Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Male Infertility
Introduction
Infertility, defined as the inability to conceive after 12 months of regular, unprotected intercourse, affects 8 million couples in the United States, of which up to 50% have a male contributory factor. Overall, up to 12% of men of reproductive age worldwide suffer from male infertility. Fortunately, in the past 50 years, we have seen a tremendous increase in our understanding of male infertility and the way has been paved for novel diagnostic and therapeutic strategies to help this cohort of infertile patients. In particular, the advent of advanced reproductive technologies such as in vitro fertilization and intracytoplasmic sperm injection has enabled men for whom fatherhood could be achieved previously only through donor sperm or adoption to now father biological offspring.
In 2020, a joint guideline developed by the American Urological Association and the American Society for Reproductive Medicine advocated that the initial evaluation of the infertile couple include an investigation of both partners in parallel. In this chapter, we will provide an up-to-date outline of evaluation and treatment algorithms that guide the management of the infertile male.
Significance of Male Infertility
Male infertility is associated with an increased risk of other comorbidities. For men with abnormal semen parameters, there is an increased risk of testicular cancer. When the male infertility condition is more severe and azoospermia is present, then the risk of all cancers is increased. Similarly, mortality risks increase when semen analysis parameters are more abnormal. So, men with severe male infertility remain at significant risk of medical issues and should be monitored lifelong for the risk of cancers. With additional identification of markers that could predict specific cancer or other medical conditions, further testing of severe infertility patients is indicated.
The data on general medical consequences of male infertility are progressively evolving and difficult to interpret. In general, those individuals attempting to conceive are more healthy than the general population, since they are making an elective decision to have a family. So, a bias toward decreased risk of medical problems in couples attempting conception already exists. Despite this bias, epidemiologic studies are recognizing the relationship between a male infertility diagnosis or abnormal semen parameters and the risk of subsequent medical conditions. In addition, specific medical diagnoses such as low testosterone or Klinefelter syndrome may carry specific risks for which patients should be screened or evaluated, including cardiovascular morbidity, diabetes, and specific cancers, such as extragonadal germ cell tumors and breast cancer. This increased knowledge of medical risks, as well as the genetic basis of male infertility, will emphasize the importance of male factor evaluation.
Evaluation of Male Infertility
When and on Whom to Perform an Evaluation of Male Infertility
An initial screening evaluation on both partners is recommended if a couple has not conceived a pregnancy after 12 months of regular, unprotected intercourse. Alternatively, an earlier evaluation is justified if the female partner is older than 35 years old, if either partner has a medical history or physical findings suggestive of decreased reproductive potential, or if either partner is concerned about the male’s reproductive potential. Men who do not have a partner but who are concerned about their reproductive potential should also undergo an initial screening evaluation.
The goals of the evaluation of male infertility are to identify and treat correctable causes of male infertility that could then result in natural pregnancy, to guide treatment options in those for whom natural pregnancy is unlikely to occur, and to identify significant medical problems that are associated with infertility ( Box 24.1 ).
Box 24.1
Significant Medical Conditions That May Present as Male Infertility
Adult polycystic kidneyBrain tumorsCystic fibrosisDiabetesHemochromatosisHypopituitarismKlinefelter syndromeMultiple sclerosisPituitary adenomaProstate cancerRetroperitoneal tumorsSpinal cord tumorsTestis cancerThyroid diseaseUrinary tract infection
Initial Screening Evaluation
-
Initial screening evaluation of male infertility should include a thorough history, physical examination, and two semen analyses.
-
Semen analyses should be performed after 1 to 5 days of abstinence and preferably be spaced a month apart.
-
While not diagnostic of male infertility, semen analysis is a cornerstone in the evaluation of male infertility.
The initial screening evaluation of the male in an infertile couple should include a reproductive history and at least one semen analysis. If there are any abnormalities on initial evaluation, then a complete history, as well as physical examination by a male reproductive health expert, should be done in addition to a minimum of two semen analyses.
History and Physical Examination
A thorough reproductive history ( Table 24.1 ) is a critical component of the complete evaluation of the infertile male and should cover coital frequency and timing, duration of infertility, prior fertility, developmental history, and childhood illnesses (including hypospadias, congenital anomalies, and onset of puberty), current systemic illnesses (especially diabetes mellitus, cystic fibrosis, cancer, and infections) including recent systemic illnesses including COVID-19, surgical history (with a focus on scrotal, pelvic, retroperitoneal, and inguinal surgeries), sexual history (with a history of sexually transmitted diseases), medications and allergies, and exposure to gonadotoxins (both chemical and environmental toxins such as heat; see Table 24.2 ). Additionally, a family history of cryptorchidism, infertility, disordered sexual differentiation, hypogonadism, and/or a social history of frequent alcohol, tobacco, or recreational drug use may suggest potential etiologies for male infertility.
Table 24.1
Important Parts of the Male Infertility History
Infertility history
Sexual history
Past medical history
Medical history
Surgical history
Family history
Medications
|
Table 24.2
List of Agents and Factors With Potential Adverse Impact on Male Fertility
Medications
Environmental
|
A general physical examination with an emphasis on endocrine effects and the genitalia can also provide important information. Upon initial inspection, note should be taken of obesity, secondary sex characteristics, hair distribution, and gynecomastia. Specific examination of the genitalia should include the phallus, which should be examined for hypospadias, penile curvature, and plaques that may interfere with proper semen deposition within the vagina. Both testes should be examined for size, consistency, and the presence of masses. Eighty-five percent of testicular volume is made up of seminiferous tubules in which spermatogenesis occurs and testicles smaller than the normal adult size of 20 mL (or > 4.6 cm × 3 cm) may be associated with impaired spermatogenesis.
Careful attention should be paid to both the presence, consistency, and nodularity of the epididymides which may help to identify obstruction and/or infection while palpation of both vasa deferens can diagnose vasal agenesis, atresia, or injury. More specifically, congenital bilateral absence of the vas deferens (CBAVD) is a clinical diagnosis that can be made on physical examination. Palpation of both spermatic cords in the supine and standing positions both with and without Valsalva enables the diagnosis of varicocele, which is also a clinical diagnosis. Scrotal ultrasound may be used to confirm a diagnosis of varicocele, but those subclinical varicoceles found only on ultrasound (and not on physical exam) are unlikely to be clinically relevant. Finally, a digital rectal exam may help identify dilated seminal vesicles, ejaculatory duct cysts, or utricular cysts that may contribute to obstructive etiologies of male infertility.
Semen Analysis
Along with a thorough history and physical examination, semen analysis has long been the pillar upon which male infertility is evaluated and managed. While an abnormal semen analysis (with the exception of azoospermia) cannot delineate between fertile and sterile, abnormal semen quality is associated with decreased chances of natural conception.
To account for the large degree of biological variability between semen samples, at least two semen analyses should be performed. Patients should be given specific instructions regarding the need for 2 to 5 days of abstinence prior to undergoing semen analysis with the two semen analyses preferably spaced at least one week apart. The semen sample can be collected either by masturbation into a specimen cup or by intercourse with the use of a special semen collection condom that does not contain any spermatotoxic agents. In particular, lubricants should be avoided. If a specimen cannot be produced at the laboratory for analysis, it should be kept at room or body temperature during transport and delivered to the laboratory for analysis within one hour. Further delays can affect semen and sperm parameters such as sperm motility, which decreases dramatically after 2 hours.
Parameters examined in routine semen analysis can be broken up into macroscopic and microscopic parameters. Key macroscopic parameters include semen volume, viscosity, color, pH, and coagulation/liquefaction while key microscopic parameters include sperm count/concentration, sperm motility, and sperm morphology. After analyzing the semen analyses of 1859 new fathers from eight countries across three continents, the World Health Organization (WHO) established the normal reference ranges for most of the key parameters of semen analysis ( Table 24.3 ). To establish the reference ranges, the WHO applied a one-sided lower reference limit of the 5th percentile to the semen parameters of the 1859 new fathers. While this methodology provides lower thresholds for semen parameters in fertile men, it fails to answer the more relevant clinical question of which specific semen parameters and cutoffs are able to delineate between male fertility and subfertility. Efforts to identify specific semen parameters that can distinguish between male fertility and subfertility have instead found that while semen parameters are associated with fecundity, neither sperm concentration, morphology, nor motility could be considered diagnostic of infertility either alone or in combination. Rather than a direct diagnostic test of male infertility, the semen analysis should instead be considered an important contributor to the overall picture of male fertility.
Table 24.3
WHO Sixth Edition Reference Values for Semen Analysis
| Semen Analysis Parameter | Reference Value |
|---|---|
| Ejaculate Volume | 1.4 mL |
| Sperm concentration | 16 million sperm/mL |
| Sperm count | 39 million sperm/ejaculate |
| Total motility | 42% |
| Total progressive motility | 30% |
| Sperm morphology | 3% normal (strict criteria) |
| Sperm viability | 54% |
| Sperm agglutination | Absent |
| White blood cells | < 1 million leukocytes/mL |
Further Investigations and Complete Evaluation
-
Further investigations of male infertility are directed by the initial evaluation, which may be characterized as men with low semen volume, oligo-astheno-teratospermia, or azoospermia.
-
Initial endocrine evaluation of male infertility is indicated for men with oligospermia, impaired libido, sexual dysfunction atrophic testes, or evidence of hormonal abnormality on physical evaluation and should include at least serum testosterone and FSH. ,
A parallel in-depth assessment of potential female factors should be undertaken. However, if any abnormalities are detected in the evaluation of male infertility, further investigations (often driven by the specific abnormalities detected) are required.
Endocrine Evaluation
While a specific endocrine cause of impaired sperm production is identified in only 2% of men with male factor infertility, an endocrine evaluation is still indicated in men with abnormal semen analyses (especially in those with sperm concentrations less than 10 million/mL), impaired libido, sexual dysfunction atrophic testes, or evidence of hormonal abnormality on physical evaluation. At a minimum, an endocrine evaluation for male infertility should include serum FSH and morning testosterone levels. Men with impaired libido should also have an initial prolactin evaluation. A low serum testosterone level (< 300 ng/dL) should prompt the testing of a second-morning serum testosterone level alongside serum LH and prolactin levels. Obtaining a second-morning serum testosterone level should be considered since gonadotropins and testosterone are typically released in a pulsatile manner and testosterone levels commonly demonstrate a physiologic decline over the course of the day. ,
The characteristic hormone profiles for various etiologies of male infertility are described in Table 24.4 . For most azoospermic men, a presumptive identification of the cause of azoospermia (obstructive versus nonobstructive) can be made based on FSH and testicular exam, as well as careful exam of the epididymis. For azoospermic men with FSH > 7.6 and testis volume < 4.5 in length, over 90% of these men will have nonobstructive azoospermia. , While normal FSH levels (≤ 7.6IU/L) do not guarantee normal spermatogenesis, again, 90% of azoospermic men with testis length > 4.6 cm do have an obstruction (the majority of the remaining 10% have nonobstructive azoospermia with a diffuse pattern of maturation arrest on histology.)
Table 24.4
Characteristic Hormone Profiles for Various Etiologies of Male Infertility
| Condition | Testosterone | FSH | LH | Prolactin |
|---|---|---|---|---|
| Normal | Normal | Normal | Normal | Normal |
| Primary testicular failure | ||||
| Hypospermatogenesis | Normal/Low | High | High/Normal | Normal |
| Maturation arrest | Normal | Normal | Normal | Normal |
| Sertoli cell only | Low | Very high | High | Normal |
| Hypogonadotropic hypogonadism | Low | Low | Low | Normal |
| Hyperprolactinemia | Low | Normal/Low | Low | High |
| Klinefelter syndrome | Low | Very high | High | Normal |
For men with hypogonadotropic hypogonadism or hyperprolactinemia, an evaluation for the cause of the condition is indicated and should direct the approach to treatment. For men with hypogonadotropic hypogonadism, gonadotropin replacement with LH analogs such as hCG is typically initiated until normal endogenous testosterone levels are obtained, and FSH analogs are subsequently added. For men with hyperprolactinemia, if consistent and not attributable to another cause such as specific medications, pituitary imaging is likely to be required.
Low Semen Volume
-
Low semen volume may be attributable to ejaculatory dysfunction, hypogonadism, ejaculatory duct obstruction, or CBAVD.
-
An endocrine evaluation, postejaculatory urinalysis, and transrectal ultrasound can help identify the cause of low semen volume.
Further evaluation is warranted in the setting of low semen volume. Assessment of complete semen collection is critical as incomplete collection is the most common explanation for measured low semen volume. In the setting of low semen volume, semen pH can help assess whether there is a seminal vesicle contribution to the semen. If semen is derived from the prostate alone, then seminal pH is typically less than 7. Seminal vesicle fluid has a pH greater than 8.
Postejaculatory Urinalysis
The presence of low semen volume (< 1.0 mL) should prompt a systematic algorithm to delineate the cause ( Fig. 24.1 ). Potential etiologies for low semen volume include improper collection, CBAVD, hypogonadism, ejaculatory dysfunction, and ejaculatory duct obstruction. In men with normal serum testosterone levels and palpable vasa deferens, a postejaculatory urinalysis should be performed to rule out retrograde ejaculation. The presence of a greater sperm count in the urine specimen pellet postejaculation following centrifugation is indicative of retrograde ejaculation.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here