James M. Hotaling, MD, MS

Kelli Gross, MD; , Kevin J. Campbell, MD, MS; Darshan P. Patel, MD; Mary K. Samplaski, MD; and James M. Hotaling, MD, MS, 

discuss the case of a 45-year-old man who has been on weekly testosterone cypionate for 15 years. He and his partner are trying to conceive, but the patient is azoospermic on semen analysis.

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Approximately 15.5% of couples struggle with infertility 

 and about seven million couples seek infertility care annually in the United States 

 A component of male factor infertility is identified in about 50% of infertile couples, and a male factor is solely responsible in 20% 

Infertile couples are evaluated by a variety of different specialty providers, with the majority presenting to gynecologists or reproductive endocrinologists as women tend to initiate seeking medical care. Guidelines from the AUA 

(The optimal evaluation of the infertile male: AUA best practice statement. 2011)

 and American Society for Reproductive Medicine (ASRM) 

 have been created to assist health care providers in the management of male infertility.

These guidelines state that for all infertile couples, the male partner should have an initial screening that includes, at a minimum, a reproductive history and two semen analyses. A full evaluation by a urologist should be performed if the initial screening demonstrates any abnormality. A full male evaluation should also be considered in couples with unexplained infertility.

Despite these guidelines, many practitioners choose not to follow these recommendations. National infertility data from the U.S. show that among couples who seek infertility counseling, 18% to 27% of the male partners are not evaluated 

 According to the National Survey of Family Growth, between 2006 and 2010, only 27% of subfertile men aged 25 to 44 years had received any infertility-related advice 

 It is clear from these data that in many infertile couples, only the female partner is evaluated.

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Accordingly, many potentially treatable and/or reversible male factor fertility issues are left undiagnosed, which can lead to a loss of precious time and resources for the couple. In addition, a thorough male infertility workup can often uncover diagnoses, such as scrotal pathologies, endocrinopathies, and genetic disorders, that affect the overall health of the patient. This article briefly reviews the current guidelines and proposes a clinical care pathway for health care practitioners who perform the initial evaluation of infertile couples.

Who should be evaluated for male infertility?

The goal of the evaluation of the infertile male is to identify and treat correctable conditions in order to maximize the success of natural conception, identify couples who may need assisted reproductive technology, detect genetic causes of male infertility, and diagnose underlying medical conditions that may present as infertility. Given recent data that link male infertility to general male health, the male fertility evaluation also presents an opportunity to counsel male partners about their general health and to establish a physician-patient relationship that can lay the foundation for lifelong health.

Couples should be evaluated if they have failed to achieve a successful pregnancy following 1 year of regular unprotected intercourse (or 6 months if the female partner is over 35). The initial physician, who is often a reproductive endocrinologist, should obtain a thorough reproductive history and two semen analyses. The reproductive history should include coital frequency and timing, duration of infertility and prior fertility, childhood illnesses and developmental history, systemic medical illnesses and prior surgeries, sexual history, and gonadal toxin exposure.

If the initial evaluation is abnormal, the patient should be referred to a male infertility specialist. However, a comprehensive male fertility evaluation by a urologist rarely takes place due to local practice patterns where many couples proceed directly to in vitro fertilization (IVF) without the male having a full evaluation and the lack of availability of urologists with male infertility training.

We view this as a lost opportunity to optimize male reproductive potential, offspring health, and the general health of the male partner. Studies have shown an association between male infertility and an increased risk for testicular and high-grade prostate cancer 

 Male infertility may also serve as a biomarker for health problems, such as cardiovascular, metabolic, and autoimmune disease 

 The Centers for Disease Control and Prevention has advocated for the concept of preconception paternal health as there is significant evidence that a man’s weight as well as toxic chemical exposures can impact the epigenetic profile of his progeny for generations 

What to include in a full male evaluation

A full evaluation should include a complete medical and reproductive history, physical examination, and at least two semen analyses if not done previously. The physical should include examination of the penis, urethral meatus, testes, presence and consistency of the vasa deferentia and epididymides, presence of varicoceles, and secondary sex characteristics. With regard to the semen analyses, reference values are based on World Health Organization 2010 (table 1), although it is important to keep in mind that these cutoffs are not the minimum values needed for conception.

Based on the results of the full evaluation, other procedures, blood work, and tests may be indicated. These tests may include additional semen analyses, endocrine evaluation, imaging with ultrasonography, genetic screening, post-ejaculatory urinalysis, and specialized tests on semen and sperm.

Up to 45% of infertile men present with endocrine abnormalities 

 The AUA and ASRM recommend that an initial endocrine evaluation should include at least a serum total testosterone and follicle-stimulating hormone (FSH) level if sperm concentration is less than 10 million/mL, impaired sexual function, or other clinical findings suggestive of a specific endocrinopathy. We found that androgen deficiency was common among infertile men (43%), but it was not well associated with sperm concentration 

This suggests that there may be a greater role for routine endocrine evaluation in all male partners of infertile couples, even if they have favorable sperm concentration. The levels of hormones, such as testosterone, luteinizing hormone (LH), FSH, and prolactin, can aid in identifying an underlying clinical condition (table 2), such as hypogonadism or a prolactinoma, which can have harmful effects beyond only infertility. Accordingly, at our institution, we typically order a broader hormone panel on any patient who presents with male infertility.

Similar to the endocrine workup, imaging evaluation of the infertile male can diagnose occult pathologies that may affect the patient’s overall health. Scrotal ultrasonography is indicated in patients whose scrotal examination is difficult/ambiguous or in whom a testicular mass or varicocele is suspected. Scrotal ultrasound is inexpensive and noninvasive and can identify a potential cause of male infertility (figure 1) by evaluating the vascular environment (varicoceles, arterial resistive indices, perfusion), testicular size and volume, presence of obstruction, and occult masses/malignancy 

Testicular tumors have been found to be the cause of male infertility in up to 6% of cases 

 Some of these tumors are not palpable and are only picked up on ultrasound. These tumors include Leydig cell tumors, adrenal rests, epididymal cystadenomas, and malignancies. Men with infertility may have a two- to twenty-fold increased risk of testicular cancer, and infertility may serve as a biomarker for testicular cancer 

 In fact, about 0.5% of men evaluated for infertility are found to have a testicular malignancy. Accordingly, when male partners are not referred to urologists for evaluation, a significant number of correctable male fertility factors are not identified and serious pathology, such as testis cancer, may be missed.

Genetic abnormalities can cause infertility by affecting sperm production or transport. The three most common genetic factors related to male infertility are: cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations associated with congenital bilateral absence of the vas deferens (CBAVD), chromosomal abnormalities resulting in impaired testicular function, and Y-chromosome microdeletions (YCMD) associated with spermatogenic impairment.

In the case of CBAVD, the patient and female partner should be offered testing and counseling to identify carriers of cystic fibrosis (CF), as this may have implications for future offspring. Men with nonobstructive azoospermia or severe oligozoospermia (<5 million/mL) should be offered karyotyping and Y-chromosome analysis. Karyotyping can diagnose sex chromosome disorders like Klinefelter syndrome (KS), which is underdiagnosed and associated with low sperm production in the majority of cases. Because some of these conditions affect other aspects of the patient’s health (ie, KS, CF) and some can be passed along to offspring (ie, CF, YCMD), it is critical for health care practitioners to refer patients to urologists to do a thorough evaluation.

One factor that can account for the differences in care between female and male partners of infertile couples is the fact that the females tend to initiate the fertility evaluations. Studies have consistently shown that women utilize health care services more than men. Another major factor is that not all reproductive endocrinologists and primary care physicians (PCPs) will refer the male partner to a urologist.

Although the AUA and ASRM provide clear referral recommendations, one possible barrier toward implementation of these guidelines is a lack of awareness among other physicians, especially reproductive endocrinologists. Evaluation and management of infertility is unique in that the unit of treatment is the couple, though the focus of reproductive endocrinologists tends to be on the woman given their area of expertise. Although IVF has high success rates and can sometimes be the quickest route to pregnancy, it may not be the most cost effective or healthiest for the couple, especially if treatment of an undiagnosed male factor issue could allow for a natural pregnancy or provide further information on a man’s health.

We suspect that adherence to guidelines and clinical care pathways is higher in urologic oncology than it is in infertility. For instance, when the U.S. Preventive Services Task Force (USPSTF) recommended against PSA screening for prostate cancer in 2012, studies showed a significant decrease in PSA testing, prostate biopsy, and prostate cancer incidence in the following years due to a decrease in referrals from PCPs to urologists 

 In response to these prostate cancer screening recommendations, the Duke Cancer Institute created a multidisciplinary clinical care algorithm and embedded it into the electronic health record; thus, it was widely adopted among PCPs, leading to an increased rate of screening among all age and race categories in their community 

The problem we’re facing isn’t our guidelines but the fact that other providers aren’t aware of them and they are not easy to follow. Similar to the group at Duke, we need to engage directly with the frontline of this screening initiative (in this case, reproductive endocrinologists and PCPs) so that they will buy into the clinical care pathway (figure 2).

Data reveal timeline of post-IPP infections

A key to making this protocol successful would be to put our clinical care pathway directly into the EHR. Many reproductive endocrinologists use EHRs that link the female patient to the male partner, so it should be feasible to add a male infertility algorithm to the female partner’s EHR. For instance, for all female patients who are evaluated for infertility, there should be a male reproductive history section and order sets for two semen analyses and hormone panel that come with patient instructions. When the results of this initial evaluation return, any abnormalities should flag an automatic referral to a urologist within the EHR.

The algorithm can also automatically cue the provider to order genetic testing in azoospermic men. Ultimately, in order to ensure the success of a new clinical care pathway, we must engage and educate the physicians doing the initial evaluation. The best way to go about doing this on a larger scale would be to involve professional organizations, such as the Society for the Study of Male Reproduction and the Society for Male Reproduction and Urology.

By partnering with reproductive endocrinologists and creating an EHR-based clinical care pathway, we can improve our evaluation of male infertility and the overall health of men.

 is an andrology and reconstructive urology fellow and 

is a urology resident, University of Utah Health in Salt Lake City. 

 are assistant professors of surgery (urology) at the Center for Reconstructive Urology and Men’s Health, University of Utah Health. 

Dr. Pastuszak is an adviser, speaker, consultant, and provides research and fellowship support for Endo Pharmaceuticals; is an adviser to Boston Scientific and Antares Pharmaceuticals, and has a leadership position with Woven Health. Dr. Hotaling has received a research and fellowship grant from Endo Pharmaceuticals and a fellowship grant from Boston Scientifi c and has a leadership position/is the founder of Nanonc, StreamDx, and Andro360

 is professor of urology at the Icahn School of Medicine at Mount Sinai and director benign urologic diseases, Mount Sinai Health System, New York. Follow him on Twitter at 

Articles

This article briefly reviews the current guidelines and proposes a clinical care pathway for health care practitioners who perform the initial evaluation of infertile couples.

James M. Hotaling, MD, MS

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