The male infertility evaluation still matters in the era of high efficacy assisted reproductive technology

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 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. 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 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. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34973 DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34973 Infertility is defined as a couple’s inability to conceive after 12 months of regular, unprotected sexual intercourse (1WHOWorld Health Organization. WHO laboratory manual for the examination and processing of human semen. 6th ed. World Health Organization, Department of Reproductive Health and Research. Geneva, Switzerland. WHO Press 2021.https://www.who.int/publications/i/item/9789240030787Date accessed: January 31, 2022Google Scholar). Current estimates place the global burden of infertility at 48 million couples (2Boivin J. Bunting L. Collins J.A. Nygren K.G. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care.Hum Reprod. 2007; 22: 1506-1512Crossref PubMed Scopus (1375) Google Scholar). 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 (3Patel A.S. Leong J.Y. Ramasamy R. Prediction of male infertility by the World Health Organization laboratory manual for assessment of semen analysis: a systematic review.Arab J Urol. 2018; 16: 96-102Crossref PubMed Scopus (45) Google Scholar). 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 (4Eisenberg M.L. Lathi R.B. Baker V.L. Westphal L.M. Milki A.A. Nangia A.K. Frequency of the male infertility evaluation: data from the national survey of family growth.J Urol. 2013; 189: 1030-1034Crossref PubMed Scopus (61) Google Scholar). Evaluation of the male often is neglected because women are the usual drivers of care-seeking for fertility treatment (5Culley L. Hudson N. Lohan M. Where are all the men? The marginalization of men in social scientific research on infertility.Reprod Biomed Online. 2013; 27: 225-235Abstract Full Text Full Text PDF PubMed Google Scholar). 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 (6Turner K.A. Rambhatla A. Schon S. Agarwal A. Krawetz S.A. Dupree J.M. et al.Male infertility is a women’s health issue—research and clinical evaluation of male infertility is needed.Cells. 2020; 9: 990Crossref Scopus (0) Google Scholar, 7Aitken R.J. Not every sperm is sacred; a perspective on male infertility.Mol Hum Reprod. 2018; 24: 287-298PubMed Google Scholar). 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 (8Kolettis P.N. Sabanegh E.S. Significant medical pathology discovered during a male infertility evaluation.J Urol. 2001; 166: 178-180Crossref PubMed Google Scholar). 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 (9Schlegel P.N. Sigman M. Collura B. de Jonge C.J. Eisenberg M.L. Lamb D.J. et al.Diagnosis and treatment of infertility in men: AUA/ASRM Guideline Part I.J Urol. 2021; 205: 36-43Crossref PubMed Scopus (31) Google Scholar). Per guidelines, men with ≥1 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 poses a significant burden. Thus, having return of sperm to the ejaculate or increasing 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 (10Asanad K. Jarvi K. Laj-kosz K. Smith J. Lau S. Lo K.C. et al.Total motile sperm count is associated with icsi success using sperm obtained by TESE.Fertil Steril. 2021; 116: e24Abstract Full Text Full Text PDF Google Scholar). Historic and modern cost-benefit analyses show that male infertility interventions can reduce the cost per conception (11Penson D. Paltiel A. Krumholz H.M. Palter S. The cost-effectiveness of treatment for varicocele related infertility.J Urol. 2002; 168: 2490-2494Crossref PubMed Google Scholar, 12Dubin J.M. Greer A.B. Kohn T.P. Masterson T.A. Ji L. Ramasamy R. Men with severe oligospermia appear to benefit from varicocele repair: a cost-effectiveness analysis of assisted reproductive technology.Urology. 2018; 111: 99-103Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 13Schlegel P.N. Is assisted reproduction the optimal treatment for varicocele-associated male infertility? a cost-effectiveness analysis.Urology. 1997; 49: 83-90Abstract Full Text PDF PubMed Scopus (150) Google Scholar, 14Meng M.V. Greene K.L. Turek P.J. Surgery or assisted reproduction? A decision analysis of treatment costs in male infertility.J Urol. 2005; 174: 1926-1931Crossref PubMed Scopus (102) Google Scholar). Assisted reproductive technology in many ways has revolutionized the field and allowed for 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. A thorough history and physical examination of the male partner is the first step to assess risk factors that could contribute to reduced fertility (See Table 1 [15Jarow J. Sigman M. Kolettis P.N. Lipshultz L.R. Mcclure R.D. Nangia A.K. et al.The optimal evaluation of the infertile male: AUA Best Practice Statement. Baltimore, MD: American Urological Association Education and Research, Inc., 2010.https://www.auanet.org/documents/education/clinical-guidance/Male-Infertility-d.pdfGoogle Scholar, 16Chow V. Cheung A.P. Male infertility.J Reprod Med. 2006; 51: 149-156PubMed Google Scholar]). Reproductive history should include a thorough assessment of prior paternity, sexual history, medical, and surgical history, gonadotoxic exposures, and family history (17Agarwal A. Baskaran S. Parekh N. Cho C.L. Henkel R. Vij S. et al.Male infertility.Lancet. 2021; 397: 319-333Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Manual of men’s health: primary care guidelines for APRNs & PAs - Google Books [Internet]. [cited 2022 Feb 21].https://books.google.com/books?hl=en&lr=&id=RqRWDwAAQBAJ&oi=fnd&pg=PA349&dq=cultural+thoughts+on+masturbation+infertility+evaluation&ots=pPfyYxMhCU&sig=fgH3_OUsX8sKtSUzC1UQnswTXMk#v=onepage&q=cultural%20thoughts%20on%20masturbation%20infertility%20evaluation&f=falseGoogle Scholar).Table 1Male history and physical for the reproductive endocrinology and infertility providerHistoryPhysical examInfertility historyGeneral-Duration of infertility, attempts at conception-Body habitus-overweight/obesity-Previous pregnancies/births, patient, and partner-Hair pattern/virilization/androgen status-Previous fertility investigation and treatment, prior ARTSexual historyAbdominal Exam-Decreased libido or ED (possible Testosterone deficiency)-Prior abdominal/pelvic surgical scars-Ejaculatory dysfunction – premature vs. anejaculationMedical historyPhallus-Cryptorchidism, history of testicular torsion/trauma-Meatal location (hypospadias/epispadias), or phimosis-Timing of puberty-Penile plaque and/or curvature (Peyronie’s disease)-Diabetes-Penile lesions/ulcers/discharge-Neurological conditions, spinal cord injury-Infections (urinary infections, epididymitis, or prostatitis, mumps orchitis, recent febrile illness)Scrotum/TestesSurgical history-Prior scars suggesting prior scrotal surgery/trauma-Orchiopexy/herniorrhaphy (Iatrogenic obstruction)-Testicular size/consistency (masses)-Retroperitoneal or pelvic surgery (anejaculation)-Epididymides: fullness or spermatocele (obstruction), atrophy (CFTR)-Vasectomy, or other scrotal surgery-Vas deferens: agenesis (CBAVD v CUAVD)-Bladder or prostate surgery (Retrograde ejaculation)The presence/location of any vasectomy defect or granuloma should also be assessedGonadotoxin exposures-Medications (endocrine modulators, antihypertensives, antibiotics, antipsychotics)Digital rectal exam-Environmental (pesticides, heavy metals)-Midline prostatic cysts (EDO)-Chemotherapy or radiotherapy-Dilated seminal vesicles (EDO)Family history-Bogginess/pain (prostatitis)-Infertility-Cystic fibrosisAdapted from the from the 2021 AUA Guidelines, and Chow and Cheung 2006 (15Jarow J. Sigman M. Kolettis P.N. Lipshultz L.R. Mcclure R.D. Nangia A.K. et al.The optimal evaluation of the infertile male: AUA Best Practice Statement. Baltimore, MD: American Urological Association Education and Research, Inc., 2010.https://www.auanet.org/documents/education/clinical-guidance/Male-Infertility-d.pdfGoogle Scholar,16Chow V. Cheung A.P. Male infertility.J Reprod Med. 2006; 51: 149-156PubMed Google Scholar).-Androgen receptor deficiencyLifestyle/social history (tobacco, vaping, recreational drugs, anabolic steroids)CBAVD = congenital bilateral absence of the vas deferens; CFTR = cystic fibrosis transmembrane conductance regulator; ED= erectile dysfunction; EDO= Ejaculatory duct obstruction Open table in a new tab CBAVD = congenital bilateral absence of the vas deferens; CFTR = cystic fibrosis transmembrane conductance regulator; ED= erectile dysfunction; EDO= Ejaculatory duct obstruction This initial evaluation may be the first instance in which libido and erectile function are discussed with the patient. Furthermore, this may be a unique opportunity to assess the patient’s psychosocial, interpersonal, and emotional health. An infertility diagnosis itself can engender shame, guilt, anger and sadness, and feeling of loss of control in men (19Holley S.R. Pasch L.A. Bleil M.E. Gregorich S. Katz P.K. Adler N.E. Prevalence and predictors of major depressive disorder for fertility treatment patients and their partners.Fertil Steril. 2015; 103: 1332-1339Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). When relevant, a referral to sex/relationship therapy is encouraged. Some often overlooked challenges include cultural perceptions on masturbation, or psychogenic erectile dysfunction, secondary to the stress of an infertility diagnosis, which have been shown to be an impediment to male fertility evaluation(19Holley S.R. Pasch L.A. Bleil M.E. Gregorich S. Katz P.K. Adler N.E. Prevalence and predictors of major depressive disorder for fertility treatment patients and their partners.Fertil Steril. 2015; 103: 1332-1339Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 20Pottinger A.M. Carroll K. Mason G. Male attitude towards masturbating: an impediment to infertility evaluation and sperm parameters.Andrologia. 2016; 48: 774-778Crossref PubMed Scopus (7) Google Scholar). These and other unique challenges often are better dealt with via a licensed mental health professional (21Grill E, Perelman M.The role of sex therapy for male infertility. (2013). Available from: https://www.researchgate.net/publication/258847688_The_role_of_sex_therapy_for_male_infertility. Accessed May 23, 2002.Google Scholar). If any questions or abnormalities are discovered on REI evaluation, referral to urology is appropriate, where time and attention can be paid to fully elucidate the male partner's barriers to conception. A comprehensive male genitourinary examination is the cornerstone of the physical exam, and should include examination of the penis, size and consistency of the testes, presence of vas deferens and epididymides, presence of a varicocele (see below), and digital rectal examination (See Table 1). In experienced hands, varicoceles are palpated, midline cystic structures are identified on digital rectal examination, and in rare cases hypospadias is identified that can hyroid cancer, leukemia and near the cervix (17Agarwal A. Baskaran S. Parekh N. Cho C.L. Henkel R. Vij S. et al.Male infertility.Lancet. 2021; 397: 319-333Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 22Cheng G. Liu B. Song Z. Xu A. Song N. Wang Z. A novel surgical management for male infertility secondary to midline prostatic cyst.BMC Urol. 2015; 15: 18Crossref PubMed Scopus (9) Google Scholar). Varicoceles are common in the general population, and roughly 40% of male patients seeking infertility care present with a varicocele (23Naughton C.K. Nangia A.K. Agarwal A. Varicocele and male infertility: part II: pathophysiology of varicoceles in male infertility.Hum Reprod Update. 2001; 7: 473-481Crossref PubMed Scopus (0) Google Scholar). Examination should be performed with and without Valsalva maneuver, as the earliest stages of varicocele can be detected only with the aid of the increased abdominal pressure that this provides (24Stahl P. Schlegel P.N. Standardization and documentation of varicocele evaluation.Curr Opin Urol. 2011; 21: 500-505Crossref PubMed Scopus (25) Google Scholar). In the case of an equivocal examination, a scrotal Doppler ultrasound with standing Valsalva can clarify the diagnosis. The relationship between varicoceles, oxidative stress, and its impact on spermatogenesis has been established (25Agarwal A. Makker K. Sharma R. Clinical relevance of oxidative stress in male factor infertility: an update.Am J Reprod Immunol. 2008; 59: 2-11Crossref PubMed Scopus (531) Google Scholar, 26Agarwal A. Sharma R.K. Desai N.R. Prabakaran S. Tavares A. Sabanegh E. Role of oxidative stress in pathogenesis of varicocele and infertility.Urology. 2009; 73: 461-469Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Surgical varicocelectomy should be considered in men attempting to conceive who have palpable varicocele, infertility, and abnormal semen parameters (9Schlegel P.N. Sigman M. Collura B. de Jonge C.J. Eisenberg M.L. Lamb D.J. et al.Diagnosis and treatment of infertility in men: AUA/ASRM Guideline Part I.J Urol. 2021; 205: 36-43Crossref PubMed Scopus (31) Google Scholar). The largest meta-analysis to date showed a pregnancy rate of 42% (95% confidence interval [CI], 26%–61%) with microsurgical varicocelectomy compared with 17% without treatment (27Wang J. Xia S. Liu Z. Tao L. Ge J. Xu C. et al.Inguinal and subinguinal micro-varicocelectomy, the optimal surgical management of varicocele: a meta-analysis.Asian J Androl. 2015; 17: 74-80Crossref PubMed Scopus (42) Google Scholar). A recent Cochrane review in 2021 identified similar results and concluded that treatment of varicoceles improved pregnancy rates compared with delayed or no treatment (28Persad E. O’Loughlin C.A.A. Kaur S. Wagner G. Matyas N. Hassler-Di Fratta M.R. et al.Surgical or radiological treatment for varicoceles in subfertile men.Cochrane Database of Syst Rev. 2021; 2021CD00479PubMed Google Scholar). Although somewhat controversial, the significant benefit of varicocelectomy may even extend to men with nonobstructive azoospermia. In one meta-analysis of azoospermic patients with varicoceles, Esteves et al. (29Esteves S.C. Miyaoka R. Roque M. Agarwal A. Outcome of varicocele repair in men with nonobstructive azoospermia: systematic review and meta-analysis.Asian J Androl. 2016; 18: 246-253Crossref PubMed Scopus (67) Google Scholar). found that varicocelectomy led to return of sperm to the ejaculate in 43.9% of patients and was associated with a 13.6% natural spontaneous pregnancy rate. A meta-analysis by Coward (30Coward R.M. Evolving role of varicocele repair in the era of assisted reproduction.Fertil Steril. 2017; 108: 596-597Abstract Full Text Full Text PDF PubMed Google Scholar) and Kirby et al. (31Kirby E.W. Wiener L.E. Rajanahally S. Crowell K. Coward R.M. 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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 (1WHOWorld Health Organization. WHO laboratory manual for the examination and processing of human semen. 6th ed. World Health Organization, Department of Reproductive Health and Research. Geneva, Switzerland. WHO Press 2021.https://www.who.int/publications/i/item/9789240030787Date accessed: January 31, 2022Google Scholar), 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 (36Cooper T.G. 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