Precise review of a male's infertility assessment from a men's health specialist prospective

Abstract

Infertility is a pervasive issue affecting a considerable proportion of couples in their reproductive years, with a projected 10%–15% prevalence. It is characterized by the incapability to achieve conception following a year of consistent, unprotected intercourse, and its far-reaching consequences can take a profound emotional, psychological, and social toll on couples, inducing feelings of melancholy, exasperation, and anxiety. The appraisal of infertile couples' cases is a multifaceted and daunting process, necessitating a holistic understanding of the intricate underlying factors contributing to their infertility. Consequently, an individualized evaluation should be conducted, considering diverse parameters, such as the couple's medical history, age, infertility duration, and other relevant criteria. This paper will provide an in-depth overview of the current approaches utilized in the evaluation of men with infertility, including the commonly employed diagnostic tools and procedures. Enhancing our comprehension of infertility assessment and management holds the promise of helping couples achieve their ultimate desire of conceiving and enriching their overall quality of life.

Graphical abstract

Keywords

genetic karyotyping / history and physical examination / male endocrine profile / male infertility / management guidance / semen analysis / varicocele

1 INTRODUCTION

Male infertility is a common and distressing condition that affects approximately 7% of men worldwide. Infertility is defined as the inability to achieve pregnancy after 1 year of regular, unprotected intercourse, and male factor infertility accounts for approximately 30%–50% of all cases[1]. Male infertility can be caused by a variety of factors, including abnormalities in sperm production or function, hormonal imbalances, anatomical abnormalities, genetic disorders, or environmental and lifestyle factors[2].

Male infertility has numerous potential causes that can be challenging to enumerate. However, for simplicity, they can be broadly categorized into three main categories based on their relation to the testes: “Pre-testicular,” “Testicular,” and “Post-testicular” causes. These etiologies can be congenital, acquired, or iatrogenic in nature. Figure 1 provides a detailed overview of some of the etiologies within each category, serving as a useful reference for clinicians during their male fertility assessment.

A comprehensive evaluation can help to identify potential contributing factors and guide treatment decisions. In recent years, advances in diagnostic techniques and treatment options have led to improved outcomes for couples struggling with male infertility.

This review aims to provide an overview of the numerous factors that contribute to male infertility and the available diagnostic options. Recently, the American Urological Association (AUA) and the American Society of Reproductive Medicine (ASRM) have published updated guideline statements for “Diagnosis and Treatment of Infertility in Men,” which helped to support the current evidence of various associations and correlations to male infertility. Ultimately, the goal is for a better understanding of male infertility and its management, which can help to improve fertility outcomes and quality of life for couples struggling with this condition.

2 MEDICAL HISTORY

The acquisition of a comprehensive medical history is an essential aspect of patient evaluation in a clinical context. It provides invaluable information regarding a patient's present and past health status, encompassing medical conditions, allergies, medications, and family history of illness, as well as social and environmental factors such as occupation, lifestyle habits, and living conditions. An exhaustive medical history aids healthcare providers in identifying potential risk factors, arriving at an accurate diagnosis, and creating a suitable management strategy for the patient.

AUA/ASRM guideline statement:[3]

For initial infertility evaluation, both male and female partners should undergo concurrent assessment. (Expert Opinion)

Men with one or more abnormal semen parameters or presumed male infertility should be evaluated by a male reproductive expert for complete history and physical examination as well as other directed tests when indicated. (Expert Opinion)

Furthermore, a medical history enables healthcare providers to establish an excellent rapport with patients, encouraging better communication and understanding of the patient's concerns and expectations[4]. During history taking of an infertile male, it is essential to cover the following aspects and correlate each with his complaints:

1. Duration and type of infertility: The duration of time the couple has been trying to conceive can provide important information about the potential causes of infertility. Primary infertility is defined as couples who have been unsuccessful in achieving pregnancy after 1 year of continuous unprotected intercourse, while secondary infertility refers to couples who are unable to have further pregnancies after previously conceiving[5]. Distinguishing between primary and secondary infertility can guide physicians in identifying possible causes of infertility, such as congenital issues that may be more likely to contribute to primary infertility. Inquiring about the number of children and the age of the youngest child is also important for determining possible causes of secondary infertility, such as recent infections or surgeries that may have affected reproductive function[6].

Identifying the duration of infertility is important since couples who have only been trying to conceive for a few months may not meet the 12-month requirement for infertility. Moreover, the duration of infertility can affect management decisions, such as considering assisted reproductive technology (ART) for couples with long-term infertility[7].

Ascertaining the presence of both partners during the 1-year trial of conceiving is also crucial, as consistent travel may have shortened the actual period that the couple spent together, which could affect fertility. Lastly, clarifying whether the couple had unprotected sex is important, as couples may have varying levels of knowledge about safe sex and contraception. Ensuring that the couple had sufficient opportunity to conceive naturally before proceeding with diagnostic and treatment measures is a critical role of fertility specialists[8].

2. Past medical history: Another important aspect of history taking is the inquiry about previous medical conditions that could be significant to the etiology of infertility. This is not limited to the following examples:

– Infections: Such as sexually transmitted diseases, epididymo-orchitis, urinary tract infections, and mumps infections can cause infertility. Their mechanisms could be attributed to the imbalance between free radicals and antioxidants causing a state of oxidative stress and subsequential increased DNA fragmentation[9], while chronic and recurrent infections cause fibrosis, scarring, atrophy with possible pathway obstruction, and sperm immaturity. Urinary tract infections prompt specifically cellular and humoral immune system activation[10], while before childhood vaccinations, mumps orchitis was a prevalent cause of testicular atrophy and abnormal sperm parameters[11].

– Medications and supplements effect: Misuse or abuse of certain medications and supplements that may not be Food and Drug Administration approved could impact infertility. Examples of such are exogenous testosterone therapy, anabolic steroids, herbal remedies, and chemotherapeutic agents. Sperm production and quality are affected by various factors such as hypothalamic-pituitary axis suppression[12], endocrine dysfunction, and direct or indirect antiandrogenic effects on spermatogenesis. Therefore, questioning the type, dose, and duration of each and correlating it with the patient's complaints is essential[13,14].

– Trauma: Trauma to the scrotum, and testes, with possible rupture and loss of testicular tissue impacts sperm production and testosterone secretion, in addition to the formation of antisperm antibodies (ASAs)[15,16]. All of which could be factors associated with male infertility. Moreover, it has been reported that spinal cord injury patients suffered impaired semen quality in addition to the sexual dysfunction of anejaculation and erectile dysfunction[17].

– Pubertal history: Examining the timing of puberty initiation and the progression of secondary sexual characteristics in patients may reveal the presence of congenital disorders that impact male hormone and sperm production, such as Klinefelter syndrome and Kallmann syndrome[18].

– Malignancy: Cancers in general and testicular cancer in specific have their share in developing infertility in men. It may be through a direct gonadotoxic effect on the testicles affecting sperm production, hormonal imbalance, general cachexia, and malnutrition effects or through treatment effects of chemotherapy, surgery, and radiotherapy[19,20].

In cases of radiotherapy, inquiry about radiation doses, fraction numbers, and location with regards to testes are important[21]. The main theory behind infertility in such cases is related to the loss and destruction of the testicular germ cells, which could be irreversible in some situations[22].

AUA/ASRM guideline statement:[3]

Clinicians should discuss the effects of gonadotoxic therapies and other cancer treatments on sperm production with patients prior to commencement of therapy. (Moderate Recommendation; Evidence Level: Grade C)

Clinicians should inform patients undergoing chemotherapy and/or radiation therapy to avoid pregnancy for a period of at least 12 months after completion of treatment. (Expert Opinion)

Clinicians should encourage men to bank sperm, preferably multiple specimens when possible, prior to commencement of gonadotoxic therapy or other cancer treatment that may affect fertility in men. (Expert Opinion)

Clinicians should consider informing patients that a SA performed after gonadotoxic therapies should be done at least 12 months (and preferably 24 months) after treatment completion. (Conditional Recommendation; Evidence Level: Grade C)

− Chronic diseases: The presence of chronic illnesses, their duration, in addition to treatments provided, and whether it is controlled or not, all could account for infertility. For example, liver and renal diseases affect hormone production[23,24], and thyroid disorders alter sperm parameters by changing sex steroid levels and binding globulin[25].

AUA/ASRM guideline statement:[3]

Clinicians should counsel infertile men or men with abnormal semen parameters of the health risks associated with abnormal sperm production. (Moderate Recommendation; Evidence Level: Grade B)

Infertile men with specific, identifiable causes of male infertility should be informed of relevant, associated health conditions. (Moderate Recommendation; Evidence Level: Grade B)

3. Age: Advanced male age has recently been considered as a key player in male infertility. Different studies reported that impaired semen parameters affected sperm DNA integrity, in addition to lowering success rates in ART, reduced embryo quality, diminished implantation rates, and an increase in genetic abnormalities in offspring[26–28].

AUA/ASRM guideline statement:[3]

Clinicians should advise couples with advanced paternal age (≥40) that there is an increased risk of adverse health outcomes for their offspring. (Expert Opinion)

4. Past surgical history: The surgical history of a patient can provide invaluable insights into their past medical conditions, particularly those pertaining to fertility, which may have been overlooked or omitted. Common correlations have been reported in vas deferens injury with inguinal hernial repairs, testicular atrophy due to arterial injury with varicocele repair, testicular dysfunction with cryptorchidism or delayed torsion repair, and finally ejaculation disorders with prostatic surgeries[29].

5. Sexual history: This includes intercourse frequency, specific patterns, relation to partner's ovulation period, rigidity of erections, intravaginal ejaculation or other related disorders, low libido, and use of lubricants. These factors could unmask the presence of challenges of semen disposition into the vagina, underlying hormonal dysfunction, or even direct spermicidal effect and increased sperm DNA fragmentation caused by specific lubricants[30–32].

6. Family history: A family history of infertility among siblings or relatives, or the presence of genetic disorders can be relevant in the evaluation of male infertility. Studies have shown that a genetic component could contribute to 8%–19% of male infertility depending on the condition[33]. Additionally, the potential impact of consanguinity between the couple or their parents, which may be prevalent in certain regions, should also be taken into account during the evaluation[34].

7. Lifestyle factors: The effects of social habits such as smoking, alcohol use, and drug use (detailing on amount, dose, and duration) on infertility should be included in any infertility comprehensive assessment. Reports of semen affection via the oxidative stress theory with smoking, testosterone level reduction with excessive alcoholism, or both mechanisms with drugs have been published[35–38].

8. Occupational history: Exposure to chemicals, radiation, or other toxins (heavy metals, pesticides, and increased heat) could occur during one's occupation. This would not be revealed unless asked. Oxidative stress, direct testosterone, and spermatogenesis affection have all been postulated as mechanisms that have a negative impact on male fertility[39–41].

AUA/ASRM guideline statement:[3]

Clinicians may discuss risk factors (i.e., lifestyle, medication usage, environmental exposures) associated with male infertility, and patients should be counseled that the current data on the majority of risk factors are limited. (Conditional Recommendation; Evidence Level: Grade C)

9. Psychological factors: Stress, anxiety, and depression can also contribute to male infertility, and should be considered as part of the medical history.

10. Previous fertility treatment: As part of the patient evaluation process, it is essential to collect thorough information regarding the individual's medical and surgical history related to infertility, including any prior experiences with assisted reproductive techniques such as intrauterine insemination (IUI), in vitro fertilization, or intracytoplasmic sperm injection (ICSI). By utilizing this data, valuable insights can be gained into the potential underlying causes of infertility, which can then be used to guide subsequent investigations and treatment plans accordingly.

11. Female partner: When taking a history from a couple, it is important to ask about the partner/spouse's age, menstrual cycle regularity, reproductive endocrinologist evaluation, medical/surgical history, comorbidities, and family history. This helps to assess the overall fertility status and determine if the infertility issue is solely related to male factors or if both partners may be contributing to it.

3 PHYSICAL EXAMINATION

The physical examination plays a pivotal role in the assessment of male infertility. It provides valuable insights into the patient's overall health, reproductive anatomy, and potential underlying conditions that may be contributing to infertility. It aids in formulating an accurate diagnosis and appropriate treatment plan via appropriate ordering of laboratory tests and imaging studies. Thus, a thorough physical examination is an indispensable component of male infertility assessment, enabling clinicians to identify potential contributing factors and provide targeted interventions to optimize fertility outcomes.

1. General appearance: The primary objective of conducting a general exam during infertility evaluation is to identify signs of hypogonadism, which could manifest in the form of increased central obesity, underdeveloped secondary sexual characteristics (such as sparse body, facial, and pubic hair), disproportionate body habitus, or the presence of gynecomastia. These signs are indicative of hormonal imbalance, which could impact fertility[42].

Obesity as an example has been reported to disrupt the hormonal axis, steroidogenesis, and spermatogenesis through the conversion of testosterone to estrogen. In addition, studies have shown sperm affection, high DNA sperm fragmentation, and lower success rates of ART with obesity[43–47]. On the other hand, bariatric surgery weight loss has shown improved outcomes in previously obese patients with deranged semen parameters[48].

2. Abdominal exam: Careful inspection for scars from previous surgeries, such as hernia repair, varicocele repair, or pelvic trauma, is conducted. Additionally, an assessment of hernial orifices is performed to identify any potential anatomical abnormalities or disruptions that may be contributing to infertility.

3. Genital exam: This includes examining both testes, epididymis, spermatic cord, phallus, and executing a digital rectal exam.

− Testes: Assessment and comparison of both testicles for their size (discrepancy), consistency (firm/rubbery, or soft, or hard), tenderness (suspected orchitis), and presence of abnormal lesions (masses/cysts) guides the clinician toward suspecting a unilateral varicocele, or testicular mass for example[49–51].

− Epididymis: Assessment for the presence/absence of one or both epididymis is initially performed. Palpation for the presence of epididymal tenderness or fullness, and masses/cysts. A meticulous epididymal exam could guide a clinician toward the diagnosis of Wolffian duct malformation, epididymitis, obstructive azoospermia, and so on[52–54].

− Spermatic cord: Initial identification of the presence or absence of the vas is essential to preclude conditions like cystic fibrosis and congenital absence of unilateral/bilateral vas. Moreover, the presence of thickened cord-like vas could be a sign of tuberculosis[55,56]. The second step in the spermatic cord examination is the detection of varicocele, grade, and laterality. This is best performed during a relaxed state and compared during Valsalva maneuver. Different grading systems for varicocele have been reported. The most common is the Dubin and Amelar classification[57], which divides varicocele into:

∘ Grade 1: Varicocele is felt with Valsalva maneuver only.

∘ Grade 2: Varicocele is felt with palpation in a relaxed state and cannot be seen through the scrotal skin.

∘ Grade 3: Varicocele is seen through the scrotal skin without Valsalva maneuver, they named it “bag of worms appearance.”

− Phallus: The patient's phallus is examined, noting the circumcision status. Foreskin retraction, if still present, to inspect the glans, presence of any suspicious lesions, meatal location, and urethral discharge. Inquiry about penile curvature with palpation of penile plaques or chordee should not be forgotten[58].

− Digital rectal exam: This includes assessment of anal tone, prostate size, presence of nodules or masses, tenderness of the prostate, seminal vesicle (SV) masses, cysts, and also tenderness. Each finding could aid in diagnosing prostatitis, benign prostatic hyperplasia, prostate cancer, and SV infection or blockage[59,60].

4 MALE FERTILITY RELATED TESTS

After the completion of a full detailed history and performing the necessary physical examination, certain infertility investigations play a critical role in providing valuable information to identify the underlying causes and guide appropriate treatment strategies. They typically involve various diagnostic tests and assessments to evaluate sperm quality, hormonal levels, genetic factors, and anatomical abnormalities.

4.1 Semen analysis

A semen specimen should be examined in all couples presenting with infertility. A good and reliable semen analysis result starts from semen collection. The specimen could be obtained by masturbation into a sterile collection cup or through intercourse with a special condom (nonlatex, noncoated with nonoxynol-9, which is spermicidal)[61]. The collection is done on-site or at home. If performed at home, the sample should be kept at room temperature (no direct sunlight exposure) and delivered to the lab within 1 h for analysis. Other certain collection precautions are handed to the patient in advance, including a 2–5 day of abstinence, passing urine before collection, hand washing with soap, and adequate drying[62]. Due to the high variations in semen analysis, two samples are required 1 week apart at least, following the same collection instructions[63].

AUA/ASRM guideline statement:[3]

Initial evaluation of the male for fertility should include a reproductive history. (Clinical Principle)

Initial evaluation of the male should also include one or more semen analyses (SAs). (Strong Recommendation; Evidence Level: Grade B)

Semen analysis could be classified into basic and advanced sperm function tests. In basic tests, semen is macroscopically evaluated for volume, pH, appearance, and viscosity (liquefaction), while the sperm is microscopically assessed for count, concentration, vitality, motility, progression, morphology, immature germ cells, leukocytes, and viability.

On the other hand, advanced sperm function tests include measurement of sperm DNA fragmentation, oxidation–reduction potential (ORP), ASAs, sperm–cervical mucus interaction, acrosome reaction, nuclear maturity tests, and sperm penetration assay. These are used in certain indications and vary from case to case[64].

Semen analysis is one of the foundations of infertility evaluation in men. The World Health Organization (WHO) over the past decades published regular updates for the semen parameter standard evaluation in the laboratory manual for the examination and processing of human semen. The latest published is the WHO 2021 Laboratory Manual 6th Edition for semen analysis[65]. The latest semen parameters are outlined below in Table 1.

There are imperative terminologies used in interpreting a semen analysis among fertility experts. The numbers/percentages usually change according to the laboratory manual, latest edition, by the WHO.

Currently, oligozoospermia is defined as a sperm concentration less than 16 × 10⁶/mL or a total sperm number less than 39 × 10⁶/mL. Azoospermia is the absence of spermatozoa in the ejaculate, while aspermia means the absence of semen from the ejaculate. For spermatozoan motility, asthenozoospermia describes a reduced progressive motility below 30% or if the total motility was below 42%. While teratozoospermia describes morphologically normal sperm of less than 4% of the analyses sample. Oligoasthenoteratozoospermia would be defined as deranged levels for all parameters.

The presence of more than one million round cells in the ejaculate could be mistakenly termed as leukocytospermia or pyospermia. This should be further evaluated to distinguish between immature germ cells (normally present in semen and no treatment required) and inflammatory white blood cells (which contribute to infertility and is treatable). A pyospermia stain (immunocytologic staining or peroxidase staining) could be used to differentiate between both[66].

Advanced sperm function assays: They are a group of tests that further explore the function and intermolecular integrity of sperm. Clinicians proceed with requesting them upon moderate/severe derangement of the basic semen analysis and in cases of unexplained infertility between couples. Understanding each test's indication, mechanism, result interpretation, and management of abnormalities is pivotal. We will mention below some of the most used sperm function tests.

Sperm–cervical mucus interaction: Also termed as “postcoital test.” It is performed by cervical mucus examination after intercourse (within 8 h), for viable sperm, done just prior to ovulation (1–2 days). Its indicated in cases of semen hyperviscosity, volume discrepancy with normal sperm density, and unexplained infertility. The presence of 10–20 motile sperm per 400 high-power fields is rendered a normal sperm–cervical mucus interaction, while abnormal results could suggest an involved female cervical factor[67].

Vitality tests: The interpretation of sperm viability is of paramount significance. A male can present with adequate sperm concentrations in his semen analysis, yet mostly nonviable (dead) or the percentage of sperm viability in the fresh semen sample is less than 54%. This is termed as necrozoospermia. This is indicated in cases of low sperm motility (less than 5%–10%). Multiple available tests are used to distinguish between both for diagnostic purposes and during sperm selection for ICSI.

Sperm vitality staining: The theory underlying this test is that only dead sperm can be stained by special dyes on a test slide.

Hypoosmotic swelling test: The theory underlying this test is that dead sperm will not swell with exposure to very dilute solutions[68].

ASA: It is the formation of antibodies against sperm affecting its motility, transport in the female tract, fertilization, and other sperm function processes. There are different quantitative and qualitative methods used for its detection. Indications for testing, besides increased sperm agglutination on semen analysis, include very low sperm motility, couples with unexplained infertility, history of blood testes barrier damage via scrotal surgeries, and trauma[69].

Sperm DNA fragmentation testing: Sperm DNA integrity has been reported as a reliable predictor for fertility. Increased levels of DNA fragmentation affect fertilization, implantation, and pregnancy outcome. It is believed that this process occurs due to a defect in the repair system of sperm DNA during late spermatogenesis. Measuring the percentage of fragmentation is warranted in cases of unexplained infertility, recurrent miscarriages, and failure of IUI and IVF attempts. Multiple different tests have been performed and applied, each with a different measurement method and results interpretation. The most frequently used tests nowadays are terminal deoxynucleotidyl transferase dUTP nick-end labeling, sperm chromatin dispersion, single-cell gel electrophoresis (COMET assay), and sperm chromatin structure assay[70].

Abnormal results guide clinicians in identifying the cause of elevated DNA fragmentation and managing it. Moreover, in situations where couples elect for ART, testicular sperm source has been reported as a better alternative in high percentages of sperm DNA damage[71].

Reactive oxygen species testing: An imbalance between free radicals and antioxidants causes a state of oxidative stress, which affects several biological and physiological parameters on the cellular level of sperm and impacts its functional capability[72]. Measurement of ORP is indicated in cases of idiopathic infertility, recurrent miscarriages, repeated IUI and IVF failure, and old paternal age. Commonly used tests are the chemiluminescence test, nitroblue tetrazolium test, and MiOXYS. Findings of elevated levels of ORP play a role in understanding the underlying causes of infertility. Antioxidants are recommended in these incidents and data regarding their impact on ART is still under investigation[64].

Other advanced sperm function tests could be used to diagnose any defect in the sperm–ovum fertilization process. This is suspected and indicated when a couple presents with multiple IUI failure attempts. Examples of these tests are capacitation, acrosomal reaction, and sperm penetration assays. If results were abnormal, then ICSI is recommended for such couples[73].

AUA/ASRM guideline statement:[3]

Sperm DNA fragmentation analysis is not recommended in the initial evaluation of the infertile couple. (Moderate Recommendation; Evidence Level: Grade C).

Men with increased round cells on SA (>1 million/mL) should be evaluated further to differentiate white blood cells (pyospermia) from germ cells. (Expert Opinion)

Patients with pyospermia should be evaluated for the presence of infection. (Clinical Principle)

Antisperm antibody (ASA) testing should not be done in the initial evaluation of male infertility. (Expert Opinion)

For couples with RPL, men should be evaluated with karyotype (Expert Opinion) and sperm DNA fragmentation. (Moderate Recommendation; Evidence Level: Grade C)

4.2 Male endocrine assays

Blood tests provide information about hormones that play a role in male fertility. If sperm concentration is low or the provider suspects a hormonal problem, blood tests may be ordered to measure key important hormones in the hypothalamic-pituitary-ovarian axis that is crucial in spermatogenesis. Such hormones include total testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, prolactin, inhibin B, sex hormone-binding globulin, and albumin (the latter two to measure the bioavailable testosterone).

Sigman and Jarow in 1997 reported in their retrospective review of 1035 infertile patients that only 9.6% were found to have abnormal endocrine studies, with FSH elevation in 7.9% of patients. They concluded that endocrine abnormalities are rare if sperm counts are above 10 million/mL[74].

Therefore, the initial hormonal infertility evaluation consists of testosterone and FSH serum levels. If abnormal, then the rest of the male endocrine profile could be obtained. According to the results of testosterone, LH and FSH, a men's health specialist could interpret these into different scenarios with the combination of history, physical examination findings, and semen results, in order to reach the ultimate cause of the patient's infertility[75].

− For example, the presence of normal/low levels of FSH and LH despite low testosterone would direct toward a secondary hypogonadism cause (Kallmann syndrome or increased prolactin levels).

− The presence of high levels of FSH and LH and low testosterone directs one's attention to primary hypergonadotropic hypogonadism (Klinefelter syndrome), which would warrant genetic tests.

− Another scenario where testosterone and LH levels remain normal while FSH levels are elevated indicates primary testicular failure cause (especially if associated with low sperm counts) such as Y-chromosome microdeletion, Sertoli cell-only syndrome, or maturation arrest of intratesticular sperm development.

− Finally, the presence of normal hormones and adequate testicular size despite no sperms in the ejaculate would direct toward obstructive azoospermia (search for CFTR gene mutation and cystic fibrosis presentation if vas deferens was absent).

AUA/ASRM guideline statement:[3]

Clinicians should obtain hormonal evaluation including follicle-stimulating hormone (FSH) and testosterone for infertile men with impaired libido, erectile dysfunction, oligozoospermia or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical evaluation. (Expert Opinion)

Azoospermic men should be initially evaluated with semen volume, physical exam, and FSH levels to differentiate genital tract obstruction from impaired sperm production. (Expert Opinion)

Screening for thyroid disease and insulin disorders in male infertile patient evaluation has been increasing lately. There is evidence suggesting that thyroid hormone imbalances and insulin disorders could potentially impact male fertility by affecting sex hormone-binding globulin levels, testosterone production, and subsequently spermatogenesis. However, further research is needed to better understand the relationship between these conditions and male infertility and to establish effective treatment strategies[76–78].

4.3 Genetic studies

The three genetic tests that are mainly related to male infertility are:

1. Genetic karyotyping (assess chromosomal number and structure).

2. Y-chromosome microdeletion (assess the absence of the male azoospermia factor regions “AZF a/b/c”).

3. CFTR gene mutation related to cystic fibrosis and congenital absence of bilateral vas.

Most indications to obtain genetic tests are the presence of nonobstructive azoospermia (NOA), severe oligozoospermia <5 million/mL, recurrent miscarriages, idiopathic causes of oligoasthenozoospermia or the presence of signs and symptoms of cystic fibrosis. Conceding that results returned positive, genetic counseling is advised for the couple to better perceive the diagnosis, address their concerns and related anxiety, and discuss the possible impact on future offspring if any[79,80].

AUA/ASRM guideline statement:[3]

Karyotype and Y-chromosome microdeletion analysis should be recommended for men with primary infertility and azoospermia or severe oligozoospermia (<5 million sperm/mL) with elevated FSH or testicular atrophy or a presumed diagnosis of impaired sperm production as the cause of azoospermia. (Expert Opinion)

Clinicians should recommend Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele) in men with vasal agenesis or idiopathic obstructive azoospermia. (Expert Opinion)

For men who harbor a CFTR mutation, genetic evaluation of the female partner should be recommended. (Expert Opinion)

4.4 Radiological studies

4.4.1 Scrotal ultrasound

Routine scrotal ultrasound is not indicated in the evaluation of infertility. A proper physical examination with an experienced fertility specialist is sufficient in most patients. Yet, many clinicians would request a scrotal ultrasound for all their infertile patients as a screening tool for testicular pathologies or malignancies since its a noninvasive, safe, inexpensive, and a painless diagnostic method.

Scrotal ultrasound aids in detection and confirmation of various pathologies such as spermatoceles (size, number), varicocele (size, reflux of blood flow during Valsalva maneuver), absence of the vas on physical examination, presence of testicular microlithiasis, or any testicular lesions[81].

4.4.2 Pituitary gland imaging

The imaging history of the pituitary region has undergone significant advancements over the years, with various modalities used, including plain radiographs, computed tomography (CT), and magnetic resonance imaging (MRI).

While plain radiographs were useful in detecting pituitary fossa remodeling, erosion of the tuberculum sella, and tumoral calcification, it is not frequently used today. CT scan is less frequently used in evaluating sellar/paraseller lesions, but is useful in detecting soft tissue calcification, bony destruction, and surgically relevant bony anatomy. A CT scan can be a useful option for evaluating the pituitary gland, particularly in cases where MRI is not feasible due to contraindications such as the presence of pacemakers or metallic implants in the brain. However, identifying microadenomas with this technique may be difficult, and MRI is currently the examination of choice for sellar/suprasellar pathologies evaluation, especially with its excellent soft tissue contrast and lack of ionizing radiation. The rapid evolution of MRI techniques, such as dynamic contrast-enhanced MRI, has been a significant addition in diagnosing pituitary microadenomas, along with other advanced MR techniques[82,83].

4.4.3 Seminal vesicle imaging

Seminal vesiculography was the gold standard evaluation method for SVs. It was used for diagnosing obstructive pathologies, but was abandoned due to its invasiveness nature and iatrogenic side effect profile. It has been replaced by different other more accurate and less invasive methods. Nowadays, its performed during reconstructive surgery to validate proximal vasal patency[84].

MRI pelvis clearly demonstrates SV cystic lesions and is more accurate for staging solid neoplasms than other methods. This owes to its multiplanar imaging capabilities and superb soft tissue contrast resolution[85].

CT scan can detect calcifications, soft tissue attenuation of SVs, and inflammatory changes associated with infection or abscess.

Transrectal ultrasonography is a noninvasive, inexpensive, and easy method of evaluating the distal seminal tract integrity. It provides excellent anatomic detail of pathologic changes in the SVs and ejaculatory ducts, being superior to CT because it better delineates the internal structure of the SVs. It helps in giving clinical insight into the causes of significant genitourinary symptoms.

The standard criteria were used to evaluate the modifications of ultrasound imaging of the SVs, which include an increased thickness (anterior–posterior diameter—APD), mono- or bilateral (>14mm), asymmetry (>2.5 mm) between the two SVs, even with normal APD (7–14 mm), reduced APD, mono- or bilateral (<7mm), thickened glandular epithelium or with calcification/s, and the presence of polycyclic areas separated by hyperechoic septa (honeycomb-shaped) in one or both SV[86]. This has recently changed as currently there are no literature data about the description of the SV dilation with a volumetric cut-off. Nevertheless, an elevated volume after ejaculation is highly associated with SV anomalies, with a large prostate or with the presence of median cysts that might cause obstruction of the ejaculatory ducts[87].

SV hypoplasia is defined such by some authors when the APD of the SVs is <5mm or <7 mm, whereas other authors suggest referring to the longitudinal diameter (normal if >25 mm, hypoplastic if 16–25mm, and atrophic if <16 mm). It aids in detecting posttesticular infertility etiologies[88].

AUA/ASRM guideline statement:[3]

Scrotal ultrasound should not be routinely performed in the initial evaluation of the infertile male. (Expert Opinion)

Transrectal ultrasonography (TRUS) should not be performed as part of the initial evaluation. Clinicians should recommend TRUS in men with SA suggestive of ejaculatory duct obstruction (EDO) (i.e., acidic, azoospermic, semen volume <1.5 mL, with normal serum T, palpable vas deferens). (Expert Opinion)

Clinicians should not routinely perform abdominal imaging for the sole indication of an isolated small or moderate right varicocele. (Expert opinion)

Clinicians should recommend renal ultrasonography for patients with vasal agenesis to evaluate for renal abnormalities. (Expert Opinion)

4.5 Others

Post-ejaculation urine test: This test is considered in cases with absent/reduced semen volume, or suspected etiologies for retrograde ejaculation (history of prostate, bladder neck, and retroperitoneal lymph node dissection (RPLND) surgeries, history of ⍺-blocker treatments), or in cases of decreased/deficient SV contraction (as in spinal cord injury and EDO cases). A urine sample is taken after ejaculation (or after prostatic massage in cases of lack of contractility of the SVs) and tested for the presence of sperm, which could be specially prepared to be used in intracytoplasmic sperm injection if couples elected for ART[89,90].

Testicular biopsy: This procedure was routinely performed to investigate spermatogenic failure and in cases of suspected ductal obstruction (azoospermia with normal hormonal screening tests and normal-sized testes). Schoor et al. reported in 2002 that cases of NOA could be clinically detected without the need of a diagnostic testicular biopsy. He concluded that FSH levels of 7.6mIU/mL or higher and/or testicular long axis of 4.6 cm or less could be considered diagnostic for NOA. Precluding the need to perform a diagnostic biopsy[91].

For therapeutic testicular biopsy, sperm and testicular tissue could be cryopreserved for ART or sent for histopathology to diagnose any aberrant development of spermatogenesis if the couple decides to proceed with ART or during reconstructive surgery. Bilateral biopsies are recommended due to the variation in findings between testes to avoid potential discrepancies[92].

AUA/ASRM guideline statement:[3]

Diagnostic testicular biopsy should not routinely be performed to differentiate between obstructive azoospermia and NOA. (Expert Opinion)

5 CONCLUSION

With a meticulous history and physical examination, coupled with appropriate laboratory and radiological tests, clinicians can arrive at an accurate diagnosis and select the most appropriate treatment options, which can significantly improve the chances of a successful outcome. Therefore, it is essential for healthcare providers to prioritize a comprehensive evaluation that includes a thorough medical history, physical examination, and diagnostic tests in the assessment of infertile couples.

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