18.1 Introduction and General Remarks on the Importance of Andrological Prevention

Sexual and reproductive health is a fundamental part of a person’s health and wellbeing and it is defined by the World Health Organization (WHO) as a state of complete physical, mental and social wellbeing in all matters relating to the reproductive system. Importantly, it implies also that people should be able to have a satisfying and safe sex life and they should maintain sexual and reproductive health during their entire life. Reproductive health has emerged as an important healthcare need involving many clinical and public health issues, including sexually transmitted infections (STIs), declining fertility and rising rates of testicular cancer [1–4]. Importantly, it is now recognized that many causes and risk factors for testicular dysfunction and infertility indeed act early during life [5]. Many andrological pathologies that we see in adults actually arise at a younger age, due to the strong susceptibility and vulnerability of the male gonad to external insults, starting from gestation age and during all growth phases.

Three main phases of a man’s life are particularly susceptible for subsequent normal testis development and function (Table 18.1, Figure 18.1): the intrauterine phase, the neonatal phase comprising the so-called “minipuberty” in the first months of life, and puberty. However, even during infancy, when the testes are apparently “sleeping,” damaging causes with permanent effects on testicular function can occur. This is, for example, the case of the iatrogenic, devastating effect of chemotherapy in this period of the life. Risk factors acting via the mother during pregnancy might compromise definitively testicular function later in life, by disrupting foetal germ cell proliferation and differentiation, Sertoli cell proliferation and establishing of the Leydig cell population (Figure 18.1). Similarly, risk factors acting directly on minipuberty might compromise germ, Sertoli and Leydig cell differentiation and proliferation. Iatrogenic, environmental and lifestyle risk factors during childhood might interfere above all with the germ cell compartment and those acting during puberty might disrupt Sertoli cell maturation, the establishment of adult Leydig cell population and spermatogenesis (Figure 18.1) [5,6].

Figure 18.1 Effect of risk factors for testicular development and function from the foetal period to adulthood. SC: Sertoli cells; GC: germ cells; LC: Leydig cells.

Modified from (6).

Apart from the intrauterine phase, childhood and adolescence therefore represent key times and windows of vulnerability in which andrological prevention and early risk factor detection could take place, including: (i) correct management of pathologies of the reproductive tract (e.g. cryptorchidism, varicocele); (ii) early detection of causes and risk factors of subsequent infertility (e.g. testicular hypotrophy, Klinefelter syndrome, obesity); and (iii) identification and information on health risk behaviours and lifestyles that might compromise future fertility and testicular function (e.g. alcohol, tobacco use, drug abuse and unprotected sex) (Table 18.2) [7].

Adolescence in particular is considered a vulnerable time for the development and maturation of the genitourinary tract [8]. Risk factors and lifestyles adopted in adolescence may negatively affect adult health as well as that of future generations, through epigenetics. Prevention is the most efficacious way of improving sexual and reproductive health, as further confirmed by the high prevalence of undiagnosed (and hence untreated) andrological disorders. Indeed, the US Center for Disease Control and Prevention (CDC) Healthy 2020 Objectives identified several targets relevant to adolescents, focusing on weight, substance use and abuse, smoking and sexual and reproductive health [9]. According to the WHO’s 2004 Global Burden of Disease study, the main risk factors for incident disability adjusted life year (DALYs) in 10–24-year-olds are alcohol (7% of DALYs), unprotected sex (4%), lack of contraception (2%) and illicit drug use (2%) [10].

Prevention of future infertility should therefore pass through information and modification of bad lifestyles during childhood and adolescence, although definite risks are not easily defined (Table 18.3). For example, contrasting data exist regarding smoking and male fertility, the association between marijuana use and non-seminoma testicular germ cell tumours needs to be confirmed, and late effects on fertility of alcohol consumption are not clear. Indeed, some lifestyles are clearly associated with reproductive fitness and wellness [5,13]. This is the example of steroid abuse, as recently stated by the Endocrine Society [14]. About 2% of American high school students reported having used anabolic agents abuse in the previous months [14], and the detrimental effect of them on the endocrine function of the testis and spermatogenesis is well documented. The WHO estimates that adolescent alcohol abuse is increasingly widespread [10]. Binge drinking is common in this age group and is associated with reduced testosterone levels [15]. In vivo and in vitro studies showed that excessive alcohol intake suppresses the hypothalamic-pituitary-gonadal axis [16]. Importantly, in adolescents, even moderate alcohol consumption impairs pubertal development and testicular endocrine function far beyond the period of consumption [17]. Recent data also suggest that substance abuse, particularly alcohol, during adolescence is associated with impaired testicular volumetric development.

Another area of concern is related to the possible consequences on reproductive fitness and wellness of sexually transmitted infections (STIs) and diseases (STDs) during adolescence [18]. STIs represent one of the most important risk factors able to impair sexual and reproductive health, but the exact effect later in life is not well known, although predictable. Professionals in reproductive medicine should disseminate the information and be committed to appropriate studies on STIs and STDs. As reported by the WHO, about 357 million treatable STDs are detected worldwide each year, and in most countries the prevalence of STDs has increased in recent years. The prevention of STDs is at the centre of health policy guidelines worldwide, in order to halt the spread of infection.

Among STIs, human papillomavirus (HPV) is one of the most prevalent and has become a major source of morbidity and mortality worldwide. Unfortunately, the research focus has been exclusively on women for too long, but men are also affected. Indeed, the prevalence and consequences of HPV infection in males are not negligible and men might be carriers of continuous HPV transmission among sexually active couples. Furthermore, HPV infections usually clear without intervention in most cases, but can cause long-term consequences and, most importantly, might compromise the couple’s fertility [19]. However, most studies of HPV have analysed diagnosis, treatment and prevention in women. Moreover, strategies in sexual and reproductive health programmes in many countries have focused on epidemiological control in women, but they have tended to overlook the role of this infection in men, despite its high prevalence. The same is true for HPV vaccination [20]. In fact, men may constitute a reservoir for inadvertently transmitting infection to women, due to its asymptomatic nature in most cases, thus contributing to the persistence of infection and cancer.

Finally, we should bear in mind that health risk behaviours could worsen the reproductive potential in boys with andrological disorders (undescended testes, varicocele, genetic disorders). Therefore, great effort should be done to promote primary and secondary prevention in this period of life. Preventive interventions could improve the chance of healthy development [21]. Greater attention to the importance of andrological health in adolescence is needed and strategies that place the adolescent years at centre stage could offer valuable opportunities to improve fertility later in life.

We will now examine specific strategies for early detection, management and follow-up of some classic causes of infertility that can occur early in life to minimize their negative consequences on the reproductive system: undescended testes, varicocele, Klinefelter syndrome, obesity, sexually transmitted infections and diseases, health risk behaviours and abuse of substances (Table 18.4).

18.2 Prevention and Management of Defects of Testicular Descent and Their Consequences on Testicular Function

Cryptorchidism affects 3–5% of term infants and 9–30% of preterm infants. Spontaneous testicular descent in the first months of life occurs in about 50% of term infants, with a 1.5% prevalence at age one year, whereas it is more frequent in preterm infants with a 7% prevalence at age one year. The incidence of undescended testes is increasing, possibly due to in utero exposure to oestrogenic or anti-androgenic endocrine disruptors [22]. Long-term sequelae of cryptorchidism include infertility, hypogonadism and testicular cancer [22], therefore appropriate follow-up programmes should be offered to these subjects.

The prevention of cryptorchidism and other defects of testicular descent is limited to removal, when possible, of known risk factors, such as low birth weight, small for gestational age (SGA), and maternal factors such as gestational diabetes, smoking, alcohol, caffeine, and exposure to endocrine disruptors (e.g. phthalates, pesticides, herbicides, PDEs) [5]. Other possible areas of prevention could be the transmission of genetic factors involved in testicular descent and development (mutations in genes responsible for HH, INSL3, RXFP2, AR, or mutations and chromosomal alterations causing complex genetic syndromes) [22,23].

At birth, testes position should be carefully evaluated by palpation at scrotal, suprascrotal and inguinal level, together with annotation of other genital disorders, in particular hypospadias. If chromosomal and complex genetic syndrome might be suspected, specific genetic tests should be performed. Testicular position should be regularly checked in the first years of life, both to recognize spontaneous postnatal descent of testes (generally within the first 6 months of age) and to identify acquired cryptorchidism.

Early orchidopexy (1–2 years of age), although reduces the risk for infertility, hypogonadism and testicular cancer, does not completely abolish it, but it represents the ideal treatment [24].

Minipuberty, the period between birth and 6 months, represents an extraordinary window for the diagnosis of endocrine disturbances. In this period, in selected cases with suspicion of very early onset or congenital hypogonadism, hormonal assessment with determination of FSH, LH, testosterone, AMH and inhibin B could be performed. Thereafter, and until the onset of puberty, the only endocrine assessment that could be performed for early detection of hypogonadism secondary to cryptorchidism is limited to AMH and inhibin B determination and hCG stimulation test.

Ex-cryptorchid subjects should be carefully and regularly followed up during pubertal development to identify possible disorders in pubertal and testicular development involving both the spermatogenic and hormonal compartments. Testicular volumes, Tanner stages, growth curves, hormonal determinations (FSH, LH, testosterone), as well as scrotal ultrasound (US), should be monitored. Semen analysis should be considered in ex-cryptorchid subjects, ideally when Tanner V is reached, and eventual semen cryopreservation should be offered whenever abnormal findings are present and progression of testicular damage is conceivable.

In any case, andrological follow-up with physical examination, semen analysis, scrotal ultrasound and hormonal (FSH, LH, testosterone) determination should be annually offered to ex-cryptorchid patients. Furthermore, patients and parents should be informed and educated on testicular self-examination.