Our bodies evolved to be 'in tune' with their environment. This connection is vital for reproduction, as birth of the young must coincide with plentiful food, and thus a high chance of survival1. Most mammals are therefore 'seasonal breeders' and switch their sexual behaviour and fertility on and off, guided by the amount of daylight (photoperiod), but influenced also by other factors, such as energy intake/balance (that is, availability of food)1,2. Although humans are not 'seasonal breeders' — we show sexual behaviour and reproduce all year round — our fertility is influenced profoundly by our environment, including season and food intake. In recent years, the postulated threat to fertility from exposure to environmental 'endocrine disruptors' has loomed large, but proven examples are elusive3,4,5. However, it has highlighted the vital role of endogenous hormones in foetal life, which ensures future fertility. Exposure to the wrong hormones (for example, a female foetus exposed to male hormones) or inadequate amounts of the hormone in question, and the reproductive system and genitalia may not develop correctly, with resultant fertility problems in adulthood6,7. The hormones that control fertility (the sex hormones) are also influenced by other hormones, in particular those determined by our diet and sugar intake (for example, insulin)8. The progressive increase in obesity in many Western cultures therefore brings with it attendant fertility problems, mainly in women. Of more concern is that these 'lifestyle' problems in adult women can have effects even when they do achieve a pregnancy, as foetal development may be impaired and its future fertility may be compromised. Factors determining fertility — importance of foetal life Infertility is considered an 'adult problem', as this is when it manifests itself. However, many factors that impact on fertility have their origins much earlier in life, commonly during foetal development. To understand how (and when) infertility can arise, and what environmental factors can affect it, a useful starting point is the identification of key factors that determine whether a man or woman will be fertile, and when these are established. In men, the key to fertility is the ejaculation of astronomical numbers of motile sperm (40–250 million per ml)9. This requires the production of 100–200million sperm every day, and each sperm takes 10weeks to be produced. Once sperm counts fall below 14–40 million per ml, significant impairment of fertility may occur (Fig. 1). This includes an increased time to conceive10,11,12 or, at very low sperm counts (less than 5million per ml), by more intractable infertility; in these men, sperm are often abnormal in shape and function9.
The number of sperm produced per day is in turn determined by the numbers of Sertoli cells within the testes5,13. Variation in Sertoli cell number is the main factor that accounts for the wide variation in sperm counts between men13,14 (see Fig. 1). Numbers of Sertoli cells are determined largely by their rates of proliferation during foetal and neonatal (1–9 months postnatal) periods, and probably to some extent during pre-pubertal life13,15 (Fig. 1). Proliferation of Sertoli cells is controlled by a variety of hormones, including follicle-stimulating hormone (FSH), thyroid hormones, growth hormone and possibly oestrogens13. Any factor that affects these hormones, whether in foetal, neonatal or peri-pubertal life, may affect sperm counts and testicular size in adulthood (Fig. 1). At puberty, no further increase in the numbers of Sertoli cells can occur and the ceiling for sperm production and testicular size is fixed irrevocably13. To be fertile, a man must have the correct reproductive organs internally (testes, epididymides, seminal vesicles, vas deferens and prostate gland) and externally (penis and scrotum), and the testes must have descended into the scrotum6,9. Testis descent, which is a hormone-dependent process, normally occurs by birth, and incomplete descent of one or both testes (cryptorchidism) is associated with lower sperm counts/fertility in adulthood and increased risk of testicular cancer5,16,17. Cryptorchidism affects 2–3% of boys at birth, whereas testicular cancer is the most common cancer of young men and almost certainly arises from abnormal development of germ cells in the foetal testis18. Fertility also requires masculinization of the brain and the neuronal 'wiring' that controls production of the reproductive hormones, ensuring men show appropriate sexual behaviour19 and a male pattern of hormone production. Much of this is also established during foetal life. In women, the key to fertility is the monthly ovulation of a mature egg (oocyte) and a reproductive tract that has been prepared to accommodate the ovulated egg and to provide the optimum environment for fertilization, early embryo development, implantation into the uterus and normal foetal development. These processes must be carefully co-ordinated, and principally, this is driven by the cyclical changes in sex steroid production by the ovary. The production of a mature oocyte that is capable of being fertilized is a lengthy process20,21,22. The human ovary acquires its full complement of germ cells (oocytes) during foetal life (Fig. 2). Most are destined to die by atresia, so that at birth, germ cell number has fallen from approximately 7 million to 1–2 million, and less than 500 oocytes will be ovulated in adulthood. The 'primary oocytes' in the foetal ovary are arrested in the first meiotic prophase, and remain so until just before ovulation some 15–50 years later, when resumption of meiosis (maturation) is triggered by the midcycle 'surge' of luteinizing hormone (LH), which stimulates ovulation. Thus, the critical stages of germ cell production occur in the foetus and are therefore subject to influence by the maternal environment.
Development of the follicle to the point of ovulation takes several months21. Early follicular development is not dependent on LH/FSH (the 'gonadotrophins'), but the local and/or endocrine factors responsible for initiation of growth of these follicles are unclear. Later stages of follicle maturation are gonadotrophin-dependent, and in the two weeks preceding ovulation, they are precisely regulated by the cyclical changes in LH and FSH secretion. During these stages, the oocyte undergoes cytoplasmic and nuclear maturation, which enables it to resume meiosis and to prepare for fertilization20,22. During this critical phase, the endocrine environment of the follicle, which is susceptible to the external environment, can profoundly influence oocyte maturation. Unlike the foetal testis, the foetal ovary is thought to be hormonally quiescent7,16. Therefore, normal development of the internal and external reproductive organs occurs without the obvious influence of sex steroids (Fig. 2). In the adult female, cyclical changes in the levels of sex steroids drive a series of co-ordinated events in the reproductive tract. These events include modification of the cervical mucus to facilitate sperm transport, changes in tubal motility and secretions (encouraging transport and fertilization of the egg), and most importantly, secretory changes in the endometrium that allow normal implantation. In summary, the effects of environment and lifestyle on sperm count, oocyte development/ovulation, fertilization and implantation are those most likely to impact on fertility. In addition, the effects on oocyte number will determine the span of female reproductive life. Such effects might be induced early in development, in which case they are likely to be permanent. Alternatively, they may arise in adulthood, in which case they may be reversible (Fig. 2; these effects are considered separately below). Note that the effects on women are inherently more likely to induce infertility than the effects on men, as even major decreases in sperm counts in normal men may not result in infertility (Fig. 1). Environmental and lifestyle effects on fertility in adulthood The effects of photoperiod on humans are demonstrable23, as testified by 'seasonal affective disorder'. This also extends to effects on fertility. The incidence of twins and the frequency of births both show seasonal trends (especially in Northern Europe, where photoperiodic changes are most extreme and result in a peak in spring births)24. This is not caused by a seasonal variation in sexual activity, as differences also occur in fertilization rates and embryo quality in women undergoing in vitro fertilization (IVF)25. Furthermore, sperm counts in men are consistently ~30% lower during the summer than in the winter5,26. The latter effects could be caused by the higher summer temperature, which can impair sperm production (see below and Fig. 2) and conception27. However, temperature changes fail to account for all of the seasonal trends in births, especially in Northern Europe27. Presumably, the seasonal changes are a distant echo from our seasonally breeding ancestors and reflect subtle changes in the hormone drive to the reproductive system. Probably the most widespread environmental factor that reduces sperm counts in adult men is interference with the ability of the scrotum to cool the testes, as sperm production requires the testes to be 3–4 °C cooler than core body temperature5,28,29. Interference with testicular cooling has even been shown to be an effective approach to male contraception30. Although extremes of heat (for example, through occupational exposure) may pose mild risk to individuals31, every-day lifestyle factors probably have more widespread effects (Fig. 2). For example, immersion in moderately hot baths for more than 20 min will impair sperm production5,29. Another threat comes from our increasingly sedentary habits at work and leisure (for example, sitting in front of a computer or driving). Continuous temperature monitoring has shown scrotal temperature increases by 1.7–2.2 °C within 2 h of starting to drive a car32. A relationship between average daily scrotal temperature and sperm counts has been detected33, and drivers are often identified as an occupation at risk of low sperm counts/infertility9,31,34. The effect of sedentation is at its worst in paraplegic men35. Effects of lifestyle and diet Increased rates of smoking and consumption of alcohol have been identified in infertile couples11. In men, smoking can be associated with minor reductions in sperm count/morphology, but this is inconsistent and not usually associated with altered fertility36,37; however, effects on IVF outcome have been reported38. There are also concerns that smoking induces DNA damage in sperm39,40. There is no consistent relationship between moderate alcohol intake and sperm count in men9 or fertility in women41,42. However, in women, there is unequivocal evidence that smoking negatively impacts on virtually all aspects of fertility43,44,45,46,47. This includes effects on follicle development/ovulation, oocyte pick-up from the ovary and its transport down the fallopian tubes, fertilization and early embryo development. Such effects have been demonstrated by numerous studies in a variety of countries. As detailed below, when pregnancy occurs in a woman who smokes, the future fertility of the foetus (as well as its' general health and well-being), whether male or female, is also put at risk. It is now advocated that smoking should be phased out as an integral part of human infertility treatment. Bodyweight and body-mass-index have little effect on sperm count, but can have important effects on female fertility48. The control of female reproductive hormones by the brain is highly sensitive to the effects of nutrition (Fig. 3). In a female of normal weight and with a normal diet (Fig. 3a), the hormonal drive to the ovary for the regulation of follicle development and ovulation functions primarily through the gonadotrophins LH and FSH, which are released from the pituitary gland. The secretion of LH and FSH is regulated by the brain hormone, gonadotrophin releasing hormone (GnRH). FSH and LH regulate the development of follicles in the ovary, which are then stimulated to produce the sex steroids (testosterone, oestradiol and progesterone). In turn, these sex steroids affect the uterus, breast and hypothalamus/pituitary gland, which determines the timing of puberty and menarche (menstruation) in girls, and ovulation and fertility in adulthood; oestradiol and progesterone also negatively 'feed back' to the hypothalamus/pituitary to inhibit secretion of GnRH, LH and FSH.
| Fig. 3 |
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 Figure 3 | The hormonal mechanisms that link nutrition/diet and female fertility.
a, Normal ovarian function — resulting in normal puberty and reproductive competence — is controlled primarily by the gonadotrophins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) from the pituitary gland, the secretion of which is regulated by the brain hormone, gonadotrophin releasing hormone (GnRH). Nutrition is linked to the female reproductive system through the effects of a hormone emanating from fat cells (leptin) and by insulin from the pancreas, which alters the bioavailability of oestradiol (E2) and testosterone (T) by affecting production of SHBG (sex hormone-binding globulin) from the liver. Insulin can also function directly on the ovary. b, DurIng under-nutrition, when leptin secretion from fat cells plummets, the reproductive system essentially shuts down because of reduced production of GnRH and consequent reduction of LH and FSH. In turn, the absence of these hormones results in a lack of follicular development, a lack of sex steroids and an absence of ovulation. c, By contrast, in overweight women and/or those with polycystic ovary syndrome (PCOS), an increase in the number of fat cells results in a cascade of changes, involving increased leptin and insulin levels and a preferential increase in LH, but not FSH, levels. The net effect of these changes is to stimulate the partial development of follicles that secrete supranormal levels of T, but which rarely ovulate (hence low progesterone (P)). These changes are exacerbated by insulin-induced reduction in SHBG, which amplifies ovarian T production/action. In addition, there is a genetic predisposition to PCOS. It should be noted that impaired foetal growth (IUGR; see text) can also result in an increase in the number/size of fat cells and an increase in insulin resistance in adulthood, although the relationship to fertility and PCOS is still unclear.
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A normal calorie intake is necessary for normal pubertal development, the onset of menstruation and for ovulation. During adolescence, there is a change in the accumulation and distribution of fat, including an increase in abdominal adiposity that is closely associated with a reduction in sensitivity of muscle and fat to insulin (insulin resistance), and a compensatory increase in insulin secretion. This physiological elevation in circulating insulin levels results in a reduction of circulating sex hormone binding globulin (SHBG), with consequent release of 'free' (biologically active) oestrogens and androgens, thereby amplifying the effects of these hormones and facilitating sexual maturation49. Fat cells themselves produce metabolic signals — particularly leptin50 — that can influence the secretion of GnRH by the hypothalamus and thus stimulate secretion of gonadotrophins (Fig. 3). In addition to its effects on the ovary, insulin may also affect reproductive function by acting on the brain51. Underweight women (Fig. 3b), such as those suffering from anorexia nervosa, rarely ovulate and menstruate52. Ovarian function is 'switched off' through reduced production of GnRH, which results in gonadotrophin concentrations that are too low to sustain ovarian function. This may be regarded as a protective mechanism for both mother and potential conceptus, through the prevention of pregnancy (with its high energy cost) in the face of under-nutrition. Circulating leptin concentrations are low in underweight women53 and this may be the factor that switches off secretion of GnRH (Fig. 3b). Being overweight is also associated with reproductive dysfunction (Fig. 3c). Obese women are less likely to ovulate and more likely to suffer miscarriage than lean age-matched women48,54. Although obesity per se may impair fertility, there is an important interaction of overweight/obesity with polycystic ovary syndrome (PCOS). This syndrome — so-called because the ovaries contain many small follicles — is one of the commonest causes of infertility and is associated with a failure of ovulation55. Its aetiology is unclear, but genetic factors are important56,57. A tenable hypothesis is that polycystic ovaries and the associated hormone abnormalities (principally, excess secretion of testosterone by the ovary) are genetically programmed during ovarian development in the foetus58. However, there is also an interaction with key environmental factors, especially nutrition. PCOS is characterized by a cluster of metabolic abnormalities, including a tendency to accumulate abdominal fat, as well as resistance to and hyper-secretion of insulin59. This is reminiscent of, although more exaggerated than, the physiological changes at puberty (Fig. 3a). The consequences of abdominal obesity in women with PCOS include an increased chance of anovulation and infertility, excess secretion of testosterone (resulting in unwanted body hair) and, in the long term, a greatly increased risk of developing type-2 diabetes in later life59. Effects on future fertility that are induced in foetal/early life As the reproductive system and its hormonal control systems are established in foetal life, maternal factors that affect the 'foetal environment' may also influence the foetal reproductive system. Because of its own physiological processes, the foetus adapts to its 'environment' and it may be these adaptations that result in adverse effects. For example, girls who were born to mothers in developing countries and then adopted to a Western country as babies have a ~15% risk of precocious puberty at the age of 7–10 years60,61. This may result from a 'conflict' between an adaptation of the foetus to the low nutritional plane of its mother and its childhood development, when food intake is not limiting, although the cascade of physiological changes is unclear62. Exposure to environmental chemicals (for example, p,p'-dichlorodiphenyltrichloroethane (DDT) has also been suggested to cause precocious puberty63. Aside from maternal diet, smoking and exposure to other environmental chemicals are the main factors with the potential to affect the future fertility of the foetus. There is also great interest in the role of maternal nutrition and its interaction with genetic factors in determining foetal development and birth weight64. Low birth-weight is associated not only with greater morbidity and mortality during infancy, but also with a greater risk of developing cardiovascular disease, hypertension and type-2 diabetes in adulthood65,66,67. It has been suggested that these diseases (all of which are linked to insulin resistance) arise as a consequence of 'programming' of physiological systems during foetal life in response to changes in maternal environment. Such programming implies that permanent changes in gene expression occur during development, changes with consequences that last into adulthood68. In developed countries, environmental factors (such as social class and smoking) can influence birth weight, but most (although not all) epidemiological studies have concluded that maternal undernutrition is of central importance68. It is possible that intra-uterine growth retardation (IUGR), through its association with insulin resistance in later life, contributes to the pathogenesis of PCOS. However, to date, no clear relationship has been established between birth weight and the risk of developing PCOS69. Interestingly, recent studies have demonstrated insulin resistance and abdominal obesity in men, women and mice carrying inactivating mutations in the aromatase gene70,71,72. In this situation, production of oestrogen is blocked, resulting in infertility70,71,72. Although epidemiological data highlight a link between IUGR and adult disease, little is yet known about its impact on the reproductive health of the offspring. This may be particularly important if the nutritional deprivation or other 'insult' occurs during the time of gonadal development and germ cell multiplication. There are conflicting findings on the effects of IUGR on subsequent sperm counts in men73,74,75, though IUGR is an established risk factor for cryptorchidism, hypospadias (an abnormality of the penis), pseudohermaphroditism and testicular cancer7,16,17,76, consistent with a fundamental effect on the development of the reproductive system (Fig. 2). One study has reported an association between IUGR and smaller uterus and ovaries in adolescent girls77. Maternal smoking can also cause foetal IUGR, which, in turn, has numerous health consequences (see above). Smoking also has adverse effects on development of the reproductive system of foetuses of both sexes, independent of IUGR. Its main consequence in the male is to reduce future sperm counts78. redReduced Sertoli cell number is the primary mechanism by which a permanent decrease in sperm count (and testis size) can be induced (Fig. 1), and this is the probable explanation for the effect of maternal smoking. As the Sertoli cells orchestrate testicular development, effects on these cells may result in changes in other testicular cells, such as the Leydig cells and foetal germ cells7,17. Leydig cells make the testosterone responsible for masculinization, and abnormal development of the foetal germ cells probably results in testicular germ cell cancer in adulthood (Fig. 2). Testicular cancer is the most common cancer of young men and its incidence has increased progressively in Western countries in the last 50–60 years. Furthermore, there is evidence that the incidence of 'masculinization' disorders has also increased during the same period16,17. Exposure to the active chemicals in tobacco smoke or from other sources, such as combustion of fossil fuels or dietary consumption79, may have contributed to these changes (see below). Women whose mothers smoked whilst they were in utero have an earlier menopause and consequently a shorter reproductive lifespan80. These changes are determined by the number of oocytes in the ovaries, which is determined during foetal development (Fig. 2). This suggests that maternal smoking results in a loss of oocytes in the foetal ovary. Studies in mice have identified the mechanism through which this occurs. Exposure of pregnant mice to the polycyclic aromatic hydrocarbons (PAHs) present in tobacco smoke increases the number of oocytes undergoing apoptosis in female foetuses, resulting in fewer oocytes at birth and premature ovarian failure81. This occurred as a result of PAHs binding to the aromatic hydrocarbon receptor (Ah receptor) in the ovary, causing the accumulation of Bax protein in foetal germ cells, which then triggered cell death81,82. The same cascade of events can be induced in human ovarian explants81, and smoking by adult women may activate similar mechanisms, as it is associated with depleted oocyte reserves. Similar pathways may underlie the (postulated) changes in Sertoli cell numbers induced in the foetal testis by maternal smoking, as studies in rats exposed in utero to dioxin, which also binds to the Ah receptor, had reduced sperm counts in adulthood83. Past exposure to persistent environmental chemicals (for example, DDT and polychlorinated biphenyls (PCBs)) may have induced effects in humans, as it undoubtedly did in some wildlife species84. However, it is less clear that modern (non-persistent) pesticides pose a serious risk to the general public. There are instances in which exposure of men involved in the production or application of particular pesticides has been shown to cause infertility5,9,85, or where an association between pesticide usage and cryptorchidism86,87 or male infertility in farmers88 has been suggested. However, other detailed studies have failed to find a significant association between pesticide exposure and male or female infertility5,89. Similarly, there are isolated examples in which occupational exposure to non-pesticide chemicals (for example, glycol ethers) can reduce sperm counts90. It is uncertain how common such effects may be, as there are fundamental logistical problems in undertaking semen analysis studies in many groups of workers5. Perhaps the most cautious view is that individuals whose occupation/lifestyle brings them into everyday contact with chemicals known to be reproductively toxic should be considered 'at risk', whereas there is little risk to the general public. Maternal exposure to environmental chemicals that possess either intrinsic hormonal activity or can perturb endogenous hormone production/action pose a hazard to reproductive health of the foetus through the pathways outlined above. In pregnancy, exogenous exposure of humans or animals to potent oestrogens (for example, diethylstilboestrol or ethinyl oestradiol from the contraceptive pill) during the period of sexual differentiation undoubtedly results in an increased incidence of cryptorchidism, penile abnormalities, poor semen quality and probably testicular cancer4,16,17. These effects may stem from interference with androgen production/action or disturbance of the androgen–oestrogen balance91,92. Evidence that humans are exposed to numerous chemicals with weak oestrogenic potency ('environmental oestrogens') from the environment3,4 or from food (hormone growth promoters in farm animals92,93) has understandably raised concern of similar effects on reproductive health, but opinion is firmly divided on this issue3,4,5. In our opinion, the most logical risk comes from potent oestrogens, such as those produced within the body during pregnancy. Therefore, concern should be focussed on those environmental chemicals that are able to alter exposure of the foetus to endogenous oestrogens or androgens. Three recent findings highlight this possibility. First, both PCBs94 and a range of environmental polyhalogenated hydrocarbons (PAHs)95 have been shown to potently suppress activity of the enzyme oestrogen sulphotransferase (SULT1E1), through which oestrogens are inactivated. Suppression of SULT1E1 increases oestrogen bioactivity94,95. Furthermore, in human pregnancy, when oestrogen levels are extraordinarily high, this could alter exposure of the foetus to oestrogens, a change that is established to increase risk of male reproductive disorders and function, as outlined above16,17,92, and may also affect the risk of breast cancer in females96. Human exposure to PCBs and to PAHs is widespread94,95. There is also the possibility of polymorphisms in genes such as the oestrogen sulphotransferases, which may produce changes in enzyme activity that might indicate inter-individual differences in inherent or chemically induced susceptibility to oestrogen-related disorders97. Second, male rats exposed in utero to certain phthalate esters that were administered to their mothers exhibit a high frequency of cryptorchidism, hypospadias and abnormal testes, associated with suppression of testosterone levels in the foetal testis7,98,99,100. These changes are remarkably similar to the changes in human male reproductive health mentioned above, and which can be induced by over-exposure to oestrogens4,16,17. Phthalate esters have multiple and varied uses (for example, as plasticizers and spreading agents) and are the class of environmental chemicals to which there is greatest (and universal) human exposure. Though the doses of phthalates required to induce high prevalence of these disorders in rats is considerably higher than humans are exposed to, a recent study has identified a small sub-group of the general population who have unusually high exposure to phthalates, these being predominantly women of reproductive age101. Third, exposure of humans to DDT is associated with an increased incidence of IUGR102 (see Fig. 2) and a mild increase in the incidence of hypospadias and cryptorchidism103. This is consistent with the demonstration that the main metabolite of DDT is a potent anti-androgen that blocks the androgen receptor and induces these abnormalities in animals104. Future perspectives Environmental and lifestyle factors look set to become increasingly influential on human fertility if increasing trends in obesity, female smoking and sedentation at work/leisure continue. Such factors, coupled with a trend to delay first pregnancies to an older age, are likely to result in an increased incidence of infertility, especially in women. However, as many of these effects are on the foetus during pregnancy, their manifestation may be 'hidden' for several decades. Arguably, all such effects are preventable by changes in diet and lifestyle. Ultimately, all environmental/lifestyle effects on fertility, whether induced in foetal or adult life, result from hormonal changes. Genetic differences (for example SULT1E1 polymorphisms) may predispose some individuals to hormonal perturbation, and this emerging area is likely to become increasingly influential on our thinking. It has also become increasingly apparent that all hormonal (endocrine) systems have 'rippling' effects on other endocrine systems, which is why diet and season can affect fertility. Understanding the complex pathways through which these ripples work, and how common environmental chemicals can affect them, present intriguing challenges to biomedicine in an age when the focus is on genes rather than the whole body. A failure of science to meet this challenge and of individuals to amend their diet/lifestyle will hand the poisoned chalice of infertility to the next generation.
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