Pre-Testicular, Testicular, and Post- Testicular Causes of Male Infertility

Fotios Dimitriadis, George Adonakis, Apostolos Kaponis, Charalampos Mamoulakis, Atsushi Takenaka, and Nikolaos Sofikitis

Abstract Infertility is both a private and a social health problem that can be observed in 12–15% of all sexually active couples. The male factor can be diagnosed in 50% of these cases either alone or in combination with a female component. The causes of male infertility can be identified as factors acting at pre-testicular, testicular or post-testicular level. However, despite advancements, predominantly in the genetics of fertility, etiological factors of male infertility cannot be identi- fied in approximately 50% of the cases, classified as idiopathic infertility. On the other hand, the majority of the causes leading to male infertility can be treated or prevented. Thus a full understanding of these conditions is crucial in order to allow the clinical andrologist not simply to retrieve sperm for assisted reproduc- tive techniques purposes, but also to optimize the male’s fertility potential in order to offer the couple the possibility of a spontaneous conceivement. This chapter offers the clinical andrologist a wide overview of pre-testicular, testicular, and post-testicular causes of male infertility.

F. Dimitriadis Department of Urology, School of Medicine, Aristotle University, Thessaloniki, Greece e-mail: [email protected] G. Adonakis • A. Kaponis Department of Ob/Gyn, School of Medicine, Patras University, Patras, Greece C. Mamoulakis Department of Urology, School of Medicine, University of Crete, Crete, Greece A. Takenaka Department of Urology, School of Medicine, Tottori University, Yonago, Japan N. Sofikitis (*) Department of Urology, School of Medicine, Ioannina University, Ioannina, Greece e-mail: [email protected]

# Springer International Publishing AG 2017 1 M. Simoni, I. Huhtaniemi (eds.), Endocrinology of the Testis and Male Reproduction, Endocrinology 1, DOI 10.1007/978-3-319-29456-8_33-1 2 F. Dimitriadis et al.

Keywords Cryptorchidism • Hypogonadotropic hypogonadism • Idiopathic infertility • Klinefelter’s syndrome • Male infertility • Pre-testicular causes • Testicular causes • Pituitary diseases • Post-testicular causes • Sertoli cell only syndrome • Varicocele • Y chromosome microdeletions

Contents Pre-Testicular Causes of Male Infertility ...... 2 Hypogonadotropic Hypogonadism ...... 2 Pituitary Diseases ...... 3 Coital Disorders ...... 4 Testicular Causes of Male Infertility ...... 4 Varicocele...... 4 Cryptorchidism ...... 6 Noonan Syndrome ...... 8 Vanishing Testis Syndrome ...... 9 Myotonic Dystrophy ...... 9 46,XX Testicular Disorders of sex Development ...... 10 47,XYY Syndrome ...... 11 Klinefelter’sSyndrome...... 11 Y Chromosome Microdeletions ...... 12 Sertoli Cell-Only Syndrome (Germ Cell Aplasia) ...... 13 Gonadotoxins ...... 14 Systemic Diseases ...... 16 Testis Injury ...... 20 Idiopathic Infertility ...... 20 Post-Testicular Causes of Male Infertility ...... 21 Male Reproductive Tract Obstruction ...... 21 Disorders of Sperm Function or Sperm Motility ...... 26 Disorders of Coitus ...... 28 References ...... 29

Pre-Testicular Causes of Male Infertility

Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism is defined by deficient secretion of gonadotropins (FSH and LH). Testosterone secretion by testicular Leydig cells is impaired if LH and FSH stimulation is absent, and spermatogenesis is compromised. The major diagnostic categories include isolated hypogonadotropic hypogonadism (IHH) and pituitary disease (Fig. 1).

Isolated Hypogonadotropic Hypogonadism Isolated hypothalamic GnRH secretion deficiency results in the classic form of IHH (Kallmann syndrome). The syndrome is associated with KAL-1 gene mutations and follows a sex-linked pattern of inheritance with an incidence of 1 in 10,000 males (Bhagavath et al. 2006). IHH can also follow an autosomal dominant or recessive Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 3

Fig. 1 Pre-testicular causes of male infertility. IHH isolated hypogonadotropic hypogonadism, CHH congenital hypogonadotropic hypogonadism, LH luteinizing hormone, FSH follicle- stimulating hormone pattern of inheritance. However, most cases of normosmic Kallmann syndrome are sporadic (Sokol 2009). An IHH variant (adult-onset or acquired IHH) appears with impotence and/or oligospermia (Nachtigall et al. 1997).

Congenital Hypogonadotropic Hypogonadism (CHH) CHH is a very rare genetic disorder that results from deficient secretion or action of GnRH presenting as absent puberty and infertility (Krausz 2011). It is heterogeneous and clinical presentation relates to the degree of GnRH deficiency. Patients present with prepubertal testes (testicular volume < 4 mL) in adolescence or early adulthood (Georgopoulos et al. 2009). Severer forms present with cryptorchidism/micropenis at birth and complete absence of pubertal development later. Milder forms show some degree of testicular development (testicular volume > 4 mL). Anosmia may be present in about 50% of cases (Kallmann syndrome).The majority of CHH cases are sporadic, but in about a third of the cases, a familial inheritance pattern is evident (Huhtaniemi and Alevizaki 2007), including autosomal dominant, recessive, X-linked, or oligogenic forms (Sykiotis et al. 2010a). More than 20 associated loci have been detected to date acting alone or in synergy. Nevertheless, only about 35–40% of cases are currently accounted for by mutations in the identified genes. X-linked form with KAL-1 gene mutations shows the worst response to treatment and genetic counseling should be offered (Sykiotis et al. 2010b). Targeted mutation screening in affected offspring and neonatal hormonal profiling could facilitate early diagnosis (Dwyer et al. 2015). 4 F. Dimitriadis et al.

Pituitary Diseases

Isolated LH or FSH Deficiency Isolated LH deficiency (fertile eunuch syndrome) is a rare disorder characterized by normal FSH secretion that stimulates spermatogenesis but inadequate testosterone production by testicular Leydig cells leading to impaired virilization (Ma et al. 2004). Isolated FSH deficiency is extremely rare. Patients are normally virilized given a normal LH/testosterone axis.

Craniopharyngioma Craniopharyngioma derives from Rathke’s pouch remnants and usually grows slowly. It is a benign tumor often invading sella turcica leading to suppression of pituitary hormone secretion and optic chiasm compression. Patients present with pituitary hormonal dysfunction headaches, visual disturbances, impaired spermato- genesis, and impotence (Sokol 2009).

Pituitary Tumors Prolactin-producing tumors (prolactinomas) are the commonest tumors of the pitu- itary gland. Gonadotropin secretion is disturbed by pituitary compression and patients often present with impotence. Growth hormone and adrenocorticotropic hormone-secreting tumors present with gigantism or acromegaly and Cushing syn- drome, respectively. FSH-producing tumors manifest with gradual visual impair- ment, oligospermia, and impotence. Non-prolactin-producing tumors may result in modest prolactin elevation due to disruption of neurogenic pathways that attenuate dopamine release into portal circulation of the pituitary gland. They also interfere with LH/FSH secretion due gonadotropic cell compression (Sokol 2009).

Infiltrative Diseases These include histiocytosis X, amyloidosis, sarcoidosis, and infectious granuloma- tous diseases (Melmed 2008). Diseases that cause increased circulating iron levels (sickle cell anemia, thalassemia, and hemochromatosis) may also present with HH due to iron deposition in the pituitary gland.

Traumatic Brain Injury Skull base trauma can lead to decreased pituitary hormone secretion. Head trauma may be minor and have occurred as far as some decades before the diagnosis of hypopituitarism. This fact leads the physician to neglect or underestimate the importance of head trauma in the etiology of HH. Greater decrease of FSH versus LH secretion is reported in the majority of the cases of post-traumatic hypopituita- rism. Pituitary ischemia (necrosis) can be a long-term but not a permanent, irrevers- ible complication of head trauma (Sokol 2009).

Critical and Chronic Diseases Critical illnesses such as severe burns, myocardial infarction, and acquired immune deficiency syndrome (AIDS) suppress the hypothalamic–pituitary axis. Hormonal Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 5

Fig. 2 Testicular causes of male infertility. 46,XX testicular DSD 46,XX testicular disorders of sex development, SCO Sertoli cell-only syndrome, CRF chronic renal failure, CAH congenital adrenal hyperplasia, HIV human immunodeficiency virus suppression level is related to disease severity. Chronic diseases suppress the axis but also the testes directly. Obesity, metabolic syndrome, and diabetes mellitus may affect the production of testosterone (Ding et al. 2006).

Coital Disorders

Sexual dysfunction including erectile and ejaculatory disorders represents rare causes of male infertility and they will discussed later in this session.

Testicular Causes of Male Infertility

Varicocele

Varicocele represents a vascular abnormality of the venous drainage system of the testes. The abnormally dilated veins may concern either the pampiniform or the cremasterium plexus. Varicocele has been considered as a cause responsible for the infertile phenotype in 35% or 81% of men with infertility problems or men with secondary infertility, respectively (Clarke 1966; Gorelick and Goldstein 1993) (Fig. 2). 6 F. Dimitriadis et al.

Increases in testicular temperature, deficiency of the hypothalamic–pituitary– testicular axis, abnormal flow of adrenal or renal metabolites down the left spermatic vein, testicular hypoxia, testicular metabolic defects, and cadmium accumulation in testicular venous blood are theories that have been suggested to explain the damag- ing effect of left varicocele on the left testis (Sofikitis et al. 1992b, 1993a; Hendin et al. 1999; Benoff et al. 2004; Khera and Lipshultz 2008; Pasqualotto et al. 2008; Dimitriadis et al. 2009; Smit et al. 2010). It should be emphasized that left varicocele has a deleterious consequence on the contralateral testicular function (Sofikitis et al. 1993b, 2014; Ozturk et al. 2001). Clinical examination with Valsalva maneuver, Doppler ultrasonography, and thermography is important for the diagnosis of varicocele. For varicocele repair, several techniques have been employed (Goldstein et al. 1992;Sofikitis et al. 1994; Hirsch et al. 1998; Matthews et al. 1998; Giannakis et al. 2004; Cayan et al. 2009; Baazeem et al. 2011; Giagulli and Carbone 2011), but the gold standard approach appears to be the microsurgical subinguinal varicocelectomy because this approach allows identification of the testicular arteries, identification and preservation of the lymphatics of the spermatic cord, and ligation of both the pampiniform plexus-internal spermatic vein venous plexus system and the cremasterium plexus-external spermatic vein venous plexus system.

Cryptorchidism

Cryptorchidism is the commonest congenital abnormality of male genitalia with an incidence of nearly 1% at the end of infancy (Jungwirth et al. 2016). Normal descent of the testes (DT) represents a complex multistage procedure that involves several anatomical elements, genes, and hormonal and environmental factors, but its pur- pose and the exact etiology of cryptorchidism remain unknown (Hutson et al. 2010; Mamoulakis et al. 2015). Hormonal deficiencies are uncommon causes despite the fact that DT presupposes a normally functioning hypothalamic–pituitary–gonadal axis (Toppari and Kaleva 1999). Several factors acting in utero, such as environ- mental or maternal lifestyle factors, might interfere with normal DT as well (Bay et al. 2011). Genetic factors have also been implicated in the etiology under certain conditions by gene–environment interactions, and there is evidence that at least some cases have a genetic basis (Massart and Saggese 2009; Hutson et al. 2010; Jensen et al. 2010). Several known genetic factors have been investigated in many studies concluding that these are responsible for a small proportion of cryptorchid cases (Bay et al. 2011) and that novel candidate genes warrant testing (Mamoulakis et al. 2013a, b, 2014). Cryptorchidism, hypospadias, testicular cancer, and poor semen quality are nowadays considered symptoms of a sole underlying entity, the testicular dysgenesis syndrome (TDS), which is the result of gonadal development disruption in utero by adverse environmental effects possibly acting on a susceptible genetic background (Skakkebaek et al. 2001). TDS manifestation varies with the severity of testicular dysgenesis. Based on epidemiological data, a hypothesis warranting further testing Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 7 has been set forth, according to which relatively lower hCG levels at early (8th–9th week) or late gestational stage (26th week) are manifested as cryptorchidism or hypospadias, respectively (Mamoulakis et al. 2002). A biphasic model has been proposed to explain normal DT in the human (Hutson 1985). According to this model, the first phase of DT, from its initial position near the kidney to the internal inguinal ring (transabdominal DT, TDT), is regulated by a non-androgenic hormone/factor, and it is accomplished during the first trimester of the gestation. The second phase of DT, from the internal inguinal ring to the scrotum (inguinoscrotal DT, ISDT), is regulated by androgens, and it is accomplished during the third trimester of the gestation (Backhouse 1982; Heyns 1982). Caudal gubernacular enlargement (gubernacular swelling reaction) caused by rapid cell proliferation with increase in glycosaminoglycans/hyaluronic acid (Backhouse 1982; Heyns et al. 1986, 1990) is closely associated with TDT (Hutson et al. 1997). Insulin-like 3 (INSL3), a hormone produced by Leydig cells, has been shown in animal models to govern TDT by controlling gubernacular differentiation through its receptor (LGR8) (Kumagai et al. 2002). Many studies have investigated the possibility that human INSL3 gene alterations are implicated etiologically in DT impairment with the vast majority failing to indicate such an association (Mamoulakis et al. 2014). The cumulative incidence of INSL3 gene mutations in cryptorchidism is relative low (1.6–2.2%), without a definite evidence of a causal role for most of them; on the other hand, INSL3 mutations undoubtedly represent the first description of specific genetic alterations related to DT impairment in the human (Mamoulakis et al. 2015). The potential role of the LGR8 gene alterations in cryptorchidism has been investigated as well showing a modest cumulative fre- quency of mutations (2.9%) (Mamoulakis et al. 2015). Most studies have focused on T222P, a missense mutation that reduces LGR8 expression on cell surface membrane potentially leading to cryptorchidism. This hypothesis is supported by mutation screening studies in Italy but has not been confirmed in other countries leading to the notion that cryptorchid phenotype may be dependent on genetic and/or environ- mental background. Based on these results, it has been concluded that INSL3/LGR8 gene mutations are rare causes of cryptorchidism (Mamoulakis et al. 2015). ISDT is governed by androgens but the exact mode of their action is unclear (Hutson et al. 2013). They possibly act indirectly rather than directly on the gubernaculum, through the genitofemoral nerve. Their action results in calcitonin gene-related peptide (CGRP) release by the nerve, a neurotransmitter acting as second messenger of androgenic stimulation on the gubernaculum to promote ISDT (Hutson et al. 2013; Mamoulakis et al. 2015). The clinical significance of cryptorchidism is underlined by a close association with testicular cancer and infertility. Cryptorchidism is the only well-established risk factor of testicular cancer (UK_Testicular_Cancer_Study_Group 1994a, b). The higher the testis position, the higher the relative risk, which is up to 50 times that of the general population. Cryptorchidism is also an important etiologic factor of impaired male fertility. Azoospermia is seen in around 0.5% of the general popula- tion (Hadziselimovic and Herzog 2001), in around 13% of unilaterally cryptorchid patients regardless if they are treated or not but it affects almost 100% of untreated 8 F. Dimitriadis et al. bilaterally cryptorchid patients, while up to 70% of untreated unilaterally cryptorchid patients are azoospermic or oligozoospermic (Hadziselimovic 2002). Paternity rates are reduced significantly in males with a history of bilateral cryptorchidism (61.5–65.3%) in contrast to those with a history of unilateral cryptorchidism (89.7%) compared to the general population (93.2–94.6%), while paternity rates of males having only one testis for whatever reason are similar to those of men with treated cryptorchidism or normal controls (Lee and Coughlin 2002). Preoperative testicular location and small testicular size at orchidopexy in males with a history of unilateral cryptorchidism are not major determinants of fertility (Lee et al. 2000). The exact pathogenesis of reduced fertility in cryptorchidism is not fully clarified. Some of the potential mechanisms include malformations of the epididymis, reduced numbers of spermatogonia containing tubules/spermatogonia per tubule, mild con- current hypogonadism, sperm antibodies’ formation, damage of the contralateral testis, and increased apoptosis of germ cells (Mamoulakis et al. 2004, 2012). Based on the EAU guidelines, the following evidence summary/recommendations apply for the management of cryptorchidism (Tekgül et al. 2016): Treatment should start early in life to rescue spermatogenic potential and reduce future testicular cancer risk. The later the intervention, the higher the fertility impairment/testicular malig- nancy risk. The treatment of choice is surgical placement of the testis in the scrotum, usually by either inguinal or laparoscopic approach for palpable testes or non-palpable testes, respectively. Retractile testes necessitate close follow-up until puberty without any medical or surgical treatment. Orchidopexy is strongly recommended prior to 12 months and by 18 months at the latest. In cases that both testes are non-palpable, male neonates should be investigated for potential disorders of sex development (DSD). If there is no DSD evidence, laparoscopy is preferred due to high specificity/sensitivity in intra-abdominal testes detection and the possi- bility for concurrent treatment. Two types of medical treatment exist (hCG and GnRH) that stimulate the hypothalamic–pituitary–gonadal axis, increasing therefore testosterone production. However, the value of hormonal treatment is controversial; adjuvant/neoadjuvant medical treatment is not routinely recommended and each case must be evaluated individually. Medical treatment is recommended in bilater- ally cryptorchid cases. For unilaterally cryptorchid cases at postpubertal age and beyond, testis removal should be discussed due to the theoretical risk of malignancy in the future.

Noonan Syndrome

Noonan syndrome (NS) is a disorder of variable expression affecting multiple systems, inherited by the autosomal dominant mode, with an estimated prevalence of 1 in 1000–2500 (Mendez and Opitz 1985). The diagnosis is principally based on clinical observation of cardinal features, including developmental delay, short stat- ure, typical facies changing considerably with age, posteriorly rotated ears with fleshy helices, wide-spaced eyes with blue or blue-green irises, thick eyelids and epicanthus, webbed neck, peculiar chest, low-set nipples, heart defect, lymphatic Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 9 dysplasias, defects of coagulation, and uni- or bilateral cryptorchidism generally present in up to 80% of the cases and in 94% of those bearing PTPN11 mutations in particular (Allanson and Roberts 2001). Deficient spermatogenesis may be related to cryptorchidism, but an intrinsic gonadal defect attributed to a primary Sertoli cell dysfunction cannot be ruled out (Allanson and Roberts 2001; Roberts et al. 2013). The genes involved in NS encode proteins integral to the RAS–MAPK pathway with mutations usually enhancing signal flow (Schubbert et al. 2007; Roberts et al. 2013). NS is identified using molecular genetic testing that may detect mutations in PTPN11 (50%), SOS1 (13%), RAF1 (3–17%), KRAS (<5%), or other genes (NRAS, BRAF, and MAP2K1; <1%). Mutations appear de novo but an affected parent is found in up to 75% of families. A number of Noonan-like syndromes should be distinguished, especially those with greatest overlap such as Turner syndrome, cardiofaciocutaneous syndrome, Costello syndrome, and Aarskog syn- drome (Allanson and Roberts 2001; Roberts et al. 2013). Guidelines for the man- agement of NS have been recently developed (Allanson 2007; van der Burgt 2007; Romano et al. 2010).

Vanishing Testis Syndrome

Testicular regression or vanishing testis syndrome (VTS) is attributed to a subse- quent disappearance/atrophy in utero of an initially normal testis (Hegarty et al. 2007). VTS is seen in <5% of cryptorchid cases (Spires et al. 2000), accounting for 35–60% of those with non-palpable testis that consist a 10–20% of cryptorchid cases (Elder 1994; Rozanski et al. 1996; Koyama et al. 1997; Cendron et al. 1998; Storm et al. 2007). VTS is commoner than testicular agenesis (Merry et al. 1997) with a prevalence of around 1/1250 males (Grady et al. 1998). VTS is considered to result from thrombosis, torsion, or endocrinopathy, with more recent studies favoring the theory of vascular accident/antenatal torsion (Wright 1986; Bar-Maor et al. 1993; Rozanski et al. 1996; Papparella et al. 1999). It has also been sporadically associated with genetic abnormalities like Yq11 microdeletions and persistent Müllerian duct syndrome (Calogero et al. 2001). VTS presents more commonly as a unilateral entity or, far less frequently, bilaterally with complete or partial testicular tissue absence and normal external genitalia. The phenotype is usually masculine, but although uncommon, it may vary from normal male with non-palpable testis unilaterally to female (Josso and Briard 1980), probably depending on the intrauterine event extent/timing in relation to sexual development. These 46, XY patients lack detectable testicular structures and Müllerian duct system (Coulam 1979; Naffah 1989; Selby 1992). Viable germ cells/ seminiferous tubules are present in 0–16% of excised testicular remnants (Smith et al. 1991; Rozanski et al. 1996; Merry et al. 1997; Cendron et al. 1998; Spires et al. 2000; Van Savage 2001; Emir et al. 2007; Storm et al. 2007). Presence of germ cells might indicate a germ cell-derived cancer risk. Nevertheless, no association with germ cell tumors has been reported (Pirgon and Dundar 2012). Optimal management 10 F. Dimitriadis et al. remains therefore controversial. Routine removal of testicular remnants is suggested to prevent future malignancy, while this notion has been disputed by others (Plotzker et al. 1992; Cendron et al. 1998; Van Savage 2001).

Myotonic Dystrophy

Myotonic dystrophy (dystrophia myotonica, DM) is an autosomal dominant multi- system disorder with two major types: type 1 (DM1) or Steinert disease (Bird 1993–2016 [updated 2015 Oct 22]) and type 2 (DM2) or proximal myotonic myopathy (Dalton et al. 1993–2016. 2006 Sep 21 [updated 2013 Jul 3]). The prevalence is approximately 1/8000 (Dalton et al. 1993–2016. 2006 Sep 21 [updated 2013 Jul 3]). The proportions of DM1 and DM2 cases are not known. DM1 is caused by expansion to 50–5000 copies of a CTG trinucleotide repeat sequence, an unstable motif found in the 30 untranslated region (normally containing 5–34 copies) of the dystrophia myotonica protein kinase (DMPK) gene (Brook et al. 1992; Mahadevan et al. 1992; Bird 1993–2016 [updated 2015 Oct 22]). DM2 is caused by a CCTG expansion of a complex repeat motif [(TG)n(TCTG)n(CCTG)n] contained in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene. The overall normal CCTG repeat tract ranges from 11–26 CCTG repeats, while pathogenic alleles show a mean of ~5000 CCTG repeats (Liquori et al. 2001, 2003). DM1 affects the skeletal/ smooth muscles, central nervous system, heart, eye, and endocrine system. Three somewhat overlapping phenotypes are seen: mild, classic, and congenital. DM2 presents with myotonia (90%) rarely causing severe symptoms, muscle dysfunction (82%), cataracts (36–78%), primary testicular failure (29–65%), diabetes mellitus (25–75%), and cardiac conduction defects (19%). Reproductive abnormalities are a well-recognized finding in both types. Progres- sive testicular atrophy is a prominent feature occurring in about 80% and up to 60% of DM1 and DM2 cases, respectively. Histological abnormalities include complete hyalinization, atrophy, fibrosis of the seminiferous tubules, and reduced sperm numbers (Sarkar et al. 2004). Oligospermia/azoospermia is reported in about 73% of patients with DM1 (Klesert et al. 1997). The most prominent physical manifes- tation of gonadal failure is small testes. Testosterone is usually low but LH is high in about half of the cases (Sagel et al. 1975). Seminiferous tubule failure may be seen (rise in FSH with normal testosterone). No therapy exists for seminiferous tubule failure. Symptomatic patients with low testosterone require replacement therapy.

46,XX Testicular Disorders of sex Development

The prevalence of nonsyndromic 46,XX testicular DSD is around 1/20,000 males. Algorithms have been developed for evaluation/diagnosis (Barseghyan et al. 2015). The diagnosis is suspected by clinical and/or laboratory findings (Délot and Vilain 1993–2016. 2003 Oct 30 [updated 2015 May 7]). External genitalia are masculine with both testes present but range from typical to ambiguous (penoscrotal Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 11 hypospadias) without evidence of Müllerian structures’ presence. Laboratory find- ings include a 46,XX karyotype, hypergonadotropic hypogonadism secondary to testis failure (Perez-Palacios et al. 1981), and azoospermia. Testis biopsy shows decreased size and number of seminiferous tubules, peritubular fibrosis, germ cell absence, and Leydig cell hyperplasia (Délot and Vilain 1993–2016. 2003 Oct 30 [updated 2015 May 7]). The diagnosis is established in an individual with the clinical features, a 46,XX karyotype and evidence of presence of either SRY (SRY-positive 46,XX testicular DSD) or copy number variants/rearrangements in/around SOX9 (SOX9-related 46,XX testicular DSD) or SOX3 (SOX3-related 46,XX testicular DSD); the last two are collectively referred as SRY-negative 46,XX testicular DSD. About 15% of patients with 46,XX testicular DSD are born with ambiguous genitalia: typically penoscrotal hypospadias with or without chordee (Zenteno-Ruiz et al. 2001). The majority is SRY negative (Fechner et al. 1993; McElreavey et al. 1993; Boucekkine et al. 1994). About 85% of patients with 46,XX testicular DSD present with normal pubic hair/penile size, small testes, gynecomastia, and azoo- spermia after puberty (Zenteno-Ruiz et al. 2001). The vast majority of them are SRY positive (McElreavey et al. 1993). The testes are usually soft but may become firmer in time. A minority presents with cryptorchidism and/or anterior hypospadias (Boucekkine et al. 1994). Management is similar to that for other causes of testos- terone deficiency.

47,XYY Syndrome

It is the commonest sex chromosome anomaly following Klinefelter’s syndrome (Hook and Hamerton 1977; Gekas et al. 2001; Rives et al. 2005a), occurring in around 1/1000 males born alive (Morel et al. 1999; Rives et al. 2005a). Non-mosaic form results from paternal nondisjunction at second meiosis, leading to passage of an extra Y chromosome to the offspring (Wong et al. 2008; El-Dahtory and Elsheikha 2009). Passage following parental nondisjunction after postzygotic mitosis results in mosaic (46,XY/47,XYY) (Moretti et al. 2008; El-Dahtory and Elsheikha 2009). Patients often present delayed speech, learning disabilities, and behavioral problems, but the majority is diagnosed late due to indistinguishable phenotypical characteris- tics from 46,XY individuals (Stochholm et al. 2010). Sperm counts range from normal to azoospermia (Faed et al. 1976; Lim et al. 1999; Egozcue et al. 2000; Rives et al. 2005a; Abdel-Razic et al. 2012; Kim et al. 2013). Fertility may be impaired (Speed et al. 1991; Blanco et al. 1997; Chevret et al. 1997; Morel et al. 1999; Gonzalez-Merino et al. 2007), but many are fertile (Rives et al. 2005a; Moretti et al. 2008; Wong et al. 2008; El-Dahtory and Elsheikha 2009). Overall, 47,XYY negatively affects sperm count and maturation (Kim et al. 2013). Pregnancy can spontaneously be achieved, but in vitro fertilization/intracytoplasmic sperm injection is often required and genetic counseling is recommended (Gonzalez- Merino et al. 2007). 12 F. Dimitriadis et al.

Klinefelter’s Syndrome

Klinefelter’s syndrome (47,XXY) is the most common sex chromosome abnormality (Davila Garza and Patrizio 2013) and the most common genetic reason for azoo- spermia: approximately 14% of azoospermic cases (Turek 2008).The 47,XXY genotype is found in 90% of Klinefelter’s men, whereas 10% are mosaic, with a combination of 47,XXY/46,XY chromosomes. While newborns with Klinefelter’s syndrome demonstrate no significant dysmorphism, typically, as adult men they have small firm testicles, gynecomastia, and azoospermia (Turek 2008). However, the phenotype varies from a normally virilized man to one with signs of androgen deficiency, including delayed sexual maturation, scant body hair, female hair distribution, as well as long arms and legs. The testes are less than 3.5 cm, and the histologic pattern reveals degeneration of the seminiferous tubules, progressive hyalinization, fibrosis (Turek 2008), and hyperplasia of Leydig cells. Leydig cell secretory function is impaired leading to a reduced capacity for testosterone synthesis (Wang et al. 1975). Thus 63–85% of men have low testosterone levels (Groth et al. 2013). Approximately 8% of Klinefelter’s syndrome men have sperm in the ejaculate, whereas the rest are azoospermic (Oates 2012). Thus, paternity with this syndrome is rare but more likely in the mosaic or to hidden mosaicism with 46,XY cells in the gonads (Wieacker 2006). In patients with azoospermia, the therapeutic approach should include TESE (or micro-TESE) since spermatozoa can be found in about 30% of cases (Tournaye et al. 1996; Kamischke et al. 2003) especially if biopsy is done at younger age. Therefore, even if Klinefelter’s syndrome men in their early twenties may not desire immediate conception, a preventive testicular or ejaculated sperm recovery and cryopreservation of the recovered spermatozoa should be a correct way to preserve their future fertility. ICSI after testicular sperm extraction offer a potential fertility to non-mosaic Klinefelter’s syndrome patients. Men with Klinefelter’s syndrome require a close follow-up (possibly every year). Androgen replacement therapy should be start after the appearance of fertility problems and when testosterone level is in the range of hypoandrogenism.

Y Chromosome Microdeletions

The human Y chromosome is one of the smallest chromosomes in humans (approx- imately 60 mega base pairs), containing many of the genes crucial for the develop- ment of the male gonads and the spermatogenesis (Tilford et al. 2001; Navarro-Costa 2012). In fact, the long arm of the Y chromosome contains three partially over- lapping but discrete regions that regulate spermatogenesis (Vogt et al. 1996). The loss of one of these regions, indicated as AZF (azoospermia factor)a, AZFb (P5/proximal P1), AZFc (b2/b4), and AZFbc (with two variants differing in the proximal breakpoint: P5/distal P1 and P4/distal P1), can lead to infertility (Skaletsky et al. 2003). These deletions are thought to occur between the palindromic and direct repeats (Repping et al. 2002). Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 13

The incidence of AZF deletions is 15–20% in idiopathic azoospermic men and 7–10% in idiopathic severe oligozoospermic men (Kraus et al. 2005). Y chromo- some microdeletions are extremely rare in infertile men with sperm concentration more than 5 million/ml. AZFc deletions are most common (65–70%) (Simoni et al. 2008), followed by Y microdeletions of the AZFb and AZFb + c or AZFa + b + c regions (25–30%). AZFa region microdeletions are rare (5%) (Massart et al. 2012). Infertile men with Y chromosome microdeletions generally have no apparent symptoms and present severely disturbed spermatogenesis. Testicular histopathol- ogy varies from complete or focal SCO syndrome to spermatogenic arrest or hypospermatogenesis (Simoni et al. 2008). However, microdeletions are not found in normozoospermic men suggesting a direct relationship between Y deletions and spermatogenic failure (Krausz et al. 2003). Azoospermic men present the highest frequency of Y microdeletions (8–12%), followed by oligozoospermic (3–7%) men (Simoni et al. 1997). Complete deletion of the AZFa region leads to SCO syndrome, while complete deletion of the AZFb region causes spermatogenic arrest. On the other hand, men carrying complete AZFc deletions have severe oligozoospermia in about 50% of cases, and in azoospermic carriers, successful TESE seems possible in about half of them (Mulhall et al. 1997; Brandell et al. 1998; Kamp et al. 2001; Zhou-Cun et al. 2006; Jungwirth et al. 2016). Complete AZF deletions are not associated with higher risk for cryptorchidism or testicular cancer (Krausz and Degl’Innocenti 2006). In most cases, the son will have the same microdeletion as his father (Krausz et al. 2014) or occasionally the son may have a larger one (Stuppia et al. 1998). Recently, new “partial deletions” of AZFc region have been reported (Repping et al. 2003) deleting approximately half of the gene content of AZFc region (including two DAZ copies and one CDY1 copy). Among them, gr/gr partial deletion is believed to cause spermatogenic impairment especially oligozoospermia (Repping et al. 2003; Giachini et al. 2005; Giachini et al. 2008; Visser et al. 2009). This type of deletion arises by homologous recombination and has been extensively examined in large groups of men worldwide conferring a 2.5–8-fold increased risk for oligozoospermia (Giachini et al. 2008; Visser et al. 2009; Navarro-Costa et al. 2010; Stouffs et al. 2011; Krausz et al. 2014). Other microdeletions in the AZFc region most commonly reported in the litera- ture are encompassing copies of the DAZ gene (previously known as SPGY), which is believed to be integrally associated with spermatogenesis (Saxena et al. 2000). DAZ protein is cytoplasmic, and its expression is limited to the male germ line regulating gametogenesis and protein translation during spermatogenesis. DAZ is detected only in humans and old-world primates. The rest of the mammals possess an autosomal homologue (DAZL) which in mice is located on chromosome 17. The corresponding human autosomal homologue is also present and located on chromo- some 3p24 (Dorfman et al. 1999). DAZL is required for the fertility of male and female mice since homozygous knockout DAZL mice of both sexes are infertile (Saunders et al. 2003). 14 F. Dimitriadis et al.

Sertoli Cell-Only Syndrome (Germ Cell Aplasia)

Sertoli cell-only (SCO) syndrome also known as germ cell aplasia, rather than a diagnosis, represents a histopathologic phenotype (Del Castillo et al. 1947). Nieschlag et al. reported that about 30% of their infertile patients presented focal or complete SCO syndrome, and in 8% of them, SCO syndrome was bilateral (Nieschlag et al. 2010). Complete germ cell aplasia is characterized by spermatic tubules, with decreased diameter, totally devoid of germ cells and containing only Sertoli cells. The interstitial tissue, as well as the basement membranes and the Sertoli cells, is normal with the later ones presenting an increased apoptotic index (Kim et al. 2007). The patients representing this histologic pattern are always infertile. However, more often the SCO syndrome is focal with varying percentage of tubules containing germ cells. In these tubules spermatogenesis is often in both quantitatively and qualitatively limited (hypospermatogenesis) (Nieschlag et al. 2010). In these later cases, germ cells such as elongated spermatids may be found in the biopsy which are suitable for intracytoplasmic sperm injection (ICSI). The SCO syndrome is one common cause of nonobstructive azoospermia (NOA) (Nieschlag et al. 2010). SCO syndrome can be due to lack of migration of the primordial germ cells from the yolk sac into the future gonads or due to their succumb in the spermatic epithelium after their migration. The molecular mechanisms leading to completion of spermatogenesis are still under investigation. Common reasons of complete loss of germ cells are antineoplastic treatment such as chemotherapy or radiation, mumps orchitis, maldescended testes, androgen resistance (Nieschlag et al. 2010; Walsh and Smith 2013), and chromosomal abnormalities, especially Y chromosome micro- deletions (Foresta et al. 1998). The testicular volume is usually reduced or in the lower normal range (Nieschlag et al. 2010). The histology of Sertoli cells represents normal but with an increased apoptotic index (Kim et al. 2007). In the interstitial tissue, Leydig cells are usually not affected so that patients have usually normal testosterone levels and infertility is the only reason to seek medical consultation (Nieschlag et al. 2010); only few patients have hypoandrogenism requiring treat- ment. On the other hand, FSH is usually elevated (Bergmann et al. 1994). Inhibin B correlates negatively with the degree of testicular failure, improving the diagnostic sensitivity, but it cannot predict with high diagnostic accuracy the presence or absence of foci of advanced spermatogenesis (von Eckardstein et al. 1999). The diagnosis of SCO syndrome requires testicular biopsy. However, in certain SCO syndrome patients, the testicular biopsy was positive for sperm retrieval by microsurgical testicular sperm extraction (micro-TESE) (Schulze et al. 1999) suggesting a marked discordance of spermatogenic phenotype pattern between both testes that can be detected in about 28% of patients (McLachlan et al. 2007). At the moment, there is no treatment for the spermatogenic failure of complete SCO syndrome patients that leads to improvement of spermatogenesis. Micro-TESE should therefore be planned as both a diagnostic and therapeutic procedure (Sabanegh and Agarwal 2012). Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 15

Gonadotoxins

Effects of Radiation The testis represents high sensitivity to radiation. Radiation has its most potent effect upon spermatogonia, especially upon spermatogonia type B (Beretta 2015). Sper- matocytes, on the other hand, are less sensitive and spermatids are rather radio- resistant. The likeliness of infertility after radiation depends mainly on the dose to the testes but also on the shielding and fractionation (multiple doses) (Meistrich and Beck 1990). A temporary reduction in sperm count occurs after a radiation dose of 0.15 Gy, while single exposures above 2 Gy may cause azoospermia (Rowley et al. 1974). Higher doses cause delay in recovery of sperm output, which is proportional to dose and beyond 4Gy the spermatogenic damage is persistent for up to 5 years or may produce irreversible damage, consistent with spermatogonial eradication. Frac- tionation has a more favorable effect in terms of side effects but causes more damage to sperm than a larger, single radiation dose (Beretta 2015). Leydig cells are less sensitive to the effects of radiation, with damage occurring at 30 Gy in mature males and 20 Gy in prepubescent males. High-frequency electromagnetic radiation (from 300 kHz to 300 mHz) is non- ionizing radiation transmitted by cellular phones, among other devices or related to occupational exposure such as in employees working with thermal plastic sealing, physiotherapy, and military radar equipment. Early studies showed that the apparent effect of high-frequency electromagnetic radiation on semen quality may be due to the heating effect associated with the radiation. Cell phone usage has been associated with decreased sperm progressive motility, decreased sperm viability, increased levels of reactive oxygen species, decreased sperm counts, and increased abnormal sperm morphology (Kilgallon and Simmons 2005; Agarwal et al. 2008).

Effects of Drugs, Lifestyle, and Toxicants A variety of prescription drugs can impair fertility by direct toxic effect on germ cells or interfere with the reproductive axis. Ketoconazole and spironolactone disrupt testicular steroidogenesis and lower serum testosterone levels. Cimetidine acts as an androgen antagonist (Turek 2008). Antihypertensive agents decrease sperm motility and interfere with the ability of spermatozoa to penetrate and fertilize the ova. In addition antihypertensive agents cause decreased libido and/ or sexual dysfunction. Antibiotics including erythromycin, nitrofurantoin, gentamycin, and tetracycline demonstrate direct gonadotoxicity or adversely affect sperm function. Sulfasalazine, a medicine used for the treatment of ulcerative colitis, is linked with reversible impairment of basic sperm parameters (Toth 1979). Cancer chemotherapy has been considered to eradicate rapidly dividing cells leading to undesirable cytotoxic effect on normal tissues such as the spermatogenic epithelium especially the differentiating spermatogonia (Turek 2008). Cyclophosphamide, chlorambucil, and nitrogen mus- tard are examples of alkylating agents with severe gonadotoxic effects (Turek 2008). Exogenous androgens suppress gonadotropins, thus acting against fertility at a pre-testicular level. The overall effect is suppression of sperm production. 16 F. Dimitriadis et al.

Recreational drugs have also demonstrated gonadotoxic effect. They are thought to disrupt hormone secretion at more than one level of the reproductive axis. Tobacco smoking has been linked with an enhanced frequency of sperm cell aneuploidies (Harkonen et al. 1999). Moreover, tobacco smoking may cause decreased sperm concentration, forward motility, morphology, and viability (Vine 1996), as well as declines in sperm penetration ability (Sofikitis et al. 1995; Joesbury et al. 1998). Pesticides include a vast and heterogeneous group of chemical compounds designed to produce deleterious effects on living organisms. The most well- established example of occupational adverse effects on male reproduction is nema- tocide dibromochloropropane (DBCP). Its deleterious action is likely to be mediated through an estrogen-like activity (Turek 2008). Several other pesticides in current use, such as chloroprene, para-tertiary butyl acid, and 2,4-dichlorophenoxyacetic acid (Lerda and Rizzi 1991), are also suspected for reproductive toxicity (Bonde and Toppari 2010). Other gonadotoxic compounds which may affect the male reproductive health mainly due to occupational exposure include inorganic lead, cadmium, mercury, manganese, and organic solvents (Lee and Dixon 1975; Lauwerys et al. 1985; McGregor and Mason 1990; Vanhoorne et al. 1994; Kolstad et al. 1999; Bonde 2006).

Systemic Diseases

Chronic Renal Failure Chronic renal failure (CRF) affects hypothalamic–pituitary–gonadal axis both cen- trally and peripherally. Uremia has been shown to be linked with reduced fertility potential, decreased sexual activity and libido, and gynecomastia (Turek 2008). In addition, CRF causes direct testicular effects; often testicular atrophy (Handelsman et al. 1995) with manifestations suggesting both endocrine and exocrine testicular dysfunction (Mastrogiacomo et al. 1984; Prem et al. 1996). The underlying mechanism of hypogonadism in CRF is still eluding and likely multifactorial. Testosterone levels are usually diminished and associated with ele- vated FSH and LH levels (Turek 2008). In 25% of patients suffering from CRF, serum prolactin levels are raised (Kheradmand and Javadneia 2003; Turek 2008). In addition, it is probable that the estrogen excess which has been described in patients with CRF may have a detrimental effect on testicular steroid biosynthesis (Mahmoud and Comhaire 2006). Hemodialysis may improve sperm motility (Kheradmand and Javadneia 2003). However, the only effective treatment is renal transplantation (Prem et al. 1996). Subfertile CRF men with untreatable severely impaired semen quality may partici- pate in assisted reproductive technology trials (Bonde and Toppari 2010). Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 17

Liver Failure Liver diseases, particularly liver cirrhosis, cause reproductive dysfunction regardless of the reason for cirrhosis (i.e., hepatitis or excessive alcohol intake). Liver failure is associated with loss of libido, sexual dysfunction and reduced fertility and secondary sexual characteristics, as well as testicular atrophy, and gynecomastia (Sartorius and Handelsman 2010). The pathogenesis of hypogonadism in liver cirrhosis is not fully elucidated and may include various contributing factors. It has been recorded an augmented con- version of androgens to estrogens by aromatases that produce excess of serum estradiol (Kaymakoglu et al. 1995; Baker 1998). Testosterone levels are low, while sex hormone-binding globulin is elevated, further reducing the bioavailable testos- terone level. Gonadotropins are elevated or may remain unchanged (Luppa et al. 2006). The severity of the liver disease determines the deterioration of the repro- ductive functions. Liver transplantation can normalize the hypothalamic–pituitary–testicular hor- mone axis and gonadal tissue function in the majority of the cases (Handelsman et al. 1995).

Hematological Diseases

Sickle Cell Disease Men with sickle cell disease display eunuchoid skeletal proportions, reduced testicular volume, decreased muscle mass, and decreased hair (Landefeld et al. 1983; el-Hazmi et al. 1992). Sickle cell anemia can cause hypogonadism and spermatogenic failure as a result of thromboses and multiple microinfarcts, both in the hypothalamus and in the testes. In a significant proportion of patients with sickle cell disease, serum testosterone levels are low, and gonadotropin levels are variable (Walsh and Smith 2013).

β-Thalassemia Patients with β-thalassemia undergo regular transfusions that produce iron overload leading to decreased gonadotropin levels and subsequent hypogonadotropic hypo- gonadism with impaired semen parameters (Safarinejad 2008). However, if fully sexually maturated, 45% of β-thalassemic subjects will have normal sperm count and motility (De Sanctis et al. 1989). Prepubertal onset of iron chelation therapy may potentially reverse fertility- related complications in β-thalassemic patients (Bronspiegel-Weintrob et al. 1990; Farmaki et al. 2010).

Alcoholism While small amounts of alcohol intake seem to have no negative effect on male fertility (Bonde and Toppari 2010), acute excessive alcohol intake causes sharp drop of peripheral testosterone levels and should be taken into consideration when counseling men with pregnancy plans (Bonde and Toppari 2010). Excessive alcohol 18 F. Dimitriadis et al. intake interferes with the endocrine system and causes systemic pathologies in organs that can compromise fertility such as the gonads and the liver (Mahmoud and Comhaire 2006). Chronic alcoholism disturbs the peripheral hormonal metab- olism (Bonde and Toppari 2010). It has been shown experimentally that blood testosterone concentrations decrease within hours after ingesting a sufficient amount of alcohol to produce hangover (Bonde and Toppari 2010). Likewise, in chronic alcoholism, the levels of testosterone are low (Bonde and Toppari 2010). Other manifestations of chronic alcoholism include reduced libido, sexual dysfunction, gynecomastia, testicular atrophy, and reduced sperm count and thus reduced fertility (Bonde and Toppari 2010), and furthermore on a nearly daily basis of alcohol abuse, these effects are more prominent. The elevated LH levels suggest that high ethanol concentration in peripheral blood may exert direct toxic effect on the testis (Pajarinen and Karhunen 1994, Pajarinen et al. 1997). Moreover, in chronic alcoholism the serum concentrations of estrogens are usually increased due to the increased con- version of androgens to estrogens in the liver and fat cells (Bonde and Toppari 2010). Chronic alcoholism is also linked with extensive suppression of the hypo- thalamic–pituitary–gonadal axis suggesting a detrimental effect of alcohol at pre-testicular level as well (Salonen et al. 1992).

Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia (CAH) includes various autosomal recessive pathol- ogies caused by gene mutation coding enzymes involved in the biochemical steps of steroidogenesis (Warrell 2005). Any alteration in the production of sex steroids may adversely interfere with the primary or secondary male sex characteristics (Milunsky and Milunsky 2010). If it is not treated adequately, CAH may be accompanied by infertility, reduced testes volume, decreased sperm counts even up to azoospermia, and decreased gonadotropic levels (Winters 1999). Adequate restoration of gluco- corticoids and mineralocorticoids levels normalizes spermatogenesis (Winters 1999).

Chronic Gastrointestinal Diseases Chronic inflammatory bowel diseases (i.e., ulcerative colitis and Crohn’s disease) are often linked with impaired fertility and a delayed puberty. The underlying mecha- nisms may involve a combined effect of chronic inflammation factors such as fever, undernutrition, and cytokines (i.e., as TNFa) which frequently impair spermatogen- esis (Farthing and Dawson 1983). Celiac disease has controversial effect on male fertility. Some investigators associate celiac disease with delayed puberty, subfertility, and reduced sperm param- eters (Bona et al. 2002), while others do not find any major influence of untreated celiac disease on male reproductive health (Lohi et al. 2009).

Fever Fever may affect sperm parameters (Carlsen et al. 2003). The adverse effect of the fever depends on the duration of the elevated temperature (Carlsen et al. 2003). Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 19

Other studies associated fever with sperm DNA damage (Evenson et al. 2000). However, these effects appear to be temporary.

Human Immunodeficiency Virus (HIV) Infection The prevalence of hypogonadism in patients with HIV infection under antiretroviral therapy ranges from 20% to 25% (Rietschel et al. 2000; Crum et al. 2005). Primary hypogonadism in HIV-infected men could be caused by malignancies or testicular atrophy due to opportunistic infections (Baker 1998; Umapathy et al. 2001). Sec- ondary hypogonadism is more commonly associated with fertility problems in HIV-positive patients. The popular use of anabolic steroids in these patients is another cause of hypogonadism (Pena et al. 2003). In addition, cytokine release may affect the reproductive axis in HIV patients (Mylonakis et al. 2001). Interleukin-1 interferes with gonadotropin release and LH binding to Leydig cells leading to decreased testosterone levels (Mylonakis et al. 2001). It has been reported that serum hormone-binding globulin increases as the disease progresses in HIV/AIDS syndrome resulting in decreased bioavailable testosterone (Poretsky et al. 1995). When assisted reproductive techniques are required to overcome fertility issues in HIV-infected hypogonadal men, it is necessary to separate accurately the spermato- zoa from the leukocytes during semen laboratory manipulation since the HIV virus is transferred by leukocytes and not by spermatozoa (Sauer 2005).

Oncological Diseases Neoplasms in general can severely compromise spermatogenesis (Costabile and Spevak 1998). Although nowadays an increasing proportion of cancer patients will survive their disease due to the improvements in cancer therapy, cancer therapy itself may have detrimental and sometimes irreversible impact on the individual’s fertility. Particular malignancies such as Hodgkin disease have gonadotoxic effects even before administration of treatment due to endocrinopathies, germ cell genetic abnor- malities, and cytokine production interfering deleteriously to both the seminiferous tubules and the interstitial testicular tissue (Rueffer et al. 2001). Other mechanisms leading to decreased spermatogenesis include destruction of the surrounding tissue by the neoplasm, alterations in the local testicular blood flow with intrascrotal temperature elevation, and local production of hCG and other paracrine agents. Pelvic radiation treatment may cause permanent spermatogenic arrest and azoosper- mia (Rowley et al. 1974), and therefore appropriate protection of the gonads during treatment is crucial (Mahmoud and Comhaire 2006). Chemotherapy can cause irreversible damage especially when alkylating agent-based regimens are employed (Colpi et al. 2004). Therefore, multiple semen samples should be cryopreserved prior to radiotherapy or chemotherapy in all cases when fertility is desired (Meistrich 1993). If the patient cannot ejaculate (i.e., pediatric patients), the use of a vibrator may be attempted. However, due to practical issues, testicular tissue recovery and freezing may be more feasible in these cases. Freezing spermatozoa or their pre- cursors gives the probability to these patients to father their own biological children. 20 F. Dimitriadis et al.

Orchitis Epididymo-orchitis is commonly caused by bacterial infections of the testicular tissue (Turek 2008). Viral infections and more frequently infectious parotitis (mumps), coxsackie, or herpes are also seen (Mahmoud and Comhaire 2006). Mumps orchitis in postpubertal men is a common complication of infectious paro- titis affecting approximately 20–30% of cases. The pathogenic mechanism leading to compromised fertility is not fully elucidated. Most probably the testicular inflam- mation and the subsequent edema increase the intratesticular pressure leading to testicular atrophy (Bartak 1973). In cases of azoospermia, testicular sperm extraction is indicated even with high concentrations of FSH and LH (Masuda et al. 2011).

Obesity Fertility status in men is also linked to alimentary factors (Pusch 1996). It has been shown that overweight in the male is independently contributing up to 50% higher rate of fertility problems in comparison with non-obese men (Pauli et al. 2008). Obesity associated infertility is mainly linked with increased estradiol to androgen ratio due to enhanced androgen to estrogen conversion in the adipose tissue (Mahmoud and Comhaire 2006) with suppressing effects on pituitary gonadotropin secretion (FSH and LH) affecting negatively spermatogenesis (Schlegel 2012). Other mechanisms include increased leptin production in the adipose tissue with detrimental effect on the sperm functionality (Hofny et al. 2010) and hyper- insulinemia which is related to inhibition of spermatogenesis, damage in sperm DNA, and subsequent reduction in fertility (Agbaje et al. 2007).

Testis Injury

Testicular Torsion Testicular torsion is an urgent medical condition threatening the viability of the testis. Prompt surgical approach may rescue the torsed testis but infertility remains one of the main potential sequela (Bartsch et al. 1980). The “normal” non-torsed contralateral testis may also present histologic alterations (Turek 2008). The principal pathophysiologic mechanism in testicular torsion is ischemia–re- perfusion (IR) injury which probably involves the production of reactive oxygen species (Anim et al. 2005). Reactive oxygen species cause DNA damage, germ cell necrosis/apoptosis in both testes, and loss of spermatogenesis (Prillaman and Turner 1997; Turner et al. 1997; Lysiak et al. 2001). This loss of spermatogenesis may be attributed to germ cell-specific apoptosis. So far experimental data from animal models offer some interesting new modal- ities to overcome the detrimental effect of IR injury to the testis. Among them the use of sivelestat, a neutrophil elastase inhibitor, has been found to reduce the oxidative stress and partially prevent the testicular damage both in the ischemic and in the contralateral testis (Tsounapi et al. 2011). Likewise, cromakalim, a KATP channel opener, shows a beneficial effect against IR-induced testicular damage (Tsounapi Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 21 et al. 2012). Moreover, ischemic post-conditioning, a surgical maneuver including rapid intermittent suspensions of blood supply in the early stage of reperfusion, may also protect both testes after unilateral testicular ischemia and reperfusion (Shimizu et al. 2011).

Trauma The testis represents an immunologically privileged site in the body, and because of this peculiar immunological status, trauma to the testis can raise a nonphysiological immune response potentially leading to infertility. In contrast, minor scrotal injuries are common but usually without any impact to fertility (Mahmoud and Comhaire 2006). The effect of testicular injury on semen characteristics is highly variable and depends on the extent and the type of the testicular trauma (Rowe et al. 2000).

Idiopathic Infertility

Idiopathic infertility is characterized by oligospermia and/or asthenospermia and/or teratospermia with no observable cause and applies approximately for the 30% of infertile men (Nieschlag 1997). Infective agents such as chlamydia trachomatis and adenovirus infections have been associated with idiopathic oligoasthenotera- tospermia (iOAT) (Eggert-Kruse et al. 1997). On the other hand, noninflammatory functional alterations of male accessory glands appear to play a more important role in some cases of iOAT. For example, low prostatic secretory function (Carpino et al. 1994), diminished epididymal neutral α-glycosidase, or modification of epididymal methylation of spermatogenesis-related genes may also be involved in some cases of iOAT (Ariel et al. 1995). Gene mutations in the X chromosome (Turek 2008), subtle hormonal alterations and molecular variants of LH are some other possible expla- nations of human iOAT cases (Ramanujam et al. 2000). Moreover, environmental pollutants and lifestyle characteristics may also deteriorate semen quality. The consequences of decreased physical activity, obesity, alcohol, tobacco use, psycho- logical stress, and cellular phone usage on male infertility have been investigated, but further well-designed placebo-controlled trials are necessary in order to extrap- olate solid conclusions (Walsh and Smith 2013). Due to the absence of obvious causality in the cases of iOAT, the therapeutic approach involves the employment of empiric medical treatment or assisted repro- ductive techniques (Siddiq and Sigman 2002).

Post-Testicular Causes of Male Infertility

The post-testicular causes of infertility include obstruction or stricture of the ductal system of the male reproductive tract (Fig. 3). In contrast with testicular disorders, post-testicular abnormalities are commonly treatable. Thus, restoration of fertility potential may be possible. 22 F. Dimitriadis et al.

Fig. 3 Post-testicular causes of male infertility. CBAVD congenital bilateral absence of the vas deferens, CUAVD congenital unilateral absence of vas deferens, IEO idiopathic epididymal obstruc- tion, APKD adult polycystic kidney disease, BEDO bilateral ejaculatory duct obstruction, ICS immotile cilia syndrome, HPV human papillomavirus, HSV herpes simplex virus, HBV hepatitis B virus, HCV hepatitis C virus, HCMV human cytomegalovirus

Male Reproductive Tract Obstruction

A certain number of infertile men have normal spermatic epithelium, and it is the lumen of the male genital tract that does not allow the spermatozoa to reach the external urethral orifice.

Congenital Bilateral Absence of the VD (CBAVD) Cystic fibrosis (CF): CF affects approximately 1 in 2000 newborns. Progressive pancreatic insufficiency and bronchopulmonary disease are common clinical Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 23 manifestations (Welsh et al. 1995). It is an autosomal recessive disease commonly found in Caucasians. ΔF508 is a major gene mutation in the encoding area of CF transmembrane regulator (CFTR) that can be identified in over 75% of patients with CF. Infertility due to obstructive azoospermia is very common (Kaplan et al. 1968; Heaton and Pryor 1990). Clinical features of the disease include azoospermia, acidic (pH < 7.2) ejaculate of decreased volume (<2 mL), as well as decreased seminal plasma levels of epididymal and seminal vesicle markers. Pancreatic insufficiency, bronchopulmonary disease, and malformations of the genital tract in CF are consequences of mutations in the CF transmembrane conduc- tance regulator (CFTR) gene (Kerem and Kerem 1996). Sperm obtained from men with both CFTR mutations and CBAVD were linked with increased risk of miscar- riage and stillbirth after ICSI as compared with men without either CFTR mutations or CBAVD (Lu et al. 2014). Decreased motility and fertilizing capacity in sperma- tozoa obtained from elderly men with CFTR mutations (Diao et al. 2013) and downregulation of CFTR protein in testicular samples were observed (Xu et al. 2011). Thus an additional role for CFTR (to that related to CF disease) was indicated. Genetic links between CF and CAVD have been established due to the increased frequency of the p.Phe508del mutation described in CAVD patients (Anguiano et al. 1992). The p.Arg117His, p.Phe508del, and T5 allele have been proposed to be the commonest CFTR mutations in Caucasians with CAVD phenotype (Chillon et al. 1995; De Braekeleer and Ferec 1996). New mutations for CF are continuously discovered. Four novel mutations of the CFTR gene are discovered (Yang et al. 2015). The gene mutation spectrum of CFTR varies markedly among populations (mutations in Indian CAVD males are different from those observed in Caucasians) (Sharma et al. 2014). Congenital blockage: CBAVD is a genital tract pathology, genetically related to CF but with a distinct clinical pattern. A certain number of patients present a history of chronic sinusitis, nonprogressive bronchitis, and pneumonia in infancy but their main complaint as adults is infertility (Augarten et al. 1994; Casals et al. 1995). The semen parameters are similar as in men with CF disease (Oates and Amos 1994). VD aplasia is accompanied by epididymal tail aplasia and several anatomical or func- tional abnormalities of the SV (Mercier et al. 1995) (Table 1).

Congenital Unilateral Absence of VD (CUAVD) Unilateral VD obstruction is compatible with natural fertility. Therefore, CUAVD is believed to remain in the most cases undiagnosed. CUAVD is attributable to defective organogenesis of the Wolffian duct system. Renal agenesis is a common clinical feature as well. Also, bilateral or unilateral vasal hypoplasia or unilateral absence of the VD may cause obstructive azoospermia. It was found that a high percentage of men with CUAVD demonstrated abnormalities in the contralateral ejaculatory ducts or seminal vesicles as well (Raviv et al. 2006). CUAVD is associated also with CFTR mutations (Mickle et al. 1995). 24 F. Dimitriadis et al.

Table 1 Cystic fibrosis gene (CFTR) mutations in men with various disorders of the seminal ducts and seminal vesicles. CBAVD congenital bilateral absence of the vas deferens, CUAVD congenital unilateral absence of vas deferens Author Patients % of (+) mutation CBAVD (Dumur et al. 1990) 17 20.6 (Anguiano et al. 1992)2538 (Osborne et al. 1993)2638 (Augarten et al. 1994)4738 (Culard et al. 1994)1266 (Oates and Amos 1994)4982 (Chillon et al. 1995) 102 78 (Costes et al. 1995)4589 (Jarvi et al. 1995)2580 (Le Lannou et al. 1995)2677 (Mercier et al. 1995)6766 (Rave-Harel et al. 1995)4048 (Silber et al. 1995)5270 (Zielenski et al. 1995)7079 (Dork et al. 1997) 101 84 (Attardo et al. 2001)3471 (Wang et al. 2002)9267 (Anzai et al. 2003)1958 (Grangeia et al. 2005)3158 (Radpour et al. 2006) 106 80 (Chiang et al. 2009)6357 (Bareil et al. 2007) 217 68 (Giuliani et al. 2010)2360 (Sachdeva et al. 2011) 35 100 CUAVD (Jarvi et al. 1995)250 (Mickle et al. 1995)2138 (Dork et al. 1997)475 (Grangeia et al. 2005)475 Ejaculatory duct obstruction (Meschede et al. 1997)786 Seminal vesicles anomalies (Meschede et al. 1997)1613 Young’s syndrome (Hirsh et al. 1993)729 (Le Lannou et al. 1995)120 Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 25

Young’s Syndrome Young’s syndrome is a pathophysiology presented with obstructive azoospermia chronic sinopulmonary infections and bronchiectasis. Young’s syndrome may represent genetic variations of Kartagener syndrome (Ichioka et al. 2006) or CFTR gene mutations (Goeminne and Dupont 2010). Genetic testing is required in these patients. Young’s syndrome may cause a bilateral epididymal obstruction leading to azoospermia. The obstruction is the result of the presence of an amorphous mass within the epididymal lumen (Handelsman et al. 1984). The pathophysiology may involve abnormal mucus quality or abnormal ciliary function. Patients may report sino-bronchial symptoms from early childhood on, and they can develop bronchi- ectasis over time. The surgical reconstruction is technically feasible but with poor outcomes (Hendry et al. 1993).

Idiopathic Epididymal Obstruction Epididymal obstruction (EO) is the most frequent cause of OA affecting 30–67% of men with azoospermia (Dohle et al. 2005). Idiopathic EO is a relatively uncommon pathology found in men with no other apparent health problems. Recent evidence is linking this condition to CF. The causes of EO may be infection-related, iatrogenic, trauma-related, vasectomy-related, and idiopathic (Chan et al. 2005, 2008). In a study, of 134 consecutive men with azoospermia, idiopathic EO was detected in two-thirds of the cases in which blocked reproductive duct was suspected (Peng et al. 2012). On the other hand, Chan et al. (2008) reported that the incidence of idiopathic EO in his study was only 3%. EO is assumed to take place when the pressure within the epididymal lumen surpasses the integrity of the delicate epididymal tubule leading to sperm extravasation with consequent EO (Peng et al. 2012).

Polycystic Kidney Disease Adult polycystic kidney disease (APKD) is a hereditary systemic disorder, affecting multiple organs. Patients with APKD usually have no fertility problems, though various studies have documented male infertility in these patients (Peces and Venegas 2005;Shefi et al. 2009). The most commonly reported semen aberration in these patients is asthenozoospermia (Torra et al. 2008) due to structural defects at spermatozoa tail and abnormal polycystins. The dilation of the SV noted in men with APKD usually is the result of the distal obstruction.

Ejaculatory Duct Obstruction Common reasons for a bilateral ejaculatory duct obstruction (BEDO) include exter- nal compression from neoplasms or cysts, infectious disorders, or traumas. Consti- tutional BEDO is another distinct cause of male infertility and results from CFTR gene variations (Meschede et al. 1997). Clinical features of men with BEDO are azoospermia, small semen volume, dilated SV, normal secondary sex characteristics, normal testicular volume, and normal hormonal profiles. A transrectal ultrasound may be performed to confirm the diagnosis (Hopps et al. 2002). 26 F. Dimitriadis et al.

Acquired Blockages

Iatrogenic Injuries: Groin Surgery A variety of surgical procedures in the inguinal, pelvic, and scrotal areas such as herniorrhaphy, appendectomy, renal transplant, and hydrocelectomy may cause vasal injury and postsurgical obstruction up to 25% of the cases (Steigman et al. 1999; Ridgway et al. 2002). A common reason of non-vasal obstruction is accidental injury during surgery for hernia repair which more commonly takes place when the hernia repair is performed during infancy (59%). However, it may occur after any inguinal surgery when the spermatic cord is manipulated (Matsuda et al. 1992). Postoperative inflammatory response caused by the mesh may entrap and obstruct the inguinal VD. Patients with the history of bilateral hernia reconstruction had a slightly raised risk for infertility (<1%) (Hallen et al. 2012). Surgical repair is feasible in many cases of iatrogenic injury of the vas either in the level of the inguinal canal or in the scrotum.

Infections Infection may cause OA in 8–46% of men undergoing vasal surgery in various large series (Berardinucci et al. 1998; Chan et al. 2005; Schiff et al. 2005). Common pathogens associated with epididymitis include chlamydia, gonorrhea, brucellosis, trichomonas, mycoplasma, ureaplasma, adenovirus, coliforms bacteria, and entero- virus. Epididymitis can cause an intense inflammatory reaction, leading to secondary scarring and obstruction of the epididymis. Typically, the volume of the semen is normal. Tuberculosis may be associated with nodular and enlarged vas deference, and when tuberculosis involves the SV, the volume of the ejaculate may be reduced (Baker and Sabanegh 2013). A feasible option for postinfectious obstruction of the epididymis is scrotal exploration with microsurgical reconstruction. However in the case of tuberculosis, the extensive scarring at multiple levels of the male reproduc- tive tract gives poor outcomes (Baker and Sabanegh 2013). Prevention of this terminal obstructive status based on early treatment and resolution of the inflamma- tion gives more successful results in the reappearance of spermatozoa in the ejaculate (Paick et al. 2000).

Vasectomy for Male Contraception and Demand of Vasovasostomy Vasectomy has different prevalence among countries due to religious and cultural reasons, and it is the most common cause of vas deference obstruction performed as a contraceptive measure (Costabile and Spevak 2001). The restoration of fertility after a vasectomy relies upon vasectomy reversal through microscopic reconstruc- tion of the vas deference. Vasal, epididymal, or testicular sperm retrieval and ART can be performed in couples whose male partner has a bilateral vasectomy and a concomitant female factor is present (Baker and Sabanegh 2013). The option of sperm retrieval during the surgery and the subsequent cryopreservation should be recommended to the couples (Baker and Sabanegh 2013). Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 27

Disorders of Sperm Function or Sperm Motility

Immotile Cilia Syndrome/Primary Ciliary Dyskinesia Syndrome Immotile cilia syndrome (ICS) or primary ciliary dyskinesia (PCD) is an autosomal recessive disease. Pathological features include impaired ciliary motion and abnor- mal mucociliary clearance. DNAI1 and DNAH5 are the two genes which are directly implicated in PCD. DNAI1 and DNAH5 are encoding components that constitute the outer dynein arm complex (Guichard et al. 2001; Bush and Ferkol 2006; Hornef et al. 2006). The reported frequency is 1 per 26,000–40,000 live births. Kartagener was the first to describe a syndrome characterized by situs inversus, bronchiectasis, and chronic sinusitis known as Kartagener syndrome (Kartagener 1933). Patients with this Kartagener syndrome have defects in the ciliary defects at ultrastructural level. In subsequent studies it was noticed that the cilia rather than immotile presented a disorganized and uncoordinated motion, and therefore the term immotile cilia syndrome was changed to primary ciliary dyskinesia syndrome. The term PCD describes the genetic defect differentiating it from other acquired defects (Carson et al. 1985). Seminal analysis in primary CDS demonstrates a normal number of viable but immotile spermatozoa. Spermatozoa of patients with PCD have usually decreased motion to varying degrees or are even completely motionless with defective mor- phology. ICSI represents currently the only therapeutic approach to this condition but with poorer outcomes (Abu-Musa et al. 1999) maybe due to higher incidence of aneuploid sperm, related to primary cilia abnormalities (Rives et al. 2005b). These abnormalities may also enhance the risk of genetic defects in the offspring, and the genetic evaluation of the spermatozoa is highly suggested prior to ICSI procedures (Abu-Musa et al. 1999).

Maturation Defects Maturation process of spermatozoa demands their interaction with proteins that are synthesized and secreted by the epididymis (Toshimori 1998). Posttranslational changes of existing sperm proteins are crucial for the spermatozoon to acquire its fertilizing potential. Phosphorylation and glycosylation are common posttransla- tional changes that sperm proteins undergo during their passage through the epidid- ymis resulting in modifications in protein function resulting to the development of mature spermatozoa (Cornwall 2014). Reactive oxygen species (ROS) play a key role in the physiology of the sperm function. Normal quantitative profiles of ROS are involved in the initiation and development of several sperm functions including sperm hyperactivation, sperm capacitation, and acrosome reaction (de Lamirande and Gagnon 1995; Griveau et al. 1995). On the other hand, an overproduction of ROS leads in oxidative damage of sperm membrane lipids, sperm proteins, and sperm DNA (Alvarez and Storey 1984; Aitken 1995) resulting in decreased motility, damaged acrosomal membranes, and thus inability of the spermatozoon to fertilize the oocyte. Poor sperm and decreased motility have been associated with mutations in the mitochondrial DNA (Ruiz-Pesini et al. 2000). Mitochondrial DNA is exclusively 28 F. Dimitriadis et al. inherited by the oocyte, and therefore there is an interesting probability that some types of male infertility are transmitted only through the mother (Danan et al. 1999; Rovio et al. 2001; Dacheux and Dacheux 2014).

Immunologic Infertility The term immune infertility refers to spontaneously occurring antibodies which bind to antigens of the spermatozoa impairing the interaction between sperm and oocyte. The expression of antisperm antibodies is associated with certain HLA classes (Omu et al. 1999) suggesting that immune infertility constitutes an autoimmune disorder. Abnormalities in the development of the formation of the blood–testis barrier may result in the formation antisperm antibodies (Bohring and Krause 2003). Antisperm antibodies are observed in men with testicular tissue injury (i.e., testicular torsion, surgery, or trauma). Other common reasons include infections and obstruction of sperm transport, for example, in men after vasectomy or in men diagnosed with CF or congenital agenesis of VD. In all these later conditions, the immune equilibrium within the testis may be altered (Sotolongo 1982; Vazquez-Levin et al. 1994). The diagnostic approach is based mainly on mixed antiglobulin reaction test and immunobead binding test that are used for detection of antisperm antibodies. A cutoff value of 50% of motile spermatozoa carrying antisperm antibodies has been regarded significant in the clinical practice (Vazquez-Levin et al. 2014). Antisperm antibodies may affect sperm motility and viability, sperm–oocyte interaction, early embryonic development, embryonic capacity for implantation, and fetal develop- ment (Ohl and Naz 1995; Chiu and Chamley 2004). Antisperm antibodies also affect sperm capacitation process, spermatozoal ability to undergo the acrosomal reaction and to bind to and penetrate the zona pellucida of the female gamete (Shibahara et al. 1996; Nakagawa et al. 2004). Currently, there is no standardized therapeutic option, and the actual clinical meaning of antisperm antibodies in infertile men is still debatable (Silva et al. 2008). However, a significant increase in pregnancy rates was found among anti- sperm antibody-positive men receiving prednisolone for more than 3 months com- pared to placebo group (Hendry et al. 1990). In addition assisted reproductive technologies are the treatment of choice for male infertility associated with anti- sperm antibodies. Other systemic medications that have been proposed include immunosuppressive agents (azathioprine or intravenous cyclophosphamide) and intravenous immunoglobulin (Silva et al. 2008).

Infections Bacterial pathogens in seminal plasma can reduce sperm motility, induce apoptosis or necrosis, alter sperm morphology, and thus affect directly sperm quality (Villegas et al. 2005; Isaiah et al. 2011; Rybar et al. 2012). Major bacterial sexually transmitted disease organisms affecting semen include Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma spp., Ureaplasma spp., and Treponema pallidum. Other pathogens include protozoal infections mainly Trichomonas vaginalis and viral infections such as human papillomavirus, herpes simplex virus, hepatitis B and C viruses, and human cytomegalovirus (Dejucq and Jegou 2001; Kalichman et al. Pre-Testicular, Testicular, and Post-Testicular Causes of Male Infertility 29

2008). Antiviral and antiretroviral therapies may also induce testicular damage with deleterious effects on sperm quality (Lorusso et al. 2010).

Disorders of Coitus

Sexual Dysfunction Erectile dysfunction, rather than infertility cause, represents a factor making con- ception very difficult. For the majority of men, erectile dysfunction is a greater problem than infertility. The enormous success of phosphodiesterase type 5 inhibitors in the modern industrial world and the plethora of aphrodisiac potions around the world suggest that for most men, the desire for erections is a more immediate and pressing concern than maximizing their fecundity. Furthermore, erectile dysfunction may lead to psychological distress, feeling of sexual failure, and lower self-esteem (Wibowo et al. 2016). Ejaculation disorders could be the result of:

– Functional blockages such as functional obstruction of the SV, spinal cord injury, or sympathetic nerve injury – Pharmacologic (drugs causing retrograde ejaculation)

Ejaculatory duct obstruction (EDO) has been originally diagnosed in men with azoospermia with complete ductal obstruction, but a larger number of patients have oligoasthenospermia; the latter is characteristic of partial EDO. Functional EDO is a form of ejaculatory dysfunction with a similar presentation but without physical blockage (Walsh and Turek 2006). Spinal cord injury (SCI) patients and patients after retroperitoneal lymphadenectomy experience ejaculation problems especially when the sympathetic centers which regulate the ejaculation (T9–T11 and L2–L3) are damaged (Chehensse et al. 2013). Sympathectomy including bilateral removal of the T12–L2 paravertebral sympathetic ganglia is commonly associated with impaired ejaculation (Courty and Franchebois 1952; Rose 1953). In men with SCI, sperma- tozoa can be collected by electroejaculation using a rectal probe or can be surgically retrieved from the epididymis or the testis (Brackett et al. 2010). Acetylcholinester- ase inhibitors, prostigmin, physostigmine, and midodrine, an α1-adrenergic receptor agonist, have been used to increase the rate of ejaculation in men suffering from SCI combined with penile vibratory stimulation (Soler et al. 2008). Premature ejaculation as defined by the International Society for Sexual Medicine may be lifelong or acquired (Serefoglu et al. 2014). Treatment with tricyclic antide- pressants or serotoninergic uptake inhibitors combined with sexual counseling can be very effective (Turek 2008). Delayed ejaculation and anejaculation are more common as men age and have multiplex organic and psychogenic reasons. They have a significant impact on couple’s sexual fulfillment resulting in infertility (Lue 2016). Treatment of men with delayed ejaculation or anejaculation should be cause specific, including patient/couple psychoeducation and/or psychosexual therapy, 30 F. Dimitriadis et al. pharmacotherapy, or integrated treatment. Retrograde ejaculation or anejaculation due to surgical procedures on the retroperitoneum, bladder, or pelvis may also cause infertility (Turek 2008). Ejaculation disorders may also be the result of medications such as antihypertensives especially α-blockers and thiazides, as well as antipsy- chotic drugs and antidepressants (Turek 2008).

Hypospadias Hypospadias affects 0.3–0.7% of newborns (Giwercman and Giwercman 2000). The European Surveillance of Congenital Anomalies demonstrates a trend in raising incidence of hypospadias over a period of 10 years (Loane et al. 2011). The association between reduced semen quality and hypospadias is well documented. The most likely explanation is that fathers (with reduced semen quality) and their sons (with hypospadias) share the same susceptibility genes that govern their reproductive function (Skakkebaek et al. 2001; Asklund et al. 2007).

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