MALE INFERTILITY

MALE INFERTILITY Invasive Male Infertility Therapy of the Obstructive azoospermia (OA) Comprehensive Review Article Part 4 Prof. Dr. Semir. A. Salim. Al Samarrai Obstructive azoospermia (OA): Obstructive azoospermia (OA) is the absence of spermatozoa in the sediment of a centrifuged sample of ejaculate due to obstruction [1]. Obstructive azoospermia is less common than NOA and occurs in 20-40% of men with azoospermia [2,3]. Men with OA usually have normal FSH, testes of normal size and epididymal enlargement [4]. Of clinical relevance, men with late maturation arrest may present with normal gonadotropins and testicular size and may be only distinguished from those with OA at the time of surgical exploration. The vas deferens may be absent bilaterally (CBAVD) or unilaterally (CUAVD). Obstruction in primary infertile men is more frequently present at the epididymal level. Classification of obstructive azoospermia: Intratesticular obstruction occurs in 15% of men with OA [5]. Congenital forms are less common than acquired forms (post-inflammatory or post-traumatic) (Table 1). Table 1: Causes of obstruction of the genitourinary system Vas deferens obstruction: Vas deferens obstruction is the most common cause of acquired obstruction following vasectomy [6]. Approximately 2-6% of these men request vasectomy reversal (see 2019 EAU Guidelines on Male Infertility). Vasal obstruction may also occur after hernia repair [7,8]. The most common congenital vasal obstruction is CBAVD, often accompanied by CF. Unilateral agenesis or a partial defect is associated with contralateral seminal duct anomalies or renal agenesis in 80% and 26% of cases, respectively [9]. Ejaculatory duct obstruction: Ejaculatory duct obstruction is found in 1-5% of cases of OA and is classified as cystic or post-inflammatory or calculi of one or both ejaculatory ducts [10,11]. Cystic obstructions are usually congenital (i.e., Mullerian duct cyst or urogenital sinus/ejaculatory duct cysts) and are typically midline. In urogenital sinus abnormalities, one or both ejaculatory ducts empty into the cyst [12], while in Mullerian duct anomalies, the ejaculatory ducts are laterally displaced and compressed by the cyst [13]. Paramedian or lateral intraprostatic cysts are rare [14]. Post-inflammatory obstructions of the ejaculatory duct are usually secondary to urethra-prostatitis [15]. Congenital or acquired complete obstructions of the ejaculatory ducts are commonly associated with low seminal volume, decreased or absent seminal fructose, and acidic pH. The seminal vesicles (anterior-posterior diameter > 15 mm) and ejaculatory duct (> 2.3 mm in width) are usually dilated [11,15-17]. Functional obstruction of the distal seminal ducts: Functional obstruction of the distal seminal ducts might be attributed to local neurogenic dysfunction [18]. This abnormality is often associated with urodynamic dysfunction. Impaired sperm transport can be observed as idiopathic or due to spinal cord injury, multiple sclerosis, retroperitoneal lymph node dissection, pelvic surgery, SSRIs, α-blockers and typical antipsychotic medications [19]. Diagnostic evaluation: Clinical history Clinical history-taking should follow the investigation and diagnostic evaluation of infertile men. Risk factors for obstruction include prior surgery, iatrogenic injury during inguinal herniorrhaphy, orchidopexy or hydrocelectomy. Clinical examination Clinical examination should follow the guidelines for the diagnostic evaluation of infertile men. Obstructive azoospermia is indicated by at least one testis with a volume > 15 mL, although a smaller volume may be found in some patients with: • obstructive azoospermia and concomitant partial testicular failure. • enlarged and dilated epididymis. • nodules in the epididymis or vas deferens. • absence or partial atresia of the vas deferens. Semen analysis Azoospermia means the inability to detect spermatozoa after centrifugation at ×400 magnification. At least two semen analyses must be carried out [20,21]. When semen volume is low, a search must be made for spermatozoa in urine after ejaculation. Absence of spermatozoa and immature germ cells in the semen pellet suggest complete seminal duct obstruction. Hormone levels Hormones including FSH and inhibin-B should be normal, but do not exclude other causes of testicular azoospermia (e.g., NOA). Although inhibin-B concentration is a good index of Sertoli cell integrity reflecting closely the state of spermatogenesis, its diagnostic value is no better than that of FSH and its use in clinical practice has not been widely advocated [22]. Genetic testing Inability to palpate one or both sides of the vas deferens should raise concern for a CFTR mutation. Any patient with unilateral or bilateral absence of the vas deferens or seminal vesicle agenesis should be offered CFTR testing [23]. Testicular biopsy Testicular biopsy must be combined with TESE for cryopreservation. Although studies suggest that a diagnostic or isolated testicular biopsy [24] is the most important prognostic predictor of spermatogenesis and sperm retrieval, the EAU Guidelines edition 2022 recommends not to perform testis biopsies (including fine needle aspiration [FNA]) without performing simultaneously a therapeutic sperm retrieval, as this will require a further invasive procedure after biopsy. Furthermore, even patients with extremes of spermatogenic failure (e.g., Sertoli Cell Only syndrome [SCOS]) may harbour focal areas of spermatogenesis [25,26]. Disease management: Intratesticular obstruction Only TESE allows sperm retrieval in these patients and is therefore recommended. Epididymal obstruction Microsurgical epididymal sperm aspiration (MESA) or percutaneous epididymal sperm aspiration (PESA) [27] is indicated in men with CBAVD. Testicular sperm extraction and percutaneous techniques, such as testicular sperm aspiration (TESA), are also options [28]. The source of sperm used for ICSI in cases of OA and the aetiology of the obstruction do not affect the outcome in terms of fertilisation, pregnancy, or miscarriage rates [29]. Usually, one MESA procedure provides sufficient material for several ICSI cycles [30] and it produces high pregnancy and fertilisation rates [31]. In patients with OA due to acquired epididymal obstruction and with a female partner with good ovarian reserve, microsurgical epididymovasostomy (EV) is recommended [32]. Epididymovasostomy can be performed with different techniques such as end-to-site and intussusception [33]. Anatomical recanalisation following surgery may require 3-18 months. A recent systematic review indicated that the time to patency in EV varies between 2.8 to 6.6 months. Reports of late failure are heterogeneous and vary between 1 and 50% [34]. Before microsurgery, and in all cases in which recanalisation is impossible, epididymal spermatozoa should be aspirated intra-operatively by MESA and cryopreserved to be used for

MALE INFERTILITY Epidemiology, aetiology, pathophysiology, and risk factors Comprehensive Review Article Part 1 Prof. Dr. Semir. A. Salim. Al Samarrai Definition and classification: Infertility is defined by the inability of a sexually active, non-contraceptive couple to achieve spontaneous pregnancy within 1 year [1]. Primary infertility refers to couples that have never had a child and cannot achieve pregnancy after at least 12 consecutive months having sex without using birth control methods. Secondary infertility refers to infertile couples who have been able to achieve pregnancy at least once before (with the same or different sexual partner). Recurrent pregnancy loss is distinct from infertility and is defined as two or more failed pregnancies [2,3]. Epidemiology/aetiology/pathophysiology/risk factors: Introduction About 15% of couples do not achieve pregnancy within 1 year and seek medical treatment for infertility. One in eight couples encounter problems when attempting to conceive a first child and one in six when attempting to conceive a subsequent child [4]. In 50% of involuntarily childless couples, a male-infertility-associated factor is found, usually together with abnormal semen parameters [1]. For this reason, all male patients belonging to infertile couples should undergo medical evaluation by a urologist trained in male reproduction. Male fertility can be impaired as a result of [1]: • congenital or acquired urogenital abnormalities. • gonadotoxic exposure (e.g., radiotherapy or chemotherapy). • malignancies. • urogenital tract infections. • increased scrotal temperature (e.g., as a consequence of varicocele). • endocrine disturbances. • genetic abnormalities. • immunological factors. In 30-40% of cases, no male-associated factor is found to explain impairment of sperm parameters and historically was referred to as idiopathic male infertility. These men present with no previous history of diseases affecting fertility and have normal findings on physical examination and endocrine, genetic and biochemical laboratory testing, although semen analysis may reveal pathological findings. Unexplained male infertility is defined as infertility of unknown origin with normal sperm parameters and partner evaluation. Between 20 and 30% of couples will have unexplained infertility. It is now believed that idiopathic male infertility may be associated with several previously unidentified pathological factors, which include but are not limited to endocrine disruption as a result of environmental pollution, generation of reactive oxygen species (ROS)/sperm DNA damage, or genetic and epigenetic abnormalities [5]. Advanced paternal age has emerged as one of the main risk factors associated with the progressive increase in the prevalence of male factor infertility [6–13]. Likewise, advanced maternal age must be considered over the management of every infertile couple, and the consequent decisions in the diagnostic and therapeutic strategy of the male partner [14,15]. This should include the age and ovarian reserve of the female partner, since these parameters might determine decision-making in terms of timing and therapeutic strategies (e.g., assisted reproductive technology [ART] vs. surgical intervention) [6–9]. Table 1 summarises the main male-infertility-associated factors. Table 1: Male infertility causes and associated factors and percentage of distribution in 10,469 patients Diagnostic work-up: Focused evaluation of male patients must always be undertaken and should include: a medical and reproductive history; physical examination; semen analysis – with strict adherence to World Health Organization (WHO) reference values for human semen characteristics [17], and hormonal evaluation. Other investigations (e.g., genetic analysis and imaging) may be required depending on the clinical features and semen parameters. Medical/reproductive history and physical examination: Medical and reproductive history Medical history should evaluate any risk factors and behavioural patterns that could affect the male partner’s fertility, such as lifestyle, family history (including, testicular cancer), comorbidity (including systemic diseases; e.g., hypertension, diabetes mellitus, obesity, MetS, testicular cancer, etc.), genito-urinary infections (including sexually transmitted infections), history of testicular surgery and exclude any potential known gonadotoxins [18]. Typical findings from the history of a patient with infertility include: • cryptorchidism (uni- or bilateral). • testicular torsion and trauma. • genitourinary infections. • exposure to environmental toxins. • gonadotoxic medications (anabolic drugs, chemotherapeutic agents, etc.). • exposure to radiation or cytotoxic agents. Physical examination Physical examination Focused physical examination is compulsory in the evaluation of every infertile male, including presence of secondary sexual characteristics. The size, texture and consistency of the testes must be evaluated. In clinical practice, testicular volume is assessed by Prader’s orchidometer [19]; orchidometry may overestimate testicular volume when compared with US assessment [20]. There are no uniform reference values in terms of Prader’s orchidometer-derived testicular volume, due to differences in the populations studied (e.g., geographic area, nourishment, ethnicity and environmental factors) [19–21]. The mean Prader’s orchidometer-derived testis volume reported in the European general population is 20.0 ± 5.0 mL [19], whereas in infertile patients it is 18.0 ± 5.0 mL [19,22,23]. The presence of the vas deferens, fullness of epididymis and presence of a varicocele should be always determined. Likewise, palpable abnormalities of the testis, epididymis, and vas deferens should be evaluated. Other physical alterations, such as abnormalities of the penis (e.g., phimosis, short frenulum, fibrotic nodules, epispadias, hypospadias, etc.), abnormal body hair distribution and gynecomastia, should also be evaluated. Typical findings from the physical examination of a patient with characteristics suggestive for testicular deficiency include: • abnormal secondary sexual characteristics. • abnormal testicular volume and/or consistency. • testicular masses (potentially suggestive of cancer). • absence of testes (uni-bilaterally). • gynaecomastia. • varicocele. Semen analysis A comprehensive andrological examination is always indicated in every infertile couple, both if semen analysis shows abnormalities, and even in the case of normal sperm parameters as compared with reference values [24]. Important treatment decisions are based on the results of semen analysis and most studies evaluate semen parameters as a surrogate outcome for male fertility. However, semen analysis cannot precisely distinguish fertile from infertile men [25]; therefore, it is essential that the complete laboratory work-up is standardised according to reference values (Table 2). Table 2: Lower reference limits (5th centiles and their 95% CIs) for semen characteristics There is consensus that modern semen analysis must follow these guidelines. Ejaculate analysis has been standardised by the WHO and disseminated by publication of the most updated version of the WHO Laboratory Manual