Diagnosis and Treatment of Infertility in Men: AUA/ ASRM Guideline

Purpose

• Infertility affects approximately one-half of all couples, with the male partner being a contributing factor.
• Evaluation of the male partner is crucial for appropriate therapy direction.
• Some Conditions are treatable with medical or surgical approaches.
• Other Conditions may require donor sperm or adoption.
• Some conditions can be life-threatening.
• Evaluation is important to direct the management of the couples.
• The guideline aims to outline the evaluation and management of the male in an infertile couple.
• Recommendations incorporate history, physical exam, and diagnostic testing.
• Medical therapies, surgical techniques, and assisted reproductive technologies (ART) are addressed.
• Recommendations are based on published literature evaluation using the PICO question approach.
• The term "male" refers to biological or genetic men.

Methodology

• The Emergency Care Research Institute (ECRI) conducted a search of PubMed, Embase, and Medline from January 2000 through May 2019.
• A medical librarian developed search strategies for each key question using medical subject headings and keywords.
• Evidence was assigned a strength rating of A (high), B (moderate), or C (low) based on the body of evidence.
• Clinical Principles and Expert Opinions were used when sufficient evidence was unavailable.

Guideline Statements - Assessment

• Both male and female partners should undergo concurrent assessment for initial infertility evaluation (Expert Opinion).
• Initial evaluation of the male should include a reproductive history (Clinical Principle) and semen analyses (SAs) (Strong Recommendation; Evidence Level: Grade B).
• Men with abnormal semen parameters or presumed male infertility should be evaluated by a male reproductive expert (Expert Opinion).
• Evaluation of the male should be considered in couples with failed ART cycles or recurrent pregnancy losses (RPL) (Expert Opinion).

Lifestyle Factors and Relationships Between Infertility and General Health

• Clinicians should counsel infertile men with abnormal semen parameters about the health risks associated with abnormal sperm production (Moderate Recommendation; Evidence Level: Grade B).
• Infertile men with specific causes of male infertility should be informed of relevant, associated health conditions (Moderate Recommendation; Evidence Level: Grade B).
• Couples with advanced paternal age (≥40) should be advised about increased risks for offspring (Expert Opinion).
• Clinicians may discuss risk factors associated with male infertility but should counsel patients that data are limited (Conditional Recommendation; Evidence Level: Grade C).

Diagnosis/Assessment/Evaluation

• SA results should guide patient management, with multiple abnormalities carrying greater clinical significance (Expert Opinion).
• Hormonal evaluation (FSH and testosterone) should be obtained for infertile men with impaired libido, erectile dysfunction, oligozoospermia, azoospermia, atrophic testes, or hormonal abnormality (Expert Opinion).
• Azoospermic men should be initially evaluated with semen volume, physical exam, and FSH levels to differentiate genital tract obstruction from impaired sperm production (Expert Opinion).
• Karyotype and Y-chromosome microdeletion analysis should be recommended for men with primary infertility and azoospermia or severe oligozoospermia (<5 million sperm/mL) with elevated FSH or testicular atrophy (Expert Opinion).
• Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele) should be recommended in men with vasal agenesis or idiopathic obstructive azoospermia (Expert Opinion).
• Genetic evaluation of the female partner should be recommended for men who harbor a CFTR mutation (Expert Opinion).
• Sperm DNA fragmentation analysis is not recommended in the initial evaluation of the infertile couple (Moderate Recommendation; Evidence Level: Grade C).
• Men with increased round cells on SA (>1million/mL) should be evaluated further to differentiate white blood cells (pyospermia) from germ cells (Expert Opinion).
• Patients with pyospermia should be evaluated for the presence of infection (Clinical Principle).
• Antisperm antibody (ASA) testing should not be done in the initial evaluation of male infertility (Expert Opinion).
• For couples with RPL, men should be evaluated with karyotype (Expert Opinion) and sperm DNA fragmentation (Moderate Recommendation; Evidence Level: Grade C).
• Diagnostic testicular biopsy should not routinely be performed to differentiate between obstructive azoospermia and non-obstructive azoospermia (NOA) (Expert Opinion).

Imaging

• Scrotal ultrasound should not be routinely performed in the initial evaluation of the infertile male (Expert Opinion).
• Transrectal ultrasonography (TRUS) should not be performed as part of the initial evaluation unless SA suggests ejaculatory duct obstruction (EDO) (Expert Opinion).
• Clinicians should not routinely perform abdominal imaging for an isolated small or moderate right varicocele (Expert Opinion).
• Clinicians should recommend renal ultrasonography for patients with vasal agenesis to evaluate for renal abnormalities (Expert Opinion).

Treatment- Varicocele Repair/Varicocelectomy

• Surgical varicocelectomy should be considered for men with palpable varicocele(s), infertility, and abnormal semen parameters, except for azoospermic men (Moderate Recommendation; Evidence Level: Grade B).
• Clinicians should not recommend varicocelectomy for men with non-palpable varicoceles (Strong Recommendation; Evidence Level: Grade C).
• For men with clinical varicocele and NOA, couples should be informed of the absence of definitive evidence supporting varicocele repair prior to ART (Expert Opinion).

Treatment - Sperm Retrieval

• For men with NOA undergoing sperm retrieval, microdissection testicular sperm extraction (TESE) should be performed (Moderate Recommendation; Evidence Level: Grade C).
• In men undergoing surgical sperm retrieval, either fresh or cryopreserved sperm may be used for ICSI (Moderate Recommendation; Evidence Level: Grade C).
• In men with azoospermia due to obstruction undergoing surgical sperm retrieval, sperm may be extracted from either the testis or the epididymis (Moderate Recommendation; Evidence Level: Grade C).
• For men with aspermia, surgical sperm extraction or induced ejaculation (sympathomimetics, vibratory stimulation or electroejaculation) may be performed (Expert Opinion).
• Infertility associated with retrograde ejaculation (RE) may be treated with sympathomimetics and alkalinization of urine, induced ejaculation, or surgical sperm retrieval (Expert Opinion).

Treatment - Obstructive Azoospermia, Including Post-Vasectomy Infertility

• Couples desiring conception after vasectomy should be counseled that surgical reconstruction, surgical sperm retrieval, or both reconstruction and simultaneous sperm retrieval for cryopreservation are viable options (Moderate Recommendation; Evidence Level: Grade C).
• Clinicians should counsel men with vasal or epididymal obstructive azoospermia that microsurgical reconstruction may be successful in returning sperm to the ejaculate (Expert Opinion).
• For infertile men with azoospermia and EDO, the clinician may consider transurethral resection of ejaculatory ducts (TURED) or surgical sperm extraction (Expert Opinion).

Treatment - Medical & Nutraceutical Interventions for fertility

• Male infertility may be managed with ART (Expert Opinion).
• A clinician may advise an infertile couple with a low total motile sperm count on repeated SA that IUI success rates may be reduced, and treatment with ART (IVF/ICSI) may be considered (Expert Opinion).
• The patient presenting with hypogonadotropic hypogonadism (HH) should be evaluated to determine the etiology of the disorder and treated based on diagnosis (Clinical Principle).
• Clinicians may use aromatase inhibitors (AIs), hCG, selective estrogen receptor modulators (SERMs), or a combination thereof for infertile men with low serum testosterone (Conditional Recommendation; Evidence Level: Grade C).
• For the male interested in current or future fertility, testosterone monotherapy should not be prescribed (Clinical Principle).
• The infertile male with hyperprolactinemia should be evaluated for the etiology and treated accordingly (Expert Opinion).
• Clinicians should inform the man with idiopathic infertility that the use of SERMs has limited benefits relative to results of ART (Expert Opinion).
• Clinicians should counsel patients that the benefits of supplements (e.g., antioxidants, vitamins) are of questionable clinical utility in treating male infertility (Conditional Recommendation; Evidence Level: Grade B).
• For men with idiopathic infertility, a clinician may consider treatment using an FSH analogue with the aim of improving sperm concentration, pregnancy rate, and live birth rate (Conditional Recommendation; Evidence Level: Grade B).
• Patients with NOA should be informed of the limited data supporting pharmacologic manipulation with SERMs, AIs, and gonadotropins prior to surgical intervention (Conditional Recommendation; Evidence Level: Grade C).

Treatment - Gonadotoxic Therapies and Fertility Preservation

• Clinicians should discuss the effects of gonadotoxic therapies and other cancer treatments on sperm production with patients prior to commencement of therapy (Moderate Recommendation: Evidence Level: Grade C).
• Clinicians should inform patients undergoing chemotherapy and/or radiation therapy to avoid pregnancy for a period of at least 12 months after completion of treatment (Expert Opinion).
• Clinicians should encourage men to bank sperm, preferably multiple specimens when possible, prior to commencement of gonadotoxic therapy or other cancer treatment that may affect fertility in men (Expert Opinion).
• Clinicians should consider informing patients that a SA performed after gonadotoxic therapies should be done at least 12 months (and preferably 24 months) after treatment completion (Conditional Recommendation; Evidence Level: Grade C).
• Clinicians should inform patients undergoing a retroperitoneal lymph node dissection (RPLND) of the risk of aspermia (Clinical Principle).
• Clinicians should obtain a post-orgasmic urinalysis for men with aspermia after RPLND who are interested in fertility (Clinical Principle).
• Clinicians should inform men seeking paternity who are persistently azoospermic after gonadotoxic therapies that TESE is a treatment option (Strong Recommendation; Evidence Level: Grade B).

Introduction

• Approximately 15\% of couples are unable to conceive after one year of unprotected intercourse.
• A male factor is solely responsible in about 20\% of infertile couples and informative in another 30-40\%.1
• Male factor infertility may be explained by an abnormal SA or by other sperm function defects, in the setting of a normal SA as well as functional male defects.
• Some conditions are identifiable and reversible, such as ductal obstruction and HH.
• Other conditions are identifiable and treatable but not reversible, such as bilateral testicular atrophy secondary to viral orchitis.
• Identification of the etiology of an abnormal SA is not possible in approximately 30\% of men, in which case this condition is termed idiopathic male infertility.3
• When the reason for infertility is not clear with a normal SA and partner evaluation the infertility is termed unexplained, which is found in up to approximately 25\% of couples.3
• Male infertility is associated with other comorbidities including increased mortality, while advanced paternal age is associated with some adverse outcomes in offspring.
• An appropriate male evaluation may allow the couple to better understand the basis and implications of their infertility.
• Evaluation for infertility is also guided by female age and other factors, such as an abnormal male reproductive history (e.g., history of cryptorchidism, chemotherapy, pelvic/retroperitoneal surgery, other conditions that have been associated with male infertility).
• When such factors are present, male evaluation is indicated.
• Infertility should be evaluated after 6 months of attempted conception when the female partner is over 35 years of age.
• Male infertility is typically diagnosed by one or more factors that may include abnormal semen quality or sperm functional parameters; anatomical, endocrine, genetic, functional, or immunological abnormalities of the male reproductive system (including chronic illness); or sexual conditions incompatible with the ability to deposit semen in the vagina.
• Primary male infertility refers to a male who has never initiated a clinical pregnancy and meets the criteria of being classified as infertile, whereas secondary infertility refers to a couple where the man is unable to initiate a clinical pregnancy, but who had previously initiated a clinical pregnancy (with the same or different sexual partner).

Definitions of Infertility and Treatment Success

• Infertility is defined as "a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse."
• The condition of infertility is categorized as a disease by the World Health Organization (WHO), the American Medical Association (AMA), and the American Society for Reproductive Medicine.

Assessment of tests and treatments for the male

• Assessment is challenging due to inconsistent endpoints and the observation that many of these endpoints are dependent upon and measured from the female partner.
• Ideally, the endpoint for fertility trials should be "live birth (defined as any delivery of a live infant after 20 weeks of gestation) or cumulative live birth, defined as the live birth per women over a defined time period (or number of treatment cycles.)"
• However, the high variability of SA parameters makes them difficult to use in the determination of interventions for male reproduction.

Epidemiology

• Most couples achieve a pregnancy in the first 3 to 6 months of attempted conception, with 75\% of couples achieving a pregnancy after 6 months of trying.8-11
• In general, after one year of attempting to conceive, approximately 85\% of couples will have achieved a pregnancy.
• After two full years of attempting to conceive, this statistic is increased to over 90\% of couples.
• Age of the female partner is the single most important factor when predicting the chances of conception for a couple.
• Fertility decreases by almost 50\% in women in their late 30’s compared to women in their 20’s.
• In women under 35 years of age, infertility is considered present after 12 months of attempting to conceive.
• This duration is shortened in women over the age of 35 years to 6 months.
• In up to 50\% of couples, a male factor is found as part of the etiology of the infertility.14 In addition, between approximately 25\% of couples will have unexplained infertility.
• RPL is a disease that is distinct from infertility and is defined as two or more failed pregnancies.
• The workup of RPL yields an etiology in only approximately 50\% of couples as most miscarriages are related to abnormalities within the fetus itself.
• The risk of miscarriage after two losses is at least 25\% depending on the age of the woman.
• After three consecutive losses, this risk increases to almost 50\%. Etiologic causes of recurrent miscarriages includes genetic causes (e.g., chromosomal translocations), anatomic abnormalities of the female uterus (e.g., septum, submucosal fibroids, adhesions), infections, hematologic and immunologic disorders of the female partner, female partner endocrine issues (e.g., thyroid and diabetes), and male factor issues.
• In general, for men, the common identified etiologic issues include karyotypic abnormalities and sperm DNA fragmentation.

Assessment Guideline Statment

• Couple infertility may be due to male factors, female factors or a combination of male and female factors.

• For the female partner, tests are indicated to evaluate ovarian reserve, ovulatory function, tubal structures as well as assessment of the uterine cavity.

• Maternal age is the strongest predictor of fertility outcome in couples undergoing therapy.

• Natural conception rates decrease by almost 50\% as women approach their 40’s as compared to when they are in their 20’s.

• Semen parameter values falling above or below the lower limit do not by themselves predict either fertility or infertility.

• Therefore, at least two SAs obtained a month apart are important to consider, especially if the first SA has abnormal parameters.

• The SA should include measures of semen volume, pH if indicated, sperm concentration/sperm count, sperm motility, and sperm morphology.

• Clinical conditions: Defects in spermatogenesis, genital tract anatomy, patency and function, as well as emission and ejaculation will impact the patient’s semen parameters.

• WHO 5th Edition Table
  \begin{array}{|l|l|}
  \hline
  \text { Semen Parameter } & \text { One-Sided Lower Reference Limit (Fifth Centiles With } 95 \% \text { Confidence Inter- vals) } \
  \hline
  \text { Semen Volume } & 1.5 \mathrm{~mL}(1.4-1.7) \
  \hline
  \text { Total Sperm Number } & 39 \text { million per ejaculate } (33-46) \
  \hline
  \text { Sperm Concentration } & 15 \text { million } / \mathrm{mL}(12-16 \text { million } / \mathrm{mL}) \
  \hline
  \text { Vitality } & 58 \% \text { Live }(55-63 \%) \
  \hline
  \text { Progressive Motility } & 32 \% (31-34 \%) \
  \hline
  \text { Total Motility (Progressive + Non-Progressive) } & 40 \% (38-42 \%) \
  \hline
  \text { Morphologically Normal Forms } & 4.0 \% (3.0-4.0) \
  \hline
  \end{array}

• For example, investigators suggested that varicocele treatment may be more cost-effective than ART or can lower the intensity of treatment.29-31. This may allow couples to conceive by less invasive technologies, such as pregnancy by IUI instead of IVF or pregnancy by intercourse instead of IUI.

• Infertile men also have a higher rate of medical comorbidities (e.g., hypertension, hyperlipidemia, obesity, diabetes) that can contribute to impaired fecundability.38,39

Lifestyle Factors and Relationship Between Infertility and General Health. Table 3: Possible Medical Conditions Associated with Male Infertility Condition

Possible Medical Comorbidities.
\begin{array}{|l|l|l|l|}
\hline\
\text { Possibilities } & \\text { MULTIPLE studies } & \text { SINGLE study } & \text { Evidence is UNCLEAR or } \
\text { }\text { }Possible Medical } & \text { indi- } & \text { indi- } & \text { CONFLICT- ING } \
\text { }\\text { Comorbidities } & \text { cate increased risk } & \text { cates increased risk } & \\hline\\
\text { Abnormal semen } & \text { } & \text { } & \text { }\\text { parameters } & \text { } & \text { } & \text { Testicular cancer Mortality CCI Diabetes Mul-}$\\text { tiple sclerosis Cancer } & \text { } & \text { } & \\text { Melanoma } Chronic epididymitis Prostate cancer & \text { } & \text { } & Other cancers Sexually transmitted infections Thyroid disorders\\
\hline\hline
\end{array}

Klinefelter syndrome:

• Testosterone deficiency, abnormal muscle mass and pubertal development, decreased facial/body hair, gynecomastia, autoimmune disorders, osteoporosis, and impaired spermatogenesis.57,58.

Cystic Fibrosis (CF)

• Associated with male infertility (i.e., obstructive azoospermia) as well as pulmonary problems, pancreatic deficiency, and dental carries.59
• Cryptorchidism is aIso associated with infertility as well as a higher risk of testis cancer and can occur with other.genitourinary abnormalities such as hypospadias. 44,60,61
• Testosterone deficiency is associated with impaired spermatogenesis and is a risk factor for diabetes, metabolic syndrome, cardiovascular disease (CVD), hypertension, all-cause mortality, CVD mortality, and Alzheimer’s disease.62-64

Factors of reproductive

• There are also potential impacts on the offspring. Data indicate that advanced paternal age increases de novo intra- and inter-genic germline mutations, sperm aneuploidy, structural chromosomal aberrations, birth defects, and genetically-mediated conditions (e.g., chondrodysplasia, schizophrenia, autism) in the offspring.66-68
• genetic counseling may be appropriate for couples with advanced paternal age to discuss the magnitude of these risks.
• While several putative risk factors for male factor infertility (e.g., demographic, lifestyle, medical treatments, environmental exposures) have been studied, data are limited due to the difficulty in isolating specific factors.

Lack of controls and risk of recall bias for the following:

• There is low-quality evidence for low association between diet and male infertility.
• There is low-quality evidence that poor diet results in reduced fertility.
• Similarly, low-quality evidence (due to high risk of bias) exists to link smoking with a small impact on sperm concentration, motility, and morphology.
• Further, there is low-quality evidence for no impact of anabolic steroids/exogenous testosterone on permanent infertility (not reversible); however, current use has a major impact on current fertility and spermatogenesis.
• There is moderate quality evidence of no association (except possibly sperm aneuploidy) between caffeine and male infertility, while high-quality evidence exists on the mild impact of alcohol on semen volume, sperm morphology (although not clinically significant).
• No systematic reviews met inclusion criteria for the following risk factors: recreational drug use, sleep, sports/exercise, heat exposure, type of underwear, or anatomic abnormalities of genitalia.
• Several putative toxicants: Evidence of an association between exposure and male infertility was determined to be conclusive for some heavy metals and pesticides, while further data indicate a potential association between the phthalate DEHP and male infertility

Diagnosis and Evaluation

• The individual semen parameters measured in the SA provide a weak indicator of fertility potential.
• With the exception of the aforementioned anomalies, none of the individual sperm parameters (e.g., concentration, morphology, motility) are diagnostic of infertility.
• The OR for infertility increases as the number of abnormal parameters increases.26 Clinicians managing results from a SA should counsel patients that multiple significant abnormalities in semen parameters increase their RR for infertility.

Hormonal evaluation

• Testosterone levels should be defined based upon a blood sample drawn in the morning, since levels drop during the day.
• Endocrine testing is also suggested for oligozoospermic patients, particularly, men with sperm concentrations below 10 million/mL.85
• evaluate prolactin levels and aware be of assay discrepancies, which result in false values.

Men and Assemia

• Azoospermia is defined as absence of sperm in the ejaculate.
• Azoospermia is distinguished from aspermia (absence of antegrade ejaculate; dry ejaculate) and RE (where semen with sperm are released into the prostatic urethra but travel backward (retrograde) into the bladder).
• A low volume, acidic pH, azoospermic ejaculate can be indicative of obstruction in the genital tract.92. In patients with high sperm DNA fragmentation, consider the use surgically with ICSI.
• CFTR is located at the q31.2 locus of chromosome 7 and encodes a cyclic adenosine monophosphate (cAMP) dependent chloride channel.
• CF is inherited in an autosomal recessive manner meaning that one defective allele must be inherited from each parent for a child to be affected.
• The goal of genetic testing for a CFTR mutation is to help identify the etiology of infertility as well as provide counseling on potential offspring transmission.
• In a meta-analysis, pooled data from 13 studies suggest that male partners of women with a history of RPL have a significantly higher rate of sperm DNA fragmentation compared to the partners of fertile control women: mean difference 11.91, 95% CI 4.97 to 18.86.132

Imaging with Ultrasound:

• Transrectal ultrasonography (TRUS) is not be performed as part of the initial evaluation unless SA suggests ejaculatory duct obstruction (EDO).

Treatment Varicocele Repair and Outcomes:

• Past AUA and ASRM recommendations for non-palpable varicoceles in men with concern for fertility has been to not recommend varicocelectomy, and recent studies continue to support this recommendation.
• Case series of men with NOA and clinical varicoceles have been reported.
• up to 35% of men with NOA will have sperm detected on subsequent SA without medical intervention, such case series must be interpreted with caution.159\
• In Micro-TESE surgical procedure and Testosterone levels: Conventional TESE has been associated with decreased postoperative testosterone levels, and many men with NOA have baseline testosterone deficiency levels.

Ejaculation

• For men with aspermia, surgical sperm extraction or induced ejaculation (sympathomimetics, vibratory stimulation or electroejaculation) may be performed depending on the patient’s condition and clinician’s experience.
• Surgical sperm retrieval will require the use of ART/ICSI to achieve a pregnancy.

Hypogonadotropic Hypogonadism

• Patients with HH present with deficient LH and FSH secretion.

Medical Androgenic Treatments

• AIs, hCG, and SERMs act by different mechanisms to increase endogenous testosterone production. Each agent may be used separately or in combination in an effort to increase serum testosterone concentrations without impairing spermatogenesis.
• The time course of recovery may be prolonged and can be months or rarely years for recovery sperm to in ejuaculate.
• Dopamine agonists are the first-line treatment for patients with pituitary prolactinomas.
• Clomiphene or tamoxifen are often prescribed in infertile men who have normal serum testosterone levels with the therapeutic aim of improving semen parameters and fertility outcomes. One meta-analysis reviewed 11 studies that compared either clomiphene or tamoxifen with either placebo or no treatment in men with oligozoospermia or asthenoteratospermia. Collectively, the findings suggested that SERMs may improve sperm concentration, sperm motility, and spontaneous pregnancy rate.
• Overall, sperm concentrations and pregnancy rates, both unassisted and via ART, appeared to improve in the FSH-treated men.

Conclusion

• The genomic revolution has placed us at the forefront of vastly improving our diagnostic abilities to define precise etiologies, co-morbidities, and eventually (perhaps) develop medically-based treatments for infertile men to improve not only their fertility potential, but also their overall health.