advertisement

Home Guidelines Guidelines Clinical Guidelines Male Infertility

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

Unabridged version of this Guideline [pdf]
Algorithm associated with this Guideline [pdf]

Panel Members

Peter N. Schlegel, MD; Mark Sigman, MD; Barbara Collura; Christopher J. De Jonge, PhD, HCLD(ABB); Michael L. Eisenberg, MD; Dolores J. Lamb, PhD, HCLD (ABB); John P. Mulhall, MD; Craig Niederberger MD, FACS; Jay I. Sandlow, MD; Rebecca Z. Sokol, MD, MPH; Steven D. Spandorfer, MD; Cigdem Tanrikut, MD, FACS; Jonathan R. Treadwell, PhD; Jeffrey T. Oristaglio, PhD; Armand Zini, MD

Executive Summary

Purpose

Failure to conceive within 12 months of attempted conception is due in whole or in part to the male in approximately one-half of all infertile couples. Although many couples can achieve a pregnancy with assisted reproductive technologies (ART), evaluation of the male is important to most appropriately direct therapy. Some male factor conditions are treatable with medical or surgical therapy, and others may only be managed with donor sperm or adoption. Some conditions are life threatening, while others have health and genetic implications for the patient and potential offspring. Without a male evaluation it is not possible to adequately design management of the patient and the couple.

The purpose of this guideline is to outline the appropriate evaluation and management of the male in an infertile couple. Recommendations proceed from obtaining an appropriate history and physical exam (Appendix I), as well as diagnostic testing, where indicated. Medical therapies, surgical techniques, and use of intrauterine insemination (IUI)/in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) are covered to allow for optimal patient management. Recommendations are based on a strict process of evaluation of published literature as discussed in the Methodology section. This process is based on the PICO question approach (Problem/Patient/Population, Intervention/Indicator, Comparison, and Outcome) as described in the Methodology section. In this guideline, the term “male” or “men” is used to refer to biological or genetic men.

Methodology

The Emergency Care Research Institute (ECRI) Evidence-based Practice Center team searched PubMed®, Embase®, and Medline from January, 2000 through May, 2019. An experienced medical librarian developed an individual search strategy for each individual key question using medical subject headings terms and key words appropriate for each question’s PICO framework. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions.

Guideline Statements

Assessment

1. For initial infertility evaluation, both male and female partners should undergo concurrent assessment. (Expert Opinion)

2. Initial evaluation of the male for fertility should include a reproductive history. (Clinical Principle) Initial evaluation of the male should also include one or more semen analyses (SAs). (Strong Recommendation; Evidence Level: Grade B)

3. Men with one or more abnormal semen parameters or presumed male infertility should be evaluated by a male reproductive expert for complete history and physical examination as well as other directed tests when indicated. (Expert Opinion)

4. In couples with failed ART cycles or recurrent pregnancy losses (RPL) (two or more losses), evaluation of the male should be considered. (Expert Opinion)

Lifestyle Factors and Relationships Between Infertility and General Health

5. Clinicians should counsel infertile men or men with abnormal semen parameters of the health risks associated with abnormal sperm production. (Moderate Recommendation; Evidence Level: Grade B)

6. Infertile men with specific, identifiable causes of male infertility should be informed of relevant, associated health conditions. (Moderate Recommendation; Evidence Level: Grade B)

7. Clinicians should advise couples with advanced paternal age (≥40) that there is an increased risk of adverse health outcomes for their offspring. (Expert Opinion)

8. Clinicians may discuss risk factors (i.e., lifestyle, medication usage, environmental exposures) associated with male infertility, and patients should be counseled that the current data on the majority of risk factors are limited. (Conditional Recommendation; Evidence Level: Grade C)

Diagnosis/Assessment/Evaluation

9. The results from the SA should be used to guide management of the patient. In general, results are of greatest clinical significance when multiple abnormalities are present. (Expert Opinion)

10. Clinicians should obtain hormonal evaluation including follicle-stimulating hormone (FSH) and testosterone for infertile men with impaired libido, erectile dysfunction, oligozoospermia or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical evaluation. (Expert Opinion)

11. 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)

12. 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 or a presumed diagnosis of impaired sperm production as the cause of azoospermia. (Expert Opinion)

13. Clinicians should recommend Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele) in men with vasal agenesis or idiopathic obstructive azoospermia. (Expert Opinion)

14. For men who harbor a CFTR mutation, genetic evaluation of the female partner should be recommended. (Expert Opinion)

15. Sperm DNA fragmentation analysis is not recommended in the initial evaluation of the infertile couple. (Moderate Recommendation; Evidence Level: Grade C)

16. Men with increased round cells on SA (>1million/mL) should be evaluated further to differentiate white blood cells (pyospermia) from germ cells. (Expert Opinion)

17. Patients with pyospermia should be evaluated for the presence of infection. (Clinical Principle)

18. Antisperm antibody (ASA) testing should not be done in the initial evaluation of male infertility. (Expert Opinion)

19. For couples with RPL, men should be evaluated with karyotype (Expert Opinion) and sperm DNA fragmentation. (Moderate Recommendation; Evidence Level: Grade C)

20. Diagnostic testicular biopsy should not routinely be performed to differentiate between obstructive azoospermia and non-obstructive azoospermia (NOA). (Expert Opinion)

Imaging

21. Scrotal ultrasound should not be routinely performed in the initial evaluation of the infertile male. (Expert Opinion)

22. Transrectal ultrasonography (TRUS) should not be performed as part of the initial evaluation. Clinicians should recommend TRUS in men with SA suggestive of ejaculatory duct obstruction (EDO) (i.e., acidic, azoospermic, semen volume <1.5mL, with normal serum T, palpable vas deferens). (Expert Opinion)

23. Clinicians should not routinely perform abdominal imaging for the sole indication of an isolated small or moderate right varicocele. (Expert Opinion)

24. Clinicians should recommend renal ultrasonography for patients with vasal agenesis to evaluate for renal abnormalities. (Expert Opinion)

Treatment

Varicocele Repair/Varicocelectomy

25. Surgical varicocelectomy should be considered in men attempting to conceive who have palpable varicocele(s), infertility, and abnormal semen parameters, except for azoospermic men. (Moderate Recommendation; Evidence Level: Grade B)

26. Clinicians should not recommend varicocelectomy for men with non-palpable varicoceles detected solely by imaging. (Strong Recommendation; Evidence Level: Grade C)

27. 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)

Sperm Retrieval

28. For men with NOA undergoing sperm retrieval, microdissection testicular sperm extraction (TESE) should be performed. (Moderate Recommendation; Evidence Level: Grade C)

29. In men undergoing surgical sperm retrieval, either fresh or cryopreserved sperm may be used for ICSI. (Moderate Recommendation; Evidence Level: Grade C)

30. 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)

31. 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. (Expert Opinion)

32. Infertility associated with retrograde ejaculation (RE) may be treated with sympathomimetics and alkalinization of urine with or without urethral catheterization, induced ejaculation, or surgical sperm retrieval. (Expert Opinion)

Obstructive Azoospermia, Including Post-Vasectomy Infertility

33. 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)

34. Clinicians should counsel men with vasal or epididymal obstructive azoospermia that microsurgical reconstruction may be successful in returning sperm to the ejaculate. (Expert Opinion)

35. For infertile men with azoospermia and EDO, the clinician may consider transurethral resection of ejaculatory ducts (TURED) or surgical sperm extraction. (Expert Opinion)

Medical & Nutraceutical Interventions for fertility

36. Male infertility may be managed with ART. (Expert Opinion)

37. 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)

38. The patient presenting with hypogonadotropic hypogonadism (HH) should be evaluated to determine the etiology of the disorder and treated based on diagnosis. (Clinical Principle)

39. 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)

40. For the male interested in current or future fertility, testosterone monotherapy should not be prescribed. (Clinical Principle)

41. The infertile male with hyperprolactinemia should be evaluated for the etiology and treated accordingly. (Expert Opinion)

42. Clinicians should inform the man with idiopathic infertility that the use of SERMs has limited benefits relative to results of ART. (Expert Opinion)

43. Clinicians should counsel patients that the benefits of supplements (e.g., antioxidants, vitamins) are of questionable clinical utility in treating male infertility. Existing data are inadequate to provide recommendation for specific agents to use for this purpose. (Conditional Recommendation; Evidence Level: Grade B)

44. 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)

Gonadotoxic Therapies and Fertility Preservation

46. 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)

47. 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)

48. 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)

49. 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)

50. Clinicians should inform patients undergoing a retroperitoneal lymph node dissection (RPLND) of the risk of aspermia. (Clinical Principle)

51. Clinicians should obtain a post-orgasmic urinalysis for men with aspermia after RPLND who are interested in fertility. (Clinical Principle)

52. 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

The Diagnosis and Treatment of the Male Factor Couple

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 Despite these estimates, the true prevalence of male infertility is not clearly defined due to multiple factors including variations in definitions of infertility, differences in sources of data, and the populations studied. 2 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. This document offers guidance for the optimal diagnostic evaluation and management of the male partner of an infertile couple.

Male infertility can be due to a variety of conditions. Some of these 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 In some instances, patients with normal SAs have sperm that do not function in a manner necessary for fertility.

The overall goal of the male evaluation is to identify conditions that may affect management or health of the patient or their offspring. Identification and treatment of reversible conditions may improve the male’s fertility and allow for conception through intercourse or through techniques, such as IUI or IVF, when those approaches would otherwise not be possible. Even azoospermic patients may have some degree of active sperm production within the testes or could have sperm production induced with treatment. Identification of conditions for which there is no treatment will spare couples the distress of attempting ineffective therapies and allow them to consider options, such as donor sperm or adoption, if appropriate. Male infertility is associated with other comorbidities including increased mortality, while advanced paternal age is associated with some adverse outcomes in offspring. In addition, male infertility may occasionally be the presenting manifestation of an underlying life-threatening condition. 4 Failure to identify diseases such as testicular cancer or pituitary tumors may have serious consequences, including, in rare cases, death. Detection of certain genetic causes of male infertility allows couples to be informed about the potential to transmit genetic abnormalities that may affect the health of offspring and seek genetic counseling when appropriate. Thus, an appropriate male evaluation may allow the couple to better understand the basis and implications of their infertility.

In summary, the specific goals of the evaluation of the infertile male are to identify the following:

  • potentially correctable conditions;
  • irreversible conditions that are amenable to ART using the sperm of the male partner;
  • irreversible conditions that are not amenable to the above, and for which donor insemination or adoption are possible options;
  • life- or health-threatening conditions that may underlie the infertility or associated medical comorbidities that require medical attention; and
  • genetic abnormalities or lifestyle and age factors that may affect the health of the male patient or of offspring particularly if ART are to be employed.

Definitions of Infertility and Treatment Success

A wide variety of professional and international health organizations have defined infertility in general and male infertility, specifically. Since the condition of infertility reflects the outcome of a couple’s attempt to achieve a pregnancy, the most common definition of infertility is “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.” 5 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. 6 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). Some conditions may be more common in primary or secondary infertility. Evaluation of men with secondary infertility should include a focus on conditions or exposures that have developed or occurred after initiation of the earlier pregnancy(ies).

Assessment of tests and treatments for the male 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.)" This definition was provided by the modified Consolidated Standards of Reporting Trials for Fertility, Improving the Reporting of Clinical Trials of Infertility Treatments. 7 However, due to the variety of confounding variables present in the female, it is difficult to control for many of the most important variables and still include sufficient male subjects in a clinical trial for pregnancy or birth to be a viable outcome measure.

To address this challenge, the majority of clinical trials addressing male fertility and infertility utilize surrogate outcome metrics, the most common being the SA. However, the high variability of SA parameters make them difficult to use in the determination of interventions for male reproduction. 5 Other outcome metrics with similar challenges include other types of sperm tests and ART outcomes such as fertilization, implantation, and miscarriage rates. All attempts to measure some aspect of sperm function lessens the confounder effect of a maternal outcome, yet all are also subject to their own limitations.

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. 12,13

The etiologic causes of fertility include both female and male factors. For women, these factors include ovulatory dysfunction, tubal factor, endometriosis, and uterine factors. For the woman, ovarian reserve is helpful in predicting her response to medications, but this is not an absolute predictor of fertility. 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. 6 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. 15-17 In general, for men, the common identified etiologic issues include karyotypic abnormalities and sperm DNA fragmentation.

Methodology

Panel Formation and Process

The Male Infertility Panel was created in 2017 by the American Urological Association Education and Research, Inc. (AUAER) and the American Society for Reproductive Medicine (ASRM). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chairs, who in turn appointed the additional panel members based on specific expertise in this area. The Panel included specialties from urology, andrology, endocrinology, and obstetrics & gynecology. There was also a patient advocate representative from RESOLVE: The National Infertility Association.

Search Strategy

The Emergency Care Research Institute (ECRI) Evidence-based Practice Center team searched PubMed®, Embase®, and Medline from January, 2000 through May, 2019. An experienced medical librarian developed an individual search strategy for each individual key question using medical subject headings terms and key words appropriate for each question’s PICO framework. Search strategies were reviewed by one of the project methodologists. The evidence review team also reviewed relevant systematic reviews and references provided by the Panel to identify articles that may have been missed by the database searches.

Study Selection and Data Abstraction

Study selection was based on predefined eligibility criteria for the patient populations, interventions, outcomes, and study designs of interest. Two reviewers independently screened abstracts and full text for inclusion. Conflicts between reviewers regarding eligibility of a given study were resolved through consensus.

Reviewers extracted information on study characteristics, participants, interventions, and outcomes. One reviewer completed data abstraction for each included study.

Assessment of Risk of Bias of Individual Studies

One reviewer independently assessed risk of bias (ROB) for individual studies. The Cochrane Collaboration’s tool was used for assessing the risk of bias of randomized controlled trials (RCTs). 18 For non-randomized studies of treatment interventions, the reviewers used appropriate items from the Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions (ACROBAT-NRSI). For diagnostic studies, reviewers used the quality assessment tool for diagnostic accuracy studies (QUADAS -2). 19 Single-arm studies were assessed by the following domains: prospective or retrospective design, consecutive/non-consecutive enrollment, incomplete outcome data, selective outcome reporting, and any other potential sources of bias. For systematic reviews, ROB was assigned based on the study authors’ quality assessment of the individual studies included in the review. If such an assessment was not provided, ECRI analysts assigned a ROB rating based on the author description of the selected literature base and the designs of the included studies. The evidence review team graded strength of evidence on outcomes by adapting the AUA’s three predefined levels of strength of evidence.

Determination of Evidence Strength

The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes not only the quality of individual studies but consideration of study design; consistency of findings across studies; adequacy of sample sizes; and generalizability of study populations, settings, and interventions for the purposes of the guideline. The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence has a high level of certainty, Grade B evidence has a moderate level of certainty, and Grade C evidence has a low level of certainty. 20

AUA Nomenclature: Linking Statement Type to Evidence Strength

The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk or burdens, and the Panel’s judgment regarding the balance between benefits and risks or burdens (Table 1). Strong Recommendations are directive statements that an action should (benefits outweigh risks or burdens) or should not (risks or burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks or burdens) or should not (risks or burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm or when the balance between benefits and risks or burdens is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. Conditional Recommendations also can be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks or burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risksor burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks orburdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinions with consensus achieved using a modified Delphi technique if differences of opinion emerged. A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence.

TABLE 1: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength
Evidence Strength A
(High Certainty)
Evidence Strength B
(Moderate Certainty)
Evidence Strength C
(Low Certainty)
Strong Recommendation
(Net benefit or harm substantial)
Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is substantial
Applies to most patients in most circumstances and future research unlikely to change confidence
Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is substantial
Applies to most patients in most circumstances but better evidence could change confidence
Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) appears substantial
Applies to most patients in most circumstances but better evidence is likely to change confidence
(rarely used to support a Strong Recommendation)
Moderate Recommendation
(Net benefit or harm moderate)
Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is moderate
Applies to most patients in most circumstances and future research is unlikely to change confidence
Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) is moderate
Applies to most patients in most circumstances but better evidence could change confidence
Benefits > Risks/Burdens (or vice versa)
Net benefit (or net harm) appears moderate
Applies to most patients in most circumstances but better evidence is likely to change confidence
Conditional Recommendation
(No apparent net benefit or harm)
Benefits = Risks/Burdens
Best action depends on individual patient circumstances
Future research unlikely to change confidence
Benefits = Risks/Burdens
Best action appears to depend on individual patient circumstances
Better evidence could change confidence
Balance between Benefits & Risks/Burdens unclear
Alternative strategies may be equally reasonable
Better evidence likely to change confidence
Clinical PrincipleA statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature
Expert OpinionA statement, achieved by consensus of the Panel, that is based on members clinical training, experience, knowledge, and judgment for which there is no evidence

Peer Review and Document Approval

An integral part of the guideline development process at the AUA is external peer review. The AUA conducted a thorough peer review process to ensure that the document was reviewed by experts in the diagnosis and treatment of male infertility. In addition to reviewers from the AUA PGC, Science and Quality Council (SQC), and Board of Directors (BOD), the document was reviewed by representatives from ASRM, as well as external content experts. Additionally, a call for reviewers was placed on the AUA website from January 8-15, 2020 to allow any further interested parties to request a copy of the document for review. The guideline was also sent to the Urology Care Foundation to open the document further to the patient perspective. The draft guideline document was distributed to 114 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 49 reviewers provided comments, including 24 external reviewers. At the end of the peer review process, a total of 997 comments were received. Following comment discussion, the Panel revised the draft as needed. Once finalized, the guideline was submitted for approval to the AUA PGC, SQC, and BOD for final approval. The document was also approved by the ASRM CEO Ricardo Azziz, MD, MPH, MBA, on behalf of the Board and advised by the Practice Committee.

Assessment

Guideline Statement 1

For initial infertility evaluation, both male and female partners should undergo concurrent assessment. (Expert Opinion)

Discussion


Guideline Statement 2

Initial evaluation of the male for fertility should include a reproductive history. (Clinical Principle) Initial evaluation of the male should also include one or more semen analyses (SAs). (Strong Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 3

Men with one or more abnormal semen parameters or presumed male infertility should be evaluated by a male reproductive expert for complete history and physical examination as well as other directed tests when indicated. (Expert Opinion)

Discussion


Guideline Statement 4

In couples with failed ART cycles or recurrent pregnancy losses (RPL) (two or more losses), evaluation of the male should be considered. (Expert Opinion)

Discussion


Lifestyle Factors and Relationships Between Infertility and General Health

Guideline Statement 5

Clinicians should counsel infertile men or men with abnormal semen parameters of the health risks associated with abnormal sperm production. (Moderate Recommendation; Evidence Level Grade: B)

Discussion


Guideline Statement 6

Infertile men with specific, identifiable causes of male infertility should be informed of relevant, associated health conditions (Moderate Recommendation; Evidence Level Grade: B)

Discussion


Guideline Statement 7

Clinicians should advise couples with advanced paternal age (≥40) that there is an increased risk of adverse health outcomes for their offspring. (Expert Opinion)

Discussion


Guideline Statement 8

Clinicians may discuss risk factors (i.e., lifestyle, medication usage, environmental exposures) associated with male infertility, and patients should be counseled that the current data on the majority of risk factors are limited. (Conditional Recommendation; Evidence Level Grade: C)

Discussion


Diagnosis and Evaluation

Guideline Statement 9

The results from the SA should be used to guide management of the patient. In general, results are of greatest clinical significance when multiple abnormalities are present. (Expert Opinion)

Discussion


Guideline Statement 10

Clinicians should obtain hormonal evaluation including follicle-stimulating hormone (FSH) and testosterone for infertile men with impaired libido, erectile dysfunction, oligozoospermia or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical evaluation. (Expert Opinion)

Discussion


Guideline Statement 11

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)

Discussion


Guideline Statement 12

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 or a presumed diagnosis of impaired sperm production as the cause of azoospermia. (Expert Opinion)

Discussion


Guideline Statement 13

Clinicians should recommend Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation carrier testing (including assessment of the 5T allele) in men with vasal agenesis or idiopathic obstructive azoospermia. (Expert Opinion)

Discussion


Guideline Statement 14

For men who harbor a CFTR mutation, genetic evaluation of the female partner should be recommended. (Expert Opinion)

Discussion


Guideline Statement 15

Sperm DNA fragmentation analysis is not recommended in the initial evaluation of the infertile couple. (Moderate Recommendation; Evidence Level Grade: C)

Discussion


Guideline Statement 16

Men with increased round cells on SA (>1million/mL) should be evaluated further to differentiate white blood cells (pyospermia) from germ cells. (Expert Opinion)

Discussion


Guideline Statement 17

Patients with pyospermia should be evaluated for the presence of infection. (Clinical Principle)

Discussion


Guideline Statement 18

Antisperm antibody (ASA) testing should not be done in the initial evaluation of male infertility. (Expert Opinion)

Discussion


Guideline Statement 19

For couples with RPL, men should be evaluated with karyotype (Expert Opinion) and sperm DNA fragmentation. (Moderate Recommendation; Evidence Level Grade: C)

Discussion


Guideline Statement 20

Diagnostic testicular biopsy should not routinely be performed to differentiate between obstructive azoospermia and non-obstructive azoospermia (NOA). (Expert Opinion)

Discussion


Imaging

Guideline Statement 21

Scrotal ultrasound should not be routinely performed in the initial evaluation of the infertile male. (Expert Opinion)

Discussion


Guideline Statement 22

Transrectal ultrasonography (TRUS) should not be performed as part of the initial evaluation. Clinicians should recommend TRUS in men with SA suggestive of ejaculatory duct obstruction (EDO) (i.e., acidic, azoospermic, semen volume <1.5mL, with normal serum T, palpable vas deferens). (Expert Opinion)

Discussion


Guideline Statement 23

Clinicians should not routinely perform abdominal imaging for the sole indication of an isolated small or moderate right varicocele. (Expert Opinion)

Discussion


Guideline Statement 24

Clinicians should recommend renal ultrasonography for patients with vasal agenesis to evaluate for renal abnormalities. (Expert Opinion)

Discussion


Treatment

Varicocele Repair / Varicocelectomy

Guideline Statement 25

Surgical varicocelectomy should be considered in men attempting to conceive who have palpable varicocele(s), infertility, and abnormal semen parameters, except for azoospermic men. (Moderate Recommendation; Evidence Level Grade: B)

Discussion


Guideline Statement 26

Clinicians should not recommend varicocelectomy for men with non-palpable varicoceles detected solely by imaging. (Strong Recommendation; Evidence Level Grade: C)

Discussion


Guideline Statement 27

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)

Discussion


Sperm Retrieval

Guideline Statement 28

For men with NOA undergoing sperm retrieval, microdissection testicular sperm extraction (TESE) should be performed. (Moderate Recommendation; Evidence Level Grade: C)

Discussion


Guideline Statement 29

In men undergoing surgical sperm retrieval, either fresh or cryopreserved sperm may be used for ICSI. (Moderate Recommendation; Evidence Level Grade: C)

Discussion


Guideline Statement 30

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)

Discussion


Guideline Statement 31

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. (Expert Opinion)

Discussion


Guideline Statement 32

Infertility associated with retrograde ejaculation (RE) may be treated with sympathomimetics and alkalinization of urine with or without urethral catheterization, induced ejaculation, or surgical sperm retrieval. (Expert Opinion)

Discussion


Obstructive Azoospermia, Including Post-Vasectomy Infertility

Guideline Statement 33

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)

Discussion


Guideline Statement 34

Clinicians should counsel men with vasal or epididymal obstructive azoospermia that microsurgical reconstruction may be successful in returning sperm to the ejaculate. (Expert Opinion)

Discussion


Guideline Statement 35

For infertile men with azoospermia and EDO, the clinician may consider transurethral resection of ejaculatory ducts (TURED) or surgical sperm extraction. (Expert Opinion)

Discussion


Medical and Nutraceutical Interventions for Fertility

Guideline Statement 36

Male infertility may be managed with ART. (Expert Opinion)

Discussion


Guideline Statement 37

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)

Discussion


Guideline Statement 38

The patient presenting with hypogonadotropic hypogonadism (HH) should be evaluated to determine the etiology of the disorder and treated based on diagnosis. (Clinical Principle)

Discussion


Guideline Statement 39

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)

Discussion


Guideline Statement 40

For the male interested in current or future fertility, testosterone monotherapy should not be prescribed. (Clinical Principle)

Discussion


Guideline Statement 41

The infertile male with hyperprolactinemia should be evaluated for the etiology and treated accordingly. (Expert Opinion)

Discussion


Guideline Statement 42

Clinicians should inform the man with idiopathic infertility that the use of SERMs has limited benefits relative to results of ART. (Expert Opinion)

Discussion


Guideline Statement 43

Clinicians should counsel patients that the benefits of supplements (e.g., antioxidants, vitamins) are of questionable clinical utility in treating male infertility. Existing data are inadequate to provide recommendation for specific agents to use for this purpose. (Conditional Recommendation; Evidence Level Grade: B)

Discussion


Guideline Statement 44

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)

Discussion


Guideline Statement 45

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)

Discussion


Gonadotoxic Therapies and Fertility Preservation

Guideline Statement 46

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)

Discussion


Guideline Statement 47

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)

Discussion


Guideline Statement 48

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)

Discussion


Guideline Statement 49

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)

Discussion


Guideline Statement 50

Clinicians should inform patients undergoing a retroperitoneal lymph node dissection (RPLND) of the risk of aspermia. (Clinical Principle)

Discussion


Guideline Statement 51

Clinicians should obtain a post-orgasmic urinalysis for men with aspermia after RPLND who are interested in fertility. (Clinical Principle)

Discussion


Guideline Statement 52

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)

Discussion


Future Directions

Newer research techniques, such as next generation sequencing (whole exome and whole genome sequencing) and “-omic” technologies have been applied to better identify underlying defects that may explain infertility in men. As the mechanisms of action of these genetic, genomic, epigenetic, transcriptomic, proteomic, metabolomic defects are defined, we will have further defined the etiologies of the majority of causes of male infertility. For example, damaging mutations and copy number variants (microdeletions and microduplications) may affect reproductive system development304-308 and function309-311, as well as fetal, childhood, adolescent and/or adult development and/or function of other organ systems in the body. Indeed, GeneCards312 lists >3,600 gene defects associated with human male infertility and another 3,200+ genes associated with genitourinary birth defects causing abnormal male reproductive development and function. This knowledge will improve clinical diagnosis and treatment.

The potential impact of these genetic findings is in the area of genetic and genomic-based spermiogenesis defects causing teratozoospermia and/or asthenozoospermia (multiple abnormalities of the sperm flagella and primary ciliary dyskinesia). Today, this knowledge is used clinically to counsel patients about their chances for successful ART.313,314 As many of these “infertility” genes are expressed in select other tissues or even broadly throughout the body, infertility may be the “canary in the coal mine” that portends an increased likelihood of other comorbidities. Given the wide range of types of genes required for fertility,315-317 it is not surprising that male infertility is associated with other health conditions, such as mortality, malignancies, immune dysfunction, and other non-reproductive disorders.

Therapeutic advances for male infertility (except for surgical approaches for obstructive azoospermia and NOA) remain relatively stagnant. However, in the laboratory, novel methods are under development to effectively use spermatogonial stem cells to rejuvenate spermatogenesis after gonadotoxin exposures (such as chemotherapy),318 although potential contamination of spermatogonial stem cells with malignant cells, which must be eliminated before autotransplantation, remain a concern.

Approaches using organ cultures and in vitro systems for spermatogenesis offer additional promise for the treatment of some forms of spermatogenic failure. Qualitative but not quantitative spermatogenesis has been achieved in vitro culminating in live offspring in rodents. With knowledge of the delicate microenvironment needed for completion of spermatogenesis in vitro, researchers are moving closer to achieving this goal, while still maintaining the genetic, genomic, and epigenomic integrity of the sperm.319

Finally, gene therapy approaches targeting the process of spermatogenesis are advantageous because of the continuous production of sperm throughout the adult lifespan. However, whether germline gene therapy in humans should occur is an ethical question. Questions about whether germline genome editing should be done even for genetic disorders and technical considerations remain problematic.320 Genome editing can result in off-target effects and mosaicism.

In closing, 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. Translation of the newer advances discussed above will be slower, but will eventually move from the laboratory to the clinical arena to provide more therapeutic options for men. The future looks promising for improving the health and fertility of the infertile male through precision medicine and the application of advanced technologies.

Appendices

Appendix I: Male reproductive health physical examination

The goal of the physical examination is to identify potential etiologies of reproductive impairments, health ailments, or factors that can be optimized to improve health or reproductive success.

General
  • Body habitus as overweight obesity is associated with impaired spermatogenesis.
  • Virilization to assess pubertal development/androgen status
  • Gynecomastia may be a marker for endocrine disorders
Abdominal exam
  • Examination of any scars from prior surgical procedures that may involve the pelvis or impact the urogenital system.
Phallus
  • Meatal location as hypospadias/epispadias may make semen deposition in the vagina challenging
  • Penile plaque as Peyronie’s disease may make vaginal intercourse difficult
  • Penile lesions/ulcers/discharge may be a sign of sexually transmitted infection
Scrotum/Testes
  • Examination for prior scars suggesting prior scrotal surgery/trauma
  • Location as scrotal position of the testes is important for normal function
  • Size/consistency/contours as a majority of the testis is devoted to spermatogenesis. The exam may also reveal masses consistent with a testicular cancer
Epididymides
  • Shape/consistency as normal development should be identified to determine atresia that could be identified by the presence of a CFTR mutation. Induration/dilation could suggest obstruction. Epididymal cysts or spermatoceles may also lead to obstruction.
Vas Deferens
  • Shape/consistency as normal development and contour should be confirmed to rule out agenesis as may be seen in the presence of a CFTR mutation or aberrant Wolffian duct embryogenesis
  • The presence/location of any vasectomy defect or granuloma should also be assessed
Digital Rectal Examination
  • Midline prostatic cysts or dilated seminal vesicles may assist in the diagnosis of EDO

Abbreviations

Adriamycin, Bleomycin, Vinblastine, and DacarbazineABVD
American College of Obstetricians and GynecologistsACOG
American Medical AssociationAMA
American Society of Clinical OncologyASCO
American Society for Reproductive MedicineASRM
American Urological AssociationAUA
American Urological Association Education and Research, Inc.AUAER
Antisperm AntibodyASA
Aromatase InhibitorsAIs
Assisted Reproductive TechnologiesART
Azoospermia FactorAZF
Board of DirectorsBOD
Bisphenol ABPA
Cardiovascular DiseaseCVD
Charlson Comorbidity IndexCCI
Congenital Bilateral Absence of the Vas DeferensCBAVD
Cystic FibrosisCF
Cystic Fibrosis Transmembrane Conductance RegulatorCFTR
Di-2-ethylhexyl phthalateDEHP
Ejaculatory Duct ObstructionEDO
Emergency Care Research InstituteECRI
Failure of EmissionFOE
Follicle-Stimulating HormoneFSH
Human Chorionic GonadotropinhCG
Hypogonadotropic HypogonadismHH
ImmunobeadIB
In Vitro FertilizationIVF
Intracytoplasmic Sperm InjectionICSI
Intrauterine InseminationIUI
Lower Reference LimitsLRL
Luteinizing HormoneLH
Microdissection-Testicular Sperm Extractionmicro-TESE
Non‐Obstructive AzoospermiaNOA
Odds RatioOR
Practice Guidelines CommitteePGC
Randomized Controlled TrialsRCTs
Recurrent Pregnancy LossRPL
Relative RiskRR
Retrograde EjaculationRE
Retroperitoneal Lymph Node DissectionRPLND
Risk of BiasROB
Science and Quality CouncilSQC
Selective Estrogen Receptor ModulatorsSERMs
Semen AnalysisSA
Sperm Retrieval RatesSRR
TelomereTL
Testicular Sperm ExtractionTESE
Transrectal UltrasonographyTRUS
Transurethral Resection of Ejaculatory DuctsTURED
World Health OrganizationWHO

References

  1. Thonneau P, Marchand S, Tallec A et al: Incidence and main causes of infertility in a resident population (1,850,000) of three french regions (1988-1989). Hum Reprod 1991; 6: 811.
  2. Barratt CLR, Björndahl L, De Jonge CJ et al: The diagnosis of male infertility: An analysis of the evidence to support the development of global who guidance-challenges and future research opportunities. Hum Reprod Update 2017; 23: 660.
  3. Sigman M, Lipshultz LI and SS H: Office evaluation of the subfertile male, 4 ed. New York: Cambridge University Press, p. 176, 2009
  4. Honig SC, Lipshultz LI and Jarow J: Significant medical pathology uncovered by a comprehensive male infertility evaluation. Fertil Steril 1994; 62: 1028.
  5. World Health Organization DoRHaR: Who laboratory manual for the examination and processing of human semen

5ed. Geneva, Switzerland: WHO Press, p. 287, 2010.

  1. Definitions of infertility and recurrent pregnancy loss: A committee opinion. Fertil Steril 2020; 113: 533.
  2. Improving the reporting of clinical trials of infertility treatments (imprint): Modifying the consort statement. Fertil Steril 2014; 102: 952.
  3. Infertility workup for the women's health specialist: Acog committee opinion summary, number 781. Obstet Gynecol 2019; 133: 1294.
  4. Optimizing natural fertility: A committee opinion. Fertil Steril 2017; 107: 52.
  5. Definitions of infertility and recurrent pregnancy loss: A committee opinion. Fertil Steril 2013; 99: 63.
  6. Jeve YB and Davies W: Evidence-based management of recurrent miscarriages. J Hum Reprod Sci 2014; 7: 159.
  7. Rowe T: Fertility and a woman's age. J Reprod Med 2006; 51: 157.
  8. Schwartz D and Mayaux MJ: Female fecundity as a function of age: Results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation cecos. N Engl J Med 1982; 306: 404.
  9. Kumar N and Singh AK: Trends of male factor infertility, an important cause of infertility: A review of literature. J Hum Reprod Sci 2015; 8: 191.
  10. Eimers JM, te Velde ER, Gerritse R et al: The prediction of the chance to conceive in subfertile couples. Fertil Steril 1994; 61: 44.
  11. Ramasamy R, Scovell JM, Kovac JR et al: Fluorescence in situ hybridization detects increased sperm aneuploidy in men with recurrent pregnancy loss. Fertil Steril 2015; 103: 906.
  12. World Health O: Who laboratory manual for the examination and processing of human semen, 5th ed ed. Geneva: World Health Organization, 2010
  13. Higgins J: Assessing quality of included studies in cochrane reviews. The Cochrane Collaboration Methods Groups Newsletter 2007; 11
  14. Whiting PF, Rutjes AW, Westwood ME et al: Quadas-2: A revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011; 155: 529.
  15. Faraday M, Hubbard H, Kosiak B et al: Staying at the cutting edge: A review and analysis of evidence reporting and grading; the recommendations of the american urological association. BJU Int 2009; 104: 294.
  16. Fertility problems: Assessment and treatment: National Institute for Health and Care Excellence (UK), p. 142, 2017
  17. Infertility workup for the women's health specialist: Acog committee opinion, number 781. Obstet Gynecol 2019; 133: e377.
  18. Optimizing natural fertility: A committee opinion. F&S 2017; 107: 52.
  19. Spandorfer SD, Chung PH, Kligman I et al: An analysis of the effect of age on implantation rates. J Assist Reprod Genet 2000; 17: 303.
  20. Dunson DB, Baird DD and Colombo B: Increased infertility with age in men and women. Obstet Gynecol 2004; 103: 51.
  21. Guzick DS, Overstreet JW, Factor-Litvak P et al: Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001; 345: 1388.
  22. The optimal evaluation of the infertile male: Aua best practice statement, 2010. Practice committee of the american society for reproductive medicine. Diagnostic evaluation of the infertile male: A committee opinion. Fertil Steril 2012; 98: 294.
  23. Cooper TG, Noonan E, von Eckardstein S et al: World health organization reference values for human semen characteristics. Hum Reprod Update 2010; 16: 231.
  24. Cayan S, Erdemir F, Ozbey I et al: Can varicocelectomy significantly change the way couples use assisted reproductive technologies? J Urol 2002; 167: 1749.
  25. Meng MV, Greene KL and Turek PJ: Surgery or assisted reproduction? A decision analysis of treatment costs in male infertility. J Urol 2005; 174: 1926.
  26. Schlegel PN: Is assisted reproduction the optimal treatment for varicocele-associated male infertility? A cost-effectiveness analysis. Urology 1997; 49: 83.
  27. Lee R, Li PS, Goldstein M et al: A decision analysis of treatments for obstructive azoospermia. Hum Reprod 2008; 23: 2043.
  28. Pavlovich CP and Schlegel PN: Fertility options after vasectomy: A cost-effectiveness analysis. Fertil Steril 1997; 67: 133.
  29. Kallen B, Finnstrom O, Lindam A et al: Cancer risk in children and young adults conceived by in vitro fertilization. Pediatrics 2010; 126: 270.
  30. Jensen TK, Jorgensen N, Asklund C et al: Fertility treatment and reproductive health of male offspring: A study of 1,925 young men from the general population. Am J Epidemiol 2007; 165: 583.
  31. Spector LG, Brown MB, Wantman E et al: Association of in vitro fertilization with childhood cancer in the united states. JAMA Pediatr 2019; 173: e190392.
  32. Kolettis PN and Sabanegh ES: Significant medical pathology discovered during a male infertility evaluation. J Urol 2001; 166: 178.
  33. Ventimiglia E, Capogrosso P, Boeri L et al: Infertility as a proxy of general male health: Results of a cross-sectional survey. Fertil Steril 2015; 104: 48.
  34. Eisenberg ML, Li S, Behr B et al: Relationship between semen production and medical comorbidity. Fertil Steril 2015; 103: 66.
  35. Bach PV, Patel N, Najari BB et al: Changes in practice patterns in male infertility cases in the united states: The trend toward subspecialization. Fertil Steril 2018; 110: 76.
  36. Salonia A, Matloob R, Gallina A et al: Are infertile men less healthy than fertile men? Results of a prospective case-control survey. Eur Urol 2009; 56: 1025.
  37. Oliva A and Multigner L: Chronic epididymitis and grade iii varicocele and their associations with semen characteristics in men consulting for couple infertility. Asian J Androl 2018; 20: 360.
  38. Cazzaniga W, Capogrosso P, Ventimiglia E et al: High blood pressure is a highly prevalent but unrecognised condition in primary infertile men: Results of a cross-sectional study. Eur Urol Focus 2020; 6: 178.
  39. Negri L, Benaglia R, Fiamengo B et al: Cancer risk in male factor-infertility. Placenta 2008; 29 Suppl B: 178.
  40. Hanson HA, Anderson RE, Aston KI et al: Subfertility increases risk of testicular cancer: Evidence from population-based semen samples. Fertil Steril 2016; 105: 322.
  41. Mancini M, Carmignani L, Gazzano G et al: High prevalence of testicular cancer in azoospermic men without spermatogenesis. Hum Reprod 2007; 22: 1042.
  42. Raman JD, Nobert CF and Goldstein M: Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol 2005; 174: 1819.
  43. Eisenberg ML, Betts P, Herder D et al: Increased risk of cancer among azoospermic men. Fertil Steril 2013; 100: 681.
  44. Glazer CH, Tøttenborg SS, Giwercman A et al: Male factor infertility and risk of multiple sclerosis: A register-based cohort study. Mult Scler 2018; 24: 1835.
  45. Glazer CH, Bonde JP, Giwercman A et al: Risk of diabetes according to male factor infertility: A register-based cohort study. Hum Reprod 2017; 32: 1474.
  46. Bezold G, Politch JA, Kiviat NB et al: Prevalence of sexually transmissible pathogens in semen from asymptomatic male infertility patients with and without leukocytospermia. Fertil Steril 2007; 87: 1087.
  47. Poppe K, Glinoer D, Tournaye H et al: Is systematic screening for thyroid disorders indicated in subfertile men? Eur J Endocrinol 2006; 154: 363.
  48. Glazer CH, Bonde JP, Eisenberg ML et al: Male infertility and risk of nonmalignant chronic diseases: A systematic review of the epidemiological evidence. Semin Reprod Med 2017; 35: 282.
  49. Al-Jebari Y, Elenkov A, Wirestrand E et al: Risk of prostate cancer for men fathering through assisted reproduction: Nationwide population based register study. Bmj 2019; 366: l5214.
  50. Wang NN, Dallas K, Li S et al: The association between varicocoeles and vascular disease: An analysis of u.S. Claims data. Andrology 2018; 6: 99.
  51. Treadwell JR and Oristaglio J: Aua guideline on male infertility evidence report. Edited by ECRI. Linthicum, MD, 2019
  52. Bojesen A, Stochholm K, Juul S et al: Socioeconomic trajectories affect mortality in klinefelter syndrome. J Clin Endocrinol Metab 2011; 96: 2098.
  53. Ishikawa T, Yamaguchi K, Kondo Y et al: Metabolic syndrome in men with klinefelter's syndrome. Urology 2008; 71: 1109.
  54. Pawlaczyk-Kamieńska T, Borysewicz-Lewicka M, Śniatała R et al: Dental and periodontal manifestations in patients with cystic fibrosis - a systematic review. J Cyst Fibros 2019; 18: 762.
  55. Chariatte V, Ramseyer P and Cachat F: Uroradiological screening for upper and lower urinary tract anomalies in patients with hypospadias: A systematic literature review. Evid Based Med 2013; 18: 11.
  56. Akre O, Pettersson A and Richiardi L: Risk of contralateral testicular cancer among men with unilaterally undescended testis: A meta analysis. Int J Cancer 2009; 124: 687.
  57. Zarotsky V, Huang MY, Carman W et al: Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology 2014; 2: 819.
  58. Kellesarian SV, Malmstrom H, Abduljabbar T et al: "Low testosterone levels in body fluids are associated with chronic periodontitis". Am J Mens Health 2017; 11: 443.
  59. Radhakrishnan K, Toprac P, O'Hair M et al: Interactive digital e-health game for heart failure self-management: A feasibility study. Games Health J 2016; 5: 366.
  60. Johnson SL, Dunleavy J, Gemmell NJ et al: Consistent age-dependent declines in human semen quality: A systematic review and meta-analysis. Ageing Res Rev 2015; 19: 22.
  61. Sartorius GA and Nieschlag E: Paternal age and reproduction. Hum Reprod Update 2010; 16: 65.
  62. Kong A, Frigge ML, Masson G et al: Rate of de novo mutations and the importance of father's age to disease risk. Nature 2012; 488: 471.
  63. Jónsson H, Sulem P, Kehr B et al: Parental influence on human germline de novo mutations in 1,548 trios from iceland. Nature 2017; 549: 519.
  64. Oldereid NB, Wennerholm UB, Pinborg A et al: The effect of paternal factors on perinatal and paediatric outcomes: A systematic review and meta-analysis. Hum Reprod Update 2018; 24: 320.
  65. du Fossé NA, van der Hoorn MP, van Lith JMM et al: Advanced paternal age is associated with an increased risk of spontaneous miscarriage: A systematic review and meta-analysis. Hum Reprod Update 2020; 26: 650.
  66. Welcome to reprotox. 2020. https://reprotox.org/. 08/28/2020.
  67. Bonde JP, Flachs EM, Rimborg S et al: The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: A systematic review and meta-analysis. Hum Reprod Update 2016; 23: 104.
  68. Skakkebaek NE, Rajpert-De Meyts E and Main KM: Testicular dysgenesis syndrome: An increasingly common developmental disorder with environmental aspects. Hum Reprod 2001; 16: 972.
  69. Mendiola J, Jørgensen N, Andersson AM et al: Are environmental levels of bisphenol a associated with reproductive function in fertile men? Environ Health Perspect 2010; 118: 1286.
  70. Golub: Metals, fertility and reproductive toxicity. New York, NY, 2006
  71. CDC: Lead in drinking water. 2020. https://www.cdc.gov/nceh/lead/prevention/sources/water.htm. 07/14.
  72. Koh DH, Locke SJ, Chen YC et al: Lead exposure in us worksites: A literature review and development of an occupational lead exposure database from the published literature. Am J Ind Med 2015; 58: 605.
  73. Barbosa F, Jr., Tanus-Santos JE, Gerlach RF et al: A critical review of biomarkers used for monitoring human exposure to lead: Advantages, limitations, and future needs. Environ Health Perspect 2005; 113: 1669.
  74. Zhang Y, Li S and Li S: Relationship between cadmium content in semen and male infertility: A meta-analysis. Environ Sci Pollut Res Int 2019; 26: 1947.
  75. Whorton D, Krauss RM, Marshall S et al: Infertility in male pesticide workers. Lancet 1977; 2: 1259.
  76. Martenies SE and Perry MJ: Environmental and occupational pesticide exposure and human sperm parameters: A systematic review. Toxicology 2013; 307: 66.
  77. Zota AR, Calafat AM and Woodruff TJ: Temporal trends in phthalate exposures: Findings from the national health and nutrition examination survey, 2001-2010. Environ Health Perspect 2014; 122: 235.
  78. Ha yBB, Lenters V, Giwercman A et al: Impact of di-2-ethylhexyl phthalate metabolites on male reproductive function: A systematic review of human evidence. Curr Environ Health Rep 2018; 5: 20.
  79. Diagnostic evaluation of the infertile male: A committee opinion. Fertil Steril 2015; 103: e18.
  80. Sigman M and Jarow JP: Endocrine evaluation of infertile men. Urology 1997; 50: 659.
  81. Ventimiglia E, Capogrosso P, Boeri L et al: Validation of the american society for reproductive medicine guidelines/recommendations in white european men presenting for couple's infertility. Fertil Steril 2016; 106: 1076.
  82. Olesen IA, Andersson AM, Aksglaede L et al: Clinical, genetic, biochemical, and testicular biopsy findings among 1,213 men evaluated for infertility. Fertil Steril 2017; 107: 74.
  83. Mulhall JP, Trost LW, Brannigan RE et al: Evaluation and management of testosterone deficiency: Aua guideline. J Urol 2018; 200: 423.
  84. Schoor RA, Elhanbly S, Niederberger CS et al: The role of testicular biopsy in the modern management of male infertility. J Urol 2002; 167: 197.
  85. Corona G, Wu FC, Rastrelli G et al: Low prolactin is associated with sexual dysfunction and psychological or metabolic disturbances in middle-aged and elderly men: The european male aging study (emas). J Sex Med 2014; 11: 240.
  86. Kamischke A and Nieschlag E: Treatment of retrograde ejaculation and anejaculation. Hum Reprod Update 1999; 5: 448.
  87. Oates R: Evaluation of the azoospermic male. Asian J Androl 2012; 14: 82.
  88. Behre HM, Bergmann M, Simoni M et al: Primary testicular failure. [updated 2015 aug 30]. South Dartmouth, MA: MDText.com, Inc., 2000.
  89. Zhao WW, Wu M, Chen F et al: Robertsonian translocations: An overview of 872 robertsonian translocations identified in a diagnostic laboratory in china. PLoS One 2015; 10: e0122647.
  90. Morel F, Douet-Guilbert N, Le Bris MJ et al: Meiotic segregation of translocations during male gametogenesis. Int J Androl 2004; 27: 200.
  91. Aksglaede L, Jørgensen N, Skakkebaek NE et al: Low semen volume in 47 adolescents and adults with 47,xxy klinefelter or 46,xx male syndrome. Int J Androl 2009; 32: 376.
  92. Laron Z, Dickerman Z, Zamir R et al: Paternity in klinefelter's syndrome--a case report. Arch Androl 1982; 8: 149.
  93. Terzoli G, Lalatta F, Lobbiani A et al: Fertility in a 47,xxy patient: Assessment of biological paternity by deoxyribonucleic acid fingerprinting. Fertil Steril 1992; 58: 821.
  94. Lin YM, Huang WJ, Lin JS et al: Progressive depletion of germ cells in a man with nonmosaic klinefelter's syndrome: Optimal time for sperm recovery. Urology 2004; 63: 380.
  95. Ichioka K, Utsunomiya N, Kohei N et al: Adult onset of declining spermatogenesis in a man with nonmosaic klinefelter's syndrome. Fertil Steril 2006; 85: 1511.e1.
  96. Tang D, Liu W, Li G et al: Normal fertility with deletion of sy84 and sy86 in azfa region. Andrology 2020; 8: 332.
  97. Alksere B, Berzina D, Dudorova A et al: Case of inherited partial azfa deletion without impact on male fertility. Case Rep Genet 2019; 2019: 3802613.
  98. Stouffs K, Vloeberghs V, Gheldof A et al: Are azfb deletions always incompatible with sperm production? Andrology 2017; 5: 691.
  99. Hopps CV, Mielnik A, Goldstein M et al: Detection of sperm in men with y chromosome microdeletions of the azfa, azfb and azfc regions. Hum Reprod 2003; 18: 1660.
  100. Krausz C, Hoefsloot L, Simoni M et al: Eaa/emqn best practice guidelines for molecular diagnosis of y-chromosomal microdeletions: State-of-the-art 2013. Andrology 2014; 2: 5.
  101. Reddy MM and Stutts MJ: Status of fluid and electrolyte absorption in cystic fibrosis. Cold Spring Harb Perspect Med 2013; 3: a009555.
  102. Gaillard DA, Carre-Pigeon F and Lallemand A: Normal vas deferens in fetuses with cystic fibrosis. J Urol 1997; 158: 1549.
  103. Mak V, Zielenski J, Tsui LC et al: Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. Jama 1999; 281: 2217.
  104. Chillon M, Casals T, Mercier B et al: Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995; 332: 1475.
  105. Yu J, Chen Z, Ni Y et al: Cftr mutations in men with congenital bilateral absence of the vas deferens (cbavd): A systemic review and meta-analysis. Hum Reprod 2012; 27: 25.
  106. Mehdizadeh Hakkak A, Keramatipour M, Talebi S et al: Analysis of cftr gene mutations in children with cystic fibrosis, first report from north-east of iran. Iran J Basic Med Sci 2013; 16: 917.
  107. Alper OM, Wong LJ, Young S et al: Identification of novel and rare mutations in california hispanic and african american cystic fibrosis patients. Hum Mutat 2004; 24: 353.
  108. Bobadilla JL, Macek M, Jr., Fine JP et al: Cystic fibrosis: A worldwide analysis of cftr mutations--correlation with incidence data and application to screening. Hum Mutat 2002; 19: 575.
  109. Palomaki GE, FitzSimmons SC and Haddow JE: Clinical sensitivity of prenatal screening for cystic fibrosis via cftr carrier testing in a united states panethnic population. Genet Med 2004; 6: 405.
  110. Schrijver I, Pique L, Graham S et al: The spectrum of cftr variants in nonwhite cystic fibrosis patients: Implications for molecular diagnostic testing. J Mol Diagn 2016; 18: 39.
  111. Patat O, Pagin A, Siegfried A et al: Truncating mutations in the adhesion g protein-coupled receptor g2 gene adgrg2 cause an x-linked congenital bilateral absence of vas deferens. Am J Hum Genet 2016; 99: 437.
  112. Acog committee opinion no. 762: Prepregnancy counseling. Obstet Gynecol 2019; 133: e78.
  113. Bradley CK, McArthur SJ, Gee AJ et al: Intervention improves assisted conception intracytoplasmic sperm injection outcomes for patients with high levels of sperm DNA fragmentation: A retrospective analysis. Andrology 2016; 4: 903.
  114. Deng N, Haney NM, Kohn TP et al: The effect of shift work on urogenital disease: A systematic review. Curr Urol Rep 2018; 19: 57.
  115. Mohamed EE and Mohamed MA: Effect of sperm chromatin condensation on the outcome of intrauterine insemination in patients with male factor infertility. J Reprod Med 2012; 57: 421.
  116. Simon L, Zini A, Dyachenko A et al: A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome. Asian J Androl 2017; 19: 80.
  117. Dong J, Lv Y, Zhu G et al: Effect of sperm DNA fragmentation on the clinical outcomes of two assisted reproduction methods: Ivf and icsi. Int J Clin Exp Med 2017; 10: 11812.
  118. Esteves SC, Roque M, Bradley CK et al: Reproductive outcomes of testicular versus ejaculated sperm for intracytoplasmic sperm injection among men with high levels of DNA fragmentation in semen: Systematic review and meta-analysis. Fertil Steril 2017; 108: 456.
  119. Ayad BM, Horst GV and Plessis SSD: Revisiting the relationship between the ejaculatory abstinence period and semen characteristics. Int J Fertil Steril 2018; 11: 238.
  120. Heidenreich A, Bonfig R, Wilbert DM et al: Risk factors for antisperm antibodies in infertile men. Am J Reprod Immunol 1994; 31: 69.
  121. Munuce MJ, Berta CL, Pauluzzi F et al: Relationship between antisperm antibodies, sperm movement, and semen quality. Urol Int 2000; 65: 200.
  122. Lee R, Goldstein M, Ullery BW et al: Value of serum antisperm antibodies in diagnosing obstructive azoospermia. J Urol 2009; 181: 264.
  123. Bollendorf A, Check JH, Katsoff D et al: The use of chymotrypsin/galactose to treat spermatozoa bound with anti-sperm antibodies prior to intra-uterine insemination. Hum Reprod 1994; 9: 484.
  124. Check JH, Hourani W, Check ML et al: Effect of treating antibody-coated sperm with chymotrypsin on pregnancy rates following iui as compared to outcome of ivf/icsi. Arch Androl 2004; 50: 93.
  125. Gekas J, Thepot F, Turleau C et al: Chromosomal factors of infertility in candidate couples for icsi: An equal risk of constitutional aberrations in women and men. Hum Reprod 2001; 16: 82.
  126. Check JH, Graziano V, Cohen R et al: Effect of an abnormal sperm chromatin structural assay (scsa) on pregnancy outcome following (ivf) with icsi in previous ivf failures. Arch Androl 2005; 51: 121.
  127. McQueen DB, Zhang J and Robins JC: Sperm DNA fragmentation and recurrent pregnancy loss: A systematic review and meta-analysis. Fertil Steril 2019; 112: 54.
  128. Kamkar N, Ramezanali F and Sabbaghian M: The relationship between sperm DNA fragmentation, free radicals and antioxidant capacity with idiopathic repeated pregnancy loss. Reprod Biol 2018; 18: 330.
  129. Carlini T, Paoli D, Pelloni M et al: Sperm DNA fragmentation in italian couples with recurrent pregnancy loss. Reprod Biomed Online 2017; 34: 58.
  130. Talebi AR, Vahidi S, Aflatoonian A et al: Cytochemical evaluation of sperm chromatin and DNA integrity in couples with unexplained recurrent spontaneous abortions. Andrologia 2012; 44 Suppl 1: 462.
  131. Egozcue S, Blanco J, Vendrell JM et al: Human male infertility: Chromosome anomalies, meiotic disorders, abnormal spermatozoa and recurrent abortion. Hum Reprod Update 2000; 6: 93.
  132. Rubio C, Simón C, Blanco J et al: Implications of sperm chromosome abnormalities in recurrent miscarriage. J Assist Reprod Genet 1999; 16: 253.
  133. Harton GL and Tempest HG: Chromosomal disorders and male infertility. Asian J Androl 2012; 14: 32.
  134. Hassold T and Hunt P: To err (meiotically) is human: The genesis of human aneuploidy. Nat Rev Genet 2001; 2: 280.
  135. Kohn TP, Kohn JR, Darilek S et al: Genetic counseling for men with recurrent pregnancy loss or recurrent implantation failure due to abnormal sperm chromosomal aneuploidy. J Assist Reprod Genet 2016; 33: 571.
  136. Rodrigo L, Rubio C, Peinado V et al: Testicular sperm from patients with obstructive and nonobstructive azoospermia: Aneuploidy risk and reproductive prognosis using testicular sperm from fertile donors as control samples. Fertil Steril 2011; 95: 1005.
  137. Jarow JP, Ogle SR and Eskew LA: Seminal improvement following repair of ultrasound detected subclinical varicoceles. J Urol 1996; 155: 1287.
  138. Infertility in the male, 4 ed. Cambridge: Cambridge University Press, 2009
  139. Lotti F and Maggi M: Ultrasound of the male genital tract in relation to male reproductive health. Hum Reprod Update 2015; 21: 56.
  140. Singh R, Hamada AJ, Bukavina L et al: Physical deformities relevant to male infertility. Nat Rev Urol 2012; 9: 156.
  141. Avellino GJ, Lipshultz LI, Sigman M et al: Transurethral resection of the ejaculatory ducts: Etiology of obstruction and surgical treatment options. Fertil Steril 2019; 111: 427.
  142. Biyani CS, Cartledge J and Janetschek G: Varicocele. BMJ Clin Evid 2009: ˜.
  143. Bate J: Symptomatic varicocele. Journal of Urology 1927; 18: 649.
  144. Cheungpasitporn W, Horne JM and Howarth CB: Adrenocortical carcinoma presenting as varicocele and renal vein thrombosis: A case report. J Med Case Rep 2011; 5: 337.
  145. Spittel JA, Jr., Deweerd JH and Shick RM: Acute varicocele: A vascular clue to renal tumor. Proc Staff Meet Mayo Clin 1959; 34: 134.
  146. Elmer DeWitt M, Greene DJ, Gill B et al: Isolated right varicocele and incidence of associated cancer. Urology 2018; 117: 82.
  147. Kolettis PN and Sandlow JI: Clinical and genetic features of patients with congenital unilateral absence of the vas deferens. Urology 2002; 60: 1073.
  148. Schlegel PN, Shin D and Goldstein M: Urogenital anomalies in men with congenital absence of the vas deferens. J Urol 1996; 155: 1644.
  149. Weiske WH, Salzler N, Schroeder-Printzen I et al: Clinical findings in congenital absence of the vasa deferentia. Andrologia 2000; 32: 13.
  150. Lane VA, Scammell S, West N et al: Congenital absence of the vas deferens and unilateral renal agenesis: Implications for patient and family. Pediatr Surg Int 2014; 30: 733.
  151. Wang J, Xia SJ, Liu ZH et al: Inguinal and subinguinal micro-varicocelectomy, the optimal surgical management of varicocele: A meta-analysis. Asian J Androl 2015; 17: 74.
  152. Kirby EW, Wiener LE, Rajanahally S et al: Undergoing varicocele repair before assisted reproduction improves pregnancy rate and live birth rate in azoospermic and oligospermic men with a varicocele: A systematic review and meta-analysis. Fertil Steril 2016; 106: 1338.
  153. Kim HJ, Seo JT, Kim KJ et al: Clinical significance of subclinical varicocelectomy in male infertility: Systematic review and meta-analysis. Andrologia 2016; 48: 654.
  154. Ron-El R, Strassburger D, Friedler S et al: Extended sperm preparation: An alternative to testicular sperm extraction in non-obstructive azoospermia. Hum Reprod 1997; 12: 1222.
  155. Schlegel PN and Goldstein M: Alternate indications for varicocele repair: Non-obstructive azoospermia, pain, androgen deficiency and progressive testicular dysfunction. Fertil Steril 2011; 96: 1288.
  156. Schlegel PN and Kaufmann J: Role of varicocelectomy in men with nonobstructive azoospermia. Fertil Steril 2004; 81: 1585.
  157. Bernie AM, Mata DA, Ramasamy R et al: Comparison of microdissection testicular sperm extraction, conventional testicular sperm extraction, and testicular sperm aspiration for nonobstructive azoospermia: A systematic review and meta-analysis. Fertil Steril 2015; 104: ˜.
  158. Ramasamy R, Yagan N and Schlegel PN: Structural and functional changes to the testis after conventional versus microdissection testicular sperm extraction. Urology 2005; 65: 1190.
  159. Yu Z, Wei Z, Yang J et al: Comparison of intracytoplasmic sperm injection outcome with fresh versus frozen-thawed testicular sperm in men with nonobstructive azoospermia: A systematic review and meta-analysis. J Assist Reprod Genet 2018; 35: 1247.
  160. Nicopoullos JDM, Gilling-Smith C, Almeida PA et al: Use of surgical sperm retrieval in azoospermic men: A meta-analysis. Fertil Steril 2004; 82: 691.
  161. Sigman M: Introduction: Ejaculatory problems and male infertility. Fertil Steril 2015; 104: 1049.
  162. Valerie U, De BS, De BM et al: Pregnancy after vasectomy: Surgical reversal or assisted reproduction? Hum Reprod 2018; 33: 1218.
  163. Herrel LA, Goodman M, Goldstein M et al: Outcomes of microsurgical vasovasostomy for vasectomy reversal: A meta-analysis and systematic review. Urology 2015; 85: 819.
  164. Belker AM, Thomas AJ, Jr., Fuchs EF et al: Results of 1,469 microsurgical vasectomy reversals by the vasovasostomy study group. J Urol 1991; 145: 505.
  165. Engin G: Transrectal us-guided seminal vesicle aspiration in the diagnosis of partial ejaculatory duct obstruction. Diagn Interv Radiol 2012; 18: 488.
  166. Jarow JP: Transrectal ultrasonography of infertile men. Fertil Steril 1993; 60: 1035.
  167. Meacham RB, Hellerstein DK and Lipshultz LI: Evaluation and treatment of ejaculatory duct obstruction in the infertile male. Fertil Steril 1993; 59: 393.
  168. Turek PJ, Magana JO and Lipshultz LI: Semen parameters before and after transurethral surgery for ejaculatory duct obstruction. J Urol 1996; 155: 1291.
  169. Kadioglu A, Cayan S, Tefekli A et al: Does response to treatment of ejaculatory duct obstruction in infertile men vary with pathology? Fertil Steril 2001; 76: 138.
  170. Purohit RS, Wu DS, Shinohara K et al: A prospective comparison of 3 diagnostic methods to evaluate ejaculatory duct obstruction. J Urol 2004; 171: 232.
  171. Aggour A, Mostafa H and Maged W: Endoscopic management of ejaculatory duct obstruction. Int Urol Nephrol 1998; 30: 481.
  172. Tu XA, Zhuang JT, Zhao L et al: Transurethral bipolar plasma kinetic resection of ejaculatory duct for treatment of ejaculatory duct obstruction. J Xray Sci Technol 2013; 21: 293.
  173. Schroeder-Printzen I, Ludwig M, Kohn F et al: Surgical therapy in infertile men with ejaculatory duct obstruction: Technique and outcome of a standardized surgical approach. Hum Reprod 2000; 15: 1364.
  174. El-Assmy A, El-Tholoth H, Abouelkheir RT et al: Transurethral resection of ejaculatory duct in infertile men: Outcome and predictors of success. Int Urol Nephrol 2012; 44: 1623.
  175. Netto NR, Jr., Esteves SC and Neves PA: Transurethral resection of partially obstructed ejaculatory ducts: Seminal parameters and pregnancy outcomes according to the etiology of obstruction. J Urol 1998; 159: 2048.
  176. Cohen J, Edwards R, Fehilly C et al: In vitro fertilization: A treatment for male infertility. Fertil Steril 1985; 43: 422.
  177. Sunderam S, Kissin DM, Zhang Y et al: Assisted reproductive technology surveillance - united states, 2016. MMWR Surveill Summ 2019; 68: 1.
  178. Finkelstein JS, Whitcomb RW, O'Dea LS et al: Sex steroid control of gonadotropin secretion in the human male. I. Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab 1991; 73: 609.
  179. Oliveira LM, Seminara SB, Beranova M et al: The importance of autosomal genes in kallmann syndrome: Genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab 2001; 86: 1532.
  180. Gianetti E, Hall JE, Au MG et al: When genetic load does not correlate with phenotypic spectrum: Lessons from the gnrh receptor (gnrhr). J Clin Endocrinol Metab 2012; 97: E1798.
  181. Pitteloud N, Crowley WF, Jr. and Balasubramanian R: Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism). 2020. https://www.uptodate.com/contents/isolated-gonadotropin-releasing-hormone-deficiency-idiopathic-hypogonadotropic-hypogonadism/print. 07/14.
  182. Nachtigall LB, Boepple PA, Pralong FP et al: Adult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility. N Engl J Med 1997; 336: 410.
  183. Burris AS, Rodbard HW, Winters SJ et al: Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: The response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab 1988; 66: 1144.
  184. Miyagawa Y, Tsujimura A, Matsumiya K et al: Outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers: A 30-year retrospective study. J Urol 2005; 173: 2072.
  185. Liu PY, Baker HW, Jayadev V et al: Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: Predictors of fertility outcome. J Clin Endocrinol Metab 2009; 94: 801.
  186. Whitten SJ, Nangia AK and Kolettis PN: Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate. Fertil Steril 2006; 86: 1664.
  187. Chehab M, Madala A and Trussell JC: On-label and off-label drugs used in the treatment of male infertility. Fertil Steril 2015; 103: 595.
  188. Fraietta R, Zylberstejn DS and Esteves SC: Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo) 2013; 68 Suppl 1: 81.
  189. Zumoff B, Miller LK and Strain GW: Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone. Metabolism 2003; 52: 1126.
  190. de Boer H, Verschoor L, Ruinemans-Koerts J et al: Letrozole normalizes serum testosterone in severely obese men with hypogonadotropic hypogonadism. Diabetes Obes Metab 2005; 7: 211.
  191. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World health organization task force on methods for the regulation of male fertility. Lancet 1990; 336: 955.
  192. Liu PY, Swerdloff RS, Christenson PD et al: Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: An integrated analysis. Lancet 2006; 367: 1412.
  193. Bayrak A, Saadat P, Mor E et al: Pituitary imaging is indicated for the evaluation of hyperprolactinemia. Fertil Steril 2005; 84: 181.
  194. Vilar L, Vilar CF, Lyra R et al: Pitfalls in the diagnostic evaluation of hyperprolactinemia. Neuroendocrinology 2019; 109: 7.
  195. Famini P, Maya MM and Melmed S: Pituitary magnetic resonance imaging for sellar and parasellar masses: Ten-year experience in 2598 patients. J Clin Endocrinol Metab 2011; 96: 1633.
  196. Melmed S, Casanueva FF, Hoffman AR et al: Diagnosis and treatment of hyperprolactinemia: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 273.
  197. Snyder PJ: Clinical manifestations and evaluation of hyperprolactinemia. https://www.uptodate.com/contents/clinical-manifestations-and-evaluation-of-hyperprolactinemia. 07/14.
  198. Molitch ME: Diagnosis and treatment of pituitary adenomas: A review. Jama 2017; 317: 516.
  199. Honegger J, Nasi-Kordhishti I, Aboutaha N et al: Surgery for prolactinomas: A better choice? Pituitary 2020; 23: 45.
  200. Chua ME, Escusa KG, Luna S et al: Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: A meta-analysis. Andrology 2013; 1: 749.
  201. Cannarella R, Condorelli RA, MongioAª LM et al: Effects of the selective estrogen receptor modulators for the treatment of male infertility: A systematic review and meta-analysis. Expert Opin Pharmacother 2019; 20: 1517.
  202. Steiner AZ, Hansen KR, Barnhart KT et al: The effect of antioxidants on male factor infertility: The males, antioxidants, and infertility (moxi) randomized clinical trial. Fertil Steril 2020; 113: 552.
  203. Santi D, Granata ARM and Simoni M: Fsh treatment of male idiopathic infertility improves pregnancy rate: A meta-analysis. Endocr Connect 2015; 4: R46.
  204. Attia AM, Al-Inany HG, Farquhar C et al: Gonadotrophins for idiopathic male factor subfertility. Cochrane Database Syst Rev 2007: CD005071.
  205. Ding YM, Zhang XJ, Li JP et al: Treatment of idiopathic oligozoospermia with recombinant human follicle-stimulating hormone: A prospective, randomized, double-blind, placebo-controlled clinical study in chinese population. Clin Endocrinol 2015; 83: 866.
  206. Hussein A, Ozgok Y, Ross L et al: Optimization of spermatogenesis-regulating hormones in patients with non-obstructive azoospermia and its impact on sperm retrieval: A multicentre study. BJU Int 2013; 111: E110.
  207. Cavallini G, Biagiotti G and Bolzon E: Multivariate analysis to predict letrozole efficacy in improving sperm count of non-obstructive azoospermic and cryptozoospermic patients: A pilot study. Asian J Androl 2013; 15: 806.
  208. Gül Ü and Turunç T: The effect of human chorionic gonadotropin treatment before testicular sperm extraction in non-obstructive azoospermia. J Clin Anal Med 2016; 7: 55.
  209. Aydos K, AonlA¬ C, Demirel LC et al: The effect of pure fsh administration in non-obstructive azoospermic men on testicular sperm retrieval. Eur J Obstet Gynecol Reprod Biol 2003; 108: 54.
  210. Meistrich ML: Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril 2013; 100: 1180.
  211. Lu CC and Meistrich ML: Cytotoxic effects of chemotherapeutic drugs on mouse testis cells. Cancer Res 1979; 39: 3575.
  212. Miguel F, Da Cunha MF, Meistrich ML et al: Temporary effects of a msa (4'-(9-acridinylamino) me tha nesulfon-m-anisidide) chemotherapy on spermatogenesis. Cancer 1982; 49: 2459.
  213. Rowley MJ, Leach DR, Warner GA et al: Effect of graded doses of ionizing radiation on the human testis. Radiat Res 1974; 59: 665.
  214. Howell SJ and Shalet SM: Spermatogenesis after cancer treatment: Damage and recovery. J Natl Cancer Inst Monogr 2005: 12.
  215. Hansen PV, Trykker H, Svennekjaer IL et al: Long-term recovery of spermatogenesis after radiotherapy in patients with testicular cancer. Radiother Oncol 1990; 18: 117.
  216. Meistrich M and Beek M: Radiation sensitivity of the human testis, vol. 14, pp. 227-268, 1990
  217. Jacob A, Barker H, Goodman A et al: Recovery of spermatogenesis following bone marrow transplantation. Bone Marrow Transplant 1998; 22: 277.
  218. Sanders JE, Hawley J, Levy W et al: Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996; 87: 3045.
  219. Green DM, Kawashima T, Stovall M et al: Fertility of male survivors of childhood cancer: A report from the childhood cancer survivor study. J Clin Oncol 2010; 28: 332.
  220. Tomlinson M, Meadows J, Kohut T et al: Review and follow-up of patients using a regional sperm cryopreservation service: Ensuring that resources are targeted to those patients most in need. Andrology 2015; 3: 709.
  221. Brydoy M, FossA SD, Klepp O et al: Sperm counts and endocrinological markers of spermatogenesis in long-term survivors of testicular cancer. Br J Cancer 2012; 107: 1833.
  222. Isaksson S, Eberhard J, StAhl O et al: Inhibin b concentration is predictive for long-term azoospermia in men treated for testicular cancer. Andrology 2014; 2: 252.
  223. Gandini L, SgrAý P, Lombardo F et al: Effect of chemo- or radiotherapy on sperm parameters of testicular cancer patients. Hum Reprod 2006; 21: 2882.
  224. Nurmio M, Keros V, La hteenmA ki P et al: Effect of childhood acute lymphoblastic leukemia therapy on spermatogonia populations and future fertility. J Clin Endocrinol Metab 2009; 94: 2119.
  225. Stukenborg JB, Alves-Lopes JP, Kurek M et al: Spermatogonial quantity in human prepubertal testicular tissue collected for fertility preservation prior to potentially sterilizing therapy. Hum Reprod 2018; 33: 1677.
  226. Meistrich ML, Chawla SP, Da Cunha MF et al: Recovery of sperm production after chemotherapy for osteosarcoma. Cancer 1989; 63: 2115.
  227. Russell LB, Hunsicker PR, Johnson DK et al: Unlike other chemicals, etoposide (a topoisomerase-ii inhibitor) produces peak mutagenicity in primary spermatocytes of the mouse. Mutat Res 1998; 400: 279.
  228. Schultheis B, Nijmeijer BA, Yin H et al: Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model. Leuk Res 2012; 36: 271.
  229. Brydøy M, Fosså SD, Dahl O et al: Gonadal dysfunction and fertility problems in cancer survivors. Acta Oncol 2007; 46: 480.
  230. Namekawa T, Imamoto T, Kato M et al: Testicular function among testicular cancer survivors treated with cisplatin-based chemotherapy. Reprod Med Biol 2016; 15: 175.
  231. Bahadur G, Ozturk O, Muneer A et al: Semen quality before and after gonadotoxic treatment. Hum Reprod 2005; 20: 774.
  232. Spermon JR, Ramos L, Wetzels AMM et al: Sperm integrity pre- and post-chemotherapy in men with testicular germ cell cancer. Hum Reprod 2006; 21: 1781.
  233. Bohlen D, Burkhard FC, Mills R et al: Fertility and sexual function following orchiectomy and 2 cycles of chemotherapy for stage i high risk nonseminomatous germ cell cancer. J Urol 2001; 165: 441.
  234. Schrader M, Muller M, Straub B et al: Testicular sperm extraction in azoospermic patients with gonadal germ cell tumors prior to chemotherapy--a new therapy option. Asian J Androl 2002; 4: 9.
  235. Rafsanjani KA, Faranoush M, Hedayatiasl AA et al: Gonadal function and fertility in males survivors treated for hodgkin's disease in iran. Saudi Med J 2007; 28: 1690.
  236. Hobbie WL, Ginsberg JP, Ogle SK et al: Fertility in males treated for hodgkins disease with copp/abv hybrid. Pediatr Blood Cancer 2005; 44: 193.
  237. Arush MWB, Solt I, Lightman A et al: Male gonadal function in survivors of childhood hodgkin and non-hodgkin lymphoma. Pediatr Hematol Oncol 2000; 17: 239.
  238. Romerius P, StAhl O, MoA®ll C et al: High risk of azoospermia in men treated for childhood cancer. Int J Androl 2011; 34: 69.
  239. Van Beek RD, Smit M, Van Den Heuvel-Eibrink MM et al: Inhibin b is superior to fsh as a serum marker for spermatogenesis in men treated for hodgkin's lymphoma with chemotherapy during childhood. Hum Reprod 2007; 22: 3215.
  240. Paoli D, Rizzo F, Fiore G et al: Spermatogenesis in hodgkin's lymphoma patients: A retrospective study of semen quality before and after different chemotherapy regimens. Hum Reprod 2016; 31: 263.
  241. Grigg AP, McLachlan R, Zajac J et al: Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant 2000; 26: 1089.
  242. Green DM, Zhu L, Wang M et al: Effect of cranial irradiation on sperm concentration of adult survivors of childhood acute lymphoblastic leukemia: A report from the st. Jude lifetime cohort study. Hum Reprod 2017; 32: 1192.
  243. Rendtorff R, Beyer M, Ma¬ller A et al: Low inhibin b levels alone are not a reliable marker of dysfunctional spermatogenesis in childhood cancer survivors. Andrologia 2012; 44 Suppl 1: 219.
  244. Thomson AB, Campbell AJ, Irvine DS et al: Semen quality and spermatozoal DNA integrity in survivors of childhood cancer: A case-control study. Lancet 2002; 360: 361.
  245. Andreu JAL, FernA­ndez PJ, FerrA-s IT et al: Persistent altered spermatogenesis in long-term childhood cancer survivors. Pediatr Hematol Oncol 2000; 17: 21.
  246. Relander T, Cavallin-StAhl E, Garwicz S et al: Gonadal and sexual function in men treated for childhood cancer. Med Pediatr Oncol 2000; 35: 52.
  247. Lahteenmaki PM, Arola M, Suominen J et al: Male reproductive health after childhood cancer. Acta Paediatr 2008; 97: 935.
  248. Meistrich ML: Risks of genetic damage in offspring conceived using sperm produced during chemotherapy or radiotherapy. Andrology 2019;
  249. Russell LB, Hunsicker PR and Russell WL: Comparison of the genetic effects of equimolar doses of enu and mnu: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia. Mutat Res 2007; 616: 181.
  250. Russell LB, Hunsicker PR, Kerley MK et al: Bleomycin, unlike other male-mouse mutagens, is most effective in spermatogonia, inducing primarily deletions. Mutat Res 2000; 469: 95.
  251. Yoshimoto Y, Neel JV, Schull WJ et al: Malignant tumors during the first 2 decades of life in the offspring of atomic bomb survivors. Am J Hum Genet 1990; 46: 1041.
  252. Winther JF, Boice JD, Jr., Mulvihill JJ et al: Chromosomal abnormalities among offspring of childhood-cancer survivors in denmark: A population-based study. Am J Hum Genet 2004; 74: 1282.
  253. Signorello LB, Mulvihill JJ, Green DM et al: Congenital anomalies in the children of cancer survivors: A report from the childhood cancer survivor study. J Clin Oncol 2012; 30: 239.
  254. Al-Jebari Y, Glimelius I, Berglund Nord C et al: Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study. PLoS Med 2019; 16: e1002816.
  255. Robbins WA, Meistrich ML, Moore D et al: Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm. Nat Genet 1997; 16: 74.
  256. Monteil M, Rousseaux S, Chevret E et al: Increased aneuploid frequency in spermatozoa from a hodgkin's disease patient after chemotherapy and radiotherapy. Cytogenet Cell Genet 1997; 76: 134.
  257. Martin RH, Ernst S, Rademaker A et al: Chromosomal abnormalities in sperm from testicular cancer patients before and after chemotherapy. Hum Genet 1997; 99: 214.
  258. De Mas P, Daudin M, Vincent MC et al: Increased aneuploidy in spermatozoa from testicular tumour patients after chemotherapy with cisplatin, etoposide and bleomycin. Hum Reprod 2001; 16: 1204.
  259. Martinez G, Walschaerts M, Le Mitouard M et al: Impact of hodgkin or non-hodgkin lymphoma and their treatments on sperm aneuploidy: A prospective study by the french cecos network. Fertil Steril 2017; 107: 341.
  260. Martin RH, Ernst S, Rademaker A et al: Analysis of sperm chromosome complements before, during, and after chemotherapy. Cancer Genet Cytogenet 1999; 108: 133.
  261. Bogefors K, Giwercman YL, Eberhard J et al: Androgen receptor gene cag and ggn repeat lengths as predictors of recovery of spermatogenesis following testicular germ cell cancer treatment. Asian J Androl 2017; 19: 538.
  262. Bujan L, Walschaerts M, Moinard N et al: Impact of chemotherapy and radiotherapy for testicular germ cell tumors on spermatogenesis and sperm DNA: A multicenter prospective study from the cecos network. Fertil Steril 2013; 100: 673.
  263. O'Flaherty C, Hales BF, Chan P et al: Impact of chemotherapeutics and advanced testicular cancer or hodgkin lymphoma on sperm deoxyribonucleic acid integrity. Fertil Steril 2010; 94: 1374.
  264. Di BC, Bertagna A, Composto ER et al: Effects of oncological treatments on semen quality in patients with testicular neoplasia or lymphoproliferative disorders. Asian J Androl 2013; 15: 425.
  265. Kawai K and Nishiyama H: Preservation of fertility of adult male cancer patients treated with chemotherapy. Int J Clin Oncol 2019; 24: 34.
  266. Oktay K, Harvey BE, Partridge AH et al: Fertility preservation in patients with cancer: Asco clinical practice guideline update. J Clin Oncol 2018; 36: 1994.
  267. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: A committee opinion. Fertil Steril 2019; 112: 1022.
  268. Hsiao W, Deveci S and Mulhall JP: Outcomes of the management of post-chemotherapy retroperitoneal lymph node dissection-associated anejaculation. BJU Int 2012; 110: 1196.
  269. Berookhim BM and Mulhall JP: Outcomes of operative sperm retrieval strategies for fertility preservation among males scheduled to undergo cancer treatment. Fertil Steril 2014; 101: 805.
  270. Ombelet W, Dhont N, Thijssen A et al: Semen quality and prediction of iui success in male subfertility: A systematic review. Reprod Biomed Online 2014; 28: 300.
  271. Lemmens L, Kos S, Beijer C et al: Predictive value of sperm morphology and progressively motile sperm count for pregnancy outcomes in intrauterine insemination. Fertil Steril 2016; 105: 1462.
  272. Nangia AK, Luke B, Smith JF et al: National study of factors influencing assisted reproductive technology outcomes with male factor infertility. Fertil Steril 2011; 96: 609.
  273. Williams DHt, Karpman E, Sander JC et al: Pretreatment semen parameters in men with cancer. J Urol 2009; 181: 736.
  274. Agarwal A, Shekarriz M, Sidhu RK et al: Value of clinical diagnosis in predicting the quality of cryopreserved sperm from cancer patients. J Urol 1996; 155: 934.
  275. Auger J, Sermondade N and Eustache F: Semen quality of 4480 young cancer and systemic disease patients: Baseline data and clinical considerations. Basic Clin Androl 2016; 26: 3.
  276. Grover NS, Deal AM, Wood WA et al: Young men with cancer experience low referral rates for fertility counseling and sperm banking. J Oncol Pract 2016; 12: 465.
  277. Klosky JL, Wang F, Russell KM et al: Prevalence and predictors of sperm banking in adolescents newly diagnosed with cancer: Examination of adolescent, parent, and provider factors influencing fertility preservation outcomes. J Clin Oncol 2017; 35: 3830.
  278. Sonnenburg DW, Brames MJ, Case-Eads S et al: Utilization of sperm banking and barriers to its use in testicular cancer patients. Support Care Cancer 2015; 23: 2763.
  279. Bizet P, Saias-Magnan J, Jouve E et al: Sperm cryopreservation before cancer treatment: A 15-year monocentric experience. Reprod Biomed Online 2012; 24: 321.
  280. van Casteren NJ, van Santbrink EJ, van Inzen W et al: Use rate and assisted reproduction technologies outcome of cryopreserved semen from 629 cancer patients. Fertil Steril 2008; 90: 2245.
  281. Ferrari S, Paffoni A, Filippi F et al: Sperm cryopreservation and reproductive outcome in male cancer patients: A systematic review. Reprod Biomed Online 2016; 33: 29.
  282. O'Flaherty CM, Chan PT, Hales BF et al: Sperm chromatin structure components are differentially repaired in cancer survivors. J Androl 2012; 33: 629.
  283. Weibring K, Nord C, StAhl O et al: Sperm count in swedish clinical stage i testicular cancer patients following adjuvant treatment. Ann Oncol 2019; 30: 604.
  284. Anserini P, Chiodi S, Spinelli S et al: Semen analysis following allogeneic bone marrow transplantation. Additional data for evidence-based counselling. Bone Marrow Transplant 2002; 30: 447.
  285. Rives N, Walschaerts M, Setif V et al: Sperm aneuploidy after testicular cancer treatment: Data from a prospective multicenter study performed within the french centre d'a%tude et de conservation des oeufs et du sperme network. Fertil Steril 2017; 107: 580.
  286. StAhl O, Eberhard J, Jepson K et al: Sperm DNA integrity in testicular cancer patients. Hum Reprod 2006; 21: 3199.
  287. Suzuki K, Yumura Y, Ogawa T et al: Regeneration of spermatogenesis after testicular cancer chemotherapy. Urol Int 2013; 91: 445.
  288. Alwaal A, Breyer BN and Lue TF: Normal male sexual function: Emphasis on orgasm and ejaculation. Fertil Steril 2015; 104: 1051.
  289. Jacobsen KD, Ous S, Waehre H et al: Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection. Br J Cancer 1999; 80: 249.
  290. Hsiao W, Stahl PJ, Osterberg EC et al: Successful treatment of postchemotherapy azoospermia with microsurgical testicular sperm extraction: The weill cornell experience. J Clin Oncol 2011; 29: 1607.
  291. Meseguer M, Garrido N, Remohí J et al: Testicular sperm extraction (tese) and icsi in patients with permanent azoospermia after chemotherapy. Hum Reprod 2003; 18: 1281.
  292. Dar S, Orvieto R, Levron J et al: Ivf outcome in azoospermic cancer survivors. Eur J Obstet Gynecol Reprod Biol 2018; 220: 84.
  293. Shin T, Kobayashi T, Shimomura Y et al: Microdissection testicular sperm extraction in japanese patients with persistent azoospermia after chemotherapy. Int J Clin Oncol 2016; 21: 1167.
  294. Shiraishi K and Matsuyama H: Microdissection testicular sperm extraction and salvage hormonal treatment in patients with postchemotherapy azoospermia. Urology 2014; 83: 100.
  295. Hsiao W, Stahl PJ, Osterberg EC et al: Successful treatment of postchemotherapy azoospermia with microsurgical testicular sperm extraction: The weill cornell experience. J Clin Oncol 2011; 29: 1607.
  296. Zorn B, Virant-Klun I, Stanovnik M et al: Intracytoplasmic sperm injection by testicular sperm in patients with aspermia or azoospermia after cancer treatment. Int J Androl 2006; 29: 521.
  297. Meseguer M, Garrido N, RemohA J et al: Testicular sperm extraction (tese) and icsi in patients with permanent azoospermia after chemotherapy. Hum Reprod 2003; 18: 1281.
  298. Chan PTK, Palermo GD, Veeck LL et al: Testicular sperm extraction combined with intracytoplasmic sperm injection in the treatment of men with persistent azoospermia postchemotherapy. Cancer 2001; 92: 1632.
  299. Tannour-Louet M, Han S, Corbett ST et al: Identification of de novo copy number variants associated with human disorders of sexual development. PLoS One 2010; 5: e15392.
  300. Tannour-Louet M, Han S, Louet JF et al: Increased gene copy number of vamp7 disrupts human male urogenital development through altered estrogen action. Nat Med 2014; 20: 715.
  301. Haller M, Au J, O'Neill M et al: 16p11.2 transcription factor maz is a dosage-sensitive regulator of genitourinary development. Proc Natl Acad Sci U S A 2018; 115: E1849.
  302. Haller M, Mo Q, Imamoto A et al: Murine model indicates 22q11.2 signaling adaptor crkl is a dosage-sensitive regulator of genitourinary development. Proc Natl Acad Sci U S A 2017; 114: 4981.
  303. Jorgez CJ, Rosenfeld JA, Wilken NR et al: Genitourinary defects associated with genomic deletions in 2p15 encompassing otx1. PLoS One 2014; 9: e107028.
  304. Pryor JL, Kent-First M, Muallem A et al: Microdeletions in the y chromosome of infertile men. N Engl J Med 1997; 336: 534.
  305. Vogt P, Chandley AC, Hargreave TB et al: Microdeletions in interval 6 of the y chromosome of males with idiopathic sterility point to disruption of azf, a human spermatogenesis gene. Hum Genet 1992; 89: 491.
  306. Ma K, Sharkey A, Kirsch S et al: Towards the molecular localisation of the azf locus: Mapping of microdeletions in azoospermic men within 14 subintervals of interval 6 of the human y chromosome. Hum Mol Genet 1992; 1: 29.
  307. Genecards®: The human gene database. https://www.genecards.org. 07/14.
  308. Coutton C, Escoffier J, Martinez G et al: Teratozoospermia: Spotlight on the main genetic actors in the human. Hum Reprod Update 2015; 21: 455.
  309. Wang WL, Tu CF and Tan YQ: Insight on multiple morphological abnormalities of sperm flagella in male infertility: What is new? Asian J Androl 2020; 22: 236.
  310. Matzuk MM and Lamb DJ: The biology of infertility: Research advances and clinical challenges. Nat Med 2008; 14: 1197.
  311. Matzuk MM and Lamb DJ: Genetic dissection of mammalian fertility pathways. Nat Cell Biol 2002; 4 Suppl: s41.
  312. Oud MS, Volozonoka L, Smits RM et al: A systematic review and standardized clinical validity assessment of male infertility genes. Hum Reprod 2019; 34: 932.
  313. Brinster RL: Germline stem cell transplantation and transgenesis. Science 2002; 296: 2174.
  314. Komeya M, Sato T and Ogawa T: In vitro spermatogenesis: A century-long research journey, still half way around. Reprod Med Biol 2018; 17: 407.
  315. Kubota H and Brinster RL: Spermatogonial stem cells. Biol Reprod 2018; 99: 52.

advertisement

advertisement

The New AUAnet

Tips

Website Tip!

While viewing Guideline Statements on a desktop computer, use the left navigation to jump to different parts of the page.