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