**Abstract**

Increasing concern exists regarding male reproductive health worldwide. This is due to the appearance of medical reports outlining apparent adverse trends, such as a worldwide decline in total fertility rate, and an increase in testicular disorders such as testicular cancer, cryptorchidism—in parallel with a probable decline in semen quality. This is of particular concern as there is evidence to suggest that a poor sperm count is potentially associated with overall lifelong morbidity and mortality, and is effectively a predictor of lifelong health risk. This chapter examines the evidence for this decline and its potential early life causes, from in-utero exposures to childhood development.

**Keywords:** male reproduction health, sperm, testosterone, in-utero, phthalate, BPA

## **1. Introduction**

Between 1986 and 1993, British physician and epidemiologist David Barker published a series of articles in the Lancet, proposing his hypothesis of the foetal origins of adult health and disease [1–3]. In these publications, he argued that adverse alterations in the developmental early life environment *in utero*, had potential to induce and initiate phenotypic and adaptive changes affecting an individual's responses to their later life environment, which might prove maladaptive when the early and late environments were markedly different [4, 5]. Barker's specific foetal concerns were inadequate nutrition, [6] intrauterine growth retardation, low birth weight and premature birth and their causal relationship to the origins of hypertension, coronary heart disease and non-insulin-dependent diabetes, in later life [7]. However there is now growing evidence to suggest that this 'developmental programming' and the foetal environment, which includes placental function, maternal metabolism, exposures and lifestyle factors (including maternal smoking), may influence additional systems including reproductive health and development in both males and females [5, 8].

Increasing concern exists regarding male reproductive health worldwide due to the appearance of medical reports outlining apparent adverse trends, in the context of a worldwide decline in total fertility rate (**Figure 1**) [9, 10]. This includes an increase in the incidence of the proposed 'testicular dysgenesis syndrome' [10] which encompasses a constellation of testicular disorders including testicular cancer, [11, 12] cryptorchidism and hypospadias [13]. This is in parallel with population-based evidence to suggest declining semen quality, [14] alterations in serum testosterone levels and a change in the timing of onset of male puberty [9]. Worryingly, one comprehensive review of the literature proposed that semen quality had declined by 52.4% between 1973 and 2011 among unselected men from Western countries [14]. Another recent report, published

### **Figure 1.**

*Total fertility rates for Australia, United States, Europe and Central Asia 1960–2017. Reprinted with permission from the World Bank: www.worldbank.org.*

in 2015, found that a high proportion of healthy, unselected 20-year-old Caucasian men displayed suboptimal semen quality which did not meet the lower limit of World Health Organization reference ranges for sperm concentration, motility and morphology values [15]. These findings were echoed by a further Swiss study published in 2019 where over 60% of participants displayed suboptimal median sperm concentration [12]. Sperm count is of obvious importance in fertility and reproduction, however recent studies have now demonstrated that poor sperm count is potentially associated with overall lifelong morbidity and mortality, and is effectively a 'canary in the mine' marker for lifelong health risk [14, 16–18]. To elicit a greater understanding of the early life influences on these important, early determinants of male reproduction and health are therefore of great importance.

In this chapter, we present and discuss the evidence for the developmental programming of male reproductive maturation and function.

### **2. Male reproductive development**

Male reproductive development has a long time to maturation, with onset in the embryo and completion in puberty. The critical and narrow prenatal window for the normal differentiation and growth of male reproductive tissue during which testosterone and its potent metabolite dihydrotestosterone, (DHT) masculinise the male foetus is estimated to be around 8–14 weeks of gestation [19–21]. The formation of the indifferent bipotential gonad occurs between the fourth and sixth weeks of foetal life, and male reproductive development subsequently begins when the SRY gene, encoding a 'testis-determining factor' on the Y chromosome stimulates the development of the primitive sex cords to form the medullary cords. Sertoli cells appear, and in the eighth week, Leydig cells appear and commence production of testosterone. In the presence of this testosterone, the mesonephric ducts develop to form the primary male genital ducts. They give rise to the efferent ductules, epididymis, vas deferens and seminal vesicles, whilst the paramesonephric ducts degenerate. Meanwhile, in the presence of DHT, the male external genitalia differentiate as the genital tubercle elongates to become the phallus and the urethral folds close over, forming the penile urethra.

**5**

**development**

*The Early Life Influences on Male Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.88382*

gonadal axis remains quiescent until puberty.

the G protein-coupled receptor GPR54 exist [26, 27].

that can influence physiological and pathological processes [25].

**4.1 Placental malfunction and antenatal factors**

**3. Male pubertal development**

The hypothalamic-pituitary-gonadal axis is active in the mid-gestational foetus, but silenced towards the end of gestation. This restraint is removed at birth, leading to reactivation of the axis and an increase in serum gonadotropin concentrations, often labelled the 'mini-puberty' [22, 23]. Testosterone concentration rises to a peak at age 1–3 months, but then falls in conjunction with the falling luteinising hormone (LH) concentration [22]. Prenatal and postnatal activation of the hypothalamicpituitary-gonadal axis is associated with penile and testicular growth and testicular descent, and is therefore regarded as important for the development of male genitalia. These concentrations then gradually decrease towards age 6 months when there is an active inhibition of gonadotrophin-releasing hormone (GnRH) secretion, which persists throughout childhood, [22, 24] and the hypothalamic-pituitary-

Male puberty marks the transitional period during which the infantile boy attains adult reproductive capacity with usual age of onset around 11.5 years.

Pubertal development of secondary sexual characteristics is initiated, at least in part, by a sustained increase in pulsatile release of GnRH from the hypothalamus. There is testicular growth as the seminiferous tubules are stimulated by folliclestimulating hormone (FSH), and once their volume exceeds 3–4 ml pubertal onset is confirmed. Leydig cells, stimulated by LH, produce testosterone which influences penile growth and pubic hair development. Spermatogenesis occurs under the regulation of multiple endocrine and local factors [9]. Although the exact mechanisms underlying the commencement of puberty in both males and females is unclear, there is evidence for influence of a multitude of factors including genetic, environmental factors, body composition, physical fitness, nutritional and socioeconomic status, ethnicity, residence and exposure to endocrine disrupters [25]. Other important stimulatory and inhibitory pathways involving glutamate kisspeptin and

In essence, the increase of pulsatile GnRH secretion at puberty represents the cumulative effect of highly complex and intricate hypothalamic interactions that are markedly influenced by genetic factors and environmental signals [26]. An advancement in the timing of puberty has been reported worldwide over the past two decades [28]. The timing of puberty has important public health ramifications because it is related to a number of health outcomes [29]. Early puberty is potentially associated with increased risk of testicular cancer, as well as adolescent alcohol abuse, smoking, drug use, early sexual debut, sexually transmitted infections, aggressive behaviour and poor academic performance [15, 30]. These observations urge further study of the onset of puberty as a possible sensitive and early marker of the interactions between environmental conditions and genetic susceptibility

**4. Potential influences of male reproductive development and pubertal** 

Impaired placental malfunction, which has the potential to disrupt foetal androgen production, has been theorised to affect male reproductive development, and a definite link between impaired foetal growth and reproductive function has been

*The Early Life Influences on Male Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.88382*

*Male Reproductive Health*

**Figure 1.**

are therefore of great importance.

**2. Male reproductive development**

*permission from the World Bank: www.worldbank.org.*

close over, forming the penile urethra.

in 2015, found that a high proportion of healthy, unselected 20-year-old Caucasian men displayed suboptimal semen quality which did not meet the lower limit of World Health Organization reference ranges for sperm concentration, motility and morphology values [15]. These findings were echoed by a further Swiss study published in 2019 where over 60% of participants displayed suboptimal median sperm concentration [12]. Sperm count is of obvious importance in fertility and reproduction, however recent studies have now demonstrated that poor sperm count is potentially associated with overall lifelong morbidity and mortality, and is effectively a 'canary in the mine' marker for lifelong health risk [14, 16–18]. To elicit a greater understanding of the early life influences on these important, early determinants of male reproduction and health

*Total fertility rates for Australia, United States, Europe and Central Asia 1960–2017. Reprinted with* 

In this chapter, we present and discuss the evidence for the developmental

Male reproductive development has a long time to maturation, with onset in the embryo and completion in puberty. The critical and narrow prenatal window for the normal differentiation and growth of male reproductive tissue during which testosterone and its potent metabolite dihydrotestosterone, (DHT) masculinise the male foetus is estimated to be around 8–14 weeks of gestation [19–21]. The formation of the indifferent bipotential gonad occurs between the fourth and sixth weeks of foetal life, and male reproductive development subsequently begins when the SRY gene, encoding a 'testis-determining factor' on the Y chromosome stimulates the development of the primitive sex cords to form the medullary cords. Sertoli cells appear, and in the eighth week, Leydig cells appear and commence production of testosterone. In the presence of this testosterone, the mesonephric ducts develop to form the primary male genital ducts. They give rise to the efferent ductules, epididymis, vas deferens and seminal vesicles, whilst the paramesonephric ducts degenerate. Meanwhile, in the presence of DHT, the male external genitalia differentiate as the genital tubercle elongates to become the phallus and the urethral folds

programming of male reproductive maturation and function.

**4**

The hypothalamic-pituitary-gonadal axis is active in the mid-gestational foetus, but silenced towards the end of gestation. This restraint is removed at birth, leading to reactivation of the axis and an increase in serum gonadotropin concentrations, often labelled the 'mini-puberty' [22, 23]. Testosterone concentration rises to a peak at age 1–3 months, but then falls in conjunction with the falling luteinising hormone (LH) concentration [22]. Prenatal and postnatal activation of the hypothalamicpituitary-gonadal axis is associated with penile and testicular growth and testicular descent, and is therefore regarded as important for the development of male genitalia. These concentrations then gradually decrease towards age 6 months when there is an active inhibition of gonadotrophin-releasing hormone (GnRH) secretion, which persists throughout childhood, [22, 24] and the hypothalamic-pituitarygonadal axis remains quiescent until puberty.

### **3. Male pubertal development**

Male puberty marks the transitional period during which the infantile boy attains adult reproductive capacity with usual age of onset around 11.5 years.

Pubertal development of secondary sexual characteristics is initiated, at least in part, by a sustained increase in pulsatile release of GnRH from the hypothalamus. There is testicular growth as the seminiferous tubules are stimulated by folliclestimulating hormone (FSH), and once their volume exceeds 3–4 ml pubertal onset is confirmed. Leydig cells, stimulated by LH, produce testosterone which influences penile growth and pubic hair development. Spermatogenesis occurs under the regulation of multiple endocrine and local factors [9]. Although the exact mechanisms underlying the commencement of puberty in both males and females is unclear, there is evidence for influence of a multitude of factors including genetic, environmental factors, body composition, physical fitness, nutritional and socioeconomic status, ethnicity, residence and exposure to endocrine disrupters [25]. Other important stimulatory and inhibitory pathways involving glutamate kisspeptin and the G protein-coupled receptor GPR54 exist [26, 27].

In essence, the increase of pulsatile GnRH secretion at puberty represents the cumulative effect of highly complex and intricate hypothalamic interactions that are markedly influenced by genetic factors and environmental signals [26]. An advancement in the timing of puberty has been reported worldwide over the past two decades [28]. The timing of puberty has important public health ramifications because it is related to a number of health outcomes [29]. Early puberty is potentially associated with increased risk of testicular cancer, as well as adolescent alcohol abuse, smoking, drug use, early sexual debut, sexually transmitted infections, aggressive behaviour and poor academic performance [15, 30]. These observations urge further study of the onset of puberty as a possible sensitive and early marker of the interactions between environmental conditions and genetic susceptibility that can influence physiological and pathological processes [25].

### **4. Potential influences of male reproductive development and pubertal development**

### **4.1 Placental malfunction and antenatal factors**

Impaired placental malfunction, which has the potential to disrupt foetal androgen production, has been theorised to affect male reproductive development, and a definite link between impaired foetal growth and reproductive function has been

established. Consequences on gonadal differentiation, sexual organ development, onset of puberty, gamete quality, hormonal status and fertility have been observed [31, 32]. Several studies have described an association between foetal growth restriction and an increased risk of male reproductive health problems, including hypospadias, cryptorchidism and testicular cancer [13, 33, 34]. In addition, twin or triplet pregnancy and preterm birth have also been shown to be associated with non-gestational-related impaired reproductive development [35]. One study demonstrated an inverse relationship between the incidence of cryptorchidism, and decreasing gestational age at birth, suggesting that premature delivery is important in view of the timing of testicular descent in foetal life [36]. A strong association between low birth weight and hypospadias has been demonstrated [37, 38].

Increasing birth weight in males has also been shown to be positively correlated with adult serum testosterone levels, however no effect on other reproductive hormone levels has been shown [39]. Adult men born with lower birth weights have, in another study, been shown to display features of hypogonadism, with reduced testicular size, lower testosterone levels and higher LH values, than controls born with appropriate weights [39]. Male children with early onset of their pubertal growth spurt are more likely to have been born underweight [40]. In a cohort of Australian men followed from birth, men born with gestational appropriate birth weights were significantly less likely to be grouped in the lowest quartile for their total motile sperm counts. Those men who were born preterm demonstrated reduced serum testosterone levels in adulthood, suggesting an adverse influence of growth restraint and prematurity on later life testicular function [41]. A prospective Danish birth cohort study of more than 2500 live born males found statistically significant associations between cryptorchidism and low birth weight, prematurity, being small for gestational age, substantial vaginal bleeding in pregnancy and breech presentation, which is in accordance with other studies [42].

### **4.2 Maternal medical complications of pregnancy**

Abnormal maternal glucose metabolism in pregnancy may be associated with an increased risk of genital malformation for the male offspring [8, 43]. In women with gestational diabetes, the risk of delivering a male infant with cryptorchidism is increased by a factor of four compared to women without diabetes [43]. It is postulated that early growth delay of the foetus in the first trimester might play a role. This early failure of normal growth has been demonstrated even in children of diabetic mothers who are ultimately born large for gestational age [44]. The evidence is conflicting however, as no association between gestational diabetes and cryptorchidism was found in another registry-based study from Israel [45]. Maternal hypertension during pregnancy and preeclampsia are associated with hypospadias and other genital malformations, [37, 46] suggesting that placental insufficiency may play an important role in male foetal genital development.

### **4.3 Maternal undernutrition**

The 5 month Dutch Winter Hunger Famine in 1944 gave rise to the suggestion that maternal nutrient restriction may play a role in determination of subsequent pathologic outcomes [47, 48]. This relationship has been demonstrated in several animal models [49–51]. Whilst the exact mechanism is unknown, it is theorised that maternal nutrient restriction might reprogram the development of the pituitary-adrenal axis, alter the male pituitary response to GnRH, lead to excess glucocorticoid exposure and thus exert an adverse effect on gonadal development and function [49]. This may vary according to the timing and magnitude of the

**7**

*The Early Life Influences on Male Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.88382*

window in the foetus [50].

**4.4 Maternal obesity**

**4.5 Maternal smoking**

sperm concentration [8, 56].

**4.6 Maternal gestational stress**

undernutrition. More studies in both humans and animals are required to further explore the effect of maternal undernutrition during the critical programming

The prevalence of overweight and obese individuals in their reproductive years is increasing worldwide, and there is an established link between obesity and reduced fecundity in men and women [52]. Maternal obesity (and potentially paternal obesity around the time of conception) creates an adverse intrauterine environment for the developing foetus, and may have a detrimental reprogramming effect on offspring [52, 53]. Maternal obesity may alter the molecular composition of gametes, leading to epigenetic changes which impair the developmental trajectory of the resultant embryo and of future generations [32]. In male rats, maternal obesity during pregnancy and lactation has been shown to increase testicular and sperm oxidative stress leading to premature ageing of reproductive capacity [54]. In humans, one epidemiologic study reported a detrimental influence of high maternal body mass index (BMI) on the semen quality and plasma concentration of inhibin B of male offspring, [31, 52] a finding confirmed by other studies [52]. The exact processes through which maternal nutrition or maternal environment affect reproductive function in the offspring remain unclear, and may be due to an alteration of oestrogen exposure with the hormonal control of the development of the male foetal urogenital organs. Epigenetic modifications are also a clear link [31].

Exposure to cigarette smoking *in utero* has consistently been shown to negatively impact on male reproductive development, and in fact maternal smoking exposure during pregnancy may have a stronger effect on subsequent spermatogenesis than a man's own smoking in later life [8]. Reductions in median sperm output and total motile sperm are evident, and substantial [41]. One Danish cross-sectional study showed maternal smoking during pregnancy to be associated with earlier onset of puberty, lower final adult height, higher BMI, reduced testicular volume, lower total sperm count, reduced spermatogenesis-related hormones (inhibin-B and FSH) and higher free testosterone [55]. Likewise, a study of 1770 young men from the general population in Denmark, Norway, Finland, Lithuania and Estonia reported that maternal smoking during pregnancy was associated with a 20% reduction in

The effect of prenatal exposure to maternal cigarette smoke has been evaluated in another study where human gonadal cell numbers were examined by histopathological analysis following first trimester termination of pregnancy. A significant reduction in the number of germ cells and somatic cells in embryonic male (and female) gonads and the effect was dose dependent in heavy smokers [57].

Maternal exposure to stress in pregnancy has been shown to be a significant determinant of male reproductive development later in life. One prospective longitudinal cohort study examined this association in almost 650 males at 20 years of age. Maternal gestational stress, measured by exposure to stressful life events in early gestation was associated with lower total sperm counts, reduced number of progressive motile sperm and lower morning serum testosterone concentration. There was no effect of stressful events in late pregnancy (beyond 18 weeks'

undernutrition. More studies in both humans and animals are required to further explore the effect of maternal undernutrition during the critical programming window in the foetus [50].
