Committee I

Committee XIV

Male Infertility

Prof. Ayman Rashed, MD, PhD, Professor of Urology, 6th October University, Cairo, Egypt

Prof. Maged Ragab, MD, PhD,Professor of Urology, Urology Department, Tanta University, Tanta, Egypt

Prof. Alayman Hussein, MD, PhD,Professor of Urology, Urology Department, Minya University, Minya, Egypt

Assis. Prof. Khaled Almekaty, MD, PhD,Assistant Professor of Urologt, Tanta University, Tanta, Egypt

Dr. Salah Elbashir, MD, PhD,Lecturer of Urology, Urology Department, Benha University, Benha, Egypt

Dr. Mohamed Zahran, MD, PhD,Lecturer of Urology, Urology Department, Mansoura University, Mansoura, Egypt

Dr. Yasmin Magdi, PhD,Consultant of Gynecology, Al-Yasmeen Fertility and Gynecology Center, Benha, Egypt

Dr. Ahmed Eissa, MD,Assistant Lecturer of Urology, Tanta University, Tanta, Egypt

Contents
XIV.1 List of Abbreviations
  • ARTs - Assisted Reproductive Techniques
  • AZF - Azoospermia Factor Gene
  • CBAVD - Congenital Bilateral Absence Of Vasa
  • CFTR gene - Cystic Fibrosis Transmembrane Conductance Regulator gene mutation
  • DFI - Defragmentation Index
  • EDO - Ejaculatory Duct Obstruction
  • E2 - Estradiol
  • FISH - Fluorescent In-Situ Hybridization
  • GnRH - Gonadotropin Releasing Hormone
  • hCG - Human Chorionic Gonadotropin
  • HPG - Hypothalamo Pituitary-testis
  • IVF - In vitro Fertilization
  • ICSI - IntraCytoplasmic Sperm Injection
  • ITT - Intra-Testicular Testosterone
  • IUI - Intrauterine Insemination
  • LH - Luteinizing Hormone
  • MENA - Middle East and North Africa
  • NOA - Non-Obstructive Azoospermia
  • OATs - OAT Syndrome
  • OA - Obstructive Azoospermia
  • OAT - Oligo-Astheno-Teratozoospermia
  • PGD - Pre-Implantation Diagnosis
  • PGT - Preimplantation Genetic Testing
  • ROS - Reactive Oxygen Species
  • US - Ultrasound
  • SERM - Selective Estrogen Receptors Modulators
  • SCD - Sperm Chromatin Dispersion
  • SCSA - Sperm Chromatin Structure Assay
  • SDF - Sperm DNA fragmentation
  • SRR - Sperm Recovery Rate
  • ASRM - The American Society for Reproductive Medicine
  • TT - Total Testosterone
  • TRUS - Trans-Rectal Ultrasound
  • YCMD - Y- Chromosome Microdeletion

XIV.2 Abstract

XIV.2.1 Objective
The Urologic Egyptian Guidelines on Female Urology aim to help and guide clinical practitioners to have knowledge of the incidence, standard definitions, diagnosis, therapy, and follow-up of male infertility. This chapter integrates recent international guidelines with local experts’ opinions based on Egyptian healthcare and socioeconomic circumstances.
XIV.2.2 Methods
Databases searched included Medline, Cochrane Libraries, EAU and AUA guidelines. Review of several meta-analyses, leading institutional protocols and relevant Egyptian publications were taken into consideration. All statements were graded according to 2 parameters: Level of evidence and strength of recommendation. Each information was given a strength rating (strong or weak).

XIV.2.3 Results
These guidelines represent the best clinical evidence-based medicine available. These guidelines are not solely based upon the level of evidence of the international publications but also include expertise of the treating doctor and expectations of every patient.

XIV.2.4 Conclusions
These guidelines provide practical evidence-based guidance on the clinical aspect of many male infertility. The main target is entirely focused on assessment and treatment, reflecting the recommended clinical practice. This can provide the basis for thinking through patient’s management and also for planning and designing clinical services.

XIV.3 ASSESSMENT OF MALE INFERTILITY
XIV.3.1 Definition and classification
Infertility is the inability of a couple to achieve pregnancy within 12 months of active, non-contraceptive sexual life. It is subdivided into; primary infertility in which the couple never had child nor achieve pregnancy, and secondary infertility in which the couple had previous child or at least achieved one pregnancy before (1).

XIV.3.2 Epidemiology
The overall percentage of infertile couples is 15%, of which, male factor accounts for at least 50% (2). Those figures are higher in the Middle East and North Africa (MENA) region according to a recent systematic review and meta-analysis of prevalence surveys on infertility in this region, which, concluded that the overall infertility rate is 22.6%. Unfortunately, there is no recent accurate data or registry that can reflect the actual percentage of male infertility in Egypt, however, there is a consensual opinion from expertise that male infertility rate in Egypt is significantly increasing which favors the aforementioned studies (3,4).

XIV.3.3 Etiology
Male infertility could be due to:
  • Increased scrotal temperature
  • Hormonal disruption
  • Environmental factors
  • Congenital genital anomalies
  • Genetic abnormalities
  • Erectile dysfunction
  • Genital infection
  • Immunological factors
  • Malignancy
  • Idiopathic

Male infertility can be classified according to the topographic localization of the cause (e.g. central, peripheral). Subsequently, it can be subclassified according to the nature of cause (e.g. genetic, congenital, endocrine, inflammatory, environmental, …etc.).

Interestingly, despite abnormal semen analysis is the main finding in infertile male, normal semen analysis does not exclude other male factors that may play a role in male infertility. This is a clear finding in couples with idiopathic infertility (6).

Table XIV:1 Recommendations for epidemiology and etiology of male fertility

Recommendation

Strength Rating
1. Every couple seeking conception should be investigated to define which partner is the cause of the problem. Strong
2. Even in secondary infertility, either partners should not be excluded from investigation work up (Masculinity cultural concept). Strong
3. Normally appeared semen analysis does not exclude male factor and more investigations may be needed particularly in couples with unexplained infertility. Strong
XIV.4 Evaluation of male infertility
XIV.4.1 Why to evaluate?
The aim of evaluation of infertile male is to recognize the following (6):
  • Correctable diagnosed conditions.
  • Irreversible conditions that are amenable to assisted reproductive techniques (ARTs).
  • Irreversible conditions that is not amenable to treatment or ARTs, to save time and cost of unnecessary procedures. In such cases it is better to direct the treatment to other condition e.g. erectile dysfunction due to hypogonadism.
  • Underlying life-threatening conditions that may presented by infertility (e.g. testicular tumor).
  • Genetic abnormalities that may have impact on the offspring.

XIV.4.2 Timing of evaluation?
The Egyptian culture may have an impact on infertile couples as males usually seek infertility evaluation after thorough examination of their female partners at more than one gynecologist. This cultural concept may cause some potential delay in the evaluation of the male partner.

In the era of assisted reproductive techniques (ARTs), female age above 35 years is another risk factor that may influence the treatment protocol of male factor. This is a potential factor as the fertilization, implantation and pregnancy rates are significantly lower in female above 35 years old compared to females below this age when using ARTs (6–8).

XIV.4.3 Medical history
Medical history should include:
  • Duration of infertility and if primary or secondary infertility.
  • Partner age and relevant history.
  • Sexual history including (erectile function, intercourse rate, ejaculatory disorders, STDs)
  • Childhood relevant diseases (e.g. mumps orchitis) and developmental and pubertal history (e.g. undescended testes, hypospadias, …etc.)
  • Gonadotoxins exposure e.g. chemotherapy, radiotherapy, medications, heat, ...etc.
  • Systemic medical diseases (e.g.,DM, dyslipidemia and upper respiratory diseases)
  • History of previous relevant surgeries e.g. herniorrhaphy, varicocelectomy, hydrocelectomy, urethral surgery, abdomino-perineal surgery, …etc.

XIV.4.4 Physical examination
XIV.4.4.1 General Examination
As usual for any other medical condition with concentration directed to the following:
  • Scars of relevant previous operations
  • General facies status of the patient
  • Hair distribution
  • Body proportion and fat distribution
  • Gynecomastia
  • Any apparent congenital anomalies

XIV.4.4.2 Local Examination
Should be concentrated on genitalia including:
  • Penile examination for size and position of external meatus
  • Scrotal examination for development of scrotal sac, and size and consistency of both testes, examination of epididymis and vasa differentia, and examination for varicocele, hydrocele or masses

XIV.4.5 Laboratory investigations
Table XIV:2 Minimal normal semen parameters

Parameter

Lower reference limit
Semen volume (ml) 1.5 (1.4-1.7)
Total sperm number (106 per ejaculate) 39 (33-46)
Sperm concentration (106 per ml) 15 (12-16)
Total motility (PR+NP, %) 40 (38-42)
Progressive motility (PR, %) 32 (31-34)
Vitality (live spermatozoa, %) 58 (55-63)
Sperm morphology (normal forms, %) 4 (3.0-4.0)
Other consensus threshold values
pH ≥7.2
Peroxidase-positive leukocytes (106 per ml) <1.0
MAR test (motile spermatozoa with bound particles, %) <50
Immunobead test (motile spermatozoa with bound beads, %) <50
Seminal zinc (μmol/ejaculate) ≥2.4
Seminal fructose (μmol/ejaculate) ≥13
Seminal neutral glucosidase (mU/ejaculate) ≥20
XIV.4.5.1 Semen Analysis
Semen analysis is the basic and initial investigative tool. According to the WHO 2010 manual of examination and processing of human semen, 5th edition, the sample should be collected after a minimum of 2 days and a maximum of 7 days of sexual abstinence. If additional follow up samples are required, the days of sexual abstinence should be the same as the previous sample. The minimal requirements of normal semen analysis (5 centiles and their 95% confidence interval) below which male sub-fertility is considered are shown in below table, as per WHO 5th edition (9)

XIV.4.5.2 Semen cryopreservation
Semen cryopreservation is an essential procedure for a category of patients with high risk of fertility problems. Semen analysis in these patients should be done at well-equipped andrology laboratory with facility of semen banking.

XIV.4.5.2.1 Indications for semen cryopreservation are:

  • Cases of severe oligozoospermia (<5 mil/cc): should utilize semen cryopreservation before starting treatment. This makes it easy to concentrate considerable count for artificial insemination (IUI) or In-vitro-fertilization (IVF)(10)
  • Cases of essential relevant diseases in which loss of fertility is impending due to either surgical procedure (e.g. oncological, testicular torsion, etc.) or due to medications (e.g. chemotherapy, radiotherapy, immunosuppressive treatment, etc.)(10).
  • Cases of non-obstructive azoospermia (NOA) who are receiving specific medical treatment for specific treatable conditions (e.g. hypogonadotropic hypogonadism, Testosterone/E2 imbalance, etc.). This category of patients may have positive ejaculatory sperms, which are commonly temporary and/or severe oligozoospermia (11–14).

XIV.4.5.3 Sperm DNA fragmentation (SDF) test
SDF test is done through a variety of assays, all of which indicate a DNA defragmentation index (DFI) expressed as a percentage above which the male fertility is questionable.

Four assay tests are the most commonly used namely (15):
  • Sperm chromatin structure assay (SCSA), (n = < 30%)
  • Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNNEL), (n = < 12%)
  • Single cell gel electrophoresis (SCGE or COMET) (n= < 25%)
  • Sperm Chromatin Dispersion (SCD) (n = Large chromatin halo dispersion around the sperms)

Indications for DNA Fragmentation Testing (16):
  • Unexplained Infertility
  • Recurrent pregnancy loss either spontaneous or after IVF/ICSI
  • Recurrent IUI failure
  • Borderline abnormal or normal semen analysis with risk factors (e.g. clinical varicocele, smoking, poor lifestyle, exposure to gonadotoxins, etc).

Several studies demonstrated that high SDF is associated with impaired semen parameters, including either more than one parameter or just one parameter as isolated asthenozoospermia. High SDF was also, found to negatively affect the fertilization process, embryo quality, and pregnancy outcome during ARTs. (17-19) Moreover, male infertility factors such as unexplained infertility, varicocele, old age and obesity, have significant impact on SDF. (18,20)

SDF test practicing is still controversial. This controversy is due to different assays used to measure SDF, with different normal cutoffs and reliability as regard sensitivity and specificity of these assays. (17,19)

The American Society for Reproductive Medicine (ASRM) published an assessment of SDF testing in literature, including 62 meta-analysis and studies. They concluded that: There is fair evidence of correlation between increased SDF and male infertility. Moreover, testicular sperm proved to have lower levels of SDF when compared to ejaculated sperm (21). Couples with male high SDF may benefit from TESE /ICSI combination. However, further evidence is needed to support this practice in the routine clinical setting (22).

XIV.4.6 Hormonal evaluation
Fertility hormones evaluation is well documented as a part of male infertility assessment. Some investigators believe that it is a must in all infertile men.

Indications of hormonal evaluation: (6,7)
  • Subfertile semen analysis particularly if count < 10 mil/cc
  • Associated sexual dysfunction
  • Clinical conditions that suggest endocrinopathy

Serum FSH, LH, and Total Testosterone (TT) are the main fertility hormones to be evaluated in cases of male infertility. Serum Prolactin is usually evaluated during the work up of male infertility if it is suspected to be high (e.g. gynecomastia evident low s. TT or past history of pituitary adenoma) (6,7).

Estradiol (E2) is also another hormone, which play a role in spermatogenesis, however if elevated, it would interfere with the process, particularly, when the TT/E2 ratio is less than 10:1 (13,14).

In cases of primary testicular failure, serum FSH is usually elevated in patients with markedly reduced spermatogenesis, while in patients with maturation arrest, it may be normal or elevated. Nevertheless, serum FSH is an inaccurate predictor of spermatogenesis, particularly, if TESE or micro-TESE is planned for NOA patients before ICSI. (8,23)

XIV.4.7 Genetic tests
It is estimated that at least 15% of infertile males are related to genetic causes with chromosomal or single gene alteration (24). The most common genetic abnormalities include: numerical chromosome abnormality (e.g. XXY, Trisomy), structural chromosome abnormality (e.g. inversion, translocation, microdeletion) (8).

The importance of genetic testing in male infertility arises from:
  • Finalizing the diagnosis of infertility problem.
  • The risk of passing genetic problems to offspring.
  • Saving money and time if the male infertility due to untreatable genetic problems e.g. XX male

XIV.4.7.1 Indications for Genetic testing:
Indications for genetic testing are:(5,8,14,22,24–27)
  • Suspected obstructive azoospermia (OA)
  • Patients with sperm count < 10 mil/cc
  • Severe oligozoospermia (< 5 mil/cc), particularly, in patients, who did not show any documented sperm count above 5 mil/cc.
  • In cases of sexual differentiation disorders
  • Patients with high FSH, low TT, and low testicular volume
  • Apparent facial or body disconfiguration, or known congenital disorder relevant to male infertility (e.g. patients with, polycystic kidney disease, Prader-Willi Syndrome, Noonan Syndrome, etc.)
  • Recurrent miscarriage and/or recurrent failure of ARTs.
  • Recurrent failure of TESE/mTESE.

XIV.4.7.2 Basic Genetic Testing in Male Infertility:
XIV.4.7.2.1 Cystic Fibrosis Transmembrane Conductance Regulator gene mutation (CFTR gene)

Congenital bilateral absence of vasa (CBAVD) is strongly linked with CFTR gene mutation. Which may be found in approximately 70% of patients who have CBAVD without clinical cystic fibrosis. Clinical scrotal examination can easily detect bilateral vas absence, while in azoospermic patients with unilateral absence of vas, transrectal ultrasonography (TRUS) must be done to confirm if the contralateral vas has proximal segmental loss (6,28,29).

In such couples, it is essential to test the female partner for CF mutation before planning for ICSI, as the offspring will have 50% risk of having cystic fibrosis or/and CBAVD. The prevalence of CAVDs in men is reported to be approximately 0.1%. This figure is probably underestimated because the cases with unilateral absent vas may pass without diagnosis (28,30).

XIV.4.7.2.2 Karyotype

Karyotype is the analysis of individual chromosomes including sex chromosomes (X, Y). The test analyzes numerical (gain or loss) as well as structural (translocations, inversions, deletions and duplications) anomalies. The prevalence of chromosomal abnormality inversely proportionate to the sperm count; it comprises < 1 % in men with normospermia, 5% in men with count < 5 mil/cc and 10 – 15% in azoospermic men (6,31).

XIV.4.7.2.3 Numerical Autosomal Abnormalities

Trisomy 13 (Patau Syndrome), Trisomy 18 (Edwards Syndrome), and Trisomy 21 (Down Syndrome) are the only embryos with numerical autosomal abnormalities that can survive to birth with low percentage.

Trisomy 21 patients usually present with azoospermia or severe oligozoospermia (32). In the literature, only three male patients with Trisomy 21 had spontaneous pregnancy, which may be explained by cognitive, physical and psychological problems rendering it difficult for those patients to achieve conception. ICSI could be tried for these patients with aid of pre-implantation diagnosis (PGD) to select chromosomal abnormality-free embryos (33).

XIV.4.7.2.4 Numerical Sex Chromosome Abnormalities

The most common type is Klinefelter’s Syndrome (47XXY), the estimated prevalence is 1:700 of male newborns. Two common types are identifiable, the non-mosaic Klinefelter (47XXY) and the mosaic Klinefelter (46XY/47XXY), other types will include more X chromosomes (e.g. 48XXXY). The majority of cases is non-mosaic. The secondary male characters and normal body features reflect the Leydig cell function with normal serum testosterone level. It is estimated that 66% of these patients will have normal serum testosterone (34). Furthermore, Klinefelter syndrome is the most common chromosomal abnormality in azoospermic patients (particularly, NOA) accounting for approximately 73% of all abnormalities (35,36).

Karyotyping using multi-color fluorescent in-situ hybridization (FISH) will differentiate between non-mosaic and mosaic types. Almost all non-mosaic patients are azoospermic, while, the mosaic patients may have severe oligozoospermia as well as azoospermia with higher chance of sperm retrieval using TESE or m-TESE. Moreover, according to a recent study 7% of adolescents have seminal sperms (32,37).

A recent meta-analysis on sperm recovery and outcome of ICSI in couples where the male partner is Klinefelter, reported that sperm recovery rate (SRR) is about 40% and final birth rate is 16% (34).

Other numerical sex chromosome abnormalities include 47XYY. In these patients, sperm counts range from normal to azoospermia. Virtually, all offspring of XYY males, through spontaneous pregnancy or ICSI, are chromosomally normal (32).

XIV.4.7.2.5 Y-chromosome Microdeletion (YCMD)

Y- chromosome microdeletion (YCMD) is the second most common cytogenetic abnormality in male infertility after Klinefelter Syndrome. It is estimated to be present in 1:4000 men of general population, this prevalence is increased in azoospermic and oligospermic patients (38).

There are three regions on the Azoospermia Factor gene (AZF) on the Y-chromosome, where microdeletion takes place, namely: AZFa, AZFb, and AZFc. Microdeletion on these regions may occur solely or on a mixed pattern. The microdeletions, which are clinically observed in severe oligozoospermia and azoospermia patients are AZFa in 0.5-4%, AZFb in 1-5%, AZFc in 80%, and AZFbc in 1-3% of patients. AZFabc microdeletion may be detected in 46 XX male variants (38). The prevalence of YCMD in Egypt is approximately 12% (38).

Clinical implication of YCMD include: TESE should not be recommended in cases of complete deletion of the AZFa region, or complete deletion of AZFb or deletions of the AZFbc / AZFabc regions. Moreover, in patients with microdeletions of the AZFc region sperms can be recovered for ARTs in 50 – 75 % of patients; however, it may transmitted to male offspring. (5,7,8,38)

XIV.4.7.2.6 Reactive Oxygen Species (ROS)

Seminal leukocytes and sperms produce ROS that have a role in capacitation and acrosome reaction. On the other hand, excess ROS may interfere with male fertility through peroxidation of sperm lipid membrane and creation of toxic fatty acids, in addition to damaging of sperm DNA integrity. This negative impact could be represented in recurrent miscarriage and failed ARTs. Excess ROS is associated with poor lifestyle and environmental exposure. Unfortunately, there is no standardized method for ROS measurement. Antioxidants and improving lifestyle may help in reducing ROS and hence sperm function. However, the studies in this area are deficient and contradictory as there is no RCTs that can support usage of antioxidants. Therefore, ROS measurement is not recommended as routine and may be used in selected group of patients with recurrent miscarriage and recurrent failed ARTs (6–8).

XIV.4.8 Imaging
XIV.4.8.1 Scrotal ultrasound (US)
Although clinical examination of the scrotum is quite enough in most cases; scrotal US is a reliable, and cost-effective tool for the evaluation of difficult cases, particularly, in the assessment of testicular size and texture and in the exclusion of other pathologies (e.g. masses, calcifications, etc.) or in cases of ambiguous scrotum. Noteworthy, non-palpable varicocele detected by US is considered clinically insignificant (39).

XIV.4.8.1.1 Trans-rectal ultrasound (TRUS)

TRUS is a valuable tool in cases where CAVD or ejaculatory duct obstruction (EDO) are suspected from semen analysis. Patients with low volume, negative fructose test and acidic pH may show absent vasa and atrophic seminal vesicles in cases of CBAVD or they may show dilated seminal vesicles (>2cm in long axis or honeycomb appearance) if EDO is present. Furthermore, patients with severe oligozoospermia and low semen volume, TRUS may detect partial obstruction due to (midline prostatic cyst or ejaculatory duct cyst) (40,41)

Table XIV:3 Recommendations on Male Infertility Diagnostic Workup

Recommendation

Strength Rating
1. Evaluation of male partner should be done if no pregnancy after one year of regular unprotected sexual life Strong
2. Evaluation of male partner should be done in less than 6 months if female partner’s age above 35 years or known male or female potential fertility issue. Strong
3. Immediate evaluation of male partner should be done if known infertility factor is ensue or upon request. Strong
4. Semen analysis is the cornerstone investigation and must be done according to WHO 2010 (5th Ed.), in two separate occasions with at least one week apart Strong
5. Semen Cryopreservation is strongly recommended in patients with, or expected to be severe oliogozoospermia (< 5 mil/cc) e.g. due to chemo-radiotherapy, patients receiving medical treatment for NOA Strong
6. SDF as routine examination is recommended in selected cases e.g unexplained infertility, recurrent pregnancy loss Weak
7. Hormonal lab examination is strongly recommended in patients with oligo- or azoospermia including FSH, LH, TT Strong
8. Hormonal Lab. Investigations extending is recommended if abnormal FSH, LH, TT; to evaluate, E2, Prolactin Weak
9. Genetic testing is strongly recommended in azoospermic and severe oligozoospermic (< 1 mil/cc) males and Strong
10. Consider genetic counselling of infertile couples, if any genetic or chromosomal abnormalities are found Weak
11. Genetic counseling should be offered to sperm retrieval candidates even if abnormal genetic testing resulted negative Strong
12. Scrotal US is reliable tool for examination of scrotal contents if suspected pathology in clinical examination Weak
13. TRUS is strongly recommended if partial or complete EDO is suspected Strong
XIV.5 VARICOCELE
XIV.5.1 Definition
Varicoceles are defined as abnormally dilated veins within the scrotum (42)

XIV.5.2 Incidence
Varicoceles are present in almost 15% of men from the general healthy population. Moreover, the prevalence of varicocele is estimated to be 45% among men with primary infertility and 80% among men seeking care for secondary infertility (43). The prevalence of varicocele increases with age, it shows an about 10% increase in the incidence per each decade of life. It is rarely reported in children < 10 years of age; and affects approximately 7-14% of boys during puberty (39,44,45).

The incidence of left-sided varicoceles are 10 times more popular than on the right and occur bilaterally in fewer than 10% of patients and isolated to the right in <1% (46).

XIV.5.3 Diagnosis and classification
Physical examination is the mainstay of varicocele diagnosis. Varicocele is diagnosed clinically as a “cord like structures” felt in the scrotum above the testis in the upright position that disappears on lying down. Varicocele of any grade that does not disappear in the supine position should raise suspicion of retroperitoneal pathology (47).

According to Dubin and Amelar, varicocele can be classified into (48):
  • Grade I varicocele (palpable with Valsalva maneuver)
  • Grade II (palpable at rest, but not visible)
  • Grade III (varicocele visible without palpation).

Subclinical varicocele cannot be detected by clinical examination but is only evident during radiological examination. However, only clinically diagnosed, significant varicoceles associated with infertility have the clearest indications for repair (49). Thus, there is no need to hunt for subclinical varicocele and hence, scrotal ultrasonography, thermography, Doppler examination, radionuclide scanning, and spermatic venography, should not routinely ordered without a palpable abnormality. However, in case of inconclusive or difficulties in the physical examination due anatomic abnormalities such as in situations where a patient is obese, has had prior scrotal surgery, has a small scrotum, or has thick scrotal skin, scrotal ultrasonography is recommended (multiple spermatic veins >3.0 mm in diameter (at rest and with Valsalva) is most probably associated with the presence of clinically significant varicoceles (50).

XIV.5.4 Management
There are no effective medical treatments. Surgery remains the mainstay of management of varicocele. Although radiologic embolization is promoted as a minimally invasive procedure with less pain in infertile men with varicocele, it has interventional failure up to 27% and higher postpone complications (51). Varicocelectomy can be performed surgically with macroscopically, or microsurgical techniques with different approaches including retroperitoneal, subinguinal, and scrotal. Increasing evidence supports the superiority of open microsurgical inguinal or subinguinal varicocelectomy, owing to reduced complication rates and increased pregnancy rates compared with other techniques (51).

Much controversy exists in the literature as regards the effect of varicocelectomy on semen parameters (52). The current available evidence supports varicocele repair for infertile couples with men suffering from clinical varicocele and abnormal sperm parameters, a female partner that has no or potentially treatable cause of infertility, and the time to conception is not a concern (53).

In case of patients with subclinical varicoceles, data from RCTs and meta-analysis failed to prove such benefits (54–57). Although varicocelectomy for subclinical varicocele alone is not indicated, data demonstrated the potential role of subclinical varicocele repair in augmenting the surgical outcome of repair of clinical varicocele over the contralateral side (58,59). Also, no benefit has been proven regarding treatment of varicocele in infertile men with normal semen parameters (49). In addition, most contemporary data do not support varicocele repair based on abnormal strict morphology only without other semen parameter abnormalities (50,60,61).

Evidence from a meta-analysis of nonrandomized, retrospective studies supports that varicocele repair in in infertile couples undergoing ART, wherein the male partner has a diagnosis of oligospermia or non-obstructive azoospermia, is associated with improved pregnancy and Live birth rates (62). In this setting, several studies from the Middle East have assessed the potential benefit of varicocelectomy in the management of patients with NOA (63–66).

Firstly, most of these studies showed that a small number of motile sperms was identified in the ejaculate following varicocelectomy in 26.6% - 34% of patients, thus, enhancing the rate of spontaneous pregnancy (7.7%) (63–66). Similarly, a study from Iran supported these findings, where 14% (7 patients) of the NOA patients showed viable sperms in the ejaculate after surgery, of which, only one couple was able to achieve spontaneous pregnancy (67). On the contrary, Schlegel P et al (68), demonstrated that the role of varicocelectomy in NOA may be over-estimated.

Secondly, varicocelectomy may improve the quality of sperms and the sperm retrieval rates (69,70). Generally, several systematic reviews and meta-analysis supported the beneficial value of varicocelectomy prior to surgical sperm retrieval in patients with NOA (62,71,72).

Furthermore, strong evidence from RCTs supports varicocele repair in adolescents with clinically palpable varicocele when progressive testicular growth retardation is reported (73–75).

For patients with chronic scrotal pain associated with a varicocele that has not responded to conservative measures, a recent meta-analysis has reported that varicocelectomy has shown to be safe and effective, however, proper diagnosis of the cause of pain is necessary, many urological causes e.g. prostatitis, may cause scrotal pain, so justification of varicocele as the cause of pain must be meticulous (76). Varicocele repair may also be beneficial for men with clinically palpable varicoceles with documented low serum testosterone levels; to significantly increase and restore their testosterone levels (77,78).

Data from RCT and prospective studies indicated varicocelectomy for addressing elevated sperm DNA fragmentation, when the male partner has been found to have high DNA fragmentation of the spermatozoa with or without abnormal semen parameters (79–81).

Table XIV:4 Recommendations on the management of varicocele in infertile men

Recommendation

Strength Rating
1. Perform varicocelectomy for men with clinically palpable varicocele and abnormal sperm parameters Strong
2. No benefit has been proven regarding the treatment of varicocele in infertile men with normal semen parameters Weak
3. No benefit of varicocele repair based on abnormal strict morphology (isolated teratozoospemia) only when not accompanied by other semen parameter abnormalities Weak
4. Do not perform varicocele repair in men with subclinical varicocele Strong
5. Perform bilateral varicocelectomy in infertile men with one side clinical and subclinical in the other side Weak
6. Varicocelectomy is recommended for male with non-obstructive azoospermia or severe oligospermia undergoing ICSI treatment, unless genetic pathology is present e.g. Klinefelter’s syndrome Weak
7. Varicocelectomy is indicated for chronic scrotal pain associated with a varicocele Weak
8. Perform varicocelectomy in adolescents with clinically palpable varicocele when progressive testicular growth retardation is reported Strong
9. varicocelectomy is recommended for men with clinically palpable varicoceles with documented low serum testosterone levels. Weak
10. varicocelectomy is indicated for addressing elevated sperm DNA fragmentation, when the male partner has been found to have high DNA fragmentation of the spermatozoa with or without abnormal semen parameters. Weak
XIV.6 AZOOSPERMIA
XIV.6.1 Assessment of Azoospermia patients
Azoospermia defines a condition in which, no sperm is identified using high-powered microscope in a centrifuged semen specimen (for at least 15 minutes at room temperature). It can be found in approximately 1% of all men and 10-15% of the infertile men (82). Interestingly, prevalence of azoospermia may show some variation according to the geographical and racial differences. In this setting, several epidemiological studies from Africa showed that the prevalence of azoospermia ranges between 3.4% - 32.2% of infertile men, reflecting a potential higher prevalence in African countries (83-85). On the same hand, a study including 13,892 infertile men from different geographical regions demonstrated that the prevalence of azoospermia among MENA men is approximately 6% (3). Generally, azoospermia can be classified into OA and NOA (also known as testicular or primary spermatogenic failure) (86).

Table XIV:5 Recommendations on initial diagnosis of Azoospermia

Recommendation

Strength Rating
1. The diagnosis of azoospermia requires the absence of sperms under high-powered microscope in two separates occasions with one-month apart, and centrifuged semen specimens (for at least 15 minutes at a centrifugation speed of more than or equal 3000x at room temperature) Strong
2. The evaluation of azoospermia patients should start with a detailed medical, surgical, sexual, and reproductive history (as described before in the assessment of infertile males) Strong
3. Further initial evaluation of azoospermic patients should include physical examination by a urologist or andrologist (as described before in the assessment of infertile males) Strong
4. Some patients (with low s. testosterone levels) may extended require hormonal investigations including LH, TT, E2 and Prolactin Strong
5. TRUS is recommended in obstructive azoospermic patients with low volume semen, normal testicular volume and normal hormonal profile Strong
6. Diagnostic testicular biopsy is not recommended as a separate setting and should only be performed as a part of TESE and cryopreservation and/or IVF/ICSI Strong
7. Genetic investigations should be performed in all patients with NOA and in patients with OA due to CBAVD as described in the assessment of infertile males Strong
Semen analysis as mentioned above; is the core diagnostic test for azoospermia (87). For instance, semen volume and PH may reflect the cause of azoospermia, where a low volume ejaculate with acidic PH may indicate obstructive causes CBAVD, or bilateral ejaculatory duct obstruction, while, a normal ejaculate volume with alkaline PH demonstrate functional seminal vesicle with patent ejaculatory duct (88). Similarly, complete hormonal investigation is considered an integral part of the initial diagnosis of azoospermic patients as it is essential to plan the diagnostic and therapeutic strategies, where hypogonadism may coexist in approximately 30% of patients with NOA (89).

Routine use of scrotal and/or TRUS in the diagnosis of azoospermic patients is a matter of debate (90), However, it may be used to differentiate between OA and NOA (40,41). An interesting study from Egypt, reported that scrotal US is characterized by a sensitivity and specificity of 75% and 72%, respectively, for detection of NOA, while, for OA its sensitivity and specificity are 29.8% and 87%, respectively. Similarly, TRUS demonstrated 39% sensitivity and 88% specificity for NOA, and 45% sensitivity and 83% specificity for OA. Generally, the authors recommended that US can be used in the diagnosis of NOA (41).

XIV.6.2 Further assessment of Azoospermic patients
After the initial workup, further investigations should be directed to differentiate OA from NOA and should be tailored according to the clinical scenario. Identifying the etiology of azoospermia allows the physician to detect a potentially correctable underlying cause and decide on the best treatment options.

Etiologies of azoospermia fall into three categories: pre-testicular (2%), testicular (49%) and post-testicular (7-51%). Pre-testicular causes are the endocrinal disorders that can adversely affect spermatogenesis. Testicular causes are the factors that are intrinsic to the testes. Post-testicular factors involve either ejaculatory dysfunction or obstruction of sperm pathway from the testis to the urethral meatus (91). Generally, OA represents 30-40%, while NOA represents 60-70% of azoospermic cases (90).

Table XIV:6 Recommendations on NOA investigations

Recommendation

Strength Rating
1. Testicular biopsy in patients with NOA should ONLY be performed simultaneously with mTESE or cTESE to provide the patient with the possibility of sperm cryopreservation without the need for further invasive procedures. Strong
2. Karyotyping is strongly recommended for all patients with NOA Strong
3. Testing for Y chromosome microdeletion is recommended for all patients with NOA Strong
4. Patients with low testosterone level require extended hormonal investigations including luteinizing hormone (LH), estradiol, and prolactin Strong
The OA can be classified according to the level of obstruction into intra-testicular obstruction (15%), epididymal obstruction (30-67%), vas deferens obstruction (2-6%) that includes the CBAVD, ejaculatory duct obstruction (1-3%), and functional obstruction of distal seminal ducts (90). As regards the genetic evaluation for patients with OA, it is well documented in the literature that CBAVD is associated with high frequency of CFTR mutations (92). In this setting, almost all patients with cystic fibrosis suffer from CBAVD, of which, 70% have identifiable CFTR mutations. Similarly, 4% of the female partners may be carriers of the CFTR gene mutations that render testing of both partners an important part of the investigations of OA due to CBAVD. Furthermore, renal agenesis may occur in 11% of patients suffering from vasal agenesis. (93).

Table XIV:7 Recommendations on OA investigations

Recommendation

Strength Rating
1. In patients with unilateral or bilateral congenital absence of vas deferens, both the male and female partners should be offered genetic counseling and testing for CFTR. Strong
2. It is recommended to perform renal imaging to detect any associated abnormalities in patients with CBAVD and no evidence of CFTR Weak
3. Y chromosome microdeletion testing is not recommended in patients with OA Strong
4. Vasography should only be performed if a reconstructive surgery will be performed in the same setting Weak
5. TRUS is recommended as a minimally invasive technique for diagnosis of ejaculatory duct obstruction in patients with low ejaculate and bilateral palpable vas deferens Strong
XIV.6.3 Management of Azoospermia
A meta-analysis showed that mTESE is associated with 1.5 folds’ higher likelihood of successful sperm retrieval compared to cTESE (52% versus 35%, respectively) (94). However, a more recent systematic review and meta-analysis showed no difference between the pooled sperm retrieval rate of mTESE and cTESE. This finding was consistent when considering only randomized controlled trials or high-quality studies. On the contrary, when considering only the studies directly comparing between both techniques the sperm retrieval rate was significantly higher with the mTESE (57% versus 39%). Furthermore, this review showed that the sperm retrieval rate was not affected by age or hormonal status at diagnosis; however, it was correlated with the testicular volume. Retrieved sperms resulted in a live birth rate of 28% per ICSI cycle (95). However, mTESE may be associated with lower complication rates compared to cTESE (98). Interestingly, a recent systematic review and meta-analysis demonstrated that the outcomes of ICSI (including fertilization, implantation, and clinical pregnancy) was not affected by whether the sperm was fresh or frozen-thawed (99).

On the other hand, donor sperm has been used as a treatment for male infertility for more than a century and it has been offered for NOA patients who failed sperm retrieval However, in Arabic and Islamic countries like Egypt, this treatment modality is obsolete due to the religious and cultural constrains.

XIV.6.4 Idiopathic male infertility and Oligo-astheno-teratozoospermia (OAT)
Oligo-astheno-teratozoospermia (OAT) is a clinical condition, with a reduced number of spermatozoa in the ejaculate, which is also characterised by a reduced motility and morphology; often referred to as OAT syndrome (OATs) of unknow etiology.
  • Empirical treatments
  • Life-style modification (weak recommendation)
  • Weight loss (weak recommendation)
  • Physical activity (weak recommendation)
  • Smoking cessation (weak recommendation)
  • Alcohol consumption (weak recommendation)
  • Antioxidant treatment: oxidative stress may induce idiopathic infertility, so antioxidant may show a response in treatment of Idiopathic Male Factor Infertility (weak recommendation)
  • Idiopathic Male Factor Infertility

There is some evidence that FSH treatment increases sperm parameters in idiopathic oligozoospermic men with FSH levels within the normal range (generally 1.5 - 8 mIU/mL). It has also been reported that FSH may improve sperm DNA fragmentation rates as well as ameliorating AMH and inhibin levels. FSH treatment resulted in higher live birth and pregnancy rates compared to either placebo or no treatment. (Strong recommendation). (100)

Table XIV:8 Recommendations on the management of NOA

Recommendations

Strength Rating
1. It is strongly recommended to perform multiple testicular biopsies during the cTESE or mTESE in men with NOA to identify areas of spermatogenesis, provide sperms for cryopreservation/IVF, and diagnose germ cell neoplasia Strong
2. mTESE may be associated with higher sperm retrieval rates (SRR) compared to other techniques (cTESE and TESA) Strong
3. In patients with NOA, the results of ICSI is not affected by the status of sperm (fresh versus frozen-thawed) Strong
4. TESA is not recommended in patients with NOA due to the modest retrieval rates Strong
5. In patients with NOA due to hypogonadotropic hypogonadism, it is recommended to use hormonal treatment such as gonadotropin releasing hormone (GnRH). On the contrary, the use of testosterone is contraindicated. Strong
6. Considering the religious and cultural environment in Arabic countries, it is obsolete to offer donor sperm or adoption for NOA patients who failed sperm retrieval. Strong
Microsurgical reconstruction of the vas deferens is associated with 70-95% recovery of sperms in the normal ejaculate and may result in 30-75% normal pregnancy without the need for ARTs (101). Similarly, transurethral resection of ejaculatory duct is associated with successful normal pregnancy in 25% of patients (102).

Table XIV:9 Recommendations on the management of OA

Recommendations

Strength Rating
1. In patients with vasal or epididymal obstruction, it is recommended to perform microsurgical vasovasostomy, vasoepididymostomy or tubule-vasostomy Strong
2. Sperm retrieval may also be performed at the time of microsurgical reconstruction to provide the patient with an extra chance of success without the need of second procedure if failed reconstruction and IVF/ICSI is planned Weak
3. Transurethral resection of ejaculatory duct is considered in patients with ejaculatory duct obstruction Strong
4. Sperm retrieval techniques are only recommended if cryopreservation of the retrieved sperm is possible in the facility Strong
5. The timing of sperm retrieval in relation to the oocyte retrieval should be based on the patient preference, the surgeon expertise and available facilities Strong
XIV.7 POST- PUBERTAL CRYPTORCHIDISM
Given the small number of patients with this condition, it has been difficult to establish a standard treatment of post-pubertal cryptorchidism (103). Post-pubertal cryptorchid testes cannot produce spermatozoa, associated with impaired endocrine function but have a significant risk of malignant changes and hence orchiectomy was the standard of care (104,105). On the contrary, successful testicular sperm extraction and paternity in an azoospermic man after bilateral post- pubertal orchiopexy was reported (106-108). Orchiectomy, orchiopexy, and observation with no operation are the treatment options for post-pubertal cryptorchidism (109).

Table XIV:10 Recommendations on the management post-pubertal cryptorchidism

Recommendations

Strength Rating
1. In unilateral post-pubertal cryptorchidism with normal contralateral testis below 50 years of age, the preferred treatment is orchiectomy due to the high risk of malignancy. Strong
2. In palpable unilateral post-pubertal cryptorchidism with normal contralateral testis above 50 years of age, due to very low incidence of malignancy and the associated risk of mortality during surgery, the preferred treatment is observation. Weak
3. In bilateral cases or single testis when fertility and patient’s endocrine function is concerned, orchiopexy might be the preferred treatment with close follow up by regular self-examination. Weak
4. Laparoscopy is the preferred approach in post-pubertal cryptorchidism with non-palpable testes. Strong
XIV.8 MALE HYPOGONADISM
XIV.8.1 Introduction
Testosterone is essential for the development and maintenance of male sexual organ and function. In addition, it has a role in maintaining body composition, erythropoiesis, bone and teeth and cognitive function. Also, Intra-testicular testosterone (ITT) is an absolute prerequisite for normal spermatogenesis normally; ITT concentrations are roughly 50–100 times serum levels. Reduction of ITT to less than 20 ng/mL results in significant reduction of spermatogenesis (110).

The current guideline aims to provide practical recommendations for diagnosis and proper management of hypogonadism in infertile men.

XIV.8.2 Definition and epidemiology
Male hypogonadism is a clinical syndrome of androgen deficiency which has a negative impact on male fertility and sexual function (111-116). The incidence in men aged 40-79 varies form 2.1-5.7%. It is more prevalent in older men, obese, those with co-morbidities, and in men with poor health status (113,115-119). Moreover, 20%–30% of infertile men will be found to have low T or increased LH levels (110). Hypogonadism results from a defect at various level of hypothalamo--pituitary axis. Primary (testicular) form is the most common form associated with low T level, impaired spermatogenesis and elevated gonadotrophins. Secondary (hypogonadotropic) hypogonadism is caused by central defect in the hypothalamus or pituitary gland with reduction of gonadotrophin and or GnRH (111).

Table XIV:11 Recommendations on definition and epidemiology of hypogonadism

Recommendations

Strength Rating
1. Male hypogonadism is a clinical and biochemical syndrome of androgen deficiency which adversely affect male sexual function and infertility Strong
2. Male hypogonadism results from defects at various levels of the hypothalamo pituitary-testis (HPG) axis. Strong
3. It can result from an impairment of Testosterone action because of decreased bioavailability or because of androgen receptor alterations Strong
XIV.8.3 Evaluation of hypogonadal men
Hypogonadism is diagnosed by manifestations of T deficiency on at least two occasions. Manifestation of T deficiency vary according to the age of onset, duration and the severity of the deficiency (111–116). The cut-off value of lowest normal level of testosterone varies according to the different medical societies. Free T level is estimated if there is a discrepancy between symptoms and total testosterone level (close to lower normal value) and abnormal SHBG (113). Patients' evaluation includes; in addition, patient examination to assess symptoms, physical examination for body habitus, signs of virilization and testicular examination as well as DRE in men >50 years old. In addition, FSH and LH is recommended to be assessed in case of seeking fertility (111–116).

Table XIV:12 Recommendations on diagnosis of hypogonadism

Recommendations

Strength Rating
1. The clinical diagnosis of hypogonadism is only made when patients have low total testosterone levels below 350 ng/dl (12.1 nmol/L) combined with symptoms and/or signs of androgen deficiency. Strong
2. The diagnosis of low testosterone should be made only after s. TT measurements are taken early morning (7-11 Am) in the fasting state on two separate occasions. Strong
3. In men with low testosterone, it is recommended to measure LH to differentiate between primary and secondary hypogonadism. Strong
XIV.8.3.1 Management of infertile men with hypogonadism
Underlying causes of hypogonadism especially modifiable causes should be evaluated and properly corrected. Exogenous testosterone results in negative feedback on the hypothalamic-pituitary axis, inhibiting GnRH, and, thus, inhibition of the secretion of FSH and LH. Suppression of gonadotropins results in a decrease in ITT levels and overall T production and consequently impairs spermatogenesis. So, TRT should be avoided in infertile men who are seeking conception (120). The more appropriate approach is to increase endogenous T. This can be accomplished by human chronic gonagotrophin, anti-estrogens and aromatase inhibitors.

XIV.8.3.2 Human chorionic gonadotropin (hCG)
It stimulates testosterone production of Leydig cells. Normal physiological serum levels can be achieved with a standard dosage of 1,500-5,000 IU administered IM or SC twice weekly. Treatment for 4 months can initiate spermatogenesis. A combined treatment with FSH treatment (usually 150 IU three times weekly intramuscular or subcutaneous) is required for maintenance of quantitatively normal spermatogenesis (118,121). There is insufficient information about the therapeutic and adverse effects of long-term hCG treatment. This type of treatment can therefore not be recommended for long-term treatment of male hypogonadism, except in patients in whom fertility treatment is indicated (111).

XIV.8.3.3 Selective estrogen receptors modulators (SERM):
Clomiphene competitively binds to ERs on the hypothalamus and pituitary gland. It increases secretion of GnRH from the hypothalamus which stimulates pituitary gonadotropin production that could stimulate both testicular production of testosterone and spermatogenesis. Common dosing starts at 25 mg orally every other day with upward titration to 50 mg daily, as needed. It has been commonly used for the empiric treatment of infertile men with secondary hypogonadism (110). Enclomiphene citrate is a recently used drug with reported increased morning serum T, E2, and LH and FSH levels in men with secondary hypogonadism and preserve sperm production (122). Patients on long-term treatment should be warranted of the increased risk of venous thromboembolic complications and reduced bone density.

Tamoxifen citrate is another oral SERM. Although the studies on tamoxifen use in men have largely focused on those with infertility, its mechanism of action suggests it can also be used to raise testosterone levels in hypogonadal men with elevated estradiol level. In men with oligospermia, it was associated with statistically significant increase in serum gonadotropins, testosterone, and semen parameters (123).

XIV.8.3.4 Non-steroidal aromatase inhibitors (Anastrozole and Letrozole):
Indirectly increase serum levels of LH, FSH, and testosterone by blocking the conversion of T to estradiol which inhibit gonadotrophin secretion. Aromatase inhibitors have been used to treat men with idiopathic male infertility, primarily men with lower serum T-to-E2 ratios (<10), and men with hypogonadism, often related to obesity. They also have been used for normalization of serum T levels before microscopic testicular sperm extraction (TESE) in men with Klinefelter syndrome (110). Also, addition of anastrozole increased sperm concentration and motility in oligoasthenospermia men not responding to anti-estrogen (tamoxifen) (124). Follow-up of liver function and blood pressure are important during treatment with aromatase inhibitor. Other side effects include rash, paresthesia, malaise, aches, peripheral edema, glossitis, anorexia, nausea/vomiting, and, rarely, alopecia. Long-term suppression of E2 may be associated with osteoporosis and osteopenia (110).

In infertile men with primary hypogonadism, fertility can be treated using artificial reproductive techniques (ART) (120,121).

Table XIV:13 Recommendations on the management of infertility in hypogonadal men

Recommendations

Strength Rating
TRT is contraindicated in infertile men with hypogonadism and trying to conceive. Strong
In infertile men with hypogonadotrophic hypogonadism, hCG, hMG and FSH are the recommended treatment Strong
In primary hypogonadism wishing to conceive, ART is considered Strong
XIV.9 ART AND MALE INFERTILITY
XIV.9.1 Introduction
Male factor infertility stands as a common infertility etiology, identified partly or completely in up to 50% of infertile couples (7). When faced with medically-explained cases of infertility, the current principle recommendation given is to pharmacologic and surgical treatment therapies as the first line of treatment (125,126). For a substantial portion of men are diagnosed with idiopathic male infertility, empiric medications, nutraceuticals vitamins, and lifestyle changes based on theoretical concepts is still recommended as a first line treatment (127). Where empiric or specific treatments are not indicated, or have failed to achieve natural conception after at least two spermatogenic cycles, ARTs are recommended for alleviating male factor infertility (125,128).

Male factor infertility management should first consider optimization of the female partner. The use of ART lead rapidly to pregnancy, thus it must be considered if the female partner with advanced maternal age and/or has diminished ovarian reserve (129).

XIV.9.2 Intrauterine insemination (IUI)
IUI is a cost-effective and less invasive approach that involves placement of prepared sperm into the uterine cavity timed around ovulation (130). It is proven that IUI successfully improve the likelihood of successful pregnancy for couples with idiopathic or with mild to moderate male factor infertility, therefore it must be the first-choice option (131). The available evidence strongly recommends that IUI must be performed with semen samples with at least one million progressive motile spermatozoa (132).

Table XIV:14 Recommendations on IUI

Recommendations

Strength Rating
IUI should be the first choice for couples with idiopathic infertility with at least one million progressive motile sperm count (Not responding to treatment options) Strong
XIV.9.3 In vitro fertilization (IVF)
IVF bypasses the fallopian tubes and is usually recommended for women who have badly damaged or absent tubes or when no specific explanation for infertility. For patients with idiopathic or with mild male factor fertility, that have several failed rounds of IUI, the physician and patient should make the decision to move to IVF (133–135). IVF is not recommended for other indications of male factor infertility because it is associated with lower fertilization and pregnancy charges (136).

Table XIV:15 Recommendations on IVF

Recommendations

Strength Rating
Counsel patients with idiopathic or with mild to moderate male factor fertility, that have several failed rounds of IUI, to have IVF trail Strong
XIV.9.4 Intracytoplasmic sperm injection (ICSI)
Since 1992, the introduction of ICSI, in which a single sperm is then directly injected into the cytoplasm of an oocyte, has revolutionized the treatment of male infertility (137). ICSI has proven to be vital for couples with severe male factor infertility in whom IVF is not an option (138), including men with severely impaired semen analysis (Sperm concentration < 2 × 102 and/or sperm motility < 5% and/or strict criteria normal morphology < 4%), OA and NOA patients (138). In contrast, many studies demonstrated that routine use of ICSI in unexplained infertility was not recommended to improve the clinical outcomes (139). However, couples with unexplained or with mild to moderate male factor infertility but suffering from poor or failed fertilization after IVF are recommended to undergo ICSI treatment (140). Moreover, infertile men with retrograde ejaculation or anejaculation should be counseled for testicular sperm retrieval followed by ICSI is the best option (141). ICSI is also recommended for patients with globozoospermia to overcome the acrosome dysfunction (142). Furthermore, Necrospermic patients are recommended to undergo ICSI using testicular sperm retrieval (143,144). ICSI is also indicated for infertile men with anti-sperm antibodies (145,146).

Although ICSI is well established and provides patients with severely impaired sperm quality with an opportunity to father a child, the utilization of scarce and unselected spermatozoa in some cases with severe oligozoospermia or cryptozoospermia often have a lower ability to fertilize. Increasing evidence supports sperm retrieval from the seminiferous tubules that could provide more consistent fertilization and pregnancy outcomes than those retrieved from the ejaculate in such cases (147–149).

Table XIV:16 Recommendation on ICSI

Recommendations

Strength Rating
1. ICSI is recommended for severe oligoasthenozoospermia, obstructive azoospermia and non-obstructive azoospermia Strong
2. Couples with unexplained or with infertility but suffered from poor or failed fertilization after IVF are recommended to undergo ICSI treatment Strong
3. Infertile men with retrograde ejaculation or anejaculation should be counseled for sperm retrieval and IVF/ICSI Strong
4. ICSI is considered for patients with globozoospermia to overcome the acrosome dysfunction Weak
5. Necrospermic patients are recommended to undergo ICSI using testicular sperm retrieval Weak
6. Indicate ICSI for infertile men with anti-sperm antibodies Weak
7. Use testicular sperm for patients with cryptozoospermia undergoing ICSI treatment> Weak
XIV.9.5 Preimplantation genetic testing (PGT)
PGT is a major diagnostic tool to prevent transmission of any known genetic disorder after ICSI. Chromosomal defects in infertile men accounts for 2-15%. The chromosomal abnormalities involve the sex chromosomes in 3.8 % cases and the autosomes in 1.3 % of cases (150).Therefore, PGT is recommended for male infertility, in particular, severe cases (151–153).

Where a specific genetic disorder associated with male infertility is known or suspected, PGT should be offered. Moreover, infertile men who have genetic abnormalities after karyotype testing should be offered PGT. For example, Klinefelter’s syndrome, with either m-TESE or ejaculate, it is recommended to combine ICSI with PGT for selecting normal embryos to prevent the transmission of genetic anomalies to the offspring (154,155).

Table XIV:17 Recommendations on PGT

Recommendations

Strength Rating
Where a specific genetic disorder associated with male infertility is known or suspected, PGT should be offered. Weak
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