Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology – Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie Carl Djerassi and the World Health Organisation Special Programme of Research in Human Reproduction Benagiano G, Merialdi M J. Reproduktionsmed. Endokrinol 2011; 8 (Sonderheft 1), 10-13 www.kup.at/repromedizin Online-Datenbank mit Autoren- und Stichwortsuche Offizielles Organ: AGRBM, BRZ, DVR, DGA, DGGEF, DGRM, D·I·R, EFA, OEGRM, SRBM/DGE Indexed in EMBASE/Excerpta Medica/Scopus Krause & Pachernegg GmbH, Verlag für Medizin und Wirtschaft, A-3003 Gablitz FERRING-Symposium digitaler DVR 2021 Mission possible – personalisierte Medizin in der Reproduktionsmedizin Was kann die personalisierte Kinderwunschbehandlung in der Praxis leisten? Freuen Sie sich auf eine spannende Diskussion auf Basis aktueller Studiendaten. SAVE THE DATE 02.10.2021 Programm 12.30 – 13.20Uhr Chair: Prof. Dr. med. univ. Georg Griesinger, M.Sc. 12:30 Begrüßung Prof. Dr. med. univ. Georg Griesinger, M.Sc. & Dr. Thomas Leiers 12:35 Sind Sie bereit für die nächste Generation rFSH? Im Gespräch Prof. Dr. med. univ. Georg Griesinger, Dr. med. David S. Sauer, Dr. med. Annette Bachmann 13:05 Die smarte Erfolgsformel: Value Based Healthcare Bianca Koens 13:15 Verleihung Frederik Paulsen Preis 2021 Wir freuen uns auf Sie! C. Djerassi and WHO Carl Djerassi and the Word Health Organisation Special Programme of Research in Human Reproduction G. Benagiano, M. Merialdi Many hormonal contraceptives appropriate for use in Developing countries are not of interest to major Western, international pharmaceutical companies. For this reason, in the mid-seventies the World Health Organisation, in response to great demand for improved long-acting injectable hormonal contracep- tives, particularly in Africa and Asia, sponsored a chemical synthesis programme of long-acting progestational and androgenic steroids with Carl Djerassi as one of its main leaders. Almost 300 esters of norethisterone, levonorgestrel and testosterone were prepared by this programme in university-based research laboratories situated mainly in developing countries and then screened by the US National Institutes of Health in animal models. This paper describes the overall strategy of this research and development activity and the philosophy that served as an engine for a unique non-profit collaborative work. Among progestins three compounds, levonorgestrel-butanoate, cyclopropylcarboxylate and cyclobutyl-carboxylate, proved to be particularly long-acting when administered as microcrystalline suspensions, although – for financial reasons – only one, levonorgestrel-butanoate is being further developed. J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1): 10–3. Key words: WHO, Carl Djerassi, human reproduction Introduction nately remained unpublished, although 1973, dealt with long-acting agents for it set the tone for all later developments the regulation of human fertility [4]. Among Carl Djerassi’s many contribu- and was instrumental for the appoint- tions to science, probably the least ment, in 1963, of the first staff member known is the work he carried out with charged exclusively with research in re- The Task Force on Long- the oldest and best known research pro- production. Finally, in December 1965 a Acting Agents for the gramme ever sponsored by the World separate Human Reproduction Unit was Regulation of Human Health Organisation (WHO): “The Spe- created within the Division of Family Fertility cial Programme of Research, Develop- Health. Five years later, WHO convened ment and Research Training in Human a meeting on the “Promotion of research When the new Task Force initiated its Reproduction”, commonly known as in reproductive biomedicine including activities, the group of scientists in- HRP. fertility control”. This meeting identified volved in its work quickly realised that a number of obstacles to the develop- only two long-acting formulations were As recounted by Kessler [1], WHO’s in- ment of new fertility-regulating meth- available for national and international volvement in the field known today as ods; notable among them an insufficient programmes: the microcrystalline sus- “Reproductive Health”, dates back sixty knowledge of reproductive processes; pension of 17α-acetoxy-6α-methyl- years when, in 1951, the Government of difficulties in interfering with physi- pregn-4-ene-3,20-dione, known with the India requested assistance from the ological reproductive functions without acronym DMPA, or depot-medroxy- Organisation’s Regional Bureau for causing adverse effects; the scarcity of progesterone acetate (administered at a South-East Asia to conduct pilot studies scientists working in the area (with dose of 150 mg), and an oily solution of on the Rhythm Method of family plan- almost none in developing countries); 19-norpregn-4-en-20-yn-3-one,17α- ning in urban and rural areas [2]. This lack of interest by the pharmaceutical in- [(1-oxoheptyl)oxy], known with the ac- was not an easy decision, since at the dustry with an ensuing paucity of funds. ronym NET-EN or norethisterone enan- time the very idea of family planning (let The most important decision reached thate (administered at a dose of 200 mg). alone that of birth control) was rejected during the meeting was to conduct a fea- To properly evaluate these two long-act- by many of its Member States, with ar- sibility project to create an “Expanded ing agents (commercially known as guments such as that “family planning Programme of Research, Development Depo Provera and Noristerat), the Task will result in ageing of the population and Research Training in Human Repro- Force initiated a series of multicentre, and cause a decrease in productivity” duction” [1]. When, in 1971, this ex- multinational, comparative trials. These [3]. For this reason, it took a decade be- panded programme was formally estab- studies proved that the duration of action fore the topic of family planning would lished, one of its objectives was the cre- of DMPA is 3 months, or even longer, be brought into WHO’s agenda through ation of Task Forces for mission-ori- whereas that of NET-EN is 2 months an extensive review of research needs. ented research aimed at creating new [5–8]. At the same time, it became clear Named Biology of Reproduction, the methods for the control of human fertil- that both agents had shortcomings, espe- document reporting this review unfortu- ity. One of these Task Forces, created in cially in terms of bleeding patterns. In Received and accepted: February 24, 2011 Correspondence: Professor Giuseppe Benagiano, Department of Reproductive Health and Research, World Health Organisation, Geneva, Switzerland; e-mail: [email protected] 10 J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. C. Djerassi and WHO addition, DMPA came under strong criti- ment efforts aimed at obtaining com- eties, the CSP should aim at designing cism by consumer groups that consid- pounds outside the traditional pharma- new injectable derivatives of well-known ered its use dangerous for the health of ceutical industry mechanism. steroids. Three target areas were selected women. Although these objections were [11]: carefully analysed and disproven [9], The preliminary work carried out by the – 3–6 months progestin-only injections a number of Governments and Family Task Force-promoted CSP has been – monthly oestrogen-progestin injec- planning programme administrators felt described in an article in Science by tions that there was a need for additional for- Crabbe, Diczfalusy and Djerassi [10] – long-acting testosterone-progestin mulations having better characteristics where it was pointed out that the devel- combinations. and a duration of action of up to 6 months. opment of drugs for tropical parasitic As already mentioned, there was a com- diseases such as leishmaniasis, schisto- Besides testosterone, 2 well-known pro- plete lack of interest by the pharmaceuti- somiasis, and onchocerciasis might fol- gestin moieties known to be effective as cal industry in this area of research and low the same path. contraceptives and to be safe in human this reality made it both desirable and use were selected: norethisterone and necessary to find a new avenue for the Under the guidance of Carl Djerassi, levonorgestrel. development of such substances. a group of internationally recognised steroid chemists with past or current ex- It was also decided that to prolong the Therefore, the Task Force decided to ini- perience in the pharmaceutical industry duration of action of these three steroids, tiate a programme for the chemical syn- attended a meeting held under WHO the chemically active compound was to thesis and screening of a large number of auspices at Stanford University. Besides be transformed into a “prodrug” that steroid derivatives, with the aim of de- Carl Djerassi, then professor at the De- would slowly release the active moiety. veloping several long-acting formula- partment of Chemistry, Stanford Univer- To this aim, the free 17-hydroxyl group tions (monthly, three-monthly, and six- sity, Stanford, CA, USA, the following was to be esterified by inserting an ap- monthly) for use both in females and attended: P. Crabbe (Department of propriate acid chain; then, after adminis- males. To organise the work, a prepara-