1 Resaerch needs in male reproductive health

At the Asia and the Pacific Symposium Intraregional Cooperation in Reproductive Health Research (Shanghai, China, 12-13 October, 1998) the Symposium participants endorsed the regional reproductive health research priorities and voted for the five top priorities as follows: 
* Reproductive health at the era of RTIs/STDs and HIV/AIDS (RTIs: reproductive tract infections; STDs: sexually transmitted diseases; HIV: human immuno-deficiency virus; AIDS: acquired immunodeficiency syndrome);
* Fertility regulation;
* Adolescent reproductive health and male involvement in reproductive health;
* Unsafe abortion and safe motherhood;
* Infertility including its prevalence, management and prevention^[1].

The recommendations of regional reproductive health research priority areas are based on the following common consensus: Asia is the region with the largest population and great diversity of reproductive health status, therefore, population problem remains the top priority of Asia in the coming years.

1.1 According to United Nations global population and demographic estimates and projections, the world's population will exceed 6 billion for the first time in 1999. Of this total, some 80 per cent will be living in developing countries^[2]. Asia has the highest population of all the regions-with two countries China and India accounting for more than 40 per cent of the world population. Other countries such as Indonesia, Pakistan and Bangladesh fall among the top ten populous countries of the world. Asia's population numbers are almost 3.6 billion and currently has an average annual growth rate of 1.4 per cent. While Asia's population growth rate is lower than those of Latin America and Africa, the vast continent has three-fifths of the world's people and thus adds more people to world population than any other continent. Population density is also the greatest in Asia, with more than 108 persons per square kilometre^[3].

If taking China as an example, more than 20 million babies are born annually, pushing up the national population total by 13 million people each year. According to current projections, China's population will reach 1.3 billion in 2000, 1.4 billion in 2010, 1.5 billion in 2020 and will not reach zero growth until the mid of next century when population will be about 1.6 billion. It suggests that China will have to add another 400 million more people into its already -1.2 billion-plus size before it can reach the stabilization of its population. Thus, even though the pursuit of a low birth rate is difficult, the control of population growth remains a long-term challenge of China's population policy. Today, approximately 200 million married couples in China have taken contraceptive methods and the contraceptive prevalence rate has reached 89.63%. The contraceptive mix in China in 1997 was sterilization 49.2% (male 9.2%, female 40.0%), intrauterine devices (IUD) 43.4%, condom 4.0%, oral pills 2.1%, sub-dermal implantation 0.5%, spermicides 0.2% and others 0.6%. It is evident that the majority of currently-used contraceptives are for women, so there is an urgent need to develop new male fertility regulation methods.

1.2 Whereas women bear most of the burden of reproductive ill-health, men's involvement and cooperation is fundamental in the quest for improved reproductive health for both. Men can put themselves and women at risk of disease by their sexual practices and their behaviour towards prevention and care. As a result of increased understanding of the complex nature of reproductive health and gender dynamics, male reproductive health, their active participation and sharing of responsibility for women's reproductive health, have assumed a new reality in the 1990's. The 1994 Cairo International Conference on Population and Development affirmed the need for ensuring male participation and responsibility in reproductive health by identifying strategies that create an enabling environment.

Reproductive health research should identify the role and needs of men in reproductive health, establish acceptable options for regulation of male fertility and be responsive to their specific reproductive and sexual dysfunction problems. In addition, reproductive health research should inform decisions on policy and establish relevant care and prevention strategies as well.

The countries of Asia are characterized by extreme diversity in the status of reproductive health. In some countries in the region, fertility has declined to below replacement levels, whereas in others it remains high. The largest number of maternal deaths take place in South Asia. Both maternal mortality and infant mortality continue to be major problems in the region. Rapid demographic transition and industrialization is changing family patterns. The globalization of the world economy and the demand for cheap labour in the rapidly industrializing countries has changed migration and many of the final destinations for the migrant workers are also with Asia/Pacific. This region is also infested with the problem of human trafficking which involves a racket of prostitution, sex-tourism and sale of body parts. Later female age at marriage, a decline in the age at menarche and a decline in the age difference between spouses raise important policy issues relating to the provision of reproductive health services for unmarried adolescents and young adults^[4].

One-fifth of the world's population-over one billion people is between the ages of 10 and 19 years. Every year nearly 15 million young women under the age of 20 become mothers. Surveys in Asian developing countries show that between 9-48 per cent of the pregnancies and births to women under age 20 are mistimed or unwanted. For the adolescent, pregnancy is associated with increased risk of numerous pregnancy-related complications and higher maternal mortality. Adolescents are at greater risk of STDs because of factors such as their sexual behaviour and physiological maturation of the genital tract in addition to poor quality services from often inadequately trained health care providers. In most Asian countries, up to one-third of STDs occur among adolescents below the age of 20 years.

1.3 The global population aged over 65 years is increasing by 750 000 a month. A child born in Japan today can expect to live to 80 years old. Increases in the older population by up to 300 per cent are expected in many Asian developing countries within the next 30 years. There will be 274 million people over the age of 60 years in China alone more than the total present population of the United States^[5]. Aging, including reproductive aging, is a normal dynamic process. It is not a disease. However, many diseases such as osteoporosis, prostate and breast cancers and Alzheimer disease arise at an advanced age, and the risk increases steeply with age. While aging is inevitable and irreversible, the chronic disabling conditions that often accompany it can be prevented or delayed, not only by medical interventions but more effectively by social, economic and environmental interventions. An aged population is a basically new feature in the history of humanity, the implications of which are as yet incompletely understood. Hence, the soaring elderly population will raise major social, economic and ethical issues worldwide and may strain to the limit of the ability of health, social and economic infrastructures of many countries in Asia.

1.4 RTIs, including STDs, have been a neglected area in public health in many Asian countries, in spite of overwhelming evidence of their impact on health, particularly that of women, young people and neonates. It is estimated that there were 150 million cases of curable STDs among adults in WHO South-East Asia Region in 1995. In many of Asian countries, STDs rank among the top five conditions for which both men and women seek health care services. Multiple sex partners, the primary risk factor for STDs and RTIs, are far more common among men than women. Furthermore, men comprise the majority of the relatively small portion of STDs cases treated in the formal health sector.

The epidemic of STDs and RTIs in the developing countries is characterized by high incidence and prevalence, a high rate of complications, the problem of antimicrobial resistance, and the increased risk of HIV infection. In addition, a major cause of maternal deaths is post-abortion, postpartum and postnatal infections due to RTIs associated with STDs.

The HIV/AIDS pandemic reached the Asia relatively late, but has spread rapidly in the last few years. Infection rates have now begun to increase in the general population in addition to those in high-risk behaviour groups. It is estimated that by the end of the century, 8-10 million men, women and children are likely to become infected with HIV within WHO South-East Region, accounting for over 25 per cent of the global cumulative infections. Generally speaking, the epidemic of HIV/AIDS in Asia is still at a relatively early stage and the situation demands urgent control measures that need to be sustained.

1.5 Infertility is as much a reproductive health issue as the inability to avoid childbearing when it is not wanted. Infertility affects both men and women of reproductive age. It is estimated that 8-12 per cent of all couples experience some form of infertility during their reproductive lives, affecting at least 50 million people worldwide. While for a small proportion of couples (less than 5 per cent) the underlying causes of infertility are attributable to anatomical, endocrinological, genetic and immunological factors, problems of infertility in women arise primarily because of untreated infections, frequently linked to pelvic inflammatory disease, especially STDs. Little information is available about male infertility resulting primarily from low sperm count, often caused by untreated genital infections.

The infertile couple is subject to a variety of family and social pressures and conflicts. In many Asian countries, involuntary infertility represents a social stigma usually, not infrequently unfairly, borne by the women. Failure to bear children is an accepted basis for divorce in many Asian cultures.

In several parts of Asia, infertility services do not exist, and accessibility and availability of general health services are very limited as well. To meet existing demand, emphasis has to be put on prevention and management of infertility, starting at the primary health care level, supported by adequate and efficient referral systems.

1.6 Existing data suggest temporal changes in male reproductive function, characterised by declining semen quality and increased abnormalities of the male genitalia, including testicular cancer, hypospadias and cryptorchidism over the past 50 years^[6].

Even though semen quality and virilization show great individual variation in the normal population, it is uncertain whether this can partly be ascribed to differences in the level of reproductive hormones or other environmental factors. It has been hypothesized that environmental exposure to estrogenic chemicals (or endocrine disrupters) has the potential to disrupt the endocrine system of humans^[7]. Among these are compounds that include pesticides, industrial chemicals, synthetic products and some metals. Exposure to toxicants prior to sexual maturation can also affect reproductive capacity. Besides, the behavioural factors, including smoking, alcohol intake, narcotic and drug consume, exposure to high temperature and indulging in sensual pleasures may also do harm to one's semen quality. Stress is thought to be associated with semen quality too.

Asia is the world's most polluted and environmentally degraded region. The range of environmental problems is huge, from the degradation of rural land to the pollution and congestion of the region's megacities. At first sight, population growth and environmental degradation seem closely linked. Closer inspection, however, reveals that things are not that simple. How a population behaves is more important than how fast it grows. Slower population growth does not necessarily slow down the rate of environmental degradation. The combination of population density and poverty is more likely to imperil the environment, and in the presence of institutional failures it is more likely still. It has been suggested that the research on environmental and occupational  hazards to male and female reproductive health in Asian countries is one of the urgent needs.

Population is generally considered an integral component of government planning efforts, with most countries in Asia trying to integrate population factors into their development plans. The chief constraints include the lack of political commitment and limited human and financial resources. Moreover, the 1997/98 financial and economic crisis affecting a number of Asian countries continues to compound the challenges.

Base on the above analysis, the research needs in inventory of male reproductive health in Asia comprise at least the following 6 issues: 
* Male fertility regulation; 
* Male involvement in reproductive health especially for male adolescents; 
* Male reproductive aging; 
* Male reproductive health at the era of RTIs/STDs/ HIV; 
* Male infertility and subfertility; 
* Environment and male reproductive health.

2 Male reproductive health research agenda and priority areas

Research that addresses male reproductive health should assist in the development of reproductive health programmes and policy; identify and test new leads in male contraceptive technology; establish effective male involvement initiatives which are likely to have a positive impact on the reproductive health of men and women; guide the allocation of health care resources to ensure cost-effectiveness of interventions; generate new knowledge, develop diagnostic technology in reproductive health and offer optimal treatment/care regimens.

In considering the needs and demands of male reproductive health research, the following 6 research topics are recommended as the priority research areas: 
* Male contraceptive technology; 
* Male reproductive health behaviour and male adolescent reproductive health; 
* Male reproductive aging including male menopause and other diseases; 
* Male RTIs, STDs, HIV/AIDS; prevalence, management and prevention of male infertility; 
* Environment and semen quality and other male reproductive problems.

2.1 Male contraceptive technology

It is now generally accepted that the currently available methods of fertility regulation are inadequate to meet the varied and changing personal needs of couples at different times in their reproductive lives and in the widely different geographical, cultural, religious and service settings that exist around the world. Contraception options for men are extremely limited. By far the most common male contraceptive methods in use today are the condom, vasectomy and withdrawal. Two factors with significant impact on the field of fertility regulation that necessitated a careful review of priorities in contraceptive research and development were the increasing attention being paid to the perspectives of users and the paradigm shift from the narrow focus on family planning to the broader, holistic concept of reproductive health. Many of the changes in the fertility regulating environment have been the result of the HIV epidemic and the increase in STDs and RTIs and have resulted in calls for methods that not only protect against pregnancy but also protect against STDs, so-called `dual protection'. Both new male methods and barrier methods are among the high-priority research and development areas.

The ideal male contraceptive method should be safe, effective and reversible and should not have an effect on libido. In addition, it should be self-administered with little training and require neither elaborate surgical procedures nor prolonged periods of either abstinence or alternative contraceptive techniques to be effective. The WHO Consultative Meeting on Setting the Agenda for Fertility Regulation Technology Research in Reproductive Health for the Next Decade (Geneva, Switzerland, December 1996) identified the following two male contraceptive technologies as high priority leads^[8]:
* A three-monthly injectable levonorgestrel butanoate plus testosterone buciclate; or testosterone buciclate alone
A number of studies in animals and men have shown that the administration of androgen alone, combinations of gonadotrophin-releasing hormone and androgen, and progestogen and androgen combinations, can suppress gonadotrophin secretion and spermatogenesis either completely to azoospermia or to a sufficiently low level of oligozoopsermia to render the treated individuals infertile. Furthermore, discontinuation of treatment leads to full recovery of gonadotrophin secretion and spermatogenesis and return of fertility. The objective of ongoing studies is to establish the minimal doses of the progestogen required to ensure consistent inhibition of spermatogenesis and of the androgen required for testosterone replacement, and to evaluate contraceptive efficacy, reversibility and user acceptability of the approach.
* Non-surgical vas occlusion(silicone plugs)
It will be a reversible method by occluding the vas deferens that does not require surgery for application nor complicated microsurgery for reversal. The objective of ongoing studies is to assess the safety (local tolerableness and side-effects), contraceptive efficacy; reversibility (ease of removal of the silicone plugs); and the return to fertility after removal of the plug.

In addition to the endocrine feedback loops referred to above, there are many cellular and molecular events in the male reproductive tract that are unique to that tract, which could be considered as the potential targets for male contraceptive development^{[9, 10]}: 
* Inhibition of FSH secretion and/or FSH action;
* Control of meiosis of spermatocytes; 
* Inhibition of acrosome and tail formation; 
* Selective manipulation of sperm gene expression; 
* Alteration of sperm surface proteins during spermato-genesis and post-testicular development; 
* Interruption of sperm maturation in epididymis; 
* Regulation of the inhibition of immune reactions by sperm; 
* Induction of premature acrosome reaction; 
* Inhibition of sperm-egg interaction; 
* From an empirically discovered male infertility agent to the protein target in germ cells, and subsequently to further development of the antifertility agent; or the most straightforward strategy to identify lead-compounds is to first identify the target protein(s) and then to proceed from target to agent.

Further developments in this field can come only through interdisciplinary cooperative interactions among scientists in academia and in industry, and by prioritizing allocation of resources sufficient to achieve the goals.

2.2 Male reproductive health behaviour and male adolescent reproductive health

Whereas the process of reproduction entails mutual responsibility, men's participation in reproductive health is mostly negligible and neglected in many Asian developing countries. Thus, research that addresses the behaviour of men is seen as essential. In societies where men are the key decision-makers within the home and community, they can also be key advocates of, or opponents to, contraceptive use and/or reproductive health decisions, with personal, partner, community and demographic consequences.

Research in this field should identify men's roles and responsibility in reproductive health, giving attention to difference by culture, age, economic position, occupation and residence, including
* how men define their reproductive health and rights;
* men's views on sexuality and reproduction;
* male sexual behaviour, the level of responsibility they have for the consequences of sex for themselves and their sexual partners;
* men's needs and preferences for fertility regulating methods and services;
* men's involvement in determining contraceptive choice, continuation and discontinuation;
* men's perceptions of the risks and benefits of the various fertility regulating methods;
* men's understanding of the risks women face during pregnancy, childbirth, postpartum period and induced abortion;
* men's recognition of the sequelae associated with RTIs/STDs/HIV/AIDS in women and in themselves;
* men's perspectives on causes of infertility in women and men.

Research in this field should suggest ways of reaching men with the view to pxositively influencing their reproductive health care seeking behaviour, including participation in fertility regulation, the practice of safe sex, the early seeking of clinical care for diagnosis and treatment of STDs/RTIs, men's support for maternal health and prevention of unwanted pregnancies and unsafe abortion.

Research in this field should identify the best approaches for reaching the young men, especially the male adolescents. It is important to influence social norms before they take hold. As men become adults, behaviour patterns, values and susceptibility to peer pressure become difficult to change. Peer pressure, sex role stereotypes and misinformation play important parts in determining the sexual behaviour of male adolescents. Though less likely to be targeted in reproductive health services, young men are more likely than young women to be sexually active, to have multiple partners and to begin sexual activity early. Programmes carried out towards preventing reproductive ill-health must reach out to young people, based on their special needs, as identified through research. In a word, strategies to improve reproductive health must involve men to be successful, taking into account their roles and responsibility, needs and concerns in sexuality and reproduction.

2.3 Male reproductive aging including male meno-pause and other diseases

Female become hypogonadal and infertile with the menopause. Men do not experience an abrupt decline in fertility and endocrine gonadal function. In human male, aging is accompanied by a gradual decrease in the plasma levels of testicular and adrenal androgens, focal atrophy of the seminiferous epithelium, and increased prostate growth. In Asia, there are more than 200 million men between the ages of 40 and 55 who are now going through so-called male menopause (also called viropause or andropause). In less than 25 years, the number of men going through male menopause will grow to approximately 400 million in Asia.

Male menopause is a physical condition, similar to that suffered by women and, likewise, brought on by changing hormone levels (in particular, of the key male hormone, testosterone)^[11]. A decline in testosterone levels affects bone, joint, muscle, arteries and veins and almost every major organ system, because they all require testosterone to maintain optimum function. The most common sexual symptoms of male menopause include: reduced interest in sex, increased anxiety and fear about losing sexual potency, impotence and other sexual dysfunction problems. These changes affect all aspects of man's life.

Male menopause is thus a physical condition with psychological, interpersonal, societal and spiritual dimensions. In addition, benign prostatic hyperplasia and prostatic cancer also often arise at an advanced age.

Several important research questions have been raised in this research area:  
* How do men understand the physical and psychological consequences of aging and the symptoms of the transition to male menopause in different societies?
* What are the attitude of health providers towards male aging and male menopause and care for these men?
* The growing use of hormone replacement therapy and the adoption of new dietary and life patterns among the increasing number of men reaching male menopause in developing countries warrant a comprehensive study of their effects on sexual and social well being.

In addition, there are several important biomedical research topics that should be addressed:
* The impact of decline in androgen levels on bone, muscle, sexual function, mood and other physiological functions of men;
* Risks of androgen therapy, especially the possibility of promoting the development of prostatic cancer and benign prostatic hyperplasia;
* Develop and promote best practices for the diagnosis and management of impotence and other sexual dysfunction of men in low-resource settings.

2.4 Male reproductive tract infections, sexually transmitted diseases and HIV infection

At the Asia and the Pacific Symposium Intraregional Cooperation in Reproductive Health Research, `reproductive health at the era of RTIs/STDs and HIV/AIDS' was recognized as the top research priority area. RTIs are responsible for a significant proportion of gynaecological morbidity and maternal mortality and, in particular, both Chlamydia trachomatis and Neisseria gonorrhoeae cause salpingitis and pelvic infection resulting in tubal occlusion, pelvic adhesions, infertility and chronic pelvic pain. The burden of disease is particularly severe in South and Southeastern Asian developing countries and especially in women^[12]. However, STDs and RTIs are often easily detectable in men than women and, with prompt and complete treatment, complications in self and female partner could be avoided.

There are several research priorities in this field:
* Document the prevalence and social and behavioural determinants of STDs and consequences of STDs and non-STDs RTIs of men among different subgroups in Asian developing countries;
* Develop and promote cost-effective interventions (for example, male and female condoms or other dual protection methods) for RTIs, STDs and HIV prevention; 
* Better define characteristics of male individuals in high-risk groups for more effective screening and/or case finding including core group high frequency transmitters of RTIs;
* Improve availability and access to core group transmitters to culturally appropriate and effective counselling, diagnosis and management for both prophylaxis and treatment.

2.5 Prevalence, management and prevention of male infertility

The importance of infertility as a health and as a social problem can be judged from the perspectives of the couple, the health care providers and the society at large. The research programme in this field should focus on defining the causes and prevalence of male infertility and on improving male infertility care services in Asian developing countries with the following main research strategies:
* Document the magnitude, causes and social conse-quences of male infertility in a variety of populations in Asia;
* Develop and promote best practices for the diagnosis and management of male infertility in low-resource settings;
* Identify and promote cost-effective interventions for prevention of male infertility.

2.6 Environment and semen quality and other male reproductive problems

Although quite a few studies point out that the semen quality has deteriorated over the past 50 years in some western countries, these findings have been contested by some authors, who suggested that these studies may have been flawed by inappropriate research methods or that the differences could be geographical, and nearly no systematic and well-designed studies were conducted in developing countries in Asia, Africa and Latin America. In addition, the hypothesis that men had impaired fertility because of exposure to environmental pollution has had no scientifically-sound evidence yet. The research on environmental and occupational hazards to semen quality and other male reproductive health problems could be considered as one of the research priority areas in male reproductive health.

References

[1] UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development & Research Training in Human Reproduction. Annual Technical Report 1998 (in press) World Health Organization, Geneva, Switzerland, 1999. 
[2] United Nations Population Fund (UNFPA). A five-year review of progress towards the implementation of the programme of action of the International Conference on Population and Development. A background paper for The Hague Forum, The Hague, Netherlands, 1999 Feb 8-12.
[3] Engelman R. Why Population Matters. Population Action International, Washington, 1997.  
[4] Asian Development Bank. Emerging Asia: Changes and Challenges. An Asian Development Bank Publication, 1997. 
[5] World Health Organization. The World Health Report 1998, Life in the 21st Century: A Vision for All World Health Organization, Geneva, Switzerland, 1998.
[6] Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years. Br Med J 1992; 305: 609-13.
[7] Stone R. Environmental estrogens stir debate. Science 1994; 265: 308-10.
[8] UNDP /UNFPA/WHO/World Bank Special Programme of Research, Development & Research Training in Human Reproduction. Annual Technical Report 1997. World Health Organization, Geneva, Switzerland, 1998.
[9] Hamilton DW, Saling DW. Male Methods. Appendix B: Contraceptive Research and Development. Institute of Medicine, National Academy of Sciences, USA, 1996.
[10] Wang YF, Zhu YF. Basic science research leads toward novel male fertility regulation approaches. Chin J Androl 1998; 12: 177-82.
[11] Tenover J. Androgen deficiency in aging men. In: Waites GMH, Frick J, Baker GWH, editors. Current advances in andrology, Salzburg, Austria, 1997 May 25-29. Bologna: Monduzzi Editore; 1997. p 285-8.
[12] Rowley J, Berkley S. Sexually transmitted diseases. In: Murray CJL, Lopez AD, editors. Health dimensions of sex and Reproduction: the global burden of sexually transmitted diseases, HIV, maternal conditions, perinatal disorders, and congenital anomalies. Cambridge: Harvard University Press; 1998. p 19-110.