Chapter 35 Evaluation of Male Infertility

Dana A. Ohl, Timothy G. Schuster, Susanne A. Quallich

INTRODUCTION

A defect in male fertility can be found in up to 50% of couples with infertility. The male is the only cause of infertility in 30% of cases, and a combination of male and female factors can be found in another 20%.¹ In the past, a combination of a lack of understanding of the pathophysiology of male infertility and a paucity of successful treatment modalities often led to neglect of the male in the evaluation process. In some cases women have undergone invasive testing and treatment before evaluation of their mate, only to find on subsequent semen analysis that the male partner was the source of the couple’s infertility. In other cases, the discovery of a markedly abnormal result on semen analysis has led to the immediate application of in vitro fertilization with intracytoplasmic sperm injection (IVF/ICSI) before a full evaluation of the male partner has been undertaken. In either case, the affected couple does not receive the optimal benefit of the extensive diagnostic and treatment modalities that have been developed for male infertility over the past 20 years.

This chapter begins with an examination of the basic principles of male infertility. The standard and advanced diagnostic techniques are then detailed. Finally, the various treatment modalities and their effectiveness for specific diagnoses are elucidated.

GENERAL PRINCIPLES

When male infertility is discovered, it is imperative for the man to be evaluated by a male infertility specialist before attempting pregnancy for several reasons. In some conditions, treatment modalities can improve the prospects of a couple achieving pregnancy. In others, careful evaluation will determine the presence of associated medical problems.² For some couples with male infertility, genetic testing is essential to give prognostic information as to potential success and genetic risk assessment for the potential progeny to infertile couples considering treatment.³ In those men whose evaluation does not reveal a potentially treatable condition, contact with a male infertility specialist during the evaluation process completes the team that will implement comprehensive treatment plans that might include sperm retrieval with assisted reproductive technologies (ARTs).

Treatable Causes of Male Infertility

Many men with male infertility will be found to have conditions amenable to surgical or medical treatment. Varicocele surgery has become more reliable and less invasive due to introduction of improved surgical techniques, such as the microsurgical subinguinal approach.^4,⁵ Surgical repair of epididymal obstructions has enjoyed higher success rates with introduction of invagination techniques.⁶ In men with clear-cut endocrinopathies, medical treatments are highly successful in improving fertility.⁷

Associated Medical Problems

Male infertility increases the risk of other potentially dangerous medical problems, such as testicular cancer, spinal cord and brain tumors, genitourinary malformations, and chromosome aberrations.³ Men with severe oligospermia should be fully evaluated for these conditions before being directed toward attempts at pregnancy with IVF/ICSI. Failure to evaluate the male for these problems may delay the diagnosis of these potentially dangerous conditions.

Genetic Testing

In recent years, our understanding of the genetics of male infertility has markedly improved. For example, it is now standard to perform Y-chromosome microdeletion testing in men with azoospermia or severe oligospermia, because aberrations in spermatogenesis have been linked to Y-chromosome microdeletions.² Using this approach, an underlying genetic problem can be determined in many of these men whose abnormalities would have been designated as idiopathic in the past.

Another example is congenital bilateral absence of vas deferens, which accounts for up to 5% of all male infertility. It has been observed that men with cystic fibrosis uniformly have this condition, but most men with congenital bilateral absence of vas deferens do not have the pulmonary or gastrointestinal problems indicative of cystic fibrosis. Subsequent research has shown that more than half of all men with congenital bilateral absence of vas deferens have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the same gene responsible for cystic fibrosis. In these cases, congenital bilateral absence of vas deferens is considered to be an atypical form of cystic fibrosis and is inherited in an autosomal recessive pattern.

PATHOPHYSIOLOGY

The list of possible causes of male infertility is extensive (Table 35-1). Causative conditions and factors can almost always be identified by a detailed history, physical examination, and semen analysis. Some of the most common causes are explored below in more detail.

Table 35-1 Male Infertility Etiologies

Ejaculation Problems

Anejaculation

Retrograde ejaculation

Sexual dysfunction

Environmental

High-temperature working environments

Obstructive azoospermia

Spermatogenetic arrest

Anomalies of sperm structure

Hormonal Causes and Androgen Resistance

Hypogonadotropic hypogonadism

Hyperprolactinemia

Congenital adrenal hyperplasia

Androgen resistance syndrome

Idiopathic

Varicocele

A varicocele is the single most commonly identified surgically treatable condition found in men with abnormal results on semen analysis. It has been reported that in asymptomatic men with a palpable varicocele, an abnormality on semen analysis will be found in 70%. A varicocele is present in approximately 35% to 40% of men with primary infertility and 80% of men with secondary infertility.^8,⁹ However, not all men with a varicocele will be infertile, and this entity will be found in approximately 15% of all men. The majority of varicoceles will be found on the left side, but they can be either unilateral or bilateral.

The etiology of a varicocele remains uncertain. The finding that more varicoceles occur on the left suggests they might be due to increased hydrostatic pressure in the internal spermatic veins. Related theories include: (1) the longer internal spermatic vein on the left compared to the right, resulting in increased hydrostatic pressure on the left; (2) the acute angle of insertion of the left internal spermatic vein into the left renal vein compared to the oblique insertion of the right internal spermatic vein into the inferior vena cava; and (3) the “nutcracker phenomenon,” caused by compression of the left renal vein between the superior mesenteric artery and aorta.

The mechanism by which a varicocele causes impaired testicular function is poorly understood. It is well accepted that the presence of a varicocele is associated with progressive decline of testicular volume, impaired sperm quality, and loss of Leydig cell function.¹⁰ It has been shown that larger varicoceles are associated with greater impairment of testicular dysfunction compared to smaller varicoceles.^11,¹² Theories proposed to explain these observations include increased testicular temperature from loss of the countercurrent mechanism present in the normal spermatic cord, hypoxia, and reflux of renal or adrenal hormonal metabolites.¹³^–¹⁵

Treatment

Several techniques exist to repair a varicocele, including surgical and radiographic intervention. These techniques are described in more detail in the subsequent chapter. Repair of a varicocele has been shown to improve spermatogenesis, increase Leydig cell function, and prevent further decline in testicular size.¹⁶^–¹⁸ Many studies have evaluated the effectiveness of varicocele repair on improving pregnancy rates. However, most studies have been retrospective and poorly controlled.

To date, only two randomized, prospective, case-controlled studies of varicocele have been performed. The first study randomized patients to surgical repair, radiographic embolization, or observation.¹⁹ Unfortunately, 48% of patients in this study had a grade 1 varicocele, for which repair is of questionable value. Although there was significant improvement in semen parameters in the patients receiving intervention, no difference was seen in pregnancy rates.

The second study was a crossover design.²⁰ A total of 45 couples underwent either immediate or delayed repair of a varicocele after 1 year of observation. Pregnancy rates were 60% during the first year for those undergoing immediate repair compared to 10% for those in the observation group. For the latter group, pregnancy rates increased to 44% during the subsequent year after repair.

Genetic Causes of Male Infertility

A detailed discussion of the genetics of reproduction is given in Chapter 5.

Klinefelter’s Syndrome

Klinefelter’s syndrome is a chromosomal aberration resulting in a genotype of 47,XXY in 90% of cases or the mosaic form of 46,XY/47,XXY in the remaining 10% of patients.²¹ Classically, men present as tall, eunuchoid appearance with azoospermia, gynecomastia, and small firm testes. However, a spectrum of presentations exists, especially in the mosaic form. Diagnosis is confirmed with a karyotype. Sperm extraction with ICSI has been reported in this patient population; however, couples should undergo preoperative counseling regarding risks of genetic transmission.

Cystic Fibrosis

Cystic fibrosis is the most common autosomal recessive disorder in whites.²² It is associated with congenital bilateral absence of the vas deferens in addition to pulmonary disease and exocrine pancreas dysfunction. Patients with this disease have mutations in the CFTR gene. This gene makes a protein responsible for chloride channel formation, and these mutations result in nonfunctioning channels. The mechanism by which these mutations result in degeneration of the developing vas deferens remains to be determined.

An atypical form of cystic fibrosis should be suspected in any apparently healthy man with azoospermia and bilateral absence of the vas deferens on examination.²² More than half of these men will be found to have mutations in the CFTR gene. Because of the high carrier rate for cystic fibrosis in the population, all men with congenital bilateral absence of the vas deferens and their spouses should be screened for CFTR gene mutations. It is imperative that couples at risk for creating embryos with homozygous gene mutations for cystic fibrosis undergo genetic testing and counseling before proceeding with sperm harvesting and ICSI.

Y-Chromosome Microdeletions

The long arm (q) of the Y chromosome contains three regions where mutations may lead to azoospermia or severe oligospermia. These genetic regions, termed azoospermia factors (AZF), have been subdivided into regions a, b, and c. Testing for Y-chromosome microdeletions should be considered in men with severe oligospermia or nonobstructive azoospermia.

Successful pregnancies have been reported using ICSI for men with AZFc deletions; however, no patient with AZFa or AZFb deletions has been reported to have sperm on testicular biopsy.²³^–²⁵ Although no somatic changes are evident in the offspring of patients with AZFc deletions, couples should be counseled that the genetic mutation will be transmitted to male progeny, who will face similar fertility issues in the future.

Ejaculatory Dysfunction

Although relatively uncommon, ejaculatory dysfunction encompasses a large variety of disorders with individualized treatments. The entire spectrum of causes of ejaculatory dysfunctions cannot be covered in the scope of this chapter. However, some of the more common entities are explained here.

Medications

Several classes of frequently used medications can cause ejaculatory dysfunction. The antiadrenergic properties of antihypertensives (e.g., methyldopa, doxazosin) can cause incomplete closure of the bladder neck, leading to retrograde ejaculation or in extreme cases failure of emission. Commonly used antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs]) and antipsychotics (e.g., thioridazine, clozapine) are also well-known causes of either delayed ejaculation or anejaculation.^26,²⁷

Diabetes Mellitus

Although erectile dysfunction is a more common finding in patients with diabetes mellitus, ejaculatory dysfunction may also be present due to the autonomic neuropathic effects on the sympathetic chain controlling the bladder neck. Difficulties with ejaculation or emission are present in up to 32% of diabetic patients.²⁸

Normal levels of intratesticular testosterone are essential for normal spermatogenesis, and these levels are significantly higher than peripheral testosterone levels.³⁰ Use of anabolic steroids causes suppression of normal testicular feedback from the testes to the hypothalamus and pituitary, thus leading to decreased intratesticular testosterone levels and impaired spermatogenesis.³¹ Cessation of the exogenous androgens usually allows for resumption of normal spermatogenesis. However, there are case reports of continued disorders of the hypothalamic-pituitary-gonadal axis after discontinuation of anabolic steroid use.

Chemotherapy

Many chemotherapy agents are know to cause damage to germinal epithelium. As a general rule, the severity of gonadal toxicity is dose-dependent and is related to the class of chemotherapeutic agent used. Although some men will have recovery of spermatogenesis up to 5 years after treatment, a subset of men receiving chemotherapy will have permanent sterility.³² Before initiating chemotherapy there is currently no way to predict which men will have return of fertility. Consequently, sperm banking should be offered to all men before treatment.

EVALUATION OF THE MALE

Male Partner History

All evaluations of the infertile couple require a careful history from the male in addition to a semen analysis. In most infertility practices, physical examination of the male is performed only if the semen analysis is abnormal or if there is a history of some abnormality. An algorithm for the evaluation of male infertility is presented in Figure 35-1.

Figure 35-1 Suggested algorithm for the evaluation of male infertility.

Sexual and Fertility History

The history should include the overall pattern of sexual activity, specifically in relation to ovulation.³⁷^–³⁹ One should inquire about any previously fathered children as well as any evaluation or treatment of the female partner that may have preceded the patient’s visit, such as the use of ovulation predictor kits or medications. The couple must also be asked about the use of lubricants during sexual intercourse. Many commercially available lubricants are known to impair sperm motility.⁴⁰

The timing of sexual intercourse in relation to ovulation should be noted because simply adjusting the timing of intercourse can result in an increased chance for pregnancy. Recent data suggests that daily intercourse beginning 5 days before ovulation may be the best intercourse pattern to optimize the chance of pregnancy.³⁷

Each patient should be queried regarding erectile function, ejaculation, and libido because these issues can contribute to infertility. Typically, erectile difficulties from an organic cause are insidious and progressive and may span the course of several years. Alternatively, the patient may provide a history of relatively rapid or recent onset of a decline in erectile function, which may be associated with a history of recently starting new medication or the stress of the fertility difficulties.

The history should include several points specific to the patient’s sexual functioning: the precise nature of the dysfunction (i.e., whether the problem is attaining or sustaining an erection, insufficient rigidity, difficulty with penetration); the presence or absence of nocturnal and morning erections and their quality; and any treatments (pharmacologic and nonpharmacologic) that the patient has tried. In some cases, treatment of the underlying sexual dysfunction may be all that is needed to produce a successful conception.

If the patient complains of low libido, moodiness, loss of interest in usual activities, declining erectile function, fatigue, and diminished muscle bulk, he may be suffering from hypogonadism. One should ask if complaints are new or longstanding.

The patient should be carefully questioned about ejaculatory dysfunction, including pain with ejaculation and hematospermia. Common types of ejaculatory dysfunction include anejaculation (complete lack of ejaculation despite a normal sensation of orgasm), anorgasmia (inability to achieve climax), and retrograde ejaculation, which can appear identical to the patient to anejaculation. Anejaculation and retrograde ejaculation can be the result of a variety of surgical procedures, progressive neurologic disease, or medications.³⁸ Anorgasmia may be psychogenic or due to medications, most notably SSRIs, commonly given for depression.³⁹

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