Originalcua guideline research CUA Guideline: The workup and management of azoospermic males Keith Jarvi, MD, FRCSC;* Kirk Lo, MD, FRCSC;* Ethan Grober, MD;* Victor Mak, MD, FRCSC;* Anthony Fischer, MD, FRCSC;¥ John Grantmyre, MD, FRCSC;± Armand Zini, MD, FRCSC;+ Peter Chan, MD, FRCSC;+ Genevieve Patry, MD, FRCSC;£ Victor Chow, MD, FRCSC;§ Trustin Domes, MD, FRCSC# *Department of Urology, Mount Sinai Hospital, University of Toronto, Toronto, ON; ¥Division of Urology, McMaster University, Hamilton, ON; ±Department of Urology, Dalhousie University, Halifax, NS; +Division of Urology, McGill University Health Centre, Montreal, QC; £Hôtel-Dieu De Lévis, Lévis, QC; §Department of Urologic Sciences, University of British Columbia, Vancouver, BC; #Saskatoon Health Region, Saskatoon, SK Cite as: Can Urol Assoc J 2015;9(7-8):229-35. http://dx.doi.org/10.5489/cuaj.3209 A further group of men have a failure to ejaculate. These Published online August 10, 2015. may be men with spinal cord injury, psychogenic failure to ejaculate, or neurological damage (sympathetic nerve committee was established at the request of the damage from, for example, a retroperitoneal lymph node Canadian Urological Association to develop guide- dissection). A lines for the investigation and management of azo- To understand the management of azoospermia, it is ospermia. Members of the committee, all of whom have important to also understand the role of assisted reproduc- special expertise in the investigation and management of tive technologies (ARTs) (i.e., in-vitro fertilization) in the male infertility, were chosen from different communities treatment of azoospermia. Since the 1970s, breakthroughs across Canada. The members represent different practices in the ARTs have allowed us to offer potentially successful in different communities. treatments for up to 98% of couples with male factor infer- tility.6 These significant advances had little to do with tech- Introduction and background niques to improve the sperm quality, but relied on the use of ARTs to “treat” the male infertility. These programs used Infertility or subfertility affects 15% of couples in Canada, techniques to increase the number of mature eggs produced with a male factor contributing to the fertility problem in by the women by manipulating the hormonal environment close to 50% of these couples. Of the men presenting for in the women using exogenous hormones (ovulation induc- fertility investigation, up to 20% are found to be azoosper- tion) then used either: mic. These men can be categorized as having either: 1) Timed insemination to optimize the pregnancy rates 1) Pre-testicular azoospermia (2% of men with azo- either through intercourse or intra-uterine insemina- ospermia); tion of the partners washed sperm; a) Due to a hypothalamic or pituitary abnormal- 2) In-vitro fertilization (IVF); or oocytes are retrieved ity (diagnosed with hypo-gonadotropic-hypo- from the ovaries then are either incubated with the gonadism). sperm in a dish; or 2) Testicular failure or non-obstructive azoospermia 3) Intra-cytoplasmic sperm injection (ICSI), by inject- (49%–93% of men with azoospermia); or ing the sperm directly into the cytoplasm of the a) While the term testicular failure would seem to oocyte. indicate a complete absence of spermatogen- All of the above techniques are widely used to treat esis, men with testicular failure actually have couples with male factor infertility. In the United States either reduced spermatogenesis, maturation in 2012, over 165 000 IVF/ICSI cycles were performed. 7 arrest or a complete failure of spermatogenesis Worldwide the numbers of IVF/ICSI cycles were high. In noted with Sertoli-cell only syndrome.1-5 2013, the International Committee for Monitoring Assisted 3) Post-testicular causes for azoospermia (7%–51% of Reproductive Technology reported that in 2004 there were men with azoospermia). 954 743 IVF or ICSI cycles worldwide, with 237 809 babies a) Obstruction or ejaculatory dysfunction. born.8 b) Normal spermatogenesis but obstructive azo- Using ICSI, it is now possible to produce a pregnancy ospermia or ejaculatory dysfunction.1-5 with any live sperm (motile or not), from either the semen CUAJ • July-August 2015 • Volume 9, Issues 7-8 229 © 2015 Canadian Urological Association Jarvi et al. or any site within the male reproductive tract. Even men If the man has had exposure to any of the gonadotoxic with azoospermia can be offered sperm retrieval with ICSI. agents (Table 1), he should be taken off these medications Sperm could be retrieved from any site in the reproductive and his semen should be retested in 3 to 6 months. If the tract and used for ICSI. These are the men who previously man has had a recent serious medical illness or injury or had very limited chances to ever have biologically related he has evidence of a recent reproductive tract infection, children. Pregnancy rates of close to 50% per cycle of ICSI semen testing should be repeated at least 3 months follow- (women under 35 years of age) are expected, with the preg- ing recovery from the illness. nancy rates independent of the site of the origin of the sperm.6 The initial investigations will depend on the information obtained from the history and physical examination, in addi- History, physical exam and initial investigations for tion to the results of the semen analyses. men with azoospermia Azoospermia with reduced semen volume After at least two semen analyses have confirmed azoosper- If the semen volume is reduced (<1.5 mL) and documented mia, the men should be investigated with a thorough history on repeat testing, careful questioning should elicit whether (Table 1) and physical examination (Table 2). Most men will this is an artifact (i.e., missed the container, difficulty provid- also require laboratory and imaging studies. ing specimen) or truly a low semen volume.9 Since most of the semen comes from the seminal vesicles and prostate (>90%), low semen volume means that either: Table 1. Type of information to gather during a patient’s 1) the seminal vesicles are abnormal or obstructed; history 2) the ejaculatory ducts are obstructed; or General information Examples and areas of focus 3) there is an ejaculatory dysfunction (either failure of 1. Infertility history • Duration of infertility • Whether the infertility is emission or retrograde ejaculation). primary or secondary Physical examination will help determine if the vas def- • Any treatments to date erens is present in the scrotum. Absence of the vas deferens • Libido in the scrotum is usually associated with absence of the • Sexual function seminal vesicles and is a cause for low semen volume and • Sexual activity azoospermia. 2. The general health of the man • Diabetes; • Respiratory issues The first laboratory test is to determine if there is retro- • Recent illnesses grade ejaculation by testing the post-ejaculate urine for the 3. Any proven or suspected genito- • Sexually transmitted presence of sperm. The presence of any sperm in the urine, urinary infections, testicular infections post-ejaculation in men with azoospermia, is diagnostic of infections or inflammation8 • Epididymo-orchitis retrograde ejaculation. Since retrograde ejaculation may be • Mumps orchitis due to a failure of the bladder neck to close with orgasm, 4. Any surgery of the reproductive • Testis cancer use of an alpha agonist (pseudoephedrine or other alpha tract • Undescended testis • Hydrocelectomies agonist) before ejaculation may close the bladder neck and • Spermatocelectomies convert retrograde into ante-grade ejaculation. Diabetic men • Varicocelectomies often have retrograde ejaculation or failure of emission.10 • Vasectomies If there is no evidence of retrograde ejaculation, diagnos- 5. Exposure to medications • Hormone/steroid therapy tic imaging of the reproductive tract is usually required to and therapies which might • Antibiotics (sulphasalazine) have an adverse impact on • Alpha-blockers spermatogenesis • 5-alpha-reductase Table 2. Type of information to gather during a patient’s inhibitors physical examination • Chemotherapeutic agents Type of examination Examples and areas of focus • Radiation 1. State of virilization • Finasteride9 2. Scrotal examination • Size and consistency of the • Narcotics testis 6. Environmental exposures • Pesticides • Presence and grade of • Excessive heat on the varicoceles testicles • Palpable vas deferens 7. Any recreational drugs • Marijuana 3. Abdominal examination • Presence of scars in the • Excessive alcohol inguinal area indicative 8. History of any genetic of previous inguinal abnormalities in the patient or surgery or treatment of his family undescended testis. 230 CUAJ • July-August 2015 • Volume 9, Issues 7-8 azoospermic males identify reproductive tract obstruction or abnormalities. A Normal semen volume azoospermia transrectal ultrasound (TRUS) will determine if the seminal vesicles and vas deferens close to the prostate are normal. As stated above, the categories of azoospermia are: Obstruction of the ejaculatory duct is usually detected by a 1) Pre-testicular azoospermia; TRUS and is usually accompanied by dilation of the seminal 2) Testicular failure or non-obstructive azoospermia; vesicles (typically >1.5 cm wide).11 If absence of the vas and deferens and/or the seminal vesicle is identified, the man has 3) Post-testicular obstruction.1-5 about an 80% chance of carrying a genetic alteration associ- The category of azoospermia may often be determined by ated with cystic fibrosis.12 Cystic fibrosis