AUA2021: Male Infertility Guideline
By: Peter N. Schlegel, MD | Posted on: 06 Aug 2021
A joint guideline on male infertility developed by the American Urological Association in conjunction with the American Society for Reproductive Medicine (ASRM) and co-published in The Journal of Urology® as well as Fertility and Sterility will be reviewed in a plenary session on Monday, September 13. This guideline, developed by committee members nominated by both organizations and including a patient representative and members from ECRI (formerly the Emergency Care Research Institute), an evidence-based practice center team, reviewed a series of key questions in evaluation and treatment of male infertility. These topics were analyzed with the PICO format (Patient, Intervention, Comparison, Outcome) to help guide clinicians in their management of males presenting with infertility as a couple. A total of 52 guideline statements were developed, addressing evaluation and management of couples. Although some of the statements merely refined long-standing concepts from the last joint guideline in 2002, a number of new clinical scenarios were addressed as well. An overview algorithm for evaluation and treatment of male infertility was also provided (see figure).
In the evaluation section, an emphasis was created on the importance of a male infertility diagnosis as it relates to other medical conditions. In addition to guiding treatment options, evaluation of the infertile male is important to recognize potential life-threatening conditions that can be associated with the disease of infertility, such as germ cell tumors, as well as pituitary tumors, symptomatic hypogonadism and other conditions. Furthermore, it is now well recognized that men with lower sperm concentration are at increased future risk for developing germ cell tumors.1 It is further now known that severe male infertility, including nonobstructive azoospermia, is associated with an increased risk of cancer of a variety of different types. This may be related to the underlying genetic causes of infertility such as defects in DNA mismatch repair genes,2 although the mechanisms creating this risk have not been completely elucidated. The implications are clear, however: men cannot be simply treated for infertility, but they need to have counseling for their lifelong risk of associated diseases. Other specific medical conditions such as Klinefelter syndrome require ongoing surveillance for risk of breast neoplasms, hypogonadism and other conditions. Cystic fibrosis (CF)-associated congenital defects of the male reproductive tract similarly are associated with pulmonary and pancreatic diseases as well as tooth enamel-related defects.
For many years, it has been considered a paradigm to evaluate men with an isolated right varicocele for an abdominal mass or other cause of compression of the inferior vena cava. Based on published literature, this recommendation has been revised in the guideline, so that routine abdominal imaging is not required in this setting except in men with new, large or symptomatic right varicoceles that do not decompress in the supine position.
Specific guidelines statements were also developed to focus on men who have been diagnosed with cancer or have had prior chemotherapy and/or radiation. Counseling regarding sperm banking prior to cancer treatment seems an obvious recommendation, but fertility preservation prior to cancer treatment is only occasionally performed. Other guideline statements emphasize the increased risk of sperm abnormalities and birth defects that can occur for up to a year after chemotherapy or radiation, resulting in a guideline recommendation to avoid conception for men recently treated with gonadotoxic therapies. Such recommendations have not been clear in prior guidelines. A guideline statement to repeat semen analysis 1–2 years after chemotherapy provides additional practical advice for the management of these men after cancer treatment. Furthermore, the use of advanced fertility treatments such as testicular sperm retrieval and advanced reproductive technologies including in vitro fertilization and intracytoplasmic sperm injection (ICSI) are addressed as treatment that can be used for men with azoospermia long after chemotherapy.
The role of nonspecific therapy for male infertility includes cautions in the use of antioxidant supplements, where limited data support this intervention. Interestingly, use of both selective estrogen receptor modulators (SERMs, such as clomiphene) and exogenous follicle-stimulating hormone (FSH) in idiopathic male infertility have Level I Evidence to support their use in male infertility. However, the magnitude of benefit for each of these medical treatments is very limited. Combined data from multiple studies suggest that clomiphene may only increase the chance of natural pregnancy from 9% to 18%, and the expensive FSH agents increased pregnancy from 0.5% to 10%, far less than the nearly 40% pregnancy chance per try with interventions such as ICSI. The value of varicocele repair, on the other hand, is now strongly supported by robust evidence documenting its benefit for men with infertility, abnormal semen parameters and clinical (palpable) varicoceles for infertile couples with isolated male infertility or male and female factors when the female factors are treatable.
Management of men with the most severe defects in male fertility, including nonobstructive azoospermia, are addressed in several statements, emphasizing the value of the surgical technique of microdissection testicular sperm extraction (mTESE) as a tool for sperm retrieval, with ICSI, for these men. Other guideline statements reflect some of the limitations of published literature for making recommendations regarding care. For example, the common practice of giving medications such as clomiphene citrate or human chorionic gonadotropin (hCG) for men with nonobstructive azoospermia was recognized to have a limited evidence base, so the guideline recommends that clinicians limit statements regarding such treatment. Similarly, varicocele repair before mTESE in nonobstructive azoospermia has limited data to support the intervention. In both cases, published studies have not included appropriate controlled trials to demonstrate the potential value of these treatments. The recognition of limitations in published literature helps to guide future randomized controlled trials to address the role of such interventions in nonobstructive azoospermia. Other future directions include the need to better understand the underlying genetic conditions that may cause severe male infertility. These topics and more will be summarized in a plenary presentation on Monday, September 13 at 2:10 pm.
- Schlegel PN, Sigman M, Collura B et al: Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline part I. J Urol 2021; 205: 36.
- Mukherjee S, Ridgeway AD and Lamb DJ: DNA mismatch repair and infertility. Curr Opin Urol 2010; 20: 525.