Research resourcesPartnerships offer promise indeveloping systemic methodsof male fertility regulationArticle by Kirsten M Vogelsong (pictured), Henry L Gabelnick <strong>and</strong> Eberhard NieschlagIn response <strong>to</strong> <strong>the</strong> Programme of Action approved by 179countries at <strong>the</strong> International Conference on Population <strong>and</strong>Development (ICPD) held in Cairo in 1994, an increasingemphasis is being placed on free reproductive choice, genderequity <strong>and</strong> greater male participation in sexual <strong>and</strong> reproductive<strong>health</strong> <strong>and</strong> family planning programmes worldwide. Onemeans by which <strong>to</strong> promote partnerships with men in familyplanning is through increasing options by <strong>the</strong> development ofsafe, effective <strong>and</strong> acceptable methods of contraception formen <strong>to</strong> use.Men around <strong>the</strong> world, in a variety of countries <strong>and</strong> settings,are aware of <strong>the</strong> existence <strong>and</strong> use of methods of familyplanning; many support <strong>the</strong>ir sexual partners in using <strong>the</strong>family planning methods of <strong>the</strong>ir choice. On a global level, of<strong>the</strong> more than one billion married women of reproductive age,approximately 60% are using any method of family planning.Most of <strong>the</strong>se women report using methods that <strong>the</strong>y<strong>the</strong>mselves initiate, with fewer couples relying on <strong>the</strong> use ofcondoms (about 5%) or vasec<strong>to</strong>my (about 3.5%) <strong>to</strong> planwhe<strong>the</strong>r <strong>and</strong> when <strong>to</strong> have children. However, <strong>the</strong>se numberspresent a limited view of male participation in contraceptivebehaviour, since traditional methods like rhythm <strong>and</strong>withdrawal (each relied upon by approximately 3% of marriedwomen of reproductive age) also require <strong>the</strong> male partner’scooperation. Significant country <strong>and</strong> regional differences in <strong>the</strong>rates of use of <strong>the</strong>se methods do exist, with vasec<strong>to</strong>my,condoms <strong>and</strong> withdrawal all used by a higher proportion ofcouples in more developed regions of <strong>the</strong> world 1 .At least 120 million couples around <strong>the</strong> world do not use anymethod of family planning, despite a desire <strong>to</strong> avoid apregnancy. This unmet need for family planning is especiallyapparent in <strong>the</strong> developing world <strong>and</strong> is probably symp<strong>to</strong>maticof a variety of shortcomings in <strong>the</strong> available <strong>health</strong> care systems(lack of knowledge about contraception, lack of services ortrained medical personnel, limited supplies) as well as <strong>the</strong>limitations of <strong>the</strong> methods <strong>the</strong>mselves including real orperceived <strong>health</strong> effects, <strong>and</strong> personal <strong>and</strong> cultural objections <strong>to</strong><strong>the</strong> use of existing contraceptive technologies.In early 2007, <strong>the</strong> All Party Parliamentary Group onPopulation, Development <strong>and</strong> Reproductive Health of <strong>the</strong>United Kingdom launched its report Return of <strong>the</strong> PopulationGrowth Fac<strong>to</strong>r – Its Impact Upon <strong>the</strong> Millennium DevelopmentGoals. The evidence ga<strong>the</strong>red <strong>and</strong> reported by this groupdemonstrates that it is essential <strong>to</strong> address <strong>and</strong> meet <strong>the</strong>increasing needs for family planning worldwide, in order <strong>to</strong>achieve <strong>the</strong>se international goals. The recommendationsinclude promotion of gender equality <strong>and</strong> sustained provision ofcontraceptive commodities 2 .The World Bank, <strong>to</strong>o, has recently presented updatedevidence linking population <strong>and</strong> development <strong>and</strong> has againcommitted <strong>to</strong> working with government, country <strong>and</strong> UnitedNations partners <strong>to</strong> address family planning issues at <strong>the</strong>highest levels of country policy-setting 3 .Traditionally, women have assumed <strong>the</strong> responsibility forfamily planning. However, many women do not have access <strong>to</strong><strong>the</strong> most effective methods, find <strong>the</strong>ir side-effects in<strong>to</strong>lerable, orwould simply prefer <strong>to</strong> share this role with a partner. For <strong>the</strong>irpart, a significant proportion of men report a willingness <strong>to</strong> usea method <strong>to</strong> regulate <strong>the</strong>ir own fertility in repeated surveys invarious countries <strong>and</strong> settings, with <strong>the</strong> most recent researchconducted in Europe, <strong>the</strong> USA, Latin America <strong>and</strong> Indonesia 4<strong>and</strong> <strong>the</strong> UK, China <strong>and</strong> South Africa 5 . The Programme ofAction from <strong>the</strong> ICPD calls for increased research <strong>to</strong> developmale methods, in order <strong>to</strong> better meet individuals’ needs <strong>and</strong>rights in reproductive <strong>health</strong> 6 .For more than three decades, <strong>the</strong> public sec<strong>to</strong>r has beenworking in collaboration with major pharmaceuticalcompanies, small independently-owned companies, not-forprofi<strong>to</strong>rganizations <strong>and</strong> academic scientists on a researchagenda geared <strong>to</strong>wards <strong>the</strong> development of safe, effective <strong>and</strong>acceptable methods <strong>to</strong> regulate male fertility. Since familyplanning programmes that offer a wider variety of methods aremore successful in meeting <strong>the</strong> contraceptive needs of couples,making a method available for men <strong>to</strong> use could address <strong>the</strong>needs of a significant number of couples who are not using anymethod, or who are unsatisfied with <strong>the</strong> methods available.Successfully regulating male fertility can be achieved byexploiting one or more of several aspects of male reproduction,as long as sperm are prevented from <strong>reach</strong>ing an egg in awoman’s reproductive tract. Following <strong>the</strong> resurgence incondom promotion associated with <strong>the</strong> public <strong>health</strong>emergency of <strong>the</strong> HIV/AIDS p<strong>and</strong>emic, improved condomshave been developed, using innovative designs <strong>and</strong> alternativematerials, with <strong>the</strong> goal of increasing acceptability <strong>and</strong>,<strong>the</strong>refore, use 7,8 .In addition, researchers <strong>and</strong> small companies have128 ✜ Global Forum Update on Research for Health Volume 4
Research resourcesinvestigated <strong>the</strong> vas deferens as a site of male contraception,particularly <strong>to</strong> develop alternative approaches <strong>to</strong> malesterilization 9 . The goal of this line of research is <strong>to</strong> makeavailable, effective methods associated with less tissue trauma,faster recovery, <strong>and</strong> fewer side-effects with, in some cases,improved probability of reversal. The VasClip ® was approved formarketing in <strong>the</strong> USA in 2002, but is not widely available inthat country <strong>and</strong> not available at all outside of <strong>the</strong> USA.Research on vasec<strong>to</strong>my techniques has provided informationon <strong>the</strong> most successful surgical approaches 10 <strong>and</strong> studies ono<strong>the</strong>r physical or chemical devices <strong>to</strong> block <strong>the</strong> vas are ongoing.To date, no method is more effective, safer or more acceptablethan <strong>the</strong> no-scalpel vasec<strong>to</strong>my technique, developed in Chinain 1974 <strong>and</strong> introduced outside of China in <strong>the</strong> mid-1980s.A novel approach <strong>to</strong> male contraception is through hormonalmanipulation of <strong>the</strong> process of sperm production. Datacollected over <strong>the</strong> last 20 years have demonstrated <strong>the</strong> proof of<strong>the</strong> concept of using steroid hormones <strong>to</strong> disrupt spermproduction in men. Exogenous <strong>and</strong>rogens were initially used <strong>to</strong>suppress <strong>the</strong> hypothalamic engine of sperma<strong>to</strong>genesis 11,12 .Long-acting <strong>and</strong>rogens offer a viable method of male fertilityregulation in Chinese populations 13 ; a regimen of monthlyinjections of tes<strong>to</strong>sterone undecanoate is currently beingevaluated in a Phase III safety <strong>and</strong> efficacy trial in 10 centresin China, supported by <strong>the</strong> World Health Organization, <strong>the</strong>Chinese Government <strong>and</strong> <strong>the</strong> drug manufacturer. Combinedprogestin <strong>and</strong> <strong>and</strong>rogen regimens have been investigated asbeing more effective, <strong>and</strong> possibly safer, for a global audience 14<strong>and</strong> may very well offer <strong>the</strong> best opportunity for a marketablemale contraceptive product in <strong>the</strong> medium-term future 15 .The World Health Organization, in partnership with <strong>the</strong> USAbasedCONRAD program, is currently working <strong>to</strong> initiate aninternational, multicentre Phase II clinical trial of <strong>the</strong> safety <strong>and</strong>contraceptive efficacy of one such combined hormonalregimen. In small preliminary studies, injections of <strong>the</strong>progestin norethisterone enanthate, when given <strong>to</strong>ge<strong>the</strong>r withinjections of <strong>the</strong> long-acting <strong>and</strong>rogen tes<strong>to</strong>steroneundecanoate (both provided by Schering AG, now BayerSchering Pharma), produced profound decreases in spermoutput in men with no serious side effects 16,17,18 . The plannedstudy will enroll 400 couples in eight countries <strong>to</strong> test <strong>the</strong>efficacy of <strong>the</strong> regimen when administered every eight weeks;we expect <strong>the</strong> pregnancy rate <strong>to</strong> be no greater than <strong>the</strong> failurerate of combined oral contraceptives. Because each of <strong>the</strong>compounds is widely marketed, we do not anticipate anyserious risks or side-effects. If enrolment can begin before <strong>the</strong>end of 2007, as planned, final study results should beavailable in 2011. Keeping in mind <strong>the</strong> service delivery aspec<strong>to</strong>f product development, if <strong>the</strong> results of <strong>the</strong> planned study arepromising, <strong>the</strong> study sponsors are interested <strong>to</strong> develop acombined, single injection for delivering <strong>the</strong> steroid hormones<strong>and</strong> will test a novel formulation in a follow-on clinical trial, iffunds can be raised.Only a h<strong>and</strong>ful of pharmaceutical companies have beenactively engaged in contraceptive research <strong>and</strong> development;even fewer have supported research on methods <strong>to</strong> regulate malefertility. In 1997, investiga<strong>to</strong>rs researching hormonal regimens ofcontraception for men urged <strong>the</strong> pharmaceutical industry <strong>to</strong>become actively involved in this exciting <strong>and</strong> promising field ofwork 19 . Around this time, <strong>the</strong> large European companies Organon(Oss, <strong>the</strong> Ne<strong>the</strong>rl<strong>and</strong>s) <strong>and</strong> Schering AG (Berlin, Germany)initiated clinical research on hormonally-based methods offertility regulation for men <strong>and</strong>, in 2002, <strong>the</strong> two companieslaunched a collaborative initiative <strong>to</strong> conduct a clinical trial <strong>to</strong>explore <strong>the</strong> safety <strong>and</strong> efficacy of a combined hormonal methodof male contraception. Each company also planned <strong>to</strong> pursueindependent avenues of research related <strong>to</strong> male fertilityregulation, as did Wyeth (Madison, New Jersey, USA).Schering’s not-for-profit arm, <strong>the</strong> Ernst Schering Foundation,in collaboration with <strong>the</strong> Rockefeller Foundation, had alreadymade substantial investments in basic science research related<strong>to</strong> regulation of <strong>the</strong> male reproductive system, in particularpost-testicular activity. The AMPPA (application of molecularpharmacology for post-testicular activity) network, establishedin 1997, proved so successful in identifying new targetssuitable for drug discovery in male contraception that <strong>the</strong>project was renewed in 2002, with CONRAD replacing <strong>the</strong>Rockefeller Foundation as funding partner for <strong>the</strong> AMPPA-II(application of molecular pharmacology for post-meioticactivity) network. AMPPA-II supported work in identifying novelepididymal <strong>and</strong> testicular targets that could be exploited in <strong>the</strong>development of male contraceptives; several approaches wereselected for continued support <strong>to</strong> evaluate target validation.The significant corporate commitment <strong>to</strong> research <strong>and</strong>development of a method for male use in contraception was asignal of confidence in <strong>the</strong> potential market for such a product.In a collaborative process, pharmaceutical companies,investiga<strong>to</strong>rs <strong>and</strong> donors have proposed recommendations forregula<strong>to</strong>ry review <strong>and</strong> approval of a potential method of malefertility regulation 20 .Despite <strong>the</strong>ir combined efforts <strong>and</strong> achievements, however,<strong>the</strong> collaboration between Schering <strong>and</strong> Organon came <strong>to</strong> aclose following completion of <strong>the</strong> clinical trial in 2006, <strong>and</strong> all<strong>the</strong> large companies <strong>and</strong> <strong>the</strong>ir subsidiaries have phased out<strong>the</strong>ir programmes of research <strong>and</strong> development on male fertilityregulation, for various reasons. Both Schering <strong>and</strong> Organonwere bought by larger pharmaceutical companies that realigned<strong>the</strong>ir respective research portfolios. Even <strong>the</strong> AMPPA-IInetwork has been terminated, due <strong>to</strong> lack of funding <strong>and</strong> <strong>the</strong>change in corporate ownership at Schering. This puzzlingtransformation of research priorities in <strong>the</strong> private sec<strong>to</strong>r hasmade <strong>the</strong> efforts of <strong>the</strong> public sec<strong>to</strong>r <strong>and</strong> research institutionsparamount in <strong>the</strong> search for new methods of family planning <strong>to</strong>meet couples’ needs.The United States National Institute of Child Health <strong>and</strong>Human Development, part of <strong>the</strong> National Institutes of Health,has established a Cooperative Research Program on MaleFertility Regulation, which supports basic, applied <strong>and</strong> clinicalresearch. The Institute funds research on <strong>to</strong>pics that arerelevant <strong>to</strong> both short-term <strong>and</strong> long-term productdevelopment. This research initiative may very well lead <strong>to</strong> <strong>the</strong>development of a non-hormonal method of male fertilityregulation, with targeted action <strong>and</strong> few side-effects, which willbe an essential component of <strong>the</strong> range of methods required <strong>to</strong>meet <strong>the</strong> contraceptive needs of <strong>the</strong> next generation of youngpeople entering <strong>the</strong>ir reproductive years.Global Forum Update on Research for Health Volume 4 ✜ 129