This document was released in November 2020 and updated in August 2023. This document will continue to be periodically updated to reflect the growing body of literature related to this topic.

KEYWORDS: infertility, azoospermia, oligospermia, semen analysis, varicocele

Learning Objectives

At the end of medical school, the medical student will be able to:

1. Describe the hypothalamus-pituitary-gonadal (HPG) axis
2. Describe the workup for male infertility, including the importance of the physical exam
3. Restate the limitations of the semen analysis
4. List common reversible causes of infertility and their treatments
5. Recognize when to refer a patient for ART

Introduction

Infertility is defined as the inability to conceive despite attempting unprotected intercourse for at least one year. Approximately 15% of couples struggle with infertility. Of these couples, male factor infertility is present in an estimated 50%, and a male factor is the sole suspected etiology in approximately 20% of infertile couples. (Thonneau P, 1991) Male infertility can be due to a variety of genetic, anatomic, and environmental conditions, many of which will be briefly discussed below. A semen analysis may show abnormalities in sperm count or concentration, sperm motility, sperm morphology, and a host of other factors. When a cause for an abnormal semen analysis cannot be found, it is termed “idiopathic”. In contrast, when a man is infertile with a normal semen analysis and workup, the term “unexplained infertility” is used (presuming there is not any identifable female-factor cause). It is hypothesized that genetic defects (either not yet identified or unable to be tested for) underlie unexplained infertility in some patients. Male factor infertility also has important implications for overall health. It is estimated that me with semen analysis abnormalities have a higher risk for malignancy and even death relative to their peers.

In 2020, The American Urological Association (AUA) and American Society for Reproductive Medicine (ASRM) published a guideline on the Diagnosis and Treatment of Infertility in Men. The stated purpose of this guideline is “to outline the appropriate evaluation and management of the male in an infertile couple”.  Workup for male factor infertility is indicated for any couple who has been attempting to conceive via unprotected sexual intercourse for one year or longer without success. Men with risk factors for infertility, such as those with known hypogonadism, history of orchiopexy other testicular surgery, prior chemotherapy or pelvic radiation, or those with family history of male factor infertility should undergo more expeditious evaluation. Infertility work-up can also be considered for any many who has concerns regarding his baseline fertility status, regardless of risk factors or active attempts at conception.

The purpose of evaluation is to identify potentially treatable causes of male factor infertility or to identify non-treatable causes that may require alterative treatment pathways such as assisted reproductive techniques (intrauterine insemination, in vitro fertilization) or even the use of donor sperm or adoption. In the following sections, we will review basic male factor reproductive physiology, describe the appropriate evaluation for male factor infertility including interpretation of semen analysis, and review potential causes of and treatments for male factor infertility.

Male Factor Reproductive Physiology

Spermatogenesis refers to the process wherein germ cells known as spermatogonia (diploid, 2n) develop into spermatozoa/sperm (1n; haploid) through a complex process involving mitosis, meiosis, and spermiogenesis. This process takes approximately 75 days to complete. {Heller, 1963 #2} The majority of spermatogenesis occurs within the seminerfous tubules of the testis.  Additional maturation occurs in the epididymis, where spermatozoa are stored until ejaculation.

Spermatogenesis is regulated by intra-testicular testosterone and dihydrotestosterone, which is in turn influenced by the signaling hormones from the pituitary gland.  In response to gonadotropin releasing hormone (GnRH) secernated by the hypothalamus, the anterior pituitary gland secretes both luteinizing hormone (LH) and follicle stimulating hormone (FSH). Luteinizing hormone acts on intestinal Leydig's cells within the testes to promote testosterone production. Testosterone itself along with its metabolite estradiol (converted from testosterone via the enzyme aromatase which is predominantly found within adipose tissue) are involved in a feedback loop wherein LH secretion is decreased in response to adequate circulating testosterone levels. FSH acts at the level of the Sertoli cells to promote spermatogenesis. Sertoli cells also secrete inhibin, which acts on the pituitary gland in a negative feedback loop to decrease FSH secretion.  This complex signaling network is referred to as the hypothalamus-pituitary-gonadal axis (HPG-axis). (Figure 1) Most testosterone production within the body occurs in the Leydig cells of the testes. Derangement of one or more of these hormones can lead to fertility problems. Some of the common abnormalities will be described later in the chapter.

Figure 1: hypothalamus-pituitary-gonadal (HPG) axis

Causes of Male Factor Infertility

Many anatomic, hormonal, and genetic abnormalities can cause male infertility. Primary infertility describes a man who has never fathered a child while secondary infertility is the term used when a man has previously fathered a child but is now having trouble conceiving. Below is a short description of some of the most commonly seen diagnoses and their treatments. For those students who are interested in a more in-depth description of infertility causes and treatments, please refer to the AUA Core Curriculum chapters on male factor infertility. Semen analysis testing will be described later in this chapter. However, a few important terms to know when discussing cause of male factor infertility include:

• Aspermia: absence of ejaculate fluid
• Azoospermia: absence of sperm
• Oligozoospermia: low sperm count
• Severe Oligospermia: very low sperm count (<5 million/ml
• Asthenozoospermia: poor sperm motility
• teratozoospermia: abnormal sperm morphology
• oligoasthenoteratospermia: constellation of low sperm counts with abnormal motility and morphology

A multitude of environmental factors have been linked to male factor infertility include pesticides, pollutants, and even certain medications used to treat various medical illnesses. Chemotherapy, radiation exposure, and substance abuse (alcohol and other drugs of abuse) may also cause abnormalities in sperm production.

Specific medical conditions that may contribute to male factor infertility include obesity, diabetes mellitus, and cryptorchidism (undescended testicle). For the latter, patients with a history of bilateral cryptorchidism are at increased risk for infertility. It is recommended that patients with undescended testicles be referred to a pediatric urologist within the first 6-12 months of life for repair to mitigate ongoing negative effects to fertility.

Certain genetic conditions are known to cause male factor infertility. Examples include Klinefelter’s syndrome, Kallman syndrome, Kartagener’s syndrome, and cystic fibrosis. Please see Table 1 for more details.

Table 1: Genetic conditions contributing to male factor infertility

Azoospermia

Azoospermia refers to the absence of sperm in the ejaculate. Azoospermia can result from absent/markedly impaired sperm production within the testicle, known as “non-obstructive azoospermia”, or it can result from some type of obstruction within the genital tract, known as “obstructive azoospermia”.

Obstructive azoospermia

Obstructive azoospermia is due to an obstruction/blockage somewhere between the testicle and the seminal vesicles. In this setting, the testicle makes adequate sperm, but it is blocked from traveling to the ejaculate fluid. Examples include obstruction within the epididymis or vas deferens, or within the prostate or seminal vesicles (ejaculatory duct). Obstructive azoospermia may be iatrogenic and intentional such as occurs with a vasectomy or after prostatectomy, or it may be unintentional such as injury to the vas deferens during inguinal hernia repair. It may also occur secondary to trauma or infection, or it may be congenital. Finally, obstructive azoospermia can be caused by congenital bilateral absence of the vas deferens. This is seen when a patient is a cystic fibrosis gene carrier. In some instances, one or both vas deferens may be palpable but there may be obstruction higher up such as at the level of the seminal vesicles. When seeing a patient with this diagnosis, it is imperative to have the partner checked for their CFTR carrier status as well.

Patients with obstructive azoospermia will have a semen analysis with no sperm seen. If the obstruction is within the epididymis or vas deferens, the semen volume will usually be very normal (the majority of semen volume comes from the prostate and seminal vesicles). If the obstruction is at the level of the seminal vesicles / prostate or the ejaculatory duct, the semen volume will likely be low as well. As will be described below, using the semen analysis results (volume, pH, fructose) can help to define the location of the obstruction.

Non-obstructive azoospermia

Nonobstructive azoospermia is a failure of the testis to produce sperm. This is classically diagnosed with an elevated FSH (resulting from absence of the negative feedback at the level of the pituitary gland), small testes on exam, and normal volume azoospermia seen on semen analysis. The causes of this are multifactorial and can include genetic abnormalities, medications (chemotherapy, testosterone, radiation), infections, and idiopathic causes. The most common genetic cause is Klinefelter’s disease (a phenotypic male with 47, XYY), and other causes are listed in Table 1. Another important cause for non-obstructive azoospermia is a mutation in various regions within the y-chromosome, such as deletions with the AZF regions.

Varicocele

A varicocele refers to the abnormal dilation of the veins of the pampiniform plexus. This is the most common cause of secondary infertility and also a common cause of primary fertility. Varicoceles are seen in a large number of males in the general population with a prevalence around 20%. Most varicoceles occur on the left side owing to the insertion of the left gonadal vein perpendicular to the left renal vein within the retroperitoneum. In addition to causing abnormalities in semen parameters (count, motility, and morphology), varicoceles may also cause testicular pain/discomfort. However, many varicoceles are completely asymptomatic and many patients with varicoceles have entirely normal semen analyses. The exact etiology of how a varicocele can cause infertility is still debated, but it is most likely due to thermal dysregulation. (Tadros & Sabanegh Jr., 2017) The dilated veins cause blood to pool around the testis which causes the intratesticular temperature to increase. Since optimal spermatogenesis occurs at a temperature lower compared with internal body temperature (hence why the testes are located outside the body and in the scrotum), the increased blood pooling will cause a decrease in sperm production and quality.

Idiopathic Male Infertility

Unfortunately, many men seen for infertility and abnormal semen analyses have no obvious cause for their condition. This is frustrating for both physician and patient. While we may not know the cause of their problem, there are still some potential treatments. First line therapy includes behavioral modification including quitting smoking, weight loss if needed, avoiding activities with scrotal/perineal pressure (bike riding), and avoiding long exposure to wet heat (sauna, hot tub). In addition, as we will describe below in the treatments section, there are some medical therapies available.

An increasingly recognized cause of idiopathic infertility is oxidative stress. This may be the common pathway of many insults. In fact, a new term has been proposed, Male Oxidative Stress Infertility (MOSI). (Agarwal A, 2019) Treatment of this condition as well as many others is with antioxidants. Which antioxidants as well as the correct dose is still hotly debated and the focus of multiple research studies. (Smits RM, 2019) Commonly used antioxidants include vitamin C, vitamin E, zinc, l-carnitine, co-enzyme Q10, and many others. The jury is out on whether these antioxidants improve fertility outcomes, but the cost and side effect risk is so low that many physicians routinely recommend them to their infertile men.

Finally, assisted reproductive technologies such as intrauterine insemination (IUI) and IVF can overcome many potential causes of idiopathic infertility. This is also the treatment of choice for unexplained infertility which is infertility despite a completely normal workup of both the man and female partner.

Patient assessment – history, physical examination, and testing

History

For couples presenting with infertility, it is important that both the male and female partners undergo evaluation. In general, female partners are much more likely to pursue evaluation relative to their male counterparts. However, as noted above, nearly 50% of infertility involves male factor causes.

The initial evaluation should start with a thorough reproductive history. History and physical exam are incredibly important in the workup of the infertile male. In fact, the decision to offer certain surgeries to these patients can be based solely on physical exam findings such as the presence of a varicocele.

A thorough and complete history should include:

• Male infertility risk factors such as a history of bilateral cryptorchidism, vasectomy, chemotherapy or radiation treatments, and chemical exposures
• Female infertility risk factors, including advanced female age (over 35 years)
• Reproductive history (Table 2)
  • coital frequency and timing
  • duration of infertility and prior fertility
  • childhood illnesses and developmental history
  • systemic medical illnesses (e.g., diabetes mellitus and upper respiratory diseases)
  • sexual history including sexually transmitted infections
  • gonadal toxin exposure including heat and testosterone
• Surgical history (with a focus on genitourinary and inguinal surgery)
• A review of medications (prescription and non- prescription) as many drugs can contribute to infertility
• Lifestyle exposures such as alcohol, marijuana, and tobacco use as well as vocational exposures
• Family reproductive history

Physical exam

As mentioned before, the physical exam is very important in the workup of a man with infertility, with particular focus on the genitourinary exam. This should include:

• Examination of the penis including the location and size of the urethral meatus
• Palpation of the testes and measurement of their size
• Presence and consistency of both the vas deferens and epididymites (unilateral or bilateral)
• Presence of a varicocele
• Secondary sex characteristics including body habitus, hair distribution and breast development

A varicocele is defined as dilation of the veins within the pampiniform plexus of the spermatic cord. Varicoceles can be identified on imaging, or palpated on physical examination. The following grading scale is used to define the severity of a varicocele:

• Grade 0 (subclinical): seen on ultrasound only but not physically palpable
• Grade I: palpable only when the patient is performing the Valsalva maneuver
• Grade II: palpable with or without valsalva maneuver
• Grade III: able to visualize varicocele through scrotum (colloquially descried as a “bag of worms” appearance)

Certain causes of male factor infertility such as congenital bilateral absence of the vasa deferens (CBAVD) and varicocele are established by physical examination. Scrotal exploration or other forms of imaging are not needed to make these diagnoses, so a thorough physical exam is an extremely important part of thework up for any man presenting for infertility evaluation.

Table 2: (AUA Core Curriculum, Infertility: Physiology, Epidemiology, Pathophysiology, Evaluation)

Testing

Semen Analysis

The cornerstone of a male infertility workup is the semen analysis. The most current guidelines for this are published by the WHO (World Health Organization) and are on their 6 ^th edition. (Table 3) (World Health Organization, 2021) There are several important things to know about a semen analysis to be able to properly interpret the results. First, it should be examined under the microscope within one hour of collection and should the sample should be given after 2-3 days of abstinence. Proper semen analysis takes time and very specialized training by an andrologist, so ideally this test is performed at a lab with experience. Several companies are now offering qualitative and quantitative semen analysis testing using home kits. The utility of these home kits compared to a standard semen analysis remains under investigation. If abnormalities are seen on an initial semen analysis, it is often recommended to repeat the test approximately one month later to confirm the original findings.

For many routine laboratory tests, cutpoints for abnormal results are set by assessing the distribution of lab values found in a specific population of patients who undergo the index test. In contrast, semen analysis parameters were set arbitrarily by evaluating a large group of semen analysis results from patients who had conceived with their partner within the previous year. The WHO some arbitrarily set abnormal results at the 5^th-percentile or less. This is an important factor to consider when interpreting results and counseling patients. In essence, this suggests that a patient with a barely “normal” semen analysis still has worse semen parameters then 95% of fertile men.(Cooper TG, 2010). Despite these limitations, it is still the single best test we have when evaluating these patients. Table 2 displays the “normal” values based on the 6^th edition of the WHO laboratory manual for the examination and processing of human semen. Other semen analysis parameters that may be reported include serum pH (secretions from the prostate are alkaline), presence/absence of fructose (produced by the seminal vesicles), and the presence/concentration of leukocytes (suggestion possible genital infection/inflammation).

Table 3.

Blood Testing

Blood testing for male factor infertility is used to evaluate for hormonal and genetic causes of infertility. As described above, Figure 1 shows the important hormones involved in the hypothalamus-pituitary-gonadal (HPG) axis. The 2020 AUA-ASRM infertility guideline panel recommends that patients with alterations in sexual desire (libido), sexual dysfunction (erectile dysfunction), small testes, signs of hypogondism, and those with abnormal semen analysis should undergo laboratory testing with serum testosterone and FSH. LH and prolactin are indicated for patients with hypogonadism (i.e. low circulating testosterone levels). Primary hypogonadism refers to abnormal testosterone production at the level of the testicle, and secondary hypogonadism refers to abnormal signaling from the pituitary gland. See Table 4 for information of laboratory findings associated with hypogonadism. Hyperprolactinema results in suppression of the pituitary secretion of gonadotropins (LH, FSH). Causes of hyperprolactinemia include different types of medications such as anti-psychotics, chronic kidney disease, hypothyroidism, and even pituitary tumors (prolactinomas). If elevated prolactin levels are seen, an MRI of the pituitary gland is indicated to rule out a tumor.

Table 4.

Genetic testing (karyotype and Y-chromosome microdeletion) should be performed on any patient with severe oligospermia or azoospermia. Patients with non-palpable vas deferens bilaterally should undergo cystic fibrosis testing (CFTR testing), as should those with unilateral absent vas deferens and obstructive azoospermia. This is because patients with cystic fibrosis may have obstruction further along the genital tract, such as at the level of the seminal vesicle. More advanced testing such as sperm DNA fragmentation can also be done but is beyond the scope of this chapter.

Other testing

For patients with aspermia or low semen volumes (< 1.5 cc), a post-ejaculatory urinalysis can be used to assess for the presence of sperm within the urine. Patients who experience retrograde ejaculation where the semen preferentially enters the urinary bladder rather than being expelled antegrade through the urethra at the time of ejaculation. Retrograde ejaculation may occur as a result of bladder neck incompetence – this can be congenital or acquire such as occurs after transurethral resection of the prostate. Normally, when the bladder neck is competent, it will contract at the time of ejaculation to promote semen flow through the urethra. If the bladder neck function is altered, semen may flow through the path of least resistance towards the urinary bladder. This is not harmful from an overall health perspective but is a potential cause for male factor infertility.

Scrotal ultrasound may be considered for patients with an abnormality identified on physical examination such as a testicular or extra-testicular scrotal mass. Scrotal ultrasound can be used to identify a varicocele but is not necessary to make the diagnosis in most cases. For patients with low semen volume and abnormalities in semen pH, transrectal ultrasound can be used to evaluate for ejaculatory duct obstruction. If present, the seminal vesicles may appear dilated, and assessment of fluid after aspiration with ultrasound guidance will show copious sperm under the microscope. 

Patients with absent unilateral or bilateral vas deferens should undergo a renal ultrasound to rule out a kidney abnormality. This is based on the shared embryologic origin of these structures (Mullerian duct). Finally, as mentioned above, an MRI of the pituitary gland is indicated to rule out a tumor in the setting of hyperprolactinemia or in patients with severe secondary hypogonadism (low LH/FSH, low testosterone).

Treatment

Treatment for male factor infertility varies based on the underlying cause. Herein we will provide a basic overview of treatment for infertility. A detailed discussion of treatment options is beyond the scope of this chapter. The reader is referred to the AUA Core Curriculum chapters on treatment for Male Factor Infertility.

For patients with vasal or epididymal obstruction, such as those with a history of vasectomy or congenital epididymal obstruction, a vasectomy reversal procedure may restore reproductive tract continuity. A vasovasostomy refers to the re-connection between two segments of vas deferens, whereas a vasoepididymostomy refers to a surgical connection between a vas deferens and the epididymis. Both of these procedures require microsurgical skills to ensure the best outcomes. Vasovasostomy success rates may approach 90%, whereas vasoepididymostomy success rates are ≈ 60-70%.

As described previously, ejaculatory duct obstruction refers to block at the interface of the prostate and seminal vesicles, preventing semen from entering the urethra with ejaculation. Semen analysis will show minimal volume (the majority of ejaculate volume is produced by the seminal vesicles), acidic pH (prostatic fluid is acidic and seminal vesicle fluid is basic) and severe oligospermia. Usually there will be severe oligospermia or azoospermia. Further diagnosis can be made with a transrectal ultrasound of the prostate that will reveal dilated SVs and aspiration will often times reveal sperm. Occasionally, enough sperm can be obtained from this aspiration to be used for in-vitro fertilization (IVF) but usually a transurethral resection of the ejaculatory ducts (TURED) is needed. When this is successful the ejaculatory ducts will be resected, and patients will often have return of normal semen parameters. Sterile epididymitis is the most common side effect from the procedure because the one way valve effect of the ejaculatory duct is removed allowing urine to flow in a retrograde fashion down the vas and into the epididymis.

Alternatively, sperm can be derived directly from the testicle or epididymis through an aspiration or biopsy procedure. This sperm can then be used for assisted reproductive techniques. Examples of assisted reproductive techniques include intrauterine insemination and in-vitro fertilization. These treatments are performed under the direction of reproductive endocrinology / infertility, a sub-specialty of obstetrics/gynecology. IUI and IVF are also treatments offered for unexplained infertility, which is infertility despite a completely normal workup of both the man and female partner.

Non-obstructive azoospermia refers to the absence of sperm within the ejaculate fluid due to a testicular production cause. Despite the lack of sperm in the ejaculate, small pockets of spermatogenesis may be seen upon microscopic examination of the testicular tissue.  An operative technique known as microscopic testicular sperm extraction (microTESE) can be offered to patients with non-obstructive azoospermia. In this procedure, an operating microscope is used to carefully dissect portions of the testis parenchyma. The goal is to find the pockets of more robust-appearing testicular tubules that may be the location of active spermatogenesis. These are then resected and examined under a regular light field microscope for the presence of sperm that can then be used for subsequent invitro fertilization. Success varies greatly based on the underlying etiology. 

Treatment for a varicocele causing pain or contributing to infertility typically involves surgical ligation of the dilated veins. This can be done via multiple approaches, but the gold standard is a sub-inguinal microsurgical varicocelectomy. This procedure is carried out through a small incision just below the external inguinal ring. The spermatic cord is brought up through the incision and an operating microscope is used to identify and ligate large veins. Care is taken to not damage the arterial supply (with use of intraoperative doppler) and the vas. Alternatively, the varicocele can be addressed through an endovascular to embolize the gondal veins.

Medical therapy is an option for patients with hypogonadism. It is important to note that exogenous testosterone replacement actually contributes to male factor infertility through suppression of the pituitary LH signaling cascade, thereby leading to decrease intratesticular testosterone production and decrease spermatogenesis. For patients with secondary hypogonadism (i.e. low testosterone and low/normal LH and FSH), selective estrogen receptor modulators (SERMS) may be used. The most common medication used is clomiphene citrate, which blocks the negative feedback of estradiol on the hypothalamus and pituitary. If the anterior pituitary is intact, the result should be increased FSH and LH, which in turn can stimulate spermatogenesis within the testis. Another commonly used class of medications are the aromatase inhibitors, anastrozole being the most common in the United States. This medication acts by blocking the conversion of testosterone to estradiol in the adipose tissue, thereby increasing circulating testosterone levels. It is most effective when there is a greater than 10:1 ratio of estradiol to testosterone.

An increasingly recognized cause of idiopathic infertility is oxidative stress. This may be the common pathway of many insults. In fact, a new term has been proposed, Male Oxidative Stress Infertility (MOSI). (Agarwal A, 2019) Treatment of this condition as well as many others is with antioxidants. Which antioxidants as well as the correct dose is still hotly debated and the focus of multiple research studies. (Smits RM, 2019) Commonly used antioxidants include vitamin C, vitamin E, zinc, l-carnitine, co-enzyme Q10, and many others. The jury is out on whether or not these antioxidants improve fertility outcomes, but the cost and side effect risk is so low that many physicians routinely recommend them to their infertile men.

References

• Agarwal A, P. N. (2019). Male oxidative stress infertility (Mosi): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. World J Mens Health, 37(3), 296-312.
• Cooper TG, N. E. (2010). World Health Organization reference values for human semen characteristics. Hum Reprod Update, 16(3), 231-245.
• Eisenberg ML, L. L. (2010). Estimating the number of vasectomies performed annually in the United States: data from the National Survey of Family Growth. J Urol, 184(5), 2068-2072.
• Matsuda T, M. K. (1998). Seminal tract obstruction caused by childhood inguinal herniorrhaphy: results of microsurgical reanastomosis. J Urol(159), 837-40.
• Smits RM, M.-P. R. (2019). Antioxidants for male subfertility. Cochrane Database Syst Rev, 3, CD007411.
• Tadros, N. N., & Sabanegh Jr., E. (2017). Ch. 12: Varicocele. In Treatment of Male Infertility: a Case-based Guide for Clinicians. Springer.
• Thonneau P, M. S. (1991). Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989). Hum Reprod, 6, 811.
• World Health Organization. (2010). WHO laboratory manual for the examination and processing of human semen (5th ed.). Geneva: World Health Organization.

Authors

2023
Matthew Ziegelmann, MD
Rochester, MN
Disclosures: Endo International

Nick Tadros, MD, MCR, MBA
Springfield, IL
Disclosures: Boston Scientific

2020
Nick Tadros, MD, MCR, MBA
Springfield, IL
Disclosures: Boston Scientific

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