Chemical methods for male fertility control

CONTRACEPTION

CHEMICAL PlETHODSFOR MALE FERTILITY CONTROL Expert Consultation

of the

European Medical Research Council Advisory

Subgroup on Human Reproduction

E. Nieschlaq,

E. J. Wickinqs

and H. Breuer

The European Medical Research Council (EMRC) was founded in the early 70s as an assembly of the Directors of the Medical Research Councils in Europe. This assembly provides for the exchange of information, and should serve to coordinate research efforts in Europe. In order to improve contacts inside Europe and with the USA, representatives from the European Science Foundation (ESF) and the National Institutes of Health (NIH) also participate in the meetings. The EMRC has established several subgroups to advise on specific problems. The EMRC Advisory Subgroup on Human Reproduction was founded in 1978. The Advisory Subgroup on Human Reproduction had identified male fertility control as a priority area for research in human reproduction at one of its previous meetings and decided to organize an expert consultation on this topic. This expert consultation on "Chemical methods for male fertility control" was held on October 13/14, 1980 in Bonn with the following participants: Request for reprints should be addressed to: Prof. Dr. E. Nieschlaq, Max-Planck Clinical Research Unit for Reproductive Medicine, University Women's Hospital, Westrinq 11, D-4400 Miinster, F. R. Germany Accepted

JANUARY

for publication

December

1981 VOL. 23 NO. 1

7, 1980

CONTRACEPTION H. Breuer, Chairman of the EMRC Advisory Subgroup (Bonn, F.R. Germany); H. G. Burger (Melbourne,Australia); L. Cedardl (Paris, France): P. A. Corfman' (Bethesda, MD, USA): E. Diczfalusy (Stockholm, Sweden), P. Franchimont (Liege, Belgium); 0. Harkavy' (New York, USA); E.D.B. Johanssonl (Uppsala, Sweden); F. Labrie (Laurier, Quebec, Canada): F. Neumann (Berlin, F. R. Germany); E. Nieschlagl , Chairman of the expert consultation (Miinster, F.R. Germany); M.R.N. Prasad (WHO, Geneva, Switzerland); C. Robynl (Bruxelles, Belgium); J. Sandow (Frankfurt, F.R. Germany); R.V. Short'(Edinburgh, UK); R. Vihkol (Oulu, Finland): G.M.H. Waites (Reading, UK); E.J. Wickings (Miinster, F.R. Germany).

1

Member of the EMRC Advisory

Subgroup

The consultation provided recommendations for directing future research activities and for the allocation of research funds in Europe. These recommendations will be conveyed to decision-makers inside the various Medical Research Councils or their equivalent in Europe through the assembly of the EMRC andthe ESF. However, new or intensified research in a specific area is not only initiated by the funding agency alone. This also occurs through increased demand for research grants from scientists. Therefore, it was felt that the impact of these recommendations would be greater iftheywere also made available to researchers through publication. The discussions concentrated on a number of topics, each of which was introduced by one of the participants. The discussions resulted in recommendations.

WHO SPECIAL PROGRAMME OF RESEARCH, DEVELOPMENT TRAINING IN HUMAN REPRODUCTION

AND RESEARCH

(Topic introduced by M.R.N. Prasad) The WHO activities in the field of male fertility control through the Task Force on Methods for the Regulation of Male Fertility, within the Special Programme of Research, Development and Research Training in Human Reproduction,over the past 8 years were reviewed. The Task Force had supported extensive basic research on inhibin and epididymal physiology, evaluated approaches to interfering with sperm maturation, and conducted clinical trials with known steroidal agents.

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1981 VOL. 23 NO. 1

CONTRACEPTION Funding for the Male Task Force was discontinued in 1980. The Advisory Group to the Special Programme recognized "that new male methods of fertility regulation might find wide applicability, but in view of the high cost and long time needed for their development, scientific and financial uncertainties, and the fact that other agencies were active in this area, it recommended discontinuation of Task Force support unless considerably higher levels of funding were available". Since this level of funding was not achieved, the Task Force activities were phased out. The group unanimously expressed concern at this decision and feared that it may be misunderstood and lead to a domino effect on other funding agencies who may conclude that research on the male was unrewarding. Therefore, the need for more basic research on male reproduction was emphasized to permit identification of steps in the reproductive process vulnerable to designed interference that would serve as the basis for development of new methods. Such basic research should be supported by medical research councils and other agencies. The group recognized the crucial role of WHO-supporting mission-oriented research and in mobilizing and coordinating a global effect in this field. The group exhorted the WHO Special Programme in Human Reproduction to reinitiate the activities of the Task Force cn Methods for the Regulation of Male Fertility. R~commw~dcu2o~z: OnLy thxaugh intwG&ed btiic tie~c?u~ch in the phyALoLogy and pcLthaRogy 06 male heptoduOtiwe dun&onn PAL& it bc ponsible .tu develop mtiha& 4Oh tmLe 4etiUy cona?&. The,te@ke, ba.Ce tiebea& in m&e dcs@ZLty und 2~ nuppoti by file vtaiional junding cvgcwkCLtjoti h hoc&d be. dteng-thened.

THE CHINESE PRIORITY PROGRAMME FOR MALE FERTILITY - WILL GOSSYPOL PROVIDE THE MALE PILL?

CONTROL

(Topic introduced by E. Diczfalusy) In the People's Republic of China, which is aiming for zero population growth by the year 2000, a priority programme for achieving control of fertility in the male has been developed.Two institutes concentrating on male fertility regulation are being developed in close collaboration with WHO. The government has developed a family planning programme with large incentives to couples planning a one-child family. Vasectomy is widely practised (in one province with 97 million inhabitants, approximately 10 million men are vasectomized). However, there is an increasing demand for reversible male methods.

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1981 VOL. 23 NO. 1

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CONTRACEPTION

Gossypol has been identified as a possible agent for male fertility control, and had been used in large scale clinical trials in 8,806 men up to the year 1977. Half of these men were treated for more than 2 years. In 99.1% of the subjects the drug was effective in reducing sperm counts to less than 4 million/ml. Recovery after cessation of therapy was, however, incomplete in up to 25% of the 2000 subjects followed-up. As side effects of gossypol treatment, fatigue (12%), gastrointestinal symptoms (7%), decrease of libido or potency (6%) and hypokalemia (66 cases requiring hospitalization) had been encountered. Animal studies performed in and outside China since 1978 revealed major species differences intheantifertility effects of gossypol. While rats, hamsters, monkeys and humans are sensitive, mice,guinea pigs, rabbits, pigs, goats, sheep and cows are relatively resistant. Toxicological investigations showed hypokalemic paralysis and myocardial necrosis in dogs, but not in monkeys. Gossypol was negative in the AMES test. In a recent study from the Batelle-Institute (Geneva), tumor initiating and promoting activity was evident from skin tests in mice. However, since gossypol is still an impure product and neither the active principal nor all contaminants have been identified, the agents inducing tumors and infertility may not necessarily be the same.

LIMITATIONS STEROIDS

AND PROSPECTS OF MALE FERTILITY CONTROL WITH

(Topic introduced by E. Nieschlag) Testosterone as a single entity and cyproterone acetate or testosterone in combination with gestagens or danazol have been tested in approximately 1000 subjects with regard to their efficiency in suppressing spermatogenesis. Oral testosterone undecanoate proved ineffective, while injections of testosterone enanthate or testosterone cypionate were required at weekly intervals to induce and maintain azoospermia or sperm counts below 5 million/ml. Cyproterone acetate is also effective but it lowered testosterone levels to an unacceptable degree. The combination of monthly testosterone enanthate or cypionate injections with either depot-medroxyprogesterone acetate (DMPA) injections or oral danazol proved most effective.

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1981 VOL.23 NO. 1

CONTRACEPTION

These new steroid combinations will require extensive and very expensive toxicological investigations before clinical trials can be continued. At the present time the pharmaceutical industry is not willing to invest such large sums in the development of male contraceptive agents, because it is not known whether such agents would be acceptable and could be marketed. In addition, if some of the progestational agents used in females were used in men at higher doses, adverse reactions might occur; the adverse publicity could thus affect the market for female contraceptives. At present, public funds are not available for these toxicological studies. From the clinical trials performed so far, it can be concluded that uniform achievement of azoospermia - the only definite proof of male infertility - is not feasible with these steroid combinations. It remains unclear whether decreases in sperm counts below 5 million/ml with normal motility and morphology would be sufficient for suppressing male fertility. It appears that in addition to the classical semen analysis, new test systems are required to assess fertility.

WILL NEW STEROIDS CREATE NEW POSSIBILITES? (Topic introduced by F. Neumann) A number of D-homo-steroids have shown simultaneous androgenit and progestational effects in a single compound. So far, only data from rats are available, since there has been no further commercial development of such products. Such compounds would at least reduce the costs of toxicology testing to l/3 of that for a steroid combination. It might be worthwhile investigating these and other new steroids, butthiswould probably not require new synthetic programmes, since vast numbers of steroids have already been synthesized. However, testing the steroids would be a very costly exercise with the methods available today. New economical &-u&U techniques should be developed for screening such compounds.

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1981 VOL. 23 NO. 1

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CONTRACEPTION

CAN INHIBIN INHIBIT FERTILITY? (Topic introduced by P. Franchimont) A decade of intensive research on inhibin has not produced a pure preparation of this protein. There is no evidence that inhibincan suppress FSH levels to sufficiently induce infertility. This line of research, however, has led to the discovery of other small peptides in the testis possibly active in regulating testicular function, opening up a new and exciting research area, fundamental to our understanding of testicular physiology. Recommendtion: ldetii&&tion and chutacteniztion 06 nmc& &wSXLE~~ .pepfida and theLt mode 03 action -in the coM;DLoQ04 &htiA &n&ion dg-AulVeA kigh ptiotity. LH-RH CAN SUPPRESS TESTICULAR A FEASIBLE APPROACH IN MEN? (Topic introduced

FUMCTIONS

IN ANIMALS

- IS THIS

by J. Sandow and F. Labrie)

High-dose LH-RH analogue treatment suppresses ovulation in women and produces testicular atrophy in various species of laboratory animals bydesensitizing pituitary and gonadal hormone receptors. In rhesus monkeys and men,desensitization also occurred but effects on sperm counts were absent or marginal. Since these analogues interact at various levels of the hypothalamo-pituitary-testicular axis, more basic research on the mechanism of action of these peptides is necessary. The application in the treatment of prostatic cancer may be of benefit, depending on the outcome of ongoing clinical trials. As the analogue would have to be combined with testosterone for male fertility control, a possible advantage over steroid combinations is not evident. Recommcndtion: The o&come od intended ctiticti tia& with LH-RH&atoguti bon m&e ,jc?mtildy con#~oR nhoutd be awaited befjvhc new ti& cute in.iticctsd. ~ka~wki_Le., in&nhi&ed btiic henamch in apphophia& animaL mode& on zhe mechaninm od ac,tion 02; high-done LH-RHa?~ea&rieti ih hequiked.

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1981 VOL. 23 NO. 1

CONTRACEPTION IMMUNOLOGICAL

APPROACH

TO MALE FERTILITY

CONTROL

(Topic introduced by E. Nieschlag) Investigations in monkeys (MacacamLLeatta, M. hadkta and hf. &LAusing passive immunization against FSH have shown that the maintenance of spermatogenesis in these non-human primate species is FSH-dependent. Active immunization of rhesus monkeys with FSH over 2 years revealed considerable suppression of spermatogenesis. This may provide new leads towards male fertility control. Since possible side effects of immunization, for example due to immune complex formation, and the reversibility are incompletely comprehended, further testing in primates appears desirable. cic&wLin)

Immunization against testicular components or sperm fragments was dismissed as a possible approach to male fertility control, the first on the basis of autoimmunity, the second since sperm antibodies have not conclusively been shown to be specifically related to fertility or infertility. Where sperm antibodies may become important is in the follow-up of vasectomy patients. The results of experiments in vasectomized monkeys revealing a higher incidence of atherosclerosis are disturbing with regard to the large number of vasectomies currently being performed worldwide. However, prospective studies, although.regarded as only preliminary, have not revealed an increased risk of coronary heart disease in vasectomized men. Recommend&&n: The &ok oh FSH in human te,dicuh I(UM~~OM AholLed be 1 hXh ekuxdc&ed. Long--tetun stud&n od FSH-immunized anim& nhould !:’ i&ed to Look doti pohhib& nidc eidecti iimmune comr&x Deane eZc. i. New adjuuanti hu&b& Ao?r uhe in the human hhvuld be devQeopeh. CeOhQ coopzkax'ion wtih immunot5ogtiZn 6holLed be encowcaged.

THE HISTORY OF 6-CHLORO-6-DEOXYSUGARS: TURE RESEARCH?

A SIGNPOST FOR FU-

(Topic introduced by G.M.H. Waites) Modified sugars were investigated as male antifertility agents because the activity of a-chlorohydrin had indicated that glycolysis in spermatozoa was a potential site of attack. 6-Chloro-6-deoxyhexoses produced a reversible antifertility action in male rats and suppressed glycolysis by their spermatozoa. Eleven active compounds were discovered but activity was absent if the chlorine atom was replaced by other substituents or was located elsewhere in the sugar molecule. The most studied compound is 6-chloro-6-deoxyglucase (GCDG); 24 mg/kg/day was sufficient to produce infertility in male rats and marmoset monkeys. 6CDG (240 mg/kg/ day) produced spermatoceles in rats but was otherwise nontoxic in this species although it was neurotoxic to marmoset monkeys. 6CDG (480 mg/kg/day) was neurotoxic to mice but did

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1981 VOL.23NO.

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CONTRACEPTION not affect their fertility. The ratios of the toxic dose to the antifertility dose varied with the structure of the 6-chloro-6-deoxyhexose so it is possible that the toxic and antifertility effects are produced by different metabolites. Although these compounds cannot be applied for human use, they provide an example of how research can be activated and coordinated to produce conclusive results in the shortest possible time. Recvmmendtion: The acL&e meXabo&Xen VA 6-cMvho-6-deoxyg~ucvc,e, nhoLLed be iden&$ied. The eRu.Gdation vd the mechanihm od ation may .Eeud Xv the hynthehA o6 neu cvmpvun& acting on hpehm matWLdtivn in Rhe ep&iidymin which tip devvid vd ne.tiototiciZy. THE EPIDIDYMIS

AS A SITE FOR INTERFERENCE

WITH FERTILITY

(Topic introduced by M.R.N. Prasad) As it has become evident in recent years that the epididymis is not only an efferent duct but also plays an active role in sperm maturation, it represents a possible and perhaps easily accessible site of interference with male fertility. Recommendation:Ruetich on tithe epididymi_h hhvuld be intenhi&ed. The dofiorulucng ptiohityiztieanch been weke identi&ed: 1. Func.tionaI chaUactQhizativn 06 the epi~he.&xi! cti &ong the length 06 Zhe epkldymin. 2. ldenii&ktion 06 6 ecne,torry paoductn, ehpecia.!Xy photeiti . 3. Ahpeti 06 hpem Gotrage and &egukaXon od hpm .fxanhpoti. 4. The me&boRic phv@e 06 opehm thhvugh Rhc epididymin. 5. ldetidic&on vd huiLub.k avim& mud&. 6. The pvhhibmy 05 inXe.QeCng wtih epididymai? &ncCvn by atibodiQn. WHAT CAN WE LEARN FROM NATURE? (Topic introduced by R.V. Short) Nature uses seasonal breeding as a reversible contraceptive. In seasonally breeding male mammals,regression of spermatogenesis is always accompanied by regression in testicular endocrine function. Hence, although nature does not provide us with a model for dissociating LH and FSH secretion and their action on the testis, the annual switching on and switching off of testicular function may provide a valuable insight into the regulation of fertility. RecommendcuZon:Invtin-tigatioti i&o xhe ~untiati 04 ;the pine& giknd cOOhdinC&Oh o/j heo.honakiXy bhvuRd be encoutraged. In&Jaction b&xueen the pine& and the hypvLha&mo-ptily hyhtem, e.g. though meA?a~vtin, hhouLd be invenCgu.ted. The heChU%On ptitinh oh LH and FM in phanti o6 te,&iclLeat~ invo.Ction and tiecriudacence wii5! provide @t.thm ivLgha2 into -the mechan&m by which heUhOntiy ~2 eddeoted. cu a pvh&cb.te

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1981 VOL. 23 NO. 1

CONTRACEPTION

CAN THE STUDY OF MALE INFERTILITY LEAD TO AN APPROACH FERTILITY CONTROL ?

TO

(Topic introduced by H.G. Burger) Fertility control and infertility represent complementary areas for research. The observation that IO-15% of men with sperm counts persistently below 5 million per ml, father children within a year of presentation for infertility, indicates that approaches to male contraception will require that motility be substantially impaired in addition to sperm number. Ignorance of the aetiology in 50% of men with impaired fertility indicates the necessity for research into the underlying causes. Epidemiological studies seeking possible environmental factors deserve emphasis. Certain drugs, e.g. salazopyrine, have been recognized as impairing spermatogenesis. Rational approaches to treatment require definition of the causes. RecommendaLion: The pathogenen& &~&Zi,tq bhvuld be eRucLdcLted.

o6 bpvv~QneowLq

occwkng

~UJWA 04

ReqDRehned dhuqn nlwul!dbt inw~fion npe~~~a-tog~&eni~, a p&e&ti noz included

q&d doa ihe,& c,(zjec.& in the bcuttetry oh toxicoLogical

te~ti cut,tentiq pe,tdoruned. In addition, tutico&ogic& kepo/zti on ~xpe~211~ntde nubntancen &om pharunaceticde &LWLS should be made accennib& h0 khc& xhone kth an inhibiting expect on npe.tmaaZogentiA may bc identi&d and inwenfigated {uhthefi.

COOPERATION

AMONG RESEARCH

INSTITUTIONS

The institutions engaged in reproduction research in Europe are well suited to pursue intensive basic research in the male. However, closer cooperation between the institutions and contact between scientists would result in further improvements. Recommendation: The initiationoh exchange~elLow~kipn in hephvdutiocl .& genti& and in ma,& h&phodution h&Aeahch -in pticulah

henecv~ch

~3 kigkey denLtab& and Rhc EMRC nhoutd gharnrna in athe. immediate 6uturre.

be utged

to hti

up nuch phO-

ACKNOWLEDGMENT The participants are grateful to the Deutsche Forschungsgemeinschaft for the hospitality and for providing facilities for the meeting.

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1981 VOL. 23 NO. 1

CONTRACEPTION LITERATURE _______ (distributed before the meeting as background

reading)

Barfield, A, Melo, J, Coutinho, E, Alvarez-Sanchez, F, Faundes A, Brache,V, Leon, P, Frick, J, Bartsch, G, Weiske, W H, Brenner, P, Mishell, D, Bernstein, G and Ortiz, A. Pregnancies associated with sperm concentrations below 10 million/ml in clinical studies of a potential male contraceptive method, monthly depot-medroxyprogesterone acetate and testosterone esters. Contraception 20:121-127 (1979) Djerassi, C. Sounding board. The politics of contraception. The view from Beijing. Xew Engl J Med 303: 334-336 (1980) Breuer, H. European Medical Research Council's Recommendations of the Advisory Subgroup on Human Reproduction. Endokrinologie-Informationen 3: 99-108 (1979). Breuer, H. European Medical Research Council's Advisory Subgroup on Human Reproduction. _ Endokrinologie-Informationen 4: 210-213 (1980). Ford, WCL& Waites, GMH. The control of male fertility by 6-chloro-6-deoxysugars. Reprod Nutr Develop 20:163-171 (1980). Franchimont, P, Verstraelen-Proyard J, Hazee-Hagelstein, MT, Renard, Ch, Demoulin, A, Bourgzignon, JP and Hustin, J. Inhibin: From concept to reality. Vitamins and Hormones 37:243-302(1979). Lincoln, GA and Short, RV. Seasonal Breeding: Nature's contraceptive. Ret Progr Horm Res 36: l-52 (1980). Paulsen, CA, Leonard , JM and Bremner, WJ. The use of androgens, androgen-danazol or androgen-progestagen combinations for the regulation of male fertility. Proc. 6th Internatl Congr Endocrinol Melbourne, Australia, 1980 (in press). Sandow, J, von der Ohe, M and Kuhl H. LH-RH and its analogues in contraception. Proc 6th Internatl Congr Endocrino1 Melbourne, Australia, 1980 (in press). Sharpe, RM& Fraser, HM. hCG stimulation of testicular RH-like activity. Nature 287: 642-643 (1980).

LH-

Wickings, EJ and Nieschlag, E. Suppression of spermatogenesis over two years in rhesus monkeys actively immunized with follicle stimulating hormone. Fertil Steril 34: 269-274. (198 WHO Special Programme of Research, Development and Research Training in Human Reproduction, Evaluating the safety and efficacy of placental antigen vaccines for fertility regulation. Ciin exp. Immunol 33: 360-375 (1978). 10

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1981 VOL. 23 NO. 1