Male factor infertility

Sources of information

This case-based discussion on male infertility is based on the current Canadian Urological Association¹ and American Urological Association³ guidelines on this subject, with reference to landmark papers as appropriate from 2010 onward. All articles were retrieved through PubMed.

Case description

A 35-year-old man, whose partner is a 32-year-old woman, presents with difficulty to conceive for 1 year. What is the diagnostic workup?

Main message

Definitions of abnormal semen analysis findings. By far the most common test ordered for men with suspected infertility is semen analysis. For ordering providers, it is important to understand the different results one might encounter, as they affect subsequent diagnostic testing and treatment choices. Although there are many types of abnormal findings (Table 1),⁴ the most common include those associated with low sperm counts.⁵ This can include men with azoospermia (0 sperm noted on analysis) or oligospermia (less than 15 million sperm noted on analysis).

The diagnostic workup of men presenting with suspected infertility includes performing an in-depth history and focused physical examination. The male fertility history is one of the most comprehensive histories performed in the field of urology, focusing on the many identified risk factors (Box 1).^1,6 This history is largely focused on 2 aspects of male physiology: the hypothalamic-pituitary-gonadal (HPG) axis, and normal testicular development and function (Box 2). By identifying either inherited conditions or acquired insults to these 2 pathways, clinicians can focus their diagnostic tests or treatments to improve a patient’s fertility potential. Similarly, a focused physical examination can help identify potentially reversible findings (eg, varicocele) that patients might not have been previously aware of.

With the history and physical examination complete, the next step is to perform the initial diagnostic evaluations. Based on available urologic male infertility guidelines, investigations typically begin with completing 2 properly collected semen sample analyses.^1,3 For patients providing a semen sample at home, proper collection includes deposition of all seminal fluid into a specimen jar, keeping the specimen jar warm on the way to the laboratory (patients can be advised to place the sample in a shirt pocket), and delivering it to the laboratory within 1 hour. If the sperm concentration is less than 10 million sperm per millilitre, then a serum hormone profile might be of benefit to test the HPG axis.⁷ This is best achieved through testing the patient’s morning total testosterone and luteinizing hormone (LH) follicle-stimulating hormone (FSH) prolactin levels, and estradiol testing should be considered.¹ Abnormal results in these investigations should prompt referral to a fertility specialist.

Findings of severe oligozoospermia or azoospermia should prompt a referral and most often require additional investigations by fertility specialists to diagnose the underlying cause. Assessment of semen volume allows classification of men with azoospermia into 1 of 2 categories: low-volume (semen sample less than 1.5 mL) or normal-volume azoospermia (Figure 1).

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Figure 1.

Diagnostic algorithm for classification of men with azoospermia

For those men with low-volume semen analysis findings, it must first be determined that collection and sample submission were performed correctly. If the low semen volume is confirmed, the man can then broadly be classified as having either obstructive azoospermia (typically accompanied by lower pH semen and absence of fructose) or an ejaculatory disorder such as retrograde ejaculation. Regardless of the cause, a postejaculatory urinalysis should be the first diagnostic step, with transrectal ultrasound being reserved for those with negative postejaculatory urinalysis findings. Performing transrectal ultrasound allows assessment for seminal vesicle dilation indicating ejaculatory duct obstruction. Men with low-volume azoospermia might also have absent vas deferens on physical examination, termed congenital bilateral absence of the vas deferens. Instances where one or both vas deferens are not palpable on physical examination should be followed by CFTR (cystic fibrosis transmembrane conductance regulator gene) testing for both the patient and the partner. If CFTR test results are negative, an abdominal ultrasound should be ordered to assess for other mesonephric duct abnormalities such as renal agenesis.

For men with normal-volume azoospermia, FSH levels allow for classification of men into broad categories of pretesticular (low FSH level), testicular (high FSH level), and posttesticular (normal FSH level) causes.

Most guidelines suggest that men with nonobstructive or indeterminate azoospermia or severe oligozoospermia (less than 5 million sperm/mL) should be offered genetic testing, with karyotype and Y microdeletion testing being the 2 most commonly performed tests.^1,3 The completion of these tests typically require specialized laboratories.

Case update

The history of our patient is noncontributory, although he is noted to have small testicles bilaterally. He has no risk factors on review of history, and his partner has no fertility concerns. Findings of his semen analyses reveal normal-volume azoospermia. His FSH and LH levels are high, with a borderline low testosterone level. For now, you give him a presumptive diagnosis of nonobstructive azoospermia due to testicular failure. He requests information about possible treatments to achieve fertility and his chances of having a pregnancy with his partner.

What are the treatment options?

A comprehensive review of treatment options is presented below, although it should be noted that not all of the presented treatment options apply to the case presented.

Conservative treatment. With a thorough history, physical examination, and initial diagnostic tests completed, there is some advice that can be offered to all men dealing with infertility that might improve semen parameters and fertility.

Advising patients to optimize intercourse by having intercourse daily around partner ovulation and avoiding spermatotoxic lubricants is general advice all patients should receive. All men should be counseled to lead a healthy lifestyle, maintain a healthy body weight, and avoid alcohol and tobacco. All of these factors have previously been negatively associated with semen parameters.⁸ While conflicting studies exist, marijuana use, and certainly illicit drug use, should be stopped in men attempting to conceive with their partners.^9,10 Clinicians should caution men from having prolonged exposure to heat (hot tubs, saunas, etc), although relatively few studies exist confirming a negative association with semen parameters.¹¹

Nutritional supplements, multivitamins, and fertility supplements have gained widespread popularity in recent years, although data supporting these medications are largely lacking. Of the meta-analyses done on this topic, the only micronutrients or supplements that appear to show some benefit include selenium, l-carnitine, and coenzyme Q10, although even the authors of these analyses highlight that most studies included have substantial risk of bias and heterogeneity.¹² No current male infertility guidelines recommend standardized use of nutritional supplements, and until further studies are completed, it is likely that clinicians cannot recommend any specific agent to their patients.^1,3

Medical treatment. The hormonal manipulation of men’s HPG axis is likely best reserved for fertility specialists; however, an understanding of the currently available treatments is important given the increasingly prevalent use of these medications.

Selective estrogen receptor modulators (SERMs): Selective estrogen receptor modulators have been used for several decades to improve the hormonal profile of men, with the hopes of improving semen parameters and fertility as a result. These drugs work by blocking negative feedback of estrogen to the hypothalamus, allowing for increased levels of gonadotropins (specifically LH and FSH). However, well-controlled studies showing improved pregnancy rates have been lacking. A recent meta-analysis of the most common SERM used in male fertility, clomiphene citrate, showed a trend toward improved fertility, although no definitive conclusions could be drawn.¹³

Aromatase inhibitors: Aromatase inhibitors are another class of medications often used in men with infertility. These medications prevent the conversion of testosterone into estradiol, thereby acting to improve the hormonal profile of men and thus hopefully improve fertility. However, similar to SERMs, there are very few high-quality studies examining the benefits of this medication. The most recent systematic review on this topic failed to show any clear benefits of this medication class.¹⁴

Human chorionic gonadotropin: Human chorionic gonadotropin has been used with some effect in men with hypogonadotropic hypogonadism. In these men, a central (pituitary or hypothalamic) issue exists leading to poor or absent spermatogenesis. Restoration of a normal HPG axis can lead to a return of sperm to the ejaculate or improvement in semen parameters.^15,16 Human chorionic gonadotropin can be given alone or in combination with exogenous FSH or human menopausal gonadotropin, allowing for a more physiologic hormonal supplementation.¹⁵

Testosterone: Although spermatogenesis largely relies on high intratesticular levels of testosterone, exogenous use of testosterone and anabolic steroids shuts down gonadotropin release through negative feedback at the pituitary gland and hypothalamus. Thus, exogenous testosterone will prevent both endogenous production of testosterone in the testicle and spermatogenesis. Patients potentially interested in family planning should not be offered testosterone therapy alone. A specialist referral should be considered to evaluate for reversible underlying causes of low testosterone. Another consideration is alternative therapies that preserve spermatogenesis, such as aromatase inhibitors and SERMs, or a combination of human chorionic gonadotropin and testosterone therapy.¹⁷ For patients using exogenous testosterone who desire fertility, clinicians should recommend cessation of testosterone. This might allow natural endogenous production to ensue over several weeks to months. If this does not occur, clinicians can then consider human chorionic gonadotropin therapy to stimulate testicles to produce endogenous testosterone.¹⁸

Treatment of retrograde ejaculation: Retrograde ejaculation deserves special mention, given that men with this condition do not have derangement of their HPG axis or an inability to produce healthy sperm via spermatogenesis. Rather, their issue is the inability to ejaculate properly. Self-reports of low or absent ejaculation, causal medications (α-blocker medications), medical conditions (eg, diabetes mellitus), history of spinal cord injury, and relevant surgical history (bladder neck surgery such as transurethral resection of the prostate or retroperitoneal surgery) can raise suspicion in clinicians.¹⁹ Semen volumes of less than 1.5 mL should also signal this cause of male factor infertility to treating clinicians. Confirmation of retrograde ejaculation can be done through attainment of a postejaculation urinalysis, with the presence of sperm in the urine diagnostic of this condition in a man with azoospermia.¹⁹ The most commonly prescribed medications to treat this condition include as-needed pseudoephedrine or daily imipramine, while in cases of spinal cord injury either vibration- or electricity-assisted ejaculation might be required.^20,21

Surgical treatment. In some patients, medical management of infertility either fails or is not possible. For these men, surgical therapies might be the only option to obtain sperm.

Varicoceles: If a man has a varicocele, abnormal semen parameters, and infertility, a varicocelectomy might be of value in improving semen parameters. Although historically this procedure was associated with some controversy given the unclear effect on pregnancy rates, a more recent meta-analysis suggests this can be an effective treatment.²²

Obstructive azoospermia: For men with obstruction of the vas deferens, a vasovasostomy might be possible to bypass the obstruction. Although this procedure is commonly associated with men wishing to reverse their previously performed vasectomy, men might experience congenital or acquired causes of obstruction that can benefit from this surgery. In some instances, epididymal obstruction is present, and requires an anastomosis made directly between the epididymis and vas deferens, termed vasoepididymostomy. This procedure is much more technically demanding than the typical connection of the vas deferens and requires a skilled microsurgeon.²³ Among patients whose vas deferens cannot be reconstructed or who do not wish to undergo reconstructive surgery, many techniques exist to extract sperm from the testicle or epididymis. These include noninvasive percutaneous techniques that use a needle for sperm extraction from the epididymis, testicular sperm aspiration, microsurgical epididymal sperm aspiration, and testicular sperm extraction.

Nonobstructive azoospermia: In men with nonobstructive causes of azoospermia, the most effective solution is microscopic testicular sperm extraction (mTESE). Here, with the aid of a high-powered operating microscope, an open exploration of a testicle and its seminiferous tubules can be undertaken. This allows for real-time assessment for the presence of sperm, where surgeons might spend several hours searching through the testicle to find dilated healthy seminiferous tubules that have an increased chance of containing sperm.²⁴ With the advent of mTESE, even men with conditions traditionally associated with very poor fertility (eg, Klinefelter syndrome) now have a relatively high (44%) chance of obtaining sperm.²⁵

If microsurgical or percutaneous techniques are used to extract sperm, couples will require further assistance through techniques such as in vitro fertilization or intracytoplasmic sperm injection (ICSI). With increasing expertise in ICSI, a fertilized embryo can now be created with as little as a single viable sperm.²⁶ This is an important counseling point, given that assisted reproductive techniques can be expensive endeavours for patients. However, the high chance of success (there are estimates as high as 98% for attaining sperm from patients with obstructive azoospermia) for treatment of male factor infertility should be highlighted to inform our patients.^1,26

Case resolution

The patient is ultimately referred to a fertility specialist who suggests that he most likely requires surgical exploration to find sperm. The couple is counseled at the time of diagnosis that despite having nonobstructive azoospermia, their chance of mTESE sperm retrieval is nearly 50%, and their chance of live birth is variable but can be approximated at 25%.^27,28 They are also counseled that alternative options include sperm donation and adoption. The patient ultimately undergoes mTESE, and fortunately a small number of sperm are found; his partner undergoes egg retrieval and ICSI is carried out to achieve pregnancy.