40 Amr Abdel Raheem1,2, Rowland Rees3, and David Ralph1 1 University College London Hospitals, London, UK 2 Cairo University Hospitals, Cairo, Egypt 3 University Hospital Southampton, Southampton, UK Fertility is vital to the majority of couples in this modern era. With infertility affecting 15% of couples, knowledge of the causes, diagnosis, and treatment is essential to help in conceiving. This chapter gives an overview of the aetiology, investigations, and treatment modalities available to help couples suffering from infertility. Keywords: fertility; infertility; reproduction; azoospermia; assisted reproduction Infertility is defined as the failure to conceive after regular, unprotected intercourse for at least 12 months. Infertility affects up to 15% of couples. A male factor is solely responsible in about 20% of infertile couples and contributory in 30–40% of cases; thus it may be estimated that 7% of men have fertility problems. Female factors alone are responsible for 30%, and idiopathic infertility accounts for 10–20% of the cases [1]. The chances of natural conception are at their highest in the first three ovulatory cycles with unprotected intercourse, with a natural conception rate of 20–25% per cycle, but this rate gradually decreases with time. After one year, it drops to less than 5% per cycle. The age of the female partner is a crucial point in determining the fertility of a couple and the success of any fertility treatment. A woman’s fertility is its peak in her 20s and this gradually declines especially older than the age of 35 years. In women 40 years and older, natural conception rate is less than 5% per cycle. The understanding of infertility starts with understanding the normal male reproductive physiology, see Chapter 36. Let’s start with some definitions. History and examination are vital to help determine the aetiological factor(s) and prognosis as well as plan further investigation and treatment. A full medical history is taken, including previous reproductive history, sexual history, developmental history, general medical and surgical history, and drug history. An emphasis is made on lifestyle factors such as alcohol, tobacco, the use of recreational drugs, scrotal heat exposure, and the frequency of intercourse. The examination of the male should be conducted by a urologist. The focus of the male examination is assessment of the scrotal contents (Table 40.1). Table 40.1 Clinical examination. Chromosomal abnormalities are found in 4–15% of infertile men compared to 0.4% of the general population. The lower the sperm count the higher the prevalence [3]. Klinefelter syndrome (KS) is the most common numerical abnormality; it occurs in 1 in 500–1 in 1000 live male births and in up to 10% of men with nonobstructive azoospermia. Most cases are of the nonmosaic form, 47XXY. KS is associated with primary testicular failure. Patients present with azoospermia, hypogonadism, gynecomastia, reduced testicular size, and some may have learning difficulties. The severity of symptoms depends on the extent of Leydig cell dysfunction [4, 5]. 47XYY male syndrome is another numerical disorder occurring in 1 in 1000 births and is associated with subfertility and tall stature. Patients may also have reduced intelligence, antisocial behaviour, and a higher risk of developing leukaemia [6]. 46,XX male syndrome involves abnormal translocation of the SRY gene from the Y chromosome to the X chromosome or an autosome during meiotic division of paternal spermatogenesis. An SRY negative form involves activation of genes down the SRY cascade. Thus the gonads will develop into testes and the müllerian duct structures will regress. The testes are small however, and there is no spermatogenesis due to the absence of the azoospermia factor (AZF) region. There may also be a degree of hypogonadism, gynecomastia, ambiguous genitalia, and undescended testes due to lack of virilisation. Structural chromosomal defects include balanced Robertsonian and reciprocal translocations which are a cause of infertility and repeated abortion [7]. Because there is no loss of genetic material, patients will have normal phenotype; however, some of the sperm will lack or have excess genetic material. Abnormal sperm undergoes apoptosis, which explains why these patients present with azoospermia or oligozoospermia. During in vitro fertilisation (IVF) treatment, prenatal genetic diagnosis (PGD) is a must to avoid the transfer of embryos with unbalanced karyotype. The AZF gene is found on the long arm of the Y chromosome. Microdeletions of this gene are associated with impaired spermatogenesis. AZF microdeletions are found in 5–10% of infertile men, especially those with counts less than 2 million sperm per ml [3]. An AZFc microdeletion reduces spermatogenesis but does not stop it completely. Men with an AZFc microdeletion may be oligozoospermic and may even father children naturally. Those who are azoospermic may still have a chance of fathering children via surgical sperm retrieval and intracytoplasmic sperm injection (ICSI) [8]. However, they will pass this microdeletion to their male offspring who will therefore be infertile. AZFa and AZFb microdeletions completely inhibit spermatogenesis. Patients with such deletions will be azoospermic and will not have any intratesticular spermatogenesis; thus surgical sperm retrieval should not be offered [9]. Minimal androgen insensitivity may be suspected in an infertile male from the clinical signs of hypogonadism accompanied by elevated testosterone and luteinising hormone (LH). This confirmed by genetic studies of the androgen receptor gene which is located on the X chromosome [10]. Globozoospermia is a rare condition characterised by absence of the acrosomal cap. Sperm characteristically have a round head [11]. Primary ciliary dyskinesi includes several autosomal recessive syndromes resulting in a defect in the axoneme of ciliated cells in the respiratory tract or in the tail of sperm. Kartagener syndrome is seen in 50% of cases and consists of a triad of chronic sinusitis and bronchiectasis, dextrocardia, and infertility [11]. Dysplasia of the fibrous sheath of the sperm tail impairs sperm motility [11]. There are numerous other genes not yet identified that regulate sperm production, hormone production, and hormone receptors. Any defect in such genes will impair fertility. These defects are probably responsible for the idiopathic causes of infertility [12]. This is caused by hypothalamic–pituitary axis disorders and is characterised by low testosterone level secondary to low LH level which is usually associated with low follicle‐stimulating hormone (FSH) level. It may occur in congenital disorders or in acquired conditions such as brain tumours, head injuries, and following radiotherapy or may be idiopathic. Congenital, idiopathic, or isolated hypogonadotropic hypogonadism (IHH) has prevalence from 1 in 10000 to 1 in 86 000 [13]. IHH occurs due to a variety of gene defects which either prevent the migration of gonadotropin‐releasing hormone (GnRH) neurones during embryonic development or prevent the activation of these neurones. Kallmann syndrome occurs in 50–60% of IHH cases and is an X‐linked recessive disorder, which, in addition to the hypogonadism, is associated with anosmia and may be associated with midline facial defects, neurologic abnormalities, and unilateral renal agenesis [14, 15]. IHH is usually diagnosed earlier in life because patients present with delayed puberty; however, IHH has different phenotypes, and in some cases the hypo‐androgenisation is mild, and patients may only present with infertility and mild hypogonadism. Furthermore, some cases of IHH present in adulthood [3]. Hormonal therapy with LH/FSH preparations can induce spermatogenesis in such cases. Endocrinopathies such as thyroid gland disorders, hyperprolactinaemia, and primary hypogonadism will also impair sperm production. Varicocele is found in 11.7% of men with normal semen parameters and in 25.4% of men with abnormal semen parameters [16]. Varicocele disrupts spermatogenesis by impairing the venous drainage and interfering with the countercurrent exchange of heat mechanism from the spermatic cord which causes elevation of the scrotal temperature. Varicocele also causes hypoxia and interferes with the drainage of toxins from the testes [17]. Varicocele may be associated with progressive testicular atrophy, impaired semen parameters, and Leydig cell dysfunction [18]. Cryptorchidism occurs due to genetic, environmental, and hormonal factors which impair spontaneous testicular descent. It has an incidence of 2–5% at birth, making it the most common congenital abnormality of the male genital tract; however, spontaneous descent occurs in many cases by the age of three months, and the incidence is reduced to 1–2% [16]. A history of cryptorchidism and orchidopexy is found in 10% of infertile men [19]. Cryptorchidism is also associated with impaired spermatogenesis due to degeneration of the germ cells [20]. In men with bilateral cryptorchidism, oligozoospermia is found in 31% and azoospermia in 42% of cases. In men with bilateral cryptorchidism, paternity is only 35–53% [21]. Unilateral cryptorchidism is also associated with reduced fertility; however, paternity in men with a history of unilateral cryptorchidism is almost equal to that in the general male population (89.7 and 93.7%, respectively) [22]. In addition to subfertility, the risk of developing germ cell tumours in men with history of undescended testes is 2–6% compared to 0.001–0.01% in the general male population, and there is a history of cryptorchidism in 5–10% of testicular tumours [16, 23]. Testicular cancer occurs in 0.5–1% of infertile men compared to an incidence of 0.001–0.01% in the male general population [24]. A genetically determined testicular dysgenesis may be the cause of both conditions [25]. Testicular tumours lead to infertility by destroying and compressing the healthy testicular tissue. In addition, treatment of testicular cancer whether orchiectomy, chemotherapy, or radiotherapy impairs fertility. Several agents may affect spermatogenesis by disruption of the hypothalamo‐pituitary‐gonadal axis including heat, ionising radiation, alkylating agents, heavy metals, recreational drugs, tobacco, alcohol, insecticides, pesticide, and synthetic oestrogens. Systemic diseases whether acute such as fever, burns, and viraemia or chronic such as liver cirrhosis, renal failure, haematological disease, and endocrinopathies affect fertility by disruption of the hypothalamo‐pituitary‐gonadal axis [26]. Several drugs may have a negative impact on fertility such as anti‐androgens, steroids, radiotherapy, and chemotherapy, especially alkylating agents. Inflammation mainly affecting the testes damages the parenchyma causing nonobstructive infertility as in mumps orchitis, while inflammation of the epididymi causes obstructive infertility such as postgonococcal and ‐chlamydial infections. Infection of the urethra, prostate, seminal vesicles, and epididymis may affect fertility by the direct effect of bacterial toxins, elevated reactive oxygen species (ROS) levels, DNA fragmentation, accessory gland dysfunction, and secondary obstruction. Testicular torsion affects 1 in 4000 males younger than age of 25. Untreated torsion causes ischaemic necrosis of the seminiferous tubules and shrinking of the testis on the affected side [27]. Furthermore, disruption of the blood‐testis barrier may be followed by the production of anti‐sperm antibodies which affect the other testis. Blunt scrotal trauma can damage the testicular parenchyma and cause intratesticular haematomas, which lead to pressure atrophy of the surrounding seminiferous tubules and scarring. Testicular trauma may also lead to the disruption of the blood‐testis barrier and the production of anti‐sperm antibodies. The blood‐testis barrier, which is formed by Sertoli cells, separates germ cells from the immune system. Disruption of this barrier by trauma, orchitis, torsion, varicocele, and surgery causes the production of anti‐sperm antibodies which impair sperm motility and sperm‐ovum interactions [28]. Intratesticular obstruction occurs in 15% of obstructive azoospermia (OA). It may be congenital due to disconnection between rete testis and efferent ductules or acquired due trauma and inflammation [29]. This blockage is not amenable to surgical reconstruction. The most common cause of obstructive infertility is epididymal obstruction which accounts for 30–67% of OA [29]. Epididymal obstruction is mostly caused by epididymitis which is secondary to chlamydial or gonococcal urethritis or urinary tract infections. It may also result from scrotal trauma, surgery, or occur congenitally as in disconnection of the epididymal head and body, atresia, agenesis, and Young syndrome, which consists of a triad of chronic sinusitis, bronchiectasis, and azoospermia due to epididymal obstruction by viscid secretions. Congenital absence of the vas deferens (CBAVD) may be unilateral be or bilateral and occurs due to two types of genetic defects. CBAVD affects 1–2% of the infertile male population and 6% of men with obstructive azoospermia [30]. Men with CBAVD will have low semen volume azoospermia with an acid PH. Cystic fibrosis is an autosomal recessive disease which affects 1 : in 2500 people of Caucasian descent with a carrier frequency of 1 in 25 [30]. The cystic fibrosis gene encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein and is located on chromosome 7. Mutations in both alleles of the CFTR gene causes cystic fibrosis disease due the deficiency of CFTR protein which regulates the sodium and chloride balance in epithelial secretions and regulates their viscosity; the CFTR protein also influences the formation of the ejaculatory duct, seminal vesicles, the vas, and the distal two‐thirds of the epididymis. All men with cystic fibrosis disease have vasal aplasia in addition to obstructive pulmonary disease and pancreatic exocrine failure due to high viscosity of the epithelial secretions. Men who only present with vasal aplasia represent a mild form of cystic fibrosis disease due to milder mutations [11]. Another form of vasal aplasia found in 10–20% of cases is due to other gene mutations (non‐CFTR). This type may be associated with unilateral renal aplasia [31]. Vasal aplasia cannot be surgically corrected; however, affected men may father children via surgical sperm retrieval and ICSI. Men who test positive for CFTR gene mutations should have their female partners screened. If the female partner is a carrier for a one of the CFTR gene mutations, preimplantation genetic diagnosis before embryo transfer is a must because the couple would have a 25% chance of having an offspring with full‐blown cystic fibrosis disease. Vasectomy is a popular and effective form of male contraception; however, 2–6% of those men request a reversal [32]. Vasal obstruction not due to vasectomy occurs secondary to surgeries in the region of the inguinal canal or pelvis, such as hernia repair, bowel surgery, ureteric surgery, and orchidopexy. Ejaculatory duct obstruction (EDO), either complete or partial, can be found in 5% of infertile men. Causes of EDO are congenital and acquired. Congenital causes: Acquired causes: In addition to infertility, patients may also present with painful ejaculation and reduced force and volume of ejaculate, haemospermia, dysuria, pelvic pain, and scrotal pain [33]. Men with complete bilateral EDO will have low volume azoospermia with an acid PH. Sexual dysfunction may interfere with deposition of the semen in the vagina. Men with severe erectile dysfunction may be unable to penetrate the vagina. In severe cases, ejaculation occurs before intromission. Men with severe penile curvature whether congenital or secondary to Peyronie disease may have problems in vaginal penetration. Men with abnormal position of the urethral meatus, as in hypospadias, may have problems in sperm deposition. Anejaculation may occur secondary to injury of the sympathetic chain during pelvic or abdominal surgery or as a consequence of autonomic neuropathy as in diabetes or drugs such as antidepressants and alpha‐blockers. Primary anejaculation may occur due to psychosexual factors or decreased sensitivity of the genital organs or high threshold of the ejaculatory reflex [34]. Retrograde ejaculation is diagnosed by the presence of sperm in postorgasmic urine. It occurs due the same causes as anejaculation but represents a milder pathology in which there is emission but the bladder neck fails to contract. It can also occur after transurethral resection of the prostate and with alpha‐blockers [34]. This is the first and arguably the most direct guide is semen analysis. The results of semen analysis provide a guide to whether other investigations are needed or not (Tables 40.2 and 40.3). The results may provide a diagnostic clue for certain conditions (e.g. the presence of low volume, azoospermia, negative fructose, and an acid pH are pathognomonic of EDO or CBAVD). A second test is indicated if the first test is abnormal. A two‐ to seven‐day abstinence period is needed before collection. Table 40.2 Lower reference limits for semen analysis WHO 2010. Table 40.3 Grading of sperm motility. There are other specialised semen tests as well. This is now part of the routine semen analysis. The presence of more than 50% of sperm is bound to antibodies is a significant result and indicates immunological infertility. Found in 10% of men with infertility, antisperm antibodies form if the blood‐testes barrier is breached. The barrier is formed by tight junctions between the Sertoli cells separating the developing spermatozoa from the immune system. Any traumatic or inflammatory condition to the testes can disrupt the blood‐testes barrier, including obstruction as seen post vasectomy and in patients with CBAVD. Antibodies are either from the genital tract mucosal surface (IgA) or most likely the blood (IgI) and are only seen on mixed agglutination tests. Assisted reproductive technology (ART) is now the treatment of choice for such cases rather than the use of steroids for immunosuppression. A semen culture is indicated in the presence of chronic infections of the genital tract. This is indicated by genital pain, painful ejaculation, or the presence of white blood cells in semen >1 × 106 ml−1 [35]. ROS are produced by leucocytes and immature germ cells. Small amounts of ROS are needed for the hyperactivation and capacitation of spermatozoa, but excess ROS cause sperm damage. Causes of elevated ROS include infection, smoking, alcohol, varicocele, radiation, and toxic chemicals. Elevation of seminal ROS levels may account for some the cases of idiopathic infertility [36]. High levels of abnormal DNA (>30%) can be found in up to 8% of subfertile men who have normal semen parameters. This reduces the chances of natural conception and leads to poor intrauterine insemination and IVF outcomes. DNA damage is also associated with poor semen parameters, leukocytospermia, and high ROS levels. Causes of increased sperm DNA damage include smoking, varicocele, infection, oxidative stress (ROS), chemotherapy, testicular carcinoma, and other systemic cancers. There is a higher rate of DNA damage in ejaculated or epididymal sperm than intratesticular spermatozoa; thus, it is better to use intratesticular spermatozoa with ICSI in men with high DNA fragmentation [36]. The basic hormones that are tested are FSH, LH, prolactin, and testosterone, especially when the sperm density is <10 × 106 ml−1 (Table 40.4). Other hormone and blood tests may be tested if there is a clinical indication such as thyroid hormones and cortisol. Men who are obese should also be tested for estradiol. Table 40.4 Interpretation of male reproductive hormonal profile. Genetic profiling includes karyotype, Y chromosome microdeletions, and cystic fibrosis gene mutations (CFTR gene). Karyotyping is indicated in men with sperm counts <10 × 106 ml−1, nearly 5% of oligozoospermia and 15% of azoospermia will have an abnormal karyotype; Y chromosome microdeletion testing is indicated when the sperm density is <5 × 106 cc−1 with a frequency of up to 5 and 10% in oligozoospermic and azoospermic patients, respectively. CFTR gene mutation tests are indicated for both patient and partner in cases of vasal aplasia and other forms of congenital obstruction ot he genital tract [37–39]. Postorgasmic urine (POU) analysis is indicated in low semen volume, and dry ejaculate to diagnose retrograde ejaculation by detecting sperm in the postorgasmic urine sample. Scrotal ultrasonography is done to assess the testes and epididymi and to detect their dimensions and exclude the presence of tumours or varicocele. It will also show testicular microlithiasis, which may indicate testicular carcinoma in situ (Figures 40.1 and 40.2) [40]. Figure 40.1 Scrotal ultrasound showing intratesticular neoplasia. Figure 40.2 Scrotal ultrasound showing intratesticular neoplasia (arrow); double arrow shows foci of microlithiasis. Transrectal ultrasound (TRUS) should be performed in all cases with low semen volume and ejaculatory dysfunction to diagnose anomalies of the distal genital tract such as EDO (Figure 40.3). Figure 40.3 Transrectal ultrasound image showing a midline prostatic cyst causing ejaculatory duct obstruction. TRUS findings suggestive of EDO include: Other imaging tests icnlude: Figure 40.4 Transrectal ultrasound‐guided seminal vesiculography showing a dilated blocked ejaculatory duct. During surgical sperm retrieval, a small piece of tissue is taken to study the testicular architecture and exclude carcinoma in situ. The tissue is kept in Bouin’s solution which is a mixture of formalin, alcohol, and picric acid that prevents cellular distortion and gives a better picture of the seminiferous tubule (Figure 40.5). Figure 40.5 Testis biopsy a few tubules are snipped off and immersed in Bouin’s solution. Because spermatogenesis does not proceed at a uniform rate in every tubule in the testis, but in waves (i.e. some actively dividing and others resting) the interpretation of a biopsy makes it necessary that several tubules are present, and the opinion is based on the proportion of tubules in the biopsy which show each stage in spermatogenesis. This is the Johnsen mean score (Table 40.5). At least 10 tubules are examined. Each is assigned a score on a scale of 1–10. The normally fertile man has a mean score of 9.38 + 0.24. There is a direct correlation to the testicular volume to the Johnsen score (i.e. the smaller the testicles the more likely there will be a smaller score). Table 40.5 The Johnsen Score of testicular biopsy. Testis biopsy should not be offered as an investigation independent from surgical sperm retrieval because it would still be invasive and if sperm is found it will not be stored which would be a waste, and if sperm was not found, it would not mean that this is the picture in the rest of the testicular tissue as there may be patchy areas with active spermatogenesis. It may be possible to relieve an obstruction of the ejaculatory ducts by transurethral resection of the ejaculatory ducts (TURED) (Figure 40.6), particularly if the obstruction is found to be at the level of the prostatic urethra. This is done by injecting methylene blue into the ejaculatory system and resecting at the level of the verumontanum, while taking care not to injure the rectum. If a congenital cyst is the cause, simple deroofing can be done. Alternatively, a transurethral resection of the ejaculatory ducts is done. Patency rates of 65–95% and pregnancy rates 20–30% have been reported [33]. Figure 40.6 Transurethral resection of the ejaculatory ducts using a resectoscope. Methylene blue dye which was inserted just before resection during TRUS‐guided seminal vesiculography can be seen coming out through the resected duct indicating adequate resection. TRUS, transurethral ultrasound. This most often results from vasectomy or rarely accidental damage during inguinoscrotal surgery previously in life. If the obstruction is in an isolated segment, such as after vasectomy, the vasal ends can usually be re‐anastomosed (vaso‐vasostomy). The outcome of repair is dependent on the time interval since the vasectomy or obstruction. The best outcomes are achieved using a microsurgical technique, and in the largest series, up to 97% of patients regain sperm in the ejaculate if the vaso‐vasostomy is done within a three‐year interval since vasectomy, with a 76% pregnancy rate [41]. This involves loss of long segments of the vas on both sides and is not reconstructible. However, sperm production is usually normal, and it is easy to palpate and aspirate sperm from the head of the epididymis (see PESA below), for use in assisted conception. Where there is spermatogenesis in the presence of an obstructed segment of epididymis, it may be possible to by‐pass the obstruction by joining the vas deferens to a single tubule in the body of the epididymis (epididymo‐vasostomy) using 10/0 nylon sutures (Figure 40.7). This is technically challenging due the extremely small diameter of the epididymal tubules (~ 0.2 mm). Patency rates vary from 60 to 87%, with pregnancy rates between 10 and 43% [42]. Figure 40.7 Epididymo‐vasostomy. Source: Courtesy of Mr. Nim Christopher. It is not possible to surgically treat obstruction within the testis, and it is therefore necessary to obtain sperm through testicular sperm aspiration (TESA) or biopsy or TESE (see below). Attempted surgical sperm retrieval followed by ICSI is the mainstay of treatment for nonobstructive azoospermia (NOA). Following diagnosis of NOA, it is important to counsel the patient fully risks and benefits of surgical sperm retrieval, including the estimated chances of sperm being found. Although there is no accurate predictive factor, it is possible to give a rough estimate of the odds based on clinical and investigative parameters. Sperm can be retrieved successfully from most patients with obstruction by percutaneous epididymal sperm aspiration (PESA). This can be done under local anaesthesia. Microsurgical epididymal sperm aspiration is usually performed in cases of obstruction during microsurgical epididymo‐vasostomy. When sperm cannot be obtained from the epididymis as in cases of intratesticular obstruction or if microsurgical reconstruction is to be performed at a later date, testicular sperm aspiration can be done. Testicular sperm extraction involves delivery of the testes and taking multiple random biopsies from different quadrants. TESE was previously the technique of choice for surgical sperm retrieval in NOA; however it has now been replaced by Micro‐TESE. Microdissection TESE (Figure 40.8) Figure 40.8 Microdissection TESE: image showing the seminiferous tubules under 20× magnification. The testes are delivered and an equatorial incision involving three‐quarters of the circumference is made using the surgical microscope to avoid vascular injury, the testis is bivalved, microdissection is then performed to expose the seminiferous tubules and multiple tiny pieces of testicular tissue are taken from areas that have dilated opaque tubules which are more likely to contain sperm. This technique has been shown to be superior to standard TESE in terms of sperm retrieval rate [43]. Thus, micro‐TESE should be offered to all men with NOA. The surgical sperm retrieval rate is 100% for men with OA. In men with NOA, however, sperm can be found in approximately 50% of the cases, and although clinical and investigative parameters can be used to help with prognosis, there is no single reliable predictive factor. However, the presence of AZFa and AZFb Y chromosome micro‐deletions is a highly negative predictive factor [44]. Assisted conception techniques are usually done by the fertility clinic and will require ovarian stimulation with gonadotrophins. Malformation rates with assisted reproductive techniques are <6% (6.2% with ICSI and 4.1% with IVF) which is not significantly higher than natural pregnancy, which has a malformation rate of 4.4%. There is insufficient evidence to link varicocele repair with improved pregnancy rates [45]. However, up to 70% of patients with repaired varicocele will have improvement in their sperm parameters: on average an increase of 10 million sperms, 10% improvement in sperm motility, and 3% improvement of sperm morphology. This reflects to a 16% increase in paternity rate [45, 46]. A number of treatment options are available for varicocele treatment (Table 40.6). Of the surgical procedures, the lowest recurrence rate is following a microsurgical subinguinal approach [47]. Table 40.6 Treatment options for varicocele repair. Medical therapy can be effective for some specific causes of male fertility and is also sometimes offered as empirical therapy when there is male infertility of unknown cause. It is important to realise that the testes are responsible for the production of sperm and testosterone, and although spermatogenesis is dependent on high levels of intratesticular testosterone, exogenous administration of testosterone may inhibit spermatogenesis via a negative feedback effect via the hypothalamic–pituitary system. Deficiency of gonadotrophins (i.e. FSH and LH) such as in Kallman syndrome or idiopathic hypogonadotrophic hypogonadism results in reduced intratesticular testosterone and infertility. GnRH therapy is best given in pulsatile doses with a syringe pump and stimulates the anterior pituitary to release FSH and LH, leading to increased spermatogenesis and fertility [48]. However, it may take four months to reach maximum effect. Although there is evidence supporting the use of GnRh in hypogonadotrophic hypogonadism, there is no evidence of benefit in idiopathic infertility. Pituitary insufficiency can be be treated with synthetic gonadotrophins such as human chorionic gonadotropin (HCG), recombinant FSH and LH. There is lack of evidence for benefit in idiopathic infertility, but in hypogonadotrophic hypogonadism a combination approach using HCG and FSH can achieve pregnancy rates of up to 50% in those previously unsuccessful in achieving pregnancy [49]. Elevated prolactin levels due to a pituitary adenoma will suppress the pulsatile secretion of GnRH, and thus cause hypogonadism and infertility. The infertility can therefore be treated by a dopamine agonist such as cabergoline, which can reduce the size of prolactin‐secreting tumours and normalise prolactin levels. Anastrozole and other aromatase inhibitors have been used to increase testosterone levels and decrease oestrogen levels and act by inhibiting the conversion of testosterone to oestrogen by aromatase enzyme especially in patients who are obese because they have increased activity of aromatase enzyme in the adipose tissue. High oestrogen levels (and therefore altered testosterone‐to‐oestrogen ratio) has been shown to impair spermatogenesis and negatively feedback back to LH and FSH production. Selective oestrogen receptor modulators (SERMs) such as clomiphene citrate and tamoxifen have been used off‐label to treat male infertility. Both inhibit the negative feedback of oestrogen on the hypothalamus by blocking oestrogen receptors leading to an increase in the production of LH and FSH, with consequent increase in testosterone production and spermatogenesis. Evidence suggests that using these modulators leads to an increase in sperm concentration and pregnancy ratesl however, the evidence is scant [50]. Chronic prostato‐vesiculitis is associated with impaired semen parameters, elevated ROS and increased DNA fragmentation. It is diagnosed by the finding of white blood cells (WBCs) ≥106 per millilitre of ejaculate. Antimicrobial therapy may be of help in such cases with significant improvement in semen parameters and spontaneous pregnancy rate [51]. Antioxidants such as vitamin E, vitamin C, and L‐Carnitine have been used empirically to reduce the ROS levels. There is lack adequate data which shows benefit of such treatments.
Male Infertility
Abstract
40.1 Incidence
40.2 Definitions
40.3 History and Examination
Clinical Examination
General examination
Secondary sexual characters, body habitus, gynaecomastia
Penis
Stretched length, meatus, deformity, plaques, phimosis
Testis
Presence, size, consistency, lumps or lesions, tenderness
Epididymis
Distension, nodules, tenderness
Vas deferens
Presence, nodules
Cord
Varicocele
Digital rectal examination
Prostate cancer, midline cysts, seminal vesical dilation
40.4 Aetiology
40.4.1 Functional Causes of Male Infertility
40.4.1.1 Genetic Causes
40.4.1.1.1 Chromosomal Abnormalities
40.4.1.1.2 Y Chromosome Microdeletions
40.4.1.1.3 Androgen Receptor Gene Mutations
40.4.1.1.4 Genetic Sperm Disorders
40.4.1.1.5 Other Genetic Factors
40.4.1.2 Hormonal Causes
40.4.1.2.1 Hypogonadotropic Hypogonadism
40.4.1.2.2 Other Hormonal Abnormalities
40.4.1.3 Varicocele
40.4.1.4 Undescended Testes
40.4.1.5 Testicular Tumours
40.4.1.6 Exposure to Gonadotoxins
40.4.1.7 Systemic Diseases
40.4.1.8 Iatrogenic Factors
40.4.1.9 Orchitis
40.4.1.10 Infection of the Accessory Glands
40.4.1.11 Testicular Torsion
40.4.1.12 Testicular Trauma
40.4.1.13 Autoimmune Infertility
40.4.2 Genital Tract Obstruction
40.4.2.1 Intratesticular Obstruction
40.4.2.2 Epididymal Obstruction
40.4.2.3 Congenital Absence of the Vas Deferens
40.4.2.4 Vasal Obstruction
40.4.2.5 Ejaculatory Duct Obstruction
40.4.3 Coital Infertility
40.4.3.1 Erectile Dysfunction
40.4.3.2 Premature Ejaculation
40.4.3.3 Penile Deformities
40.4.3.4 Anejaculation
40.4.3.5 Retrograde Ejaculation
40.5 Investigations for Male Infertility
40.5.1 Semen Analysis
Parameter (a)
Lower reference limits (WHO 2010)
Volume (ml)
1.5
Total sperm number (106 per ejaculate)
39
Sperm concentration (106 per ml)
15
Total motility (%)
40
Progressive motility (%)
32
Vitality (live spermatozoa, %)
58
Sperm morphology (normal forms, %)
4
pH
≥7.2
Peroxidase‐positive leukocytes (106 per ml)
< 1.0
Time to liquefy (minutes)
5–25
Antisperm antibodies (mixed agglutination reaction test)
<50% motile spermatozoa with bound particles
Seminal Zinc (μmol per ejaculate)
>2.4
Semen Fructose (μmol per ejaculate)
>13
Grade
Motility
0
No motility
1
Sluggish; no progressive movement
2
Slow; with forward progression in a straight line
3
Moderate speed; with forward progression in a straight line
4
High speed; with forward progression in a straight line
40.5.1.1 Antisperm Antibodies
40.5.1.2 Semen Culture
40.5.1.3 Seminal ROS levels
40.5.1.4 DNA Fragmentation
40.5.2 Male Reproductive Hormonal Profile
Testosterone
FSH
LH
Prolactin
Normal or primary testicular failure
Normal
Normal
Normal
Normal
Primary testicular failure
Low
High
Normal or High
Normal
Hypogonadotropic hypogonadism
Low
Low
Low
Normal
Hyperprolactinaemia
Low
Normal or Low
Low
High
40.5.3 Male Reproductive Genetic Profile
40.5.4 Postorgasmic Urine Analysis
40.5.5 Imaging
40.5.5.1 Scrotal Ultrasound and Colour Doppler
40.5.5.2 Transrectal Ultrasound Scan
40.6 Testis Biopsy
Score
Interpretation
10
Complete spermatogenesis, many spermatozoa
9
Many spermatozoa, disorganised germinal epithelium
8
Few spermatozoa (<5–10)
7
No spermatozoa but many spermatids
6
No spermatozoa and few spermatids (<5–10)
5
No spermatozoa or spermatids, but many spermatocytes
4
Few spermatocytes (<5), no spermatozoa or spermatids
3
Spermatogonia are the only germ cells
2
Sertoli cells only
1
No cells in tubules
40.7 Treatment of Male Infertility
40.7.1 Obstructive Azoospermia
40.7.1.1 Ejaculatory Duct Obstruction
40.7.1.2 Vasal Obstruction
40.7.1.3 Congenital Bilateral Absence of the Vas Deferens
40.7.1.4 Epididymal Obstruction
40.7.1.5 Intratesticular Obstruction
40.7.2 Nonobstructive Azoospermia
40.7.3 Surgical Sperm Retrieval Techniques
40.7.3.1 PESA
40.7.3.2 MESA
40.7.3.3 TESA
40.7.3.4 TESE
40.8 Assisted Conception Techniques
40.9 Varicocele Repair
Approach
High ligation of vein and artery (Palomo)
High ligation of vein only (Bernandi)
Laparascopic high ligation
Inguinal – cremasteric and internal spermatic veins
Antegrade sclerotherapy (high scrotal incision)
Retrograde sclerotherapy (embolisation)
Subinguinal microsurgical ligation
40.10 Medical Treatment of Male Infertility
40.10.1 Endocrine Treatments
40.10.1.1 Gonadotrophin‐Releasing Hormone
40.10.1.2 Gonadotrophins
40.10.1.3 Dopamine Agonists
40.10.1.4 Aromatase Inhibitors
40.10.1.5 Selective Oestrogen Receptor Modulators
40.10.1.6 Treatment of Chronic Prostato‐vesiculitis
40.10.1.7 Treatment with Antioxidants
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