madman
Super Moderator
The male infertility evaluation still matters in the era of high-efficacy assisted reproductive technology (2022)
Joshua K. Calvert, M.D., M.P.H., Kiarad Fendereski, M.D., Mohammadali Ghaed, M.D., Priyanka Bearelly, M.D., Darshan P. Patel, M.D., and James M. Hotaling, M.D., M.S.
Today’s reproductive endocrinology and infertility providers have many tools at their disposal when it comes to achieving pregnancy. In the setting of highly efficacious assisted reproductive technology, it is natural to assume that male factor infertility can be overcome by acquiring sperm and then bypassing the male evaluation. In this review, we go through guideline statements and a stepwise male factor infertility evaluation to propose that a thorough male evaluation remains important to optimize pregnancy and live birth. The foundation of this parallel evaluation is a referral to a reproductive urologist for the optimization of the male partner, for advanced diagnostics and interventions, and for the detection of other underlying male pathology. We also discuss what future developments might have an impact on the workup of the infertile male.
BACKGROUND AND EPIDEMIOLOGY
Infertility is defined as a couple’s inability to conceive after 12 months of regular, unprotected sexual intercourse (1). Current estimates place the global burden of infertility at 48 million couples (2). Infertility affects roughly 15% of couples of reproductive age, with a male factor being solely responsible in 20% and contributory in an additional 30% of cases (3). Despite how often a male factor may contribute to infertility, up to 27% of men in a heterosexual relationship seeking fertility care may not even be offered a male factor infertility evaluation (4). Evaluation of the male often is neglected because women are the usual drivers of care-seeking for fertility treatment (5). Additionally, public and provider perception of infertility as a primarily gynecologic problem, combined with the misperception that the use of assisted reproductive technology (ART) can circumvent a male factor problem, can unwittingly minimize the importance of the male evaluation (6, 7). This trend is worrisome because a thorough male evaluation can uncover serious underlying medical conditions, such as genetic disorders, endocrine disruptions, mood disorders, or even malignancy (8).
The 2021 joint guidelines from the American Urological Association and the American Society for Reproductive Medicine emphasize the ongoing importance of the male factor evaluation in the context of an infertile couple (9). Per guidelines, men with R1 abnormal semen parameters presumed male infertility, and men in couples with failed ART cycles or recurrent pregnancy losses should be evaluated by a male fertility specialist. In addition to detecting occult male somatic pathology, evaluation of the male partner can lead to improved outcomes, cost-effectiveness, and decreased physical and emotional burden for couples (See Fig. 1).
When it comes to male fertility treatment, high out-of-pocket costs and inconsistent insurance coverage of ART in many states pose a significant burden. Thus, having a return of sperm to the ejaculate or increasing the total motile sperm count to a range more suitable for intrauterine insemination or even natural conception through the manipulation of male hormones or with surgical intervention is rewarding and financially impactful. Improving total motile sperm count can all improve in vitro fertilization (IVFF)/intracytoplasmic sperm injection (IVF/ ICSI) outcomes (10). Historic and modern cost-benefit analyses show that male infertility interventions can reduce the cost per conception (11–14).
Assisted reproductive technology in many ways has revolutionized the field and allowed couples to bypass seemingly untreatable conditions. Naturally, the question arises whether the male factor infertility evaluation still is as valuable in this era of highly efficacious ART. This review will summarize relevant guideline recommendations and recent research in the evaluation of male infertility. As the field of fertility moves forward, concurrent and collaborative evaluation of both partners is essential. A reproductive urologist can facilitate an efficient and accurate evaluation on the male side as well as work together with the reproductive endocrinology and infertility (REI) team to give the couple the best outcome.
HISTORY AND PHYSICAL
A thorough history and physical examination of the male partner is the first step to assessing risk factors that could contribute to reduced fertility (See Table 1 [15, 16]). Reproductive history should include a thorough assessment of prior paternity, sexual history, medical, and surgical history, gonadotoxic exposures, and family history (17, 18).
VARICOCELE EVALUATION AND OVERVIEW OF IMPACT ON FERTILITY OUTCOMES
Varicoceles are common in the general population and roughly 40% of male patients seeking infertility care present with a varicocele (23). An examination should be performed with and without the Valsalva maneuver, as the earliest stages of varicocele can be detected only with the aid of the increased abdominal pressure that this provides (24). In the case of an equivocal examination, a scrotal Doppler ultrasound with standing Valsalva can clarify the diagnosis.
ROLE OF THE SEMEN ANALYSIS
In addition to a history and physical, an initial evaluation of the male should include R1 semen analyses (SA) (9). The SA continues to be the cornerstone of the male fertility evaluation, driven predominately by the World Health Organization (WHO), which continues to make valuable contributions to the standardization and interpretation of SA. In the most recent edition of the WHO guidelines (1), lower reference limits (5th percentiles and their 95% CIs) were provided for semen characteristics. The validity of the WHO reference values is under ongoing debate, with many andrologists arguing that the cutoff values are not only too low, but since the values are derived from only fertile men, the values are not reflective of the typical patient seen in our clinics (36–40). On its own, SA gives insight into testicular and endocrine function, and ductal patency, and helps in the identification of reversible medical conditions that can impact fertility potential (16).
IMAGING
The main role of imaging in male infertility is the identification of reversible causes, such as congenital obstruction or decreased spermatogenesis. The use of imaging in male infertility is rare and selective; however, the most routinely used tests include, ultrasonography (US), and magnetic resonance imaging (MRI) (85, 86). Scrotal US, far and away the most common imaging modality, offers a noninvasive, inexpensive way to evaluate testicular volume, and identify paratesticular causes (varicocele, epididymal and prostatic abnormalities).
ENDOCRINE EVALUATION
The American Urological Association/American Society for Reproductive Medicine guidelines do not recommend an initial standardized hormone evaluation. Instead, they recommend blood work after an abnormal sperm analysis or clinical finding suggesting an underlying endocrinologic etiology for male infertility (9). A recent study from our institution calls this recommendation into question as a normal SA often still is accompanied by an endocrinopathy (89). Thus, many male fertility specialists still would prefer that a basic fertility panel be completed before or at the time of referral. At a minimum, morning total T (TT) and follicle-stimulating hormone (FSH) would be useful adjunct tests to the initial SA. Even more informative is the addition of Estradiol (E2), luteinizing hormone (LH), free T (FT), prolactin level, and sex hormone binding globulin along with albumin to calculate the bioavailable T (BAT) (See Table 3) (90–117).
*Follicle-Stimulating Hormone
*Testosterone
*Other Labs
GENETIC EVALUATION
Detection of certain genetic causes of infertility is important for prognostication and management, as well as important for counseling regarding the health of potential offspring. The guidelines recommend genetic testing for a subset of infertile men, specifically karyotype and Y chromosome microdeletion (YCMD) in men with signs of spermatogenic failure, as evidenced by azoospermia or oligospermia (<5 million sperm/mL) (9). The guidelines also recommend cystic fibrosis transmembrane conductance regulator mutation carrier testing in men with vasal agenesis or idiopathic obstructive azoospermia (15). It currently is thought that at least 15% of all human male infertility patients can be explained by genetic defects (7, 8).
REFERRAL FOR RECURRENT PREGNANCY LOSS AND UNEXPLAINED SPONTANEOUS ABORTION
The guidelines recommend referral for male fertility evaluation in the setting of recurrent pregnancy losses and unexplained spontaneous abortion (9); importantly, elevated sperm DNA fragmentation (SDF) has been implicated in both settings and in lower intrauterine insemination and IVF pregnancy rates (145).
MALE FERTILITY EVALUATION AS AN OPPORTUNITY TO DETECT UNDERLYING PATHOLOGY
Beyond the acquisition of healthy sperm for conception, the male fertility evaluation can be seen as an opportunity for the diagnosis, management, and referral for comorbidities in male partners. In fact, male factor infertility is itself a marker of poorer somatic health (71, 150). Up to 6% of men assessed for infertility have significant underlying pathologies discovered during assessment (8). For example, mental health disorders may be detected. Hormonal aberrations, like T deficiency, lower sex hormone binding globulin, and increased prolactin, are associated not only with abnormal semen parameters but also with increased rates of anxiety and depression (151). From a cardiovascular perspective, infertile men appear to be more likely to suffer ischemic heart disease compared with fertile men (150) and to suffer metabolic syndrome (152). Malignancies also are more common in infertile men, including a detection rate of testis cancer 1.6–2.8 times higher than age-matched controls (153), and new research suggests an increased risk of melanoma, thyroid cancer, leukemia, and lymphoma (154). Often men will present to REI providers as their first health care interaction outside of their pediatrician, so this evaluation also is an opportunity for providers to recommend establishing care with a primary care physician, smoking cessation, and other health screening.
In conclusion, a couple’s infertility assessment clearly is multidisciplinary, but the fact remains that male evaluation is led predominately by female fertility specialists. When appropriate, this initial evaluation should involve the referral of the male partner to reproductive urology, where specific resources and expertise in male genitourinary tract anatomy can be applied for the acquisition of sperm, optimization of the male partners’ hormones, and detection of underlying pathology. Working collaboratively, REI providers and reproductive urologists can expedite the parallel evaluation of the infertile couple, increase the success of ART interventions, and provide couples with evidence-based, cost-conscious care in an effort to conceive.
Joshua K. Calvert, M.D., M.P.H., Kiarad Fendereski, M.D., Mohammadali Ghaed, M.D., Priyanka Bearelly, M.D., Darshan P. Patel, M.D., and James M. Hotaling, M.D., M.S.
Today’s reproductive endocrinology and infertility providers have many tools at their disposal when it comes to achieving pregnancy. In the setting of highly efficacious assisted reproductive technology, it is natural to assume that male factor infertility can be overcome by acquiring sperm and then bypassing the male evaluation. In this review, we go through guideline statements and a stepwise male factor infertility evaluation to propose that a thorough male evaluation remains important to optimize pregnancy and live birth. The foundation of this parallel evaluation is a referral to a reproductive urologist for the optimization of the male partner, for advanced diagnostics and interventions, and for the detection of other underlying male pathology. We also discuss what future developments might have an impact on the workup of the infertile male.
BACKGROUND AND EPIDEMIOLOGY
Infertility is defined as a couple’s inability to conceive after 12 months of regular, unprotected sexual intercourse (1). Current estimates place the global burden of infertility at 48 million couples (2). Infertility affects roughly 15% of couples of reproductive age, with a male factor being solely responsible in 20% and contributory in an additional 30% of cases (3). Despite how often a male factor may contribute to infertility, up to 27% of men in a heterosexual relationship seeking fertility care may not even be offered a male factor infertility evaluation (4). Evaluation of the male often is neglected because women are the usual drivers of care-seeking for fertility treatment (5). Additionally, public and provider perception of infertility as a primarily gynecologic problem, combined with the misperception that the use of assisted reproductive technology (ART) can circumvent a male factor problem, can unwittingly minimize the importance of the male evaluation (6, 7). This trend is worrisome because a thorough male evaluation can uncover serious underlying medical conditions, such as genetic disorders, endocrine disruptions, mood disorders, or even malignancy (8).
The 2021 joint guidelines from the American Urological Association and the American Society for Reproductive Medicine emphasize the ongoing importance of the male factor evaluation in the context of an infertile couple (9). Per guidelines, men with R1 abnormal semen parameters presumed male infertility, and men in couples with failed ART cycles or recurrent pregnancy losses should be evaluated by a male fertility specialist. In addition to detecting occult male somatic pathology, evaluation of the male partner can lead to improved outcomes, cost-effectiveness, and decreased physical and emotional burden for couples (See Fig. 1).
When it comes to male fertility treatment, high out-of-pocket costs and inconsistent insurance coverage of ART in many states pose a significant burden. Thus, having a return of sperm to the ejaculate or increasing the total motile sperm count to a range more suitable for intrauterine insemination or even natural conception through the manipulation of male hormones or with surgical intervention is rewarding and financially impactful. Improving total motile sperm count can all improve in vitro fertilization (IVFF)/intracytoplasmic sperm injection (IVF/ ICSI) outcomes (10). Historic and modern cost-benefit analyses show that male infertility interventions can reduce the cost per conception (11–14).
Assisted reproductive technology in many ways has revolutionized the field and allowed couples to bypass seemingly untreatable conditions. Naturally, the question arises whether the male factor infertility evaluation still is as valuable in this era of highly efficacious ART. This review will summarize relevant guideline recommendations and recent research in the evaluation of male infertility. As the field of fertility moves forward, concurrent and collaborative evaluation of both partners is essential. A reproductive urologist can facilitate an efficient and accurate evaluation on the male side as well as work together with the reproductive endocrinology and infertility (REI) team to give the couple the best outcome.
HISTORY AND PHYSICAL
A thorough history and physical examination of the male partner is the first step to assessing risk factors that could contribute to reduced fertility (See Table 1 [15, 16]). Reproductive history should include a thorough assessment of prior paternity, sexual history, medical, and surgical history, gonadotoxic exposures, and family history (17, 18).
VARICOCELE EVALUATION AND OVERVIEW OF IMPACT ON FERTILITY OUTCOMES
Varicoceles are common in the general population and roughly 40% of male patients seeking infertility care present with a varicocele (23). An examination should be performed with and without the Valsalva maneuver, as the earliest stages of varicocele can be detected only with the aid of the increased abdominal pressure that this provides (24). In the case of an equivocal examination, a scrotal Doppler ultrasound with standing Valsalva can clarify the diagnosis.
ROLE OF THE SEMEN ANALYSIS
In addition to a history and physical, an initial evaluation of the male should include R1 semen analyses (SA) (9). The SA continues to be the cornerstone of the male fertility evaluation, driven predominately by the World Health Organization (WHO), which continues to make valuable contributions to the standardization and interpretation of SA. In the most recent edition of the WHO guidelines (1), lower reference limits (5th percentiles and their 95% CIs) were provided for semen characteristics. The validity of the WHO reference values is under ongoing debate, with many andrologists arguing that the cutoff values are not only too low, but since the values are derived from only fertile men, the values are not reflective of the typical patient seen in our clinics (36–40). On its own, SA gives insight into testicular and endocrine function, and ductal patency, and helps in the identification of reversible medical conditions that can impact fertility potential (16).
IMAGING
The main role of imaging in male infertility is the identification of reversible causes, such as congenital obstruction or decreased spermatogenesis. The use of imaging in male infertility is rare and selective; however, the most routinely used tests include, ultrasonography (US), and magnetic resonance imaging (MRI) (85, 86). Scrotal US, far and away the most common imaging modality, offers a noninvasive, inexpensive way to evaluate testicular volume, and identify paratesticular causes (varicocele, epididymal and prostatic abnormalities).
ENDOCRINE EVALUATION
The American Urological Association/American Society for Reproductive Medicine guidelines do not recommend an initial standardized hormone evaluation. Instead, they recommend blood work after an abnormal sperm analysis or clinical finding suggesting an underlying endocrinologic etiology for male infertility (9). A recent study from our institution calls this recommendation into question as a normal SA often still is accompanied by an endocrinopathy (89). Thus, many male fertility specialists still would prefer that a basic fertility panel be completed before or at the time of referral. At a minimum, morning total T (TT) and follicle-stimulating hormone (FSH) would be useful adjunct tests to the initial SA. Even more informative is the addition of Estradiol (E2), luteinizing hormone (LH), free T (FT), prolactin level, and sex hormone binding globulin along with albumin to calculate the bioavailable T (BAT) (See Table 3) (90–117).
*Follicle-Stimulating Hormone
*Testosterone
*Other Labs
GENETIC EVALUATION
Detection of certain genetic causes of infertility is important for prognostication and management, as well as important for counseling regarding the health of potential offspring. The guidelines recommend genetic testing for a subset of infertile men, specifically karyotype and Y chromosome microdeletion (YCMD) in men with signs of spermatogenic failure, as evidenced by azoospermia or oligospermia (<5 million sperm/mL) (9). The guidelines also recommend cystic fibrosis transmembrane conductance regulator mutation carrier testing in men with vasal agenesis or idiopathic obstructive azoospermia (15). It currently is thought that at least 15% of all human male infertility patients can be explained by genetic defects (7, 8).
REFERRAL FOR RECURRENT PREGNANCY LOSS AND UNEXPLAINED SPONTANEOUS ABORTION
The guidelines recommend referral for male fertility evaluation in the setting of recurrent pregnancy losses and unexplained spontaneous abortion (9); importantly, elevated sperm DNA fragmentation (SDF) has been implicated in both settings and in lower intrauterine insemination and IVF pregnancy rates (145).
MALE FERTILITY EVALUATION AS AN OPPORTUNITY TO DETECT UNDERLYING PATHOLOGY
Beyond the acquisition of healthy sperm for conception, the male fertility evaluation can be seen as an opportunity for the diagnosis, management, and referral for comorbidities in male partners. In fact, male factor infertility is itself a marker of poorer somatic health (71, 150). Up to 6% of men assessed for infertility have significant underlying pathologies discovered during assessment (8). For example, mental health disorders may be detected. Hormonal aberrations, like T deficiency, lower sex hormone binding globulin, and increased prolactin, are associated not only with abnormal semen parameters but also with increased rates of anxiety and depression (151). From a cardiovascular perspective, infertile men appear to be more likely to suffer ischemic heart disease compared with fertile men (150) and to suffer metabolic syndrome (152). Malignancies also are more common in infertile men, including a detection rate of testis cancer 1.6–2.8 times higher than age-matched controls (153), and new research suggests an increased risk of melanoma, thyroid cancer, leukemia, and lymphoma (154). Often men will present to REI providers as their first health care interaction outside of their pediatrician, so this evaluation also is an opportunity for providers to recommend establishing care with a primary care physician, smoking cessation, and other health screening.
In conclusion, a couple’s infertility assessment clearly is multidisciplinary, but the fact remains that male evaluation is led predominately by female fertility specialists. When appropriate, this initial evaluation should involve the referral of the male partner to reproductive urology, where specific resources and expertise in male genitourinary tract anatomy can be applied for the acquisition of sperm, optimization of the male partners’ hormones, and detection of underlying pathology. Working collaboratively, REI providers and reproductive urologists can expedite the parallel evaluation of the infertile couple, increase the success of ART interventions, and provide couples with evidence-based, cost-conscious care in an effort to conceive.
