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Male fertility: a window on the health of this generation and the next

Published:September 24, 2019DOI:https://doi.org/10.1016/j.rbmo.2019.09.009
      In this issue of RBMO Martín-Calvo and colleagues (
      • Martín-Calvo N.
      • Mínguez-Alarcón L.
      • Gaskins AJ.
      • Nassan F.L.
      • Williams P.L.
      • Souter I.
      • Hauser R.
      • Chavarro J.E.
      Paternal preconception folate intake in relation to gestational age at delivery and birthweight of newborns conceived through assisted reproduction.
      ) provide clinical data showing that higher paternal pre conception folate intake was significantly associated with a longer gestation time. Previous studies in mice have shown that manipulation of paternal dietary folate was associated with increased birth defects and identified marked changes in the sperm epigenome associated with health of the offspring (
      • Lambrot R.
      • Xu C.
      • Saint-Phar S.
      • Chountalos G.
      • Cohen T.
      • Paquet M.
      • Suderman M.
      • Hallett M.
      • Kimmins S.
      Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes.
      ). Whilst the potential epigenetic mechanisms remain to be elucidated fully in animals and are, at best, unclear in humans, this study puts the focus of examination on the contribution of the male to overall health of future generations.
      The wider context of this study is important. After decades of being ignored, there is a considerable reawakening of interest in male infertility and male reproductive health. It is unclear why this is happening, but there are several possibilities, some of which are concerning. For example, the comprehensive meta-analysis by
      • Levine H.
      • Jorgensen N.
      • Martino-Andrade A.
      • Mendiola J.
      • Weksler-Derri D.
      • Mindlis I.
      • Pinotti R.
      • Swan S.H.
      Temporal trends in sperm count: a systematic review and meta-regression analysis.
      presents substantive evidence for a decline in sperm total counts of around 1.6% per year between 1973 and 2011. Further, accumulating data show larger than anticipated epigenetic contributions by the male to the health of the next generation. Although the nature and mechanisms of the epigenetic impact remain to be determined, this has stimulated a ‘deep dive’ into the fundamental role of the paternal gamete (
      • Bošković A.
      • Rando O.J.
      Transgenerational Epigenetic Inheritance.
      ). However, perhaps the most galvanising factor in broadening the significance of male reproductive health to a wider audience has been the revelation that impaired semen quality/male infertility is associated with shorter life expectancy and increased long-term morbidity (
      • Eisenberg M.L.
      • Li S.
      • Behr B.
      • Cullen M.R.
      • Galusha D.
      • Lamb D.J.
      • Lipshultz L.I.
      Semen quality, infertility and mortality in the USA.
      ;
      • Eisenberg M.L.
      • Li S.
      • Behr B.
      • Pera R.R.
      • Cullen M.R.
      Relationship between semen production and medical comorbidity.
      ;
      • Latif T.
      • Kold Jensen T.
      • Mehlsen J.
      • Holmboe S.A.
      • Brinth L.
      • Pors K.
      • Skouby S.O.
      • Jorgensen N.
      • Lindahl-Jacobsen R.
      Semen Quality as a Predictor of Subsequent Morbidity: A Danish Cohort Study of 4,712 Men With Long-Term Follow-up.
      ).
      Consequently, in a relatively short time there have been a number of calls for urgent action regarding male reproductive health, with some terming the situation a ‘crisis’ (
      • Skakkebaek N.E.
      • Jorgensen N.
      • A.M. Andersson.
      • Juul A.
      • Main K.M.
      • Kold Jensen T.
      • Toppari J.
      Populations, decreasing fertility, and reproductive health.
      ,
      • Skakkebaek N.E.
      • Rajpert-De Meyts E.
      • Buck Louis G.M.
      • Toppari J.
      • Andersson A.M.
      • Eisenberg M.L.
      • Jensen T.K.
      • Jorgensen N.
      • Swan S.H.
      • Sapra K.J.
      • Ziebe S.
      • Priskorn L.
      • Juul A.
      Male Reynolds-Wright, JJ & Anderson RA Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility.
      ;
      • Barratt C.L.R.
      • De Jonge C.J.
      • Sharpe R.M.
      ‘Man Up’: the importance and strategy for placing male reproductive health centre stage in the political and research agenda.
      ;
      • De Jonge C.
      • Barratt C.L.R.
      The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap.
      ;

      Ravitsky V. and Kimmins S. The Forgotten Men: Rising rates of male infertility urgently require new approaches for its prevention, diagnosis and treatment. In Press Biology of Reproduction ioz161,https://doi.org/10.1093/biolre/ioz161

      ). A fundamental underlying theme is that the incomplete understanding of the biology of spermatogenesis and associated pathologies has greatly limited the design of meaningful diagnostic tests and, as a consequence, effective clinical treatment strategies. A sentinel example of this is the conclusion by the World Health Organization (WHO) Evidence Synthesis Group (ESG) that "there was a remarkable paucity of high-quality data on which to base key recommendations and often simple questions did not have sufficient data available to be able to formulate ‘low’ let alone ‘strong’ recommendations” (
      • Barratt C.L.R.
      • Björndahl L.
      • De Jonge C.J.
      • Lamb D.J.
      • Osorio Martini F.
      • McLachlan R.
      • Oates R.D.
      • van der Poel S.
      • St John B.
      • Sigman M.
      • Sokol R.
      • Tournaye H.
      The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities.
      ). Given the fact that assisted reproductive technology (ART) is, globally, a highly innovative and successful billion-dollar health industry, these conclusions and the use of term ‘crisis’ are, perhaps, surprising. However, with the success of IVF/ICSI we have effectively bypassed the need to further understand spermatogenesis, sperm physiology and the role the spermatozoon has on the health of future generations (
      • Aitken R.J.
      Not every sperm is sacred; a perspective on male infertility.
      ), coining this dichotomy ‘the illusion of progress’ (
      • Barratt C.L.R.
      • De Jonge C.J.
      • Sharpe R.M.
      ‘Man Up’: the importance and strategy for placing male reproductive health centre stage in the political and research agenda.
      ;
      • Barratt C.L.R.
      A Dolce & Gabbana model in every ART clinic?.
      ). So, as more is discovered – characterised as ‘men live sicker and die younger’ (
      • Rovito M.J.
      • Leonard B.
      • Llamas R.
      • Leone J.E.
      • Talton W.
      • Fadich A.
      • Baker P.
      A call for gender-inclusive global health strategies.
      ) – there is simply an inadequate foundation of scientific knowledge on male reproduction and its connection with somatic health to help address simple questions such as ‘why and what is the connection?’, let alone ‘what can we do about it?’. Suffice it to say a comprehensive global strategic roadmap is required to ensure future progress in male reproductive health (
      • Barratt C.L.R.
      • De Jonge C.J.
      • Sharpe R.M.
      ‘Man Up’: the importance and strategy for placing male reproductive health centre stage in the political and research agenda.
      ;
      • De Jonge C.
      • Barratt C.L.R.
      The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap.
      ).
      What are some of the key components in a strategic roadmap?
      • 1
        Improving our basic understanding of the underlying biology is fundamental. The WHO ESG identified a key priority as ‘a better understanding of the cellular, molecular biochemical and genetic control mechanism(s) involved in the production of a human spermatozoon’. This knowledge is critical in order to formulate appropriate diagnostic assays with good predictive accuracy, develop effective therapy for the male and to understand how external factors, such as the environment, negatively or ­positively influence these processes.
      • 2
        Another roadmap component comes from growing evidence that the environment influences male reproductive function. The concept of the ‘testicular dysgenesis syndrome’ was developed after the discovery that important clinical pathologies in male reproductive function start in utero and can lead to significant health consequences for the man (
        • Skakkebaek N.E.
        • Rajpert-De Meyts E.
        • Main K.M.
        Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects.
        ;
        • Kilcoyne K.R.
        • Mitchell R.T.
        Effect of environmental and pharmaceutical exposures on fetal testis development and function: a systematic review of human experimental data.
        ). It is vitally important to understand and characterize the relationship of in-utero exposure and lifelong male reproductive pathology. Equally important and related, it is essential to examine the long-term health outcomes of the children born with or without ART from men with compromised fertility whatever the nature of the compromising agent(s) (genetic, environmental, occupational or iatrogenic).
      • 3
        A comprehensive male contraceptive portfolio is required. Modern reproductive science has not led to the development of any new methods for men to control their fertility. A ‘male pill’ remains strikingly absent from current contraceptive options despite evidence that women as well as men would ­welcome it (
        • Glasier A.
        • Anakwe R.
        • Everington D.
        • Martin C.W.
        • van der Spuy Z.
        • Cheng L.
        • Ho P.C.
        • Anderson R.A.
        Would women trust their partners to use a male pill?.
        ). Encouragingly, there are a range of innovative hormonal and non-hormonal approaches currently in development, a number of which are funded by the United States National Institute for Child Health and Human Development (
        • Reynolds-Wright J.J.
        • Anderson R.A.
        Male contraception: where are we going and where have we been?.
        ). In stark contrast is the almost ­complete absence of pharmaceutical industry involvement in male ­contraceptive development.
      • 4
        Remarkably there is no quantitative and detailed assessment of the economic impact of male reproductive health (
        • Barratt C.L.R.
        • De Jonge C.J.
        • Sharpe R.M.
        ‘Man Up’: the importance and strategy for placing male reproductive health centre stage in the political and research agenda.
        ). Compelling evidence has been presented in almost all other disciplines simply because an accurate economic assessment is fundamental to (i) underpin scientific arguments and funding strategies, and (ii) inform and modify future policy. A good example is that of weather forecasting. The World Bank report on funding of weather forecasting suggested that meeting a worldwide investment need of US$1.5-2.0 billion and ongoing annual costs of ~US$500 million could save 23,000 lives per year and would garner up to US$30 billion per year in global economic benefits (
        • Alley R.B.
        • Emanuel K.A.
        • Zhang F.
        Advances in weather prediction.
        ). These are powerful, hard-hitting analytical statements that undoubtedly focus the minds of policy makers. There is no such equivalent data for male reproductive health.
      • 5
        The economic impact of male reproductive health is intimately connected to its social impact. As mentioned earlier, in general, men ’live sicker and die younger‘ than women. Cardiovascular disease and metabolic disorders predominate in men relative to women. Explanations include that men generally have unhealthy lifestyle factors and are less motivated to seek healthcare advice and treatment. Social norms, and a man‘s own sense of masculinity, influence male participation in healthcare. Social norms can play a positive role in men seeking healthcare if, for example, a partner or family member suggests that a man has a routine physical examination and he also sees other men doing the same. If men, their partners and their families can be made more aware that routine male reproductive health assessment can provide early detection of potential chronic illness, disease and cancer, then men may feel more inclined to participate in a preventive healthcare program. To accomplish the kind of societal transformation ­necessary requires social media formats, educational systems and the medical community. For example, Healthy Male (http://www.healthymale.org.au) is an Australian government-funded program that provides accurate information and resources to raise awareness about male reproductive health and associated chronic disease.
      In summary, studies such as those by Martín-Calvo and colleagues (
      • Martín-Calvo N.
      • Mínguez-Alarcón L.
      • Gaskins AJ.
      • Nassan F.L.
      • Williams P.L.
      • Souter I.
      • Hauser R.
      • Chavarro J.E.
      Paternal preconception folate intake in relation to gestational age at delivery and birthweight of newborns conceived through assisted reproduction.
      ) are important in highlighting the role of the male in overall reproductive health, including effects on the offspring. In response to the paucity of meaningful progress in many areas of male reproductive health, and the potential challenges that we face, we have proposed the development of a worldwide Male Reproductive Health Initiative (
      • Barratt C.L.R.
      • De Jonge C.J.
      • Sharpe R.M.
      ‘Man Up’: the importance and strategy for placing male reproductive health centre stage in the political and research agenda.
      ;
      • De Jonge C.
      • Barratt C.L.R.
      The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap.
      ). Developing and executing this on a national – let alone a global – basis presents substantial challenges. Obtaining evidence is only the first step. Critically, for us to effect a strategy we need to marshal a whole series of skills to influence policy. As Chris Tyler concluded ‘for research to truly inform policy, it is not enough to hope that the stars will align. The stars need to be wrestled into position’ (
      • Tyler C.
      Wanted: academics wise to the needs of government.
      ). It is a salient point that of the 193 United Nations states, only one – Australia – has developed an effective national male reproductive health policy. It is time for other countries across the globe to rise to this challenge.

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