What has happened to human fertility?

Human Reproduction, Vol.25, No.2 pp. 295–307, 2010 Advanced Access publication on November 19, 2009 doi:10.1093/humrep/dep390 OPINION What has happened to human fertility? Michael Joffe 1 Department of Epidemiology and Public Health, Imperial College, London W2 1PF, UK 1 Correspondence address. E-mail: Semen quality appears to have declined in recent decades in some populations, e.g. north-western Europe. At the same time, couple fertility may have increased. Hypotheses are suggested for this apparent inconsistency. Alongside the deterioration of spermatogenesis there is clear evidence of an increase in other related problems, notably testicular cancer. The sharply rising trend in this condition started a century ago—decades earlier than sometimes thought. This and other evidence clearly indicates an environmental origin, but there is also a definite genetic component. The relationship of genetics and environment is discussed in the context of the puzzle that infertility is inherited, which appears to be impossible from an evolutionary standpoint. Poor semen quality is related not only to testicular cancer but also to zygote development, in which cancer-like disruption of the genetic apparatus is observed, with serious implications for offspring health. This needs to be seen in the context that human reproduction is prone to a higher degree of impairment than that of other mammalian species, in relation to spermatogenesis, couple fertility, early pregnancy loss and embryonic aneuploidy; female- and male-mediated pathways are both implicated. It is unclear whether such human specificity originated on an evolutionary/genetic or a historico-social timescale, which is important in relation to pathogenesis. The evidence clearly indicates that the currently most popular explanation for male reproductive system impairment, the endocrine disruption hypothesis, cannot explain the main features of the descriptive epidemiology. An alternative pathogenesis is outlined, and some possible exposures considered that could be responsible. Key words: infertility / spermatogenesis / testicular cancer / embryo development / early pregnancy loss Introduction The publication of a article by Carlsen et al. (1992) in the BMJ in the early 1990s led to public concern over the possibility that human fertility has declined. Whether or not the findings in that particular report were true, the issue of human fertility is clearly important. (In this article, the term ‘fertility’ is taken to indicate biological fertility, the capacity to conceive given unprotected intercourse, in contrast to demographic fertility, the actual number of children. Sometimes the alternative term ‘fecundity’ is used for this purpose, but others use these terms the other way around.) Fertility is difficult to study in humans. It can be looked at from a functional perspective, by the use of biomarkers, or from a mechanistic viewpoint. They are complementary, and ideally each should inform the others. Functional fertility refers to how easy or difficult a couple find it to conceive, given that they are having unprotected intercourse, and tends to be assessed by looking at how long this takes, since more fertile couples tend to conceive more quickly (see below). The other two approaches are at the individual level, not the couple, and relate to the biological processes operating in each sex separately. Biomarkers can be used for descriptive purposes, e.g. to study trends, or to make other comparisons. In the case of trends, it is necessary to have repeated measures on reasonably large samples that are representative of the underlying population, which rules out invasive procedures. This means that in practice such research is restricted to the use of easily collectible biomarkers, which are not available for women, so that studies of trends in female reproductive function are confined to such things as age at menarche and menopause. As techniques improve, better information on female fertility at the population level may become available, for example blood FSH and anti-mullerian hormone concentration. In men, the situation is more fortunate, because semen is relatively easily obtained. The biomarkers of semen quality that are available over a period of time long enough to be useful in assessing trends are, in practice, limited to density (concentration), volume, number, motility and morphology (WHO, in press). The focus in much of the debate has been on density, expressed as the mean, which is unfortunate because the highly skewed distribution in humans makes it far less suitable than the median for making such a comparison. A particularly useful way of analysing semen, Sperm Chromatin Structure Assay (SCSA) (Evenson and Wixon, 2005), has unfortunately not been widely available on a population basis for a long enough period. The mechanistic approach is necessary so as to make biological sense of whatever trends or other patterns are identified: what underlying chemical and physical processes bring about the observations. This could for example involve cellular, molecular and regulatory mechanisms. It is important to recognize that a particular clinical condition, such as impaired spermatogenesis, could result from one of & The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: 296 several different types of pathogenesis; and any particular pathogenesis can typically be initiated by different exogenous and/or endogenous agents. A problem in this literature, as so often, is that scientists’ specialization means that particular issues are looked at in isolation (sometimes called ‘silos’), rather than as an integrated whole. And yet the complete picture can only be understood by looking at the entire range of evidence—epidemiology, genetic epidemiology, clinical research e.g. with infertile patients, experimental research on animals with a more mechanistic focus, as well as toxicology. This article is mainly concerned with examining trends in human fertility, and the related topic of species differences between humans and other mammals; it does not cover the related issue of infertility and toxic chemicals (Joffe, 2003), or the relevant genetic evidence (Joffe, 2007), which have been published elsewhere. Most of the available information relates to impairment of male fertility and associated conditions, so that women are comparatively neglected. The article also suggests a mechanistic basis for deteriorating male reproductive health. In this review, the focus will be on the central processes of reproduction, involving the gonads and germ cells, omitting impairments or diseases in accessory sex organs including the breast. Trends in Biomarkers of Fertility A large part of the literature on fertility trends has related to sperm concentration: this has been the focus not only of scientific but also of publ (...truncated)