Female fertility: hostage to affluence, age and the search for self-fulfilment In modern industrialized societies female fertility is compromised due to a perfect storm of social, economic, educational and political factors that far outweigh any attempt by Governments to encourage women to have more children. In affluent societies, there is no need to have a large family. Infant and childhood mortalities are low and children are not needed in the workforce to facilitate survival of the family unit. As a result of the reduction in family size, women are freed to pursue their educational and professional goals. This ultimately means that childbearing is postponed to the point that fertility goes into age-dependent decline, around the age of 35. Many women in this situation will look to the IVF industry for salvation, however live births decline with age following assisted conception just as they do in natural cycles. Oocyte donation and/or cryopreservation are the only realistic methods to address age-dependent female infertility at the present time, although even these techniques are far from infallible. As societies engage in the long march to affluence, we shall inevitably witness repeated collisions between the tectonic plates of female biology and our prosperity-driven quests for gender equality, longevity and fulfilment. Ultimately fertility is the victim.

The gathering storm – the creation of an Infertility TrapWhile previous publications have looked at individual aspects of the issues shaping our population size, the reality is that many different factors are working together to drive human fertility into a cul-de-sac of its own making. From a social perspective many young people, particularly young, educated women, do not feel that life’s purpose necessarily involves the creation of a family. As fertility rates fall, this lack of interest in procreation will be reinforced by the economic pressures placed on a dwindling workforce to achieve the productivity needed to support the swelling ranks of elderly citizens. We shall not be able to turn to immigration to solve this problem because the fall in fertility rates is global and the barriers to international movement put up by COVID will persist for some time to come. Affluent societies are also characterized by lifestyles, diets and levels of environmental pollution that negatively impact reproductive health. These features, when coupled with the lack of selection pressure on high fertility in modern industrialized societies, and the ability of ART to encourage poor fertility genotypes to remain within the population, will combine to drive fertility down to historically low levels.

A journey into the demographic heart of the matterDespite 300 years of unrelenting population growth, the world is now witnessing an unprecedented decline in human fertility. Counterintuitively, the global population continues to grow because infant mortality rates are low, lifespan is increasing, and population momentum is high. The net effect of all these factors acting together is that while global fertility rates are falling, the world’s population will level off at around 11 billion by 2100. After this zenith has been reached, the population is projected to go into rapid decline and develop a ‘super-aged’ structure. The wealthiest nations on Earth will not, as at present, be able to bolster their populations with skilled immigration programs because the traditional wellsprings of humanity, such as India, China, and Africa, will be suffering their own depopulation crises. As a result, by the end of the century, a vast majority of countries will be exhibiting fertility rates below replacement level with little chance of stabilization. Indeed, the major drivers for global fertility decline are only intensifying with the passage of time in the wake of increased global prosperity. This raises fundamental questions about the nature of these drivers and whether they can be controlled.

The miracle of conception – how we all got to be here Successful conception requires spermatozoa to exhibit a wide range of sophisticated behaviours and biochemical changes. They are capable of exhibiting rheotaxis, thermotaxis and chemotaxis on their voyage to the site of fertilization in the oviduct. Once these cells have successfully engaged the cervix and uterotubal junction they come to rest in the isthmic region of the Fallopian tubes, where they are thought to bind to the oviductal epithelium and enter a state of quiescence. They are ultimately awakened from this gentle slumber by a signal coincident with ovulation and break away from the isthmic epithelium in a frenzied state of hyperactivation. These hyperactivated cells then bring their receptors-for-the-egg to the cell surface and go in search of their prey, aided by signals given out by the egg bearing a come-hither message. At this point in development, it is a race to find the fittest spermatozoa capable of engaging in the myriad cellular interactions required to achieve fertilization. It is a race that only one cell can win out of the ~200 million that started the race. Each one of us is the result of an incredibly complex obstacle race where all of the other competitors died.

Prologue- the pending collapse of human populationsA perfect storm of social, political, environmental and biological factors is conspiring to suppress the fertility of our species. In this book, we shall explore the fundamental nature of human population dynamics and the wide range of factors responsible for the change that is about to come. Societies touched by prosperity’s wand experience many advantages including good health, education, security and longevity. However, these gifts come at a cost. Prosperous societies experience high levels of environmental pollution, psychological stress, obesity, addiction and a focus on individual fulfilment that combine to generate extremely low levels of fertility. As societies accumulate wealth, they sow the seeds of their own demise. In the short term, our ‘superaged’ societies must be supported by a shrinking, overstretched workforce, that have neither the motivational energy nor the biological capacity to procreate. In the long term, the lack of selection pressure on fertility, combined with the exponential growth of the IVF industry, will serve to drive fertility rates down still further. Unless we recognise and respond to the factors suppressing human fertility, we shall not be able to control the predictable population collapse – and escape will be challenging.

Why are men infertile?Oxidative stress is one of the major causes of male infertility can be induced by a wide range of biological (age), clinical (varicocele), lifestyle (diet) and environmental (electromagnetic radiation and chemical pollutants) factors. Oxidative stress may impact all aspects of spermatogenesis but is particularly damaging when it is experienced late in the spermatogenic process when male germ cells are differentiating into spermatozoa and are rapidly losing their capacity for DNA repair. An immediate consequence of oxidative stress is that spermatozoa lose their capacity for fertilization, thereby generating a state of infertility/subfertility. However lower levels of oxidative stress can result in spermatozoa that are still competent to fertilize ova but are carrying significant quantities of oxidative DNA damage. If this damage occurs early in spermatogenesis, it can result in a mutation that will be carried to the ovum at the moment of fertilization. Alternatively, if the oxidative DNA damage occurs late in spermatogenesis, it can become fixed as a mutation following fertilization as a result of defective DNA repair in the oocyte. Such DNA damage may be responsible for a range of congenital disorders seen in children, particularly neuropsychiatric conditions such as autism and, critically, infertility.

The Janus faces of IVFIn vitro fertilization therapy was originally pioneered by Edwards, Steptoe and Purdy in order to help women suffering from bilateral tubal occlusion. The subsequent rise of Assisted Reproductive Therapy (ART) as a default treatment for many different forms of human infertility has been successful to the point that it has now become a major industry that exists, not just to meet the needs of its desperate patients, but to satisfy the aspirations of its shareholders. The sheer scale of the demand for ART services in the future may create several issues that will have to be addressed, including the cost of providing equitable access to such therapy and meeting the long-term health needs of the children born as a result. When conducted at scale, the ART industry will also serve to retain poor fertility genes within the population. When combined with the lack of selection pressure on human fertility in advanced affluent societies, this feature will ensure that the incidence of infertility continues to rise, fuelling the need for more ART services in a self-perpetuating spiral. This may be a boon for business but will become a millstone for Governments trying to provide equitable access to healthcare services, including ART.

What is happening to the human male?Something strange is happening to the human male. The incidence of testicular cancer is increasing dramatically in all the advanced economies on Earth, male infertility has reached epidemic proportions, sperm counts are declining at an alarming rate and paternal impacts on offspring health are becoming increasingly apparent. Notably, the incidence of testicular cancer shows a strong correlation with socio-economic development such that, globally, it has become the major cancer afflicting young males. In parallel with the increased incidence of testicular cancer, sperm counts have been falling across the globe. The reason for this decline in semen quality is uncertain at the present time but it may be an indirect reflection of falling testosterone levels, possibly fuelled by oestogenic factors in the environments we inhabit, the food we eat, the water we drink, the drugs we take, the lifestyles we adopt and the metabolic patterns we experience in affluent society. The resultant oestrogenic load may impact male reproductive health at any point in sexual development from fetal life to adulthood. Controlling the exposures responsible for these impacts on male reproduction is essential because, if current trends continue unabated, it will have as major impact on the future of our species.

How do we escape the trap?Many of the social, biological and environmental mechanisms that are driving down human fertility, are self-reinforcing. They operate to accelerate the rate of fertility loss, not stabilize it. Escape from this downward spiral will involve several initiatives that, working together, may provide a measure of control over the rate and depth of fertility decline. For example, we need a complete overhaul of sex education that recognizes the fragility of human fertility and is not so focused on the prevention of teenage pregnancies. We also need to raise the profile of reproductive toxicology so that we can secure better control over the release of potentially harmful compounds into the biosphere. There is a particular need to control male exposures to oestrogens and to counteract those elements of lifestyle, metabolism and the environment, responsible for creating oxidative stress in both the male and female reproductive tract. Accommodating the ART industry would be easier if we secured a deeper understanding of the causes of human infertility so that ART does not become the default therapy for every couple and, when it is used, that IVF is preferred over ICSI. Finally, we need to engineer new social structures wherein fertility is facilitated and encouraged.

In this impressive volume, the editors have pulled together an international cast of distinguished authors, who present a detailed account of sperm function testing in terms of rationale, methodologies and clinical significance. In this introduction, my intention is to give a historical perspective on the evolution of these techniques and a view of where this field will head in the future. For what it is worth, I should also mention that these reflections are presented from the standpoint of someone who has spent the best part of half-a-century considering how we can reliably and effectively monitor the functional quality of human spermatozoa.

Apoptosis, a physiological process for the controlled deletion of cells, is critical for the regulation of cell numbers, the management of morphogenesis during embryonic development, and the orchestration of many cellular processes in the adult. Spermatogenesis, the production of functional spermatozoa from spermatogonial stem cells, is no exception. It appears that a functional apoptotic pathway is necessary for normal spermatogenesis to develop, and without it infertility ensues. Apoptosis also plays a crucial role in the maintenance of the testis and its response to external toxicants, as well as in the programmed senescence of terminally differentiated spermatozoa. This chapter focuses specifically on how apoptosis affects sperm quality and function, and the implications of this process for both embryonic development and the health and well-being of the offspring.