attractive alternative to combined contraceptive pills . The dual effect of Mifepristone on ovulation and endometrial development is also ideal for a post-coital method to avoid an unwanted pregnancy. The Stockholm Centre has also participated in several multicentre studies arranged by the programme showing that a low dose of Mifepriston is highly effective to prevent pregnancy when given within 72 hours after an unprotected intercourse. Levonorgestrel is an other possibility for emergency contraception. It has had for many years a limited use for this purpose. Our Centre has studied in detail its effect on ovulation and endometrium. The studies showed that Levonorgestrel inhibited ovulation but did not influenced endometrial maturation when given prior to ovulation. Our Centre has participated in dose-finding multicentre studies arranged by the Programme and as a result a single dose of 1.5 mg given within 72 hours following an unprotected intercourse is now a world-wide accepted method for emergency contraception. Since the treatment does not influence the endometrium and therefore not implantation it can not be regarded as an abortifacient which has increased the acceptability of the method in catholic countries. Concluding remarks The establishment of a WHO centre for research in human reproduction at the Karolinska Institute has been a success which I hope I have been able to illustrate in this summary of selected examples of the research performed during the years. I have participated in the activities of the Centre from its start in 1972 up to my retirement in 2000. For me and all the other scientists at the Centre the collaboration with the Programmes different expert groups and with other WHO Centres all over the world has been very rewarding

in many respects. We have been able to influence both the objects and the design of the research programme, have had opportunities to discuss new research projects and obtain financial support to accomplish them To finish it is appropriate to underline the great importance of three professors of Obstetrics and Gynecology at the Karolinska Institute, Kerstin Hagenfeldt, BrittMarie Landgren and Kristina GemzellDanielsson for the scientific activities at the Stockholm Centre. At the same time I think it is equally appropriate to emphasize the importance of their collaboration with WHO for the success of their research and successful academic career. The same is true for myself. It should also be mentioned that many WHO-supported projects have been the subject of a significant number of PhD thesis.

Marc Bygdeman, Essäist Levnadsbeskrivning Marc Bygdeman. Jag är född 13 februari 1934. Hösten 1953 började jag mina medicinska studier på Karolinska Institutet (KI)och blev med. lic och legitimerad läkare 1960. Min forskarutbildning fick jag under åren 1958 till 1964 på Institutionerna för Fysiologi och Kemi vid KI med två Nobelpristagare som chefer, professor Ulf von Euler och Sune Bergström. Resultatet blev en avhandling med titeln ”The effect of different prostaglandins on human myometrium in vitro”. Disputationen ägde rum i december 1964 och resulterade i en docentur i Fysiologi 1965 som 1973 överflyttades till Obstetrik och Gynekologi. Genom åren har jag publicerat över 400 original artiklar främst inom ämnesområdet human reproduktion. Min forskargrupps arbete ledde bl.a. till introduktionen av prostaglandiner som abortmedel och för igångsättning av förlossning samt utgjorde underlaget för den medicinska aborten under tidig graviditet med en kombination av ett antiprogesteron och prostaglandin som nu används över hela världen En viktig förutsättning för min vetenskapliga verksamheten var bildandet av WHO:s center för human reproduktionsforskning 1972 som innebar både ökade ekonomiska resurser och ett omfattande internationellt vetenskapligt samarbete.

Efter några år som underläkare på Allmänna BB kom jag 1965 till Kvinnokliniken på Karolinska sjukhuset där jag kom att arbeta under 35 år fram till år 2000. Jag utnämndes till professor i Obstetrik och Gynekologi vid KI 1978 och var biträdande klinikchef och klinikchef vid Kvinnokliniken under åren 1978 till 1989. Från 1989 fram till min pensionering år 2000 var jag med några års avbrott chefläkare och under ett år sjukhusdirektör vid KS. Som specialsakkunnig för kvinnosjukvården inom Landstinget fick jag möjlighet att påverka den omfattande strukturförändring som kvinnosjukvården genomgick på 1980 och 90-talet och som ordförande i vår specialistförening verka för professionens utveckling. I mitt kliniska arbete kom jag främst att ägna mig åt utredning och behandling av barnlöshet, kirurgisk rekonstruktion av gynekologiska missbildningar och ha ansvar för den avancerade kirurgiska behandlingen av patienter med gynekologisk cancer. Jag är glad över att mitt arbete rönt uppskattning dels i form av Kungens guldmedalj i 8:e storleken av serafimerordens band och utnämningar till hedersledamot av både Royal College of Obstetrics and Gynecology and American College of Obstetrics and Gynecology.

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