Fertility regulating agents from plants

Bulletin of the World Health Organization 56 (3): 343-352 (1978) Fertility regulating agents from plants D. D. SOEJARTO,1 A. S. BINGEL,2 M. SLAYTOR,3 & N. R. FARNSWORTH4 As part ofthe WHO Special Programme ofResearch, Development, andResearch Training in Human Reproduction a six-centre programme has been established that is designed to provide new fertility regulating agents from plants for use in human subjects. There are four main sources of data: articles on medical botany, reports of testing crude plant extracts for fertility regulating activity, reports of in vitro effects ofplant extracts, and reports of a limited number of experimental studies in human subjects. The shortcomings ofmany of these data arepointed out andpossible reasons for the lack of success in developing fertility regulating agents from plants are discussed. The information available from 3000 plants has been computerized and, using a weighting system, the species for which sufficient data are available have been listed in order ofpriority for further investigation by the six centres involved in the WHO programme. The implementation of the experimental phases for the programme is briefly outlined. Higher plants are a rich source of biodynamic agents of all types. In the United States ofAmerica alone it has been shown that 25 % of all prescriptions dispensed from community pharmacies contain one or more drugs extracted from higher plants as their principal active ingredient(s).a A number of problems encountered in the pharmacological evaluation of plants, many of which relate to the programme being discussed, have also been reviewed.b However, in spite of this demonstrated medical importance, the pharmaceutical industry has shown little interest in seeking new drugs from higher plants. In 1976, we published an exhaustive two-part review article on the potential value of plants as sources of new antifertility agents.c This review covered all the periodical literature published up to 1975, as well as a large body of information on the ethnomedical d use of plants for fertility regulation. In that review, we were primarily concerned with the possibility of discovering new drugs capable of regulating fertility in the female, excluding substances used by the male; we felt, at that time, that insufficient data were available 1 Honorary Associate Professor, Instituto de Ciencas Naturales, Universidad Nacional, Bogota, Colombia. Present address: Adjunct Associate Professor of Pharmacognosy, Department of Pharmacognosy and Pharma- cology, College of Pharmacy, University of Illinois, Chicago, IL 60612, USA. Associate Professor of Pharmacology, College of Pharmacy, University of Illinois. Consultant, World Health Organization, Geneva, Switzerland, and Senior Lecturer, Department of Bio- chemistry, The University of Sydney, Sydney, Australia. I Professor of Pharmacognosy, College of Pharmacy, University of Illinois. a FARNSWORTH, N. R. & MoRmis, R. W. Higher plants-the sleeping giant of drug development, Americanjournal ofpharmacy, 148: 46-52 (1976). b FARNSWORTH, N. R. & BINGEL, A. S. Problems and prospects of discovering new drugs from higher plants by pharmacological screening. In: Wagner, H. & Wolff, P., ed., New naturalproducts andplant drugs with pharmaco- logical or therapeutic activity, New York, Springer-Verlag, 1977, pp. 1-22. C FARNSWORTH, N. R. ET AL. Potential value of plants as sources of new antifertility agents. I & II. Journal ofpharmaceutical sciences, 64: 535-598, 717-754 (1976). d The term " ethnomedical " is used in preference to " folklore " since primary sources of information have been obtained through the periodical literature and scientific informants, rather than from the laity. 3697 -343- 344 D. D. SOEJARTO ET AL. concerning the latter to make it a fruitful area for investigation. Abortifacients were considered but not emphasized. These data, as well as a substantial amount of information from other sources (primarily ethnomedical) were subsequently computerized and eventually made available to a WHO Task Force that was set up to consider whether or not WHO should initiate an organized effort in this area of research. The Task Force recommended that six centres be funded to initiate appropriate pharmacological and chemical studies on promising leads in the area of fertility regulating plants. The function and role of these centres is discussed later. DATA AVAILABLE ON FERTILITY REGULATING PLANTS There are many different types of information alleging that certain plants are capable of regulating fertility in human subjects or animals. The first of these types of information we will refer to as ethnomedical reports. These are reports found in books, original research articles, or review articles on medical botany resulting from anthropological studies and field observations by botanists, physicians, social scientists, or travellers in general. Such information is also often found in field notes on herbarium specimens collected by botanists or other workers in areas where the plants may have been used. Ethnomedical reports vary, however, from specially designed scientific studies to secondhand reports of vague origin. As a result, the amount of detail available with regard to the method of administra- tion of these plants for fertility regulation often provides an inadequate basis on which to assess the possible mechanism of action. However, as will be shown later, the ability to assign a possible mechanism of action forms the major basis on which plants will be selected for study in the WHO programme. In most ethnomedical reports the candidate plants are described simply as " utero- tonic ", " contraceptive ", " prevents pregnancy ", " abortifacient ", " for amenorrhoea ", "expels placenta ," " an emmenagogue ", " antifertility agent ", " oxytocic ", " ecbolic ", "promotes menstrual flow ", etc. Indeed, frequently one must question whether the author of the report was aware of the specificity of certain of these terms. The problems that this vagueness in terminology introduces into the process of selecting plants for further study will also be discussed. Second, much information exists in published reports on the testing of crude extracts of various plants for fertility regulating activity. Both positive and negative data are available, with varying degrees of credibility. The significance of positive results is often difficult to assess, since there is no prototype fertility regulating agent obtained from plants that has been found to be useful in humans. Thus, if an extract of a plant is reported to produce an 80% anti-implantation effect in rodents, it is difficult to judge whether or not this degree of activity gives any indication of the possibility of eventually isolating a 100% active compound from that plant. In a great many cases, materials found by one research group to give positive results are reported later by another research group to have no activity and vice versa. Third, perhaps an even larger body of information is available concerning the in vitro, uterine stimulant effects of plant extracts. Indeed, a large number of compounds of known structure can be cited a that have the ability to stimulate uterine muscle preparations in vitro at dilutions of 1:1000000 or greater. Unfortunately, in vivo, most of these agents a FARNSWORTH, N. R. ET AL. Potential value of plants as sources of new antifertility agents. I & II. Journar ofpharmaceutical sciences, 64: 535-598, 717-754 (1976). FERTILITY REGULATING AGENTS FROM PLANTS 345 elicit a variety of additional pharmacological effects that would preclude their application as human fertility regulating agents. Finally, results are available from a limited number of experimental studies in human subjects in which plant extracts have been tested for one or another type of fertility regulat- ing effect. The significance of such results is difficult to assess, since control data have rarely been reported. Although large numbers of pure compounds that are highly active as in vitro uterine stimulants have been isolated from plants, and thus could conceivably be useful as fertility regulating agents, there are few reports of extensive studies to establish such usefulness. Specifically, most of these compounds have not been evaluated for their oral in vivo utero- tonic effects, anti-implantation effects, estrous cycle disruption effects, anti-luteinizing hormone (LH) activity, luteolytic activity, or luteal suppressant effects, any one of which could be useful in humttn fertility regulation. Perhaps the most intriguing example of an unmodified fertility regulating agent of known structure isolated from plants, and the only such agent that has been extensively studied in humans, is m-xylohydroquinone. This was first isolated from peas (Pisum sativum L.) by Sanyal in 1952. According to Sanyal,a the population of Tibet has remained essentially static for the past 200 years, and he speculates that this might be due, at least in part, to the use of peas as a major source of dietary protein in that country. A large number of publications on the clinical effects of m-xylohydroquinone appeared in the literature up until 1960, and there is little evidence of side-effects from its use in females (oral dosage was usually 300-350 mg daily)." Sanyal (personal communication, 1977) feels that the major reason for diminished interest in m-xylohydroquinone as a fertility regulating agent is that a review of all data up to 1960 showed only 60% effectiveness. In retrospect, one has to question the relevance of much of the data on the effect of m-xylohydroquinone as an effective fertility regulator in females, because of difficulties in ascertaining patient compliance in clinical trials and in assessing the validity of the experimental designs, and because of other factors. Nevertheless, perhaps all the available data pertaining to the use of this agent as a fertility regulator in human subjects should be carefully reviewed, before the possibility of using m-xylohydroquinone as an effective fertility regulator in humans is rejected. SELECTION OF PLANTS FOR STUDY IN THE WHO PROGRAMME The initial information made available to the WHO Task Force consisted of a list of more than 3000 plant species for which fertility regulating activity had been claimed. Although the data had been computerized it was still not possible to use them to generate a list of priorities for further investigation. Many problems remained to be resolved. For example, the relevance of many of the ethnomedical data pertaining to the use of plants for fertility regulation was difficult to assess. Similarly, the reliability of a large number of reports showing interesting fertility regulating effects of plant extracts in animals (in vivo experiments) was questionable because a SANYAL, S. N. Ten years of research on an oral contraceptive from Pisum sativum Linn. Science and culture, 25: 661-665 (1960). b SANYAL, S. N. Pisum sativum (Linn): m-xylohydroquinone as an oral contraceptive. A critical evaluation. Acta endocrinologica, 28 (Suppl.): 72-82 (1956). D. D. SOEJARTO ET AL. of, inter alia, poor experimental design, lack of suitable controls, insufficient experimental details to substantiate the conclusions, and even inappropriate conclusions based on the data reported. It was necessary, on other grounds as well, to question the validity of the biological effects reported initially for certain plant extracts. Several of the most promising plants had been subsequently investigated more thoroughly, but few active compounds had resulted from these studies, making one question, on the one hand, the validity of the initial results, and on the other, whether indeed the compounds isolated during the follow-up studies were ever biologically evaluated. Regarding the latter point, there was in fact little evidence in the literature to indicate that the fertility regulating activity of such compounds had been evaluated. Also, it should be pointed out that, too often, chemists undertake to isolate constituents from plants shown to have a specific biological activity by following classical phytochemical approaches. In essence, such approaches involve the isolation and characterization of a specific type or class of chemical compound, e.g., triterpenes or indole alkaloids. Histori- cally, and perhaps to the detriment of research aimed at discovering new biologically active compounds from plants, such an approach has not been successful. Thus, if the desired end-product is a biologically-active compound, chemists must work closely with pharmacologists, and every step of the isolation work must be followed by an appropriate bioassay. It is evident from the literature that such a procedure has been neglected in follow- up chemical studies designed to isolate agents responsible for the fertility regulating effects of plant extracts. Neglect of such a procedure has probably contributed, in part, to the questionable data reported in the literature. In spite of these seemingly insurmountable problems in assessing the validity of any single piece of information on an alleged fertility regulating plant, a considerable effort has been made to evaluate the large amount of data available by means of computer analysis to produce a priority-ranking of the species for which sufficient data are available. This has involved a weighting process that is extremely complicated, involving, briefly, an assignment of positive and negative values to given plants based on specific data con- cerning them; space does not permit us to give all of the details. Types of data available for computer analysis The types of data used in the computerized evaluation are as follows. 1. Latin binomial of each plant (genus and species) 2. Plant part(s) 3. Geographical area 4. Chemical compounds reported present in each plant (a) Compound name (b) General chemical class, e.g., indole alkaloid, diterpene, triterpene, sterol, cardenolide (c) Chemical subclass or ring system, e.g., guaiane sesquiterpene, kaurane diterpene, oleonane triterpene, iridoid monoterpene (d) Functional groups on the molecule, e.g., CN, SCN, phenolic OH, O-glycoside, C-glyco- side, ester, NO, CHO, COOH (e) Percentage of compound present in plant 346 FERTILITY REGULATING AGENTS FROM PLANTS 347 5. Biological effects of compounds present in each plant (a) In vitro (b) In vivo (c) In situ (d) In humans 6. Biological effects of extracts of each plant (a) In vitro (b) In vivo (c) In situ (d) In humans 7. Ethnomedical uses 8. Classification of biological effects (a) General effects, e.g., central nervous system, autonomic, hormonal, toxic, cardio- vascular, fertility regulating. (b) Specific effects, e.g., the following are subdivisions within the fertility regulating category: nonspecific contraceptive or antifertility effects abortifacient uterine stimulant embryotoxic labour induction menstruation induction acrosin inhibition spermicidal anti-spermatogenic anti-implantation anti-ovulatory estrus cycle disruption anti-gonadotropic (nonspecific) anti-pregnant mare's serum (PMSG) a anti-human chorionic gonadotropin (HCG) anti-LH anti-follicle stimulating hormone (FSH) galactagogue anti-galactagogue a prolactin stimulation prolactin inhibition a luteolytic luteotropic ovulation induction a fertility promotion gonadotropin synthesis inhibition (non- specific) FSH synthesis inhibition LH synthesis inhibition androgenic anti-androgenic gonadotropin release inhibition (non- specific) FSH release inhibition LH release inhibition uterus relaxation a anti-oxytocic a luteal suppression estrogenic anti-estrogenic progestagenic anti-progesterone gonadotropin synthesis stimulation (non- specific) a FSH synthesis stimulation a LH synthesis stimulation a gonadotropin release stimulation (nonspecific) a FSH release stimulation a LH release stimulation a menstruation inhibition a These categories are not useful antifertility effects. D. D. SOEJARTO ET AL. Priority types of fertility regulator Sometimes, the mechanism of action of fertility regulating plants mentioned in ethno- medical reports may be presumed from the manner in which they were administered, i.e., the dosing sequence. With experimental data relating to fertility regulation, it is not always clear which of the specific effects listed above is involved in the process that results in the regulation of fertility. For the purposes of the WHO programme only certain types of fertility regulating agent are being considered and it must be established whether the effect reported for a given plant is one that is specifically of interest to the WHO programme. The types of agent being considered by the Task Force are listed below; no attempt has been made to list them in order of priority: A. To be used by the female once per month, just prior to expected menses. B. To be used by the male. C. To be used by the female after one missed menses. D. To be used by the female following mid-cycle coitus. E. To be used by the female on a continuous basis. F. To be used by the male or female, with data insufficient to classify in any other group. G. A male antifertility agent, but used in the female. H. To be used by the female after more than one missed menses. I. To be used by the female just after menstruation. For example, if a plant were alleged in ethnomedical reports to be an " emmenagogue ", it would be assigned to categories A, C, D, and H above, indicating that there is a possibility that if the plant did indeed elicit an effect, it would be appropriate to any of the four categories indicated. On the other hand, a plant alleged to be useful as an " aborti- facient" would be assigned only to categories A, C, and H. Alternatively, if all data on plants in the computer were analysed relative to their alleged effectiveness as fertility regulators when used after one missed menses, the following types of ethnomedical informa- tion would be considered as pertinent: abortifacient, oxytocic, ecbolic, placenta expulsion after delivery, relief of postpartum bleeding, uterotonic, promotion of difficult delivery, emmenagogue, treatment of amenorrhoea, promotion of smooth menstrual flow, and related effects. Each piece of information, when computer coded, would be assigned points manually on the basis of a subjective set of criteria relating to the credibility of each partic- ular report. Duplicate sets of data for any plant would be ignored by the computer, except when the ethnomedical use pertains to more than one geographically distant country or culture. For example, a plant alleged to have been used in China as an abortifacient might be assigned 75 points. A second record for the same plant used in Japan as an abortifacient would be ignored, since it would be considered as duplicating an identical piece of information. However, if the plant were reported as being used in Paraguay and also in Kenya as an abortifacient, the computer would add 25 points to the raw score of the plant for the Paraguayan use, as well as 25 points for the Kenyan use, since its use in three geographically separated areas for the same purpose would seem to reinforce the validity of this effect. This same plant would not be afforded additional points, however, if it had been reported to be useful as an emmenagogue, ecbolic, or oxytocic since all of these terms suggest a similar mechanism of action. 348 FERTILITY REGULATING AGENTS FROM PLANTS Computerized data reported for studies on extracts of plants in vitro and in vivo, or when used in human subjects, become additive to the data assigned for ethnomedical information. These assignments are programmed and are not amenable to subjective evaluation. The programmed point values are based on whether the data are from in vitro or in vivo studies, and in the latter case, the route of administration, species of test animal, and a number of other factors. In addition to having in the data-base all the published information on ethnomedical and experimental fertility regulating activities for higher plants, we have computerized all the data reported on the biological activities and chemical constituents of plants for the period 1975 to the present. Further, a number of complete literature searches have been carried out on genera of plants having several members for which high priority scores are anticipated and the data found in these searches have also been computerized. Finally, literature searches have been carried out on all plant principles reported to have fertility regulating activities, and these data are also stored in the computer. The addition of new data from the current literature allows continuous updating of the priority rank-ordering of plants. The final computer analysis is based on identifying all data related to fertility regulation for each plant, for each of the priority categories indicated above (page 348). Thus, for each species, the computer collects information for any ethnomedical use carrying, for example, an "A" priority category number. Next, all data having an "A" priority for in vitro fertility regulating activity for the same plant are collected and analysed, followed by an analysis of in vivo and/or human data carrying the "A" priority for the same plant. Finally, for most types of data, certain weights are added into each record to reflect the credibility of data reported by the investigator. Then the computer assembles all data for each species, tallies the points, and provides a priority rank-ordered listing of plants to assist in the selection of candidates for further study. Since there may be types of information in the data-base that are not properly taken into account in the computer program, a full print-out of all data for each rank-ordered species is provided for a visual checking. Real and anticipated problems in analysing the data Our method for weighting and rank-ordering fertility regulating plants is obviously restricted to literature reports and unpublished data made available to us. Thus, if indigenous populations are using a plant for fertility regulation, and this activity has not been observed and reported in the literature, the plant will not receive a high ranking in our analysis. This is acknowledged and anticipated to some extent. A second potential major problem concerns our arbitrary assignment of weights to the various types of information. For example, we have no way of knowing whether the assignment of 200 points to a well documented and detailed report of a specific plant as an abortifacient is equivalent to 200 points assigned to a plant that has been studied in animals and found to have abortifacient effects. Similarly, we do not know whether it is justified to assign heavier weights to positive data obtained following oral (as opposed to parenteral) administration of an extract to an animal. As the project continues, it will be possible to experiment by changing various weight assignments and re-analysing the computerized data. In the final analysis, the method will be acknowledged as successful only when clinically useful fertility regulators are isolated from the candidate plants. 349 D. D. SOEJARTO ET AL. Botanical nomenclature problems In this programme, only references to plants with established scientific names (Latin binomials) have been considered in the weighting and selection process. In this respect, we anticipate that taxonomic synonymy and other nomenclatural problems of plants under consideration will cause problems in relation to weighting. This can be illustrated by one example. Literature had to be acquired for Vincetoxicum officinale Moench, and chemical and pharmacological references to this plant were found to be indexed under the binomials Cynanchum vincetoxicum Pers., Cynanchum nivale Nym., Cynanchum hirundinaria Medic., Asclepias alba Mill., Asclepias vincetoxicum L., Vincetoxicum hirundinaria Medic., and Vincetoxicum nivale Boiss. & Heldr., all of which represent the same plant. An additional 25 Latin binomials were found in the botanical literature, for the species of interest, but fortunately these complicating names were of no importance to the problem at hand. Thus, one can see that if data pertinent to the weighting process were computerized under the plant names Cynanchum vincetoxicum, Cynanchum nivale, Asclepias alba, Vincetoxicum hirundinaria, etc., when in reality all are the same plant, the points assigned to each plant would not be assigned to a single plant, and thus the total points legitimately belonging to the plant would be diluted on each of the synonymous plant names. Further, the importance of the name(s) of the authority of the plant scientific name should be stressed. In order to identify the exact plant name meant for investigation, especially when synonymy is involved, the authority must be known, and many references to the chemical and pharmacological literature on plants fail to include this information. IMPLEMENTATION OF THE WHO PROGRAMME In order to carry out the experimental phases ofthe search for effective fertility regulating agents from plants it is essential that each research group should include experts in repro- ductive biology, as well as in the chemistry of natural products. Further, both of these groups of experts should be closely related geographically, preferably within the same institution. To initiate the WHO programme, six such groups have been invited by the Task Force to submit proposals that are in concert with the guidelines established byWHO for the conduct of the research. These six groups are located at the Chinese University of Hong Kong; Natural Products Research Institute, National University, Seoul, Republic of Korea; Universidade Federale de Pernambuco, Recife, Brazil; University of Sri Lanka, Peradeniya, Sri Lanka; The City University, London, England; andthe College ofPharmacy, University of Illinois Medical Center, Chicago, Illinois,USA. Each of these groups will be assigned plants from the rank-ordered priority list as determined by the system described herein. Plants indigenous to the country where each centre is located, will be assigned to that centre whenever possible. One important guideline for the programme is that no chemical work will be initiated on any plant until the bio- logical activity is confirmed independently by two groups. The six centres will work collaboratively in this respect, in groups of three, i.e., Sri Lanka, Recife, and London will exchange samples for biological confirmation, as will the centres in Hong Kong, Seoul, and Chicago. There will be opportunities for training of technical personnel in each of the six centres, by means of programmes that will allow individuals to work in established laboratories in other countries for various periods of time. Frequent exchange of senior personnel between 350 FERTILITY REGULATING AGENTS FROM PLANTS 351 centres is also planned, for shorter periods of time, so that the progress of research will not suffer from lack of communication. Protocols have been developed, and will be followed by all of the participating centres, concerning the isolation of active constituents following bioassay of fractions from the assigned plants, as well as bioassay protocols designed especially for the unique problems encountered in working with crude extracts. All plants to be assigned to the cooperating centres will be collected by or under the direct supervision of a WHO consultant botanist, in order to eliminate the possibility of misidentification and/or deterioration of samples. Special guidelines and protocols have been developed for these activities. PARALLEL APPROACHES Although the six cooperating centres will provide the major thrust in the WHO pro- gramme, a few parallel studies will continue to be supported by WHO, based on the needs of the programme, and the merits of each study. Thus, it is envisaged that specific ethno- botanical and/or anthropological studies in certain areas will be required to complement the six-centre programme. Guidelines have been provided for these types of activity in case they are required. Specific research leads that are suggested by independent groups may also be supported independently of the six-centre programme, if they are judged as likely to provide additional information not already covered in the ongoing supported projects. ACKNOWLEDGEMENTS The computer studies described herein were supported, in part, by funds from the World Health Organization. We are grateful to the Rockefeller Foundation, USA, for making available a computerized list of data on fertility regulating plants that was complementary to, and useful in connexion with, other information acquired by the authors and WHO. RtSUM13 Regulateurs de la f6condite d'origine vegetale Les auteurs presentent le programme d'6tude des agents biodynamiques d'origine vegetale 6tabli par I'OMS dans le cadre de son programme special de recherche, de developpement et de formation a la recherche en reproduction humaine. Ils ont pendant plusieurs annees recueilli dans la litterature pertinente des donnees qui ont ensuite et6 trait6es par ordinateur et remises aL un groupe d'action special de l'OMS. Celui-ci a recommande que l'Organisation apporte une aide financiere 'a six centres charges d'entreprendre des etudes pharmacologiques et chimiques appropri6es. Les donnees disponibles sur les plantes ayant un effet regulateur de la fecondite proviennent de difftentes sources: a) des rapports 4 ethnom6dicaux * a, qui fournissent des renseignements souvent insuffisants pour connaitre le mecanisme d'action (objectif prioritaire et critere du choix des plantes a etudier dans le programme OMS); b) des rapports concernant la mise a l'essai d'ex- a Le termea ethnom6dical > d6signe ici des sources telles que des 6tudes anthropologiques ou des observations faites sur place par des botanistes, des m6decins, des sociologues ou de simples voyageurs et publi6es par la suite. D. D. SOEJARTO ET AL. traits bruts: ils sont d'appreciation malaisee et souvent contradictoires; c) des donnees publiees sur un grand nombre d'extraits de plantes produisant in vitro des effets stimulants sur l'uterus; la plupart sont inacceptables en raison de leurs effets secondaires; d) les resultats d'un nombre limite d'etudes experimentales sur des etres humains: l'absence frequente de sujets temoins ne permet pas d'apprecier leur valeur reelle. Peu d'etudes approfondies ont ete consacrees a des substances isolees de plantes qui pourraient servir d'agents regulateurs de la fecondite. En particulier on n'en a pas evalue les effets toniques sur l'uterus in vivo, les effets anti-implantation, les effets de rupture du cycle aestral, l'activite anti-hormone luteinisante ni l'activite luteolytique, etc., chacun de ces effets pouvant etre utile aux fins de regulation de la fecondite. De nombreuses etudes consacrees 'a la m-xylohydroquinone, substance isolee des pois a l'origine, ont montre' qu'elle a une activite regulatrice de la fecondite. I1 semblerait utile d'approfondir les recherches sur cette activite. Pour proceder au choix des plantes i e'tudier dans le programme OMS, le groupe d'action special de l'Organisation disposait au depart d'une liste de plus de 3000 especes vegetales passant pour exercer une certaine activite'. Les auteurs ont procede 'a un travail considerable d'analyse par ordinateur pour permettre un classement prioritaire des especes a etudier. Ce travail a comporte un processus tres complexe de ponderation, avec attribution de notes positives ou negatives, et a pris en consideration les donnees suivantes: identification de la plante et designation de ses parties, origine geographique, composes chimiques presents dans la plante, effets biologiques de ces composes, effets biologiques des extraits vegetaux, utilisations populaires (ethnomedicales) de la plante, et classement de ses effets biologiques. Aux fins du programme de I'OMS, seuls certains types d'agents regulateurs de la fecondite ont ete retenus, a savoir les agents: a utiliser par la femme une fois par mois, juste avant les regles; i utiliser par l'homme; a utiliser par la femme apres absence d'une menstruation; i utiliser par la femme dans la seconde moitie du cycle, apres coit; 'a utiliser par la femme de fason continue; a utiliser par l'homme ou la femme (en l'absence de donnees permettant le classement dans tout autre groupe); antifecondants pour l'homme mais i utiliser par la femme; a utiliser par la femme apres absence de plus d'une mens- truation; a utiliser par la femme juste apres les regles. En vue de la mise en euvre du programme OMS, six groupes d'experts ont ete invites par le groupe d'action special 'a soumettre des propositions de recherche. Comprenant chacun des experts en biologie de la reproduction et en chimie des produits naturels respectivement, ces groupes sont etablis a l'Universite chinoise de Hong Kong, aL l'Institut de Recherche sur les Produits naturels de l'Universite nationale de Seoul (Republique de Coree), i l'Universite feddrale du Pernambouc, Recife (Bresil), al'Universite de Sri Lanka, Peradenyia (Sri Lanka), a la City Univer- sity, Londres (Angleterre), et 'a l'Ecole de Pharmacie du Centre medical de l'Universite de l'Illinois, Chicago (Etat-Unis d'Amerique). Chacun de ces groupes se verra confier un contingent de plantes classees d'apres l'ordre de priorite etabli. Les plantes indigenes du pays oLu se trouve le groupe seront dans la mesure du possible confiees audit groupe. Aucune operation chimique ne sera entreprise sur une plante avant confirmation de son activite biologique, independamment par deux groupes d'experts. La collaboration entre les six centres comportera l'echange d'echantillons, la formation de personnel technique, l'echange de chercheurs confirmes, l'utilisation de protocoles de travail identiques, etc. La repartition des plantes aux groupes d'experts sera placee sous la supervision directe d'un botaniste consultant de l'OMS. 352