Abstract
There are a variety of management options for male infertility patients. Often, assisted reproductive technology allows for successful pregnancies and live births using an ejaculated semen sample. If the etiology of the infertility precludes a satisfactory ejaculated semen sample, sperm retrieval may be required. Determining if a patient is a candidate for sperm retrieval involves a thorough history and physical exam, semen analysis, endocrine evaluation and, likely, genetic assessment. Men who are candidates for sperm retrieval may be azoospermic or anejaculatory. Understanding the etiology of azoospermia is critical to determining the most effective sperm retrieval approach.
2.1 Introduction
Infertility can lead to significant distress for a couple. Approximately 15 percent of couples struggle with infertility, with 20 percent of these related solely to a male factor and an additional 30 percent with a male factor contribution [1]; despite the prevalence of male infertility, males use fertility services half as often as women do [2,3]. Assisted reproductive technology (ART) with intracytoplasmic sperm injection (ICSI) allows infertile couples to achieve pregnancy and to produce live births by manipulating sperm and egg in vitro and return the product into the female reproductive tract [4]. The process of ART requires two patients – man and woman – for its success. Urologists often work closely with female fertility specialists and/or endocrinologists to evaluate and treat an infertile couple. From the male infertility perspective, there is a variety of treatment options used – including behavioral modifications, medications, and surgical procedures – dependent on the patient’s history and clinical status, with the more severe cases requiring sperm retrieval. Sperm retrieval is the process of obtaining sperm for use in ART other than from an ejaculated semen sample; depending on the etiology of a man’s infertility, sperm can be retrieved with or without a surgical procedure. In this chapter, we discuss the evaluation of an infertile male patient, with a focus on candidates and indications for sperm retrieval.
2.2 History and Physical
Evaluation for male infertility is indicated when a couple is unable to achieve pregnancy within one year of unprotected intercourse, or sooner if the female partner is over the age of 35. A patient may also present with an abnormal semen analysis or chief complaint concerning for an abnormality of the reproductive tract [1]. As with any medical complaint, the first step in evaluating an infertile male is obtaining a detailed history and performing a thorough physical exam. For the infertile couple, female partner fertility workup should be ensured [5]. Patients should be questioned regarding prior paternity, which may indicate that a man had a functioning reproductive tract at some point and may narrow the differential for etiology. Entire past medical and surgical history should be assessed, with a focus on childhood history (e.g., history of cryptorchidism, testicular torsion, pediatric hernia/hydrocele repair), sexual function (e.g., erectile and ejaculatory function and appropriately timed intercourse), and possible exposure to spermatotoxic agents or diseases (e.g., use of chemotherapeutic agent or radiation treatment, history of infection/inflammation of any area of the reproductive tract) [6,7]. Men should also be evaluated for personal or family history of genetic disorders related to male infertility, hormonal disorders that may preclude normal testicular function or sperm production, and family history of infertility. Additionally, use of exogenous hormones or endocrine modulators may affect spermatogenesis.
On physical exam, the patient should be evaluated for presence or absence of secondary sexual characteristics that may suggest hormonal disorder. On genital exam, testis size should be evaluated, as testis size reflects spermatogenesis [8]. Epididymides should be evaluated for their presence; dilation may indicate obstruction of the reproductive tract. Presence or absence of bilateral vasa deferentia should be noted; if both are absent, cystic fibrosis gene mutation is likely [9]. Scrotum should also be examined for varicocele, which is the most common correctable cause of male infertility [10]. Scrotal ultrasound can be included for difficult or suspicious scrotal/testicular exam [6]. The phallus should be evaluated for location of urethral meatus. Digital rectal exam may provide information on whether the prostate is absent or, with suspicion of ejaculatory duct obstruction, if the seminal vesicles are dilated [7].
2.3 Semen Analysis
Semen analysis must be obtained in all patients undergoing infertility evaluation. Results of semen analysis can be highly variable; as such, two or three specimens should be obtained separated by 2–3 weeks [1,5] with 2–5 day pretest abstinence interval prior to each semen collection.
A semen sample is analyzed for semen volume, sperm concentration in the semen, total sperm number, percentage of motile sperm, and percentage of normal morphology. Clinical reference values for these parameters have been defined by the World Health Organization (WHO) (Table 2.1) [11]. A notable weakness of the WHO reference ranges is that the semen analysis data were obtained from fertile men; while these parameters are useful for classifying men as subfertile or fertile, no parameter individually can be used to diagnose infertility [11,12].
Parameter | Reference value |
---|---|
Semen volume (ml) | 1.5 |
Sperm concentration (10⁶/ml) | 15 |
Total sperm number (10⁶) | 39 |
Sperm motility (%) | 40 |
Normal sperm morphology (%) | 4 |
Still, these semen parameters provide useful information. Aspermia (absence of semen/low semen volume) may indicate anejaculation (inability to ejaculate) or retrograde ejaculation (semen enters the bladder instead of moving through the urethra during orgasm).
Azoospermia, the absence of sperm in the semen, can be classified in two modes: by the location of its etiology or by the presence or absence of obstruction of the male reproductive tract. The first set of descriptions, etiologic location, uses the testis as the focus and includes pre-testicular, testicular, and post-testicular azoospermia. Pre-testicular azoospermia involves endocrine abnormalities that negatively affect testicular development and spermatogenesis leading to secondary testicular failure. Testicular azoospermia involves pathology related to the production of sperm or testosterone, or obstruction within the testis itself, also referred to as primary testicular failure. Post-testicular azoospermia describes abnormalities of sperm delivery after the testis through the urethral meatus, which could include ejaculatory dysfunction [13]. Obstructive compared to nonobstructive azoospermia (NOA) describes obstruction of sperm passage from testis through the male reproductive tract versus testicular failure, respectively [14]. Hormonal/endocrine evaluation is recommended in azoospermic men to further delineate the etiology of infertility.
2.4 Endocrine Evaluation
Endocrine disorders are uncommon in men with normal semen parameters. An endocrine evaluation is indicated for men with oligozoospermia (low semen count) or azoospermia, impaired sexual function, or other findings suggestive of endocrine abnormality [1]. Total testosterone and follicle-stimulating hormone (FSH) levels are the minimum that should be ordered; if low total testosterone is present, confirmatory repeat total testosterone should be ordered (ensuring an early morning measurement). Since testosterone circulates in three forms – tightly bound to sex hormone binding globulin (SHBG), loosely bound to protein (most notably, albumin), and unbound – further testing should also be performed to measure the bioavailable testosterone; thus, SHBG and albumin levels should be measured. Additionally, luteinizing hormone and prolactin levels should be measured, which may aid in determination of the source of the hormonal abnormality. Estradiol measurement can also be considered, especially in the presence of gynecomastia, as an elevated level may indicate reproductive dysfunction. [1,5,15]. Table 2.2 lists clinical fertility conditions and their relationship with these hormonal levels.
Condition | FSH | LH | Testosterone | Prolactin |
---|---|---|---|---|
Normal spermatogenesis | Normal | Normal | Normal | Normal |
Hypogonadotropic hypogonadism | Low | Low | Low | Normal |
Prolactin-secreting tumor | Normal/low | Normal/low | Low | High |
Hypergonadotropic hypogonadism (primary testicular failure) | High | High | Low | Normal |
Post-testicular azoospermia | Normal | Normal | Normal | Normal |
FSH, follicle-stimulating hormone; LH, luteinizing hormone.
2.5 Specialized Semen Tests
As previously mentioned, semen analysis results can vary from test to test and the commonly measured semen parameters may not accurately predict infertility. There are a variety of secondary tests that can be used under certain circumstances that may aid in diagnosing the presence and etiology of infertility.
Pyospermia is defined as excessive numbers of leukocytes in the ejaculate, with a threshold value of one million/ml, and may be indicative of genital tract infection or inflammation [1,16].
Antisperm antibodies (ASA) can form when there is a disruption in the blood–testis barrier, such as after vasectomy, testis trauma, orchitis, cryptorchidism, testis cancer, or varicocele, leading to potentially decreased motility and sperm agglutination. Antisperm antibodies are typically managed with sperm retrieval for ICSI. Thus, testing for ASA is not needed if ICSI is already indicated.
The ultrastructural arrangement of the sperm tail is important for sperm motility. In disorders such as primary ciliary dyskinesia, this structure is disturbed, which can lead to immotile sperm [5].
Fragmentation of sperm DNA integrity may negatively affect fertility. Sperm DNA testing may be indicated for men with varicocele, lifestyle risk factors for infertility or unexplained infertility, recurrent pregnancy loss, or recurrent intrauterine insemination/ICSI failures. Men with infertility and high sperm DNA fragmentation tend to have lower sperm DNA fragmentation in their testicular sperm than in ejaculated sperm and may benefit from sperm retrieval to achieve a viable pregnancy [17].
2.6 Genetic Analysis
There are a variety of genetic conditions that may play a role in male infertility [18]. As such, genetic assessment may be indicated in men without a clear etiology for infertility. Men with NOA or severe oligozoospermia are at increased risk for having a genetic abnormality [1].
Genetic testing should include a karyotype to assess for chromosomal abnormalities. The most common chromosomal disorder is aneuploidy of the X chromosome – 47,XXY – also known as Klinefelter syndrome. Several other chromosomal abnormalities are known to cause infertility, but are rare. A complete karyotype is of further importance in men undergoing sperm retrieval for ICSI, as men with karyotypic abnormalities have higher risk for miscarriage or having children with chromosomal/congenital defects [6, 19].
The AZF region on the long arm of the Y chromosome is important for normal spermatogenesis. In men with NOA or severe oligozoospermia, testing for microdeletion of the Y chromosome is indicated [6]. This test can diagnose the etiology of azoospermia and predict the likelihood of success of sperm retrieval, and thus directly guide management decisions. Along the AZF region are three subregions – AZFa, AZFb, and AZFc – of which deletions distinctively affect male fertility. Microdeletion of AZFa or AZFb predicts poor outcomes from sperm retrieval, as no data have shown evidence of success in testicular sperm retrieval [18]. Therefore, surgical sperm retrieval is not recommended in men with AZFa or AZFb microdeletions. Alternatively, AZFc microdeletion, which is the most common microdeletion type, can be associated with successful sperm retrieval and successful ICSI outcomes [1,15,18]. It should be noted that all male offspring derived from patients with a Y microdeletion will inherit the same microdeletion and will be azoospermic.
Men with congenital bilateral absence of the vas deferens (CBAVD) often have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which has an association with cystic fibrosis. If a CFTR mutation is present, there is an increased risk for having offspring (male or female) with cystic fibrosis and increased risk of male offspring with CBAVD. Even if a CFTR abnormality is not found during genetic testing, there may still be a mutation that is unable to be identified. Thus, the female partners of all men with CBAVD should be tested to assess the risk of having a child with cystic fibrosis [6]. If a CFTR gene mutation is noted in either partner, the couple should be referred to genetic counseling. Intracytoplasmic sperm injection is often used for these situations to allow for preimplantation genetic testing to establish a pregnancy that is unaffected by cystic fibrosis [13,18].