Darshan P. Patel, MD

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.

Emerging treatment options for ED: Hope or hype?

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.

Male infertility evaluation: Time for a new clinical care pathway?

Erectile dysfunction is a common concern among aging males. Not only does ED affect quality of life, but it is also linked to cardiovascular disease, hypertension, diabetes, and overall health.

Currently, there are three categories of ED treatments. Oral medications such as phosphodiesterase type-5 (PDE-5) inhibitors (sildenafil, vardenafil, tadalafil, and avanafil) have comparable efficacy. Intracavernosal injections (alprostadil, phentolamine, papaverine, and/or atropine) or intraurethral suppositories (alprostadil) are alternatives in patients who are non-responders to oral medications or have side effects. Penile implants are the most invasive treatment but provide durable results and the highest satisfaction rates of all of treatments.

Tissue sealing sheets may improve post-RP function

Given the prevalence of ED, there is significant incentive to find more effective and less invasive treatment options. Here we review new and emerging treatment options for this common condition. We also review the use of nutraceuticals, which are not new but have seen explosive growth in recent years (see, 

PDE-5 inhibitors remain the cornerstone of oral therapies. Researchers have explored alternative pathways for novel therapeutics (table), although success has been limited. Currently, no novel oral medications are in clinical development. Prior targets have focused on central pathways (dopaminergic and melanocortin) and peripheral pathways (guanylyl cyclase and Rho-A/Rho kinase), but novel oral therapies directed at these pathways have shown limited efficacy and tolerability. An overview of the cellular pathways is shown in the figure.

 Initially, the use of dopamine agonists for Parkinson’s disease was associated with increased libido. Apomorphine is a dopamine D1 and D2 receptor agonist that was approved for ED in Europe in 2001. In a phase III double-blind, parallel-arm, crossover study of nearly 900 men with ED, more than 50% of those using apomorphine were able to obtain an erection sufficient for intercourse compared to 33% of men using placebo 

 However, the FDA did not approve the drug in the United States because of concerns about hypotension. Similar medications (ABT-724 and ABT-670) targeted to the D4 receptor have also been studied, but development was stopped after phase II studies.

Melanocortin receptor agonists including melanotan II (subcutaneous administration) and bremelanotide (intranasal administration) have been studied for ED. Both formulations improved erectile function in studied men, although they were poorly tolerated in clinical studies. Patients given melanotan II experienced severe emesis, and bremelanotide caused severe hypertension. Further clinical development has been discontinued.

Recently, a landmark study identified a single locus near the SIM1 gene that was associated with risk of ED independent of known risk factors in a large cohort 

 SIM1 encodes transcription factors involved in the leptin-melanocortin pathway and may represent an exciting target for future novel therapies.

Soluble guanylyl cyclase is a key component of the nitric oxide (NO) pathway (figure). In post-prostatectomy patients or diabetics who have severe endothelial dysfunction and cavernous nerve injury, PDE-5 inhibition does not increase endogenous NO levels sufficiently. In these patients, direct activation of soluble guanylyl cyclase may enhance erections.

In a study of human cavernosal tissue obtained from patients during penile prosthesis implantation, compared to patients undergoing transurethral surgery, a combination of vardenafil and guanylyl cyclase activator enhanced cavernosal smooth muscle relaxation 

 Unfortunately, this medication has not progressed past phase II studies.

 The RhoA/Rho kinase pathway contributes to cavernosal smooth muscle contraction, which is independent of the NO pathway. When activated, the smooth muscle myosin light chain (MLC) is phosphorylated by inhibiting MLC phosphatase, leading to calcium sensitization and smooth muscle contraction. Studies of hypertensive and diabetic rats have suggested upregulation of this pathway and a resultant worsening of erectile function. SAR407899 is a specific RhoA/Rho kinase inhibitor that induces penile erection with greater potency and longer duration than sildenafil in a diabetic rabbit model, as well as in human cavernosal tissue strips 

 However, development of this drug ceased after completion of phase II clinical trials, without reporting of results.

Topical agents for the treatment of ED are an appealing alternative for patients who experience adverse effects with the use of oral PDE-5 inhibitors and who do not desire more invasive treatments. Topical alprostadil has been studied in several double-blind, placebo-controlled trials with notable improvements in International Index of Erectile Function (IIEF) scores and few minor side effects such as erythema at the administration site.

Topical sildenafil is currently being studied for the treatment of ED. A phase I pharmacokinetic and safety trial has shown good penetration of topical sildenafil without significant side effects 

 A phase II proof-of-concept study has been completed, although results have not yet been reported. Various formulations of both topical alprostadil and sildenafil are available through online outlets and compounding pharmacies, although tissue penetration and efficacy are likely variable. While promising, considerable investigation of topical agents is still needed.

Stem cells have become an attractive therapy for ED, particularly following prostatectomy, where ED is secondary to cavernosal nerve damage. Stem cells for the treatment of ED have been derived from a number of sources, including adipose tissue, bone marrow, urine, placenta, umbilical vein endothelium, and amniotic fluid. Adipose-derived stem cells are the most studied in ED treatment in the rat model, with several studies showing an improvement in intracavernosal pressure in rats injected with stem cells directly into the corpus cavernosum.

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Additionally, combination treatment with brain-derived neurotrophic factor (BDNF), PDE-5 inhibitors, and adipose-derived stem cells have suggested a synergistic effect in improving erectile function in the rat model 

 However, data examining the therapeutic efficacy and safety of stem cells for treatment of ED in humans are limited, and this therapy remains experimental.

Platelets play an important role in inflammation, tissue remodeling, and angiogenesis. The use of autologous platelet-rich plasma (PRP) has been explored in the treatment of a number of conditions, including ED. Whole blood is obtained from the patient through venipuncture and the sample is then centrifuged to remove white and red blood cells. The supernatant contains platelets and plasma proteins, including growth factors and other components that can aid healing, which are then directly injected into the corpus cavernosum.

Wu et al performed intracavernosal injection of PRP in an animal model of ED after cavernous nerve crush injury, observing an improvement in erectile function after PRP 

 However, no studies evaluating the efficacy of PRP for ED in humans are currently available.

The safety of PRP has been suggested in a study by Matz et al in which PRP fibrin matrix was used in 16 patients for ED and/or Peyronie’s disease. There were no major complications, and minor complications included mild pain or bruising at the injection site in approximately 20% of patients 

 2018; 59:61-65). Although PRP is an interesting potential therapy for ED, further studies are warranted to evaluate its safety and efficacy.

Extracorporeal low-intensity shock wave therapy

Extracorporeal low-intensity shock wave therapy (LISWT) is an emerging treatment for ED. It has been studied previously for a number of other conditions, including tissue ischemia, wound healing, and musculoskeletal disorders. LISWT utilizes direct mechanical forces from a pulse energy source and indirect force through cavitation that is directed at the treatment target. For ED, LISWT is thought to induce microtrauma to the cavernosal tissue that upregulates angiogenic factors, resulting in new blood vessel growth.

Vardi et al were the first to systematically report their experience with LISWT for ED in 2010, and since then a number of other studies have been published suggesting some therapeutic efficacy, with minimal adverse effects 

 However, the ability to draw conclusions from the current literature is limited due to difference in treatment protocols, follow-up time, and patient selection. Several ongoing randomized clinical trials will help our understanding of the role of LISWT in the treatment of ED.

Over the last decade, we have developed a better understanding of the pathophysiology of ED. However, novel therapies-especially oral agents-with demonstrable efficacy and favorable side effect profiles are lacking. Other innovative therapies in early clinical stages show promise, but there remain unanswered questions about patient selection and efficacy. Continued technological advances and a detailed understanding of the spectrum of pathophysiologic mechanisms of ED will translate to novel therapies in the future.

Nutraceuticals are therapies that use alternative, natural, or herbal additives with claims of health benefits. Consumption of these therapies has exploded over the last decade. As a result of the Dietary Supplement Health Act of 1994, supplements are regulated as foods rather than medications. The aversion that men with ED often have to seeking medical care, in part from the negative stigma associated with the condition, has likely fueled this growing market.

Many nutraceuticals are commercially available without prescription and include up to a dozen different ingredients, including yohimbine, L-arginine, red ginseng, and 

 spp (or horny goat weed). However, the efficacy and bioavailability of these ingredients and formulations have not been well established. As such, the use of nutraceuticals for ED should be approached with caution. 

 Yohimbine is derived from the African yohimbe tree and inhibits central alpha-2 adrenergic receptors to increase libido, although the true mechanism contributing to erections is unknown. An early meta-analysis suggested yohimbine had therapeutic efficacy with few adverse effects. More recently, a study explored on-demand L-arginine glutamate and yohimbine in 45 patients with mild to moderate ED in a double-blind, placebo-controlled study 

 Those who received the combination had improved erectile function domain responses on the International Index of Erectile Function (IIEF) compared to placebo. Yohimbine is the most promising nutraceutical, although it is uncertain how it compares to current oral ED medications.

Many men undergo ART procedures without full workup

 L-arginine is a naturally occurring amino acid that is also a component of many nutraceuticals claiming to boost erectile function. It is a precursor to nitric oxide and supplementation with L-arginine can boost nitric oxide levels, leading to smooth muscle relaxation and increased blood flow. However, demonstrable efficacy of L-arginine supplementation is limited.

 Similar to L-arginine, ginseng affects the NO pathway, stimulating nitric oxide synthase (NOS). Nearly a dozen randomized studies have evaluated the use of ginseng for ED. Most have reported a positive effect, although each of these studies has methodologic flaws including selection bias, dosing, and follow-up. Adverse effects of red ginseng are generally mild and include headaches, gastrointestinal upset, skin irritation, and reports of symptomatic hypoglycemia in diabetics. However, currently there is no convincing evidence for therapeutic efficacy of this compound.

 Horny goat weed has gained popularity since it is easily marketable by its name. It is an extract from the epimedium flowering plant and contains the flavonol icariin, which has a mild PDE-5 inhibitor-like effect. Small animal studies have demonstrated an improvement in erectile function after administration of icariin. However, no human studies are available.

 is an andrology and reconstructive urology fellow, 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.

Novel therapies are promising but face questions about patient selection and efficacy.