Craig S. Niederberger, MD, FACS
Mark C. Lindgren, MD
BASICS
DESCRIPTION
• Infertility is the inability to achieve pregnancy after 1 yr of regular unprotected intercourse
• Couples achieve pregnancy by intercourse at a rate of approximately 20–25% per month, 75% by 6 mo, and 90% by 1 yr
EPIDEMIOLOGY
Incidence
• 15% of couples have infertility
• In approximately 30%, infertility is due to a significant male factor alone
• An additional 20% of couples have both male and female factors present
Prevalence
N/A
RISK FACTORS
• Anatomic: Varicocele; bilateral cryptorchidism; hypospadias; testicular trauma; testicular torsion; thermal exposure (hot baths, saunas); spinal, inguinal, or retroperitoneal surgery
• Medications: Cancer and cancer treatments (chemotherapy, radiation); recreational drugs (marijuana, cocaine); prescription meds (exogenous testosterone [T], GnRH agonists/antagonists, α-blockers, antibiotics, sulfasalazine, cimetidine, spironolactone, Ca channel blockers, colchicine, opioids, psych meds)
• Others: Heavy alcohol use; GU infections; chromosomal abnormalities; neurologic disease; endocrine disorders
Genetics
• Most common defects and % of men with nonobstructive azoospermia (NOA) or obstructive azoospermia (OA) with each:
– Klinefelter syndrome 47,XXY (10% NOA)
– Cystic fibrosis transmembrane conductance regulator protein (CFTR) found abnormal in 80% of patients with congenital bilateral absence of the vas deferens (CBAVD) (6% OA)
– Azoospermia factor (AZF) a, b, and c:
AZFa (1% NOA) predictive of testicular sperm extraction (TESE) failure
AZFb (1–3% NOA) predicts TESE failure
AZFc (13% NOA) best prognosis, can be oligospermic, if azoospermic 2/3rds have sperm on TESE
PATHOPHYSIOLOGY
3 categories:
• Pretesticular: Endocrine abnormality
• Testicular: Abnormal sperm production
• Posttesticular: Abnormal sperm transport
ASSOCIATED CONDITIONS
• Pretesticular:
– Hypogonadotropic hypogonadism: Low follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) with normal prolactin
– Hypothyroidism
– Medication use: See Risk Factors
– Elevated estradiol from morbid obesity, tumors, or hepatic dysfunction
– Kallmann syndrome: X-linked, absent GnRH secretion, absent puberty, anosmia
– Pituitary/cranial trauma, infection, or tumor
– Hyperprolactinemia: Prolactin inhibits LH action on Leydig cells. Brain MRI to evaluate for macroadenoma (>1 cm)
Macroadenoma: Refer for possible resection
Microadenoma: May respond to dopamine agonist (1st line: Cabergoline, 2nd: Bromocriptine)
• Testicular:
– Varicocele: 15% of all men, 35–40% of men with primary infertility, 70–80% of men with secondary infertility
– Bilateral cryptorchidism
– Testicular cancer—pretreatment sperm density and motility are significantly decreased
– Gonadotoxins: Radiation, chemotherapy, medications, environmental endocrine disrupting chemicals (eg, phthalates used in plastics)
– Immunologic: Antisperm antibodies; febrile infections can decrease sperm production for 3 mo; postpubertal mumps orchitis
– Sertoli-cell only syndrome: Absent germ cells
– Maturation arrest: Spermatogenesis halted at a certain stage
– Genetic/chromosomal factors:
Klinefelter: 47,XXY; small, firm testes; often azoospermic, however, mosaicism (47,XXY/46,XY) allows spermatogenesis. Up to 69% have sperm found from TESE
Y microdeletions: AZFa, b and c: See Genetics
Androgenization disorders: Defects in synthesis of T, androgen receptor, and 5α reductase
47,XYY: Usually fertile due to mosaicism with XYY cells arresting in meiosis and XY cells producing mature sperm
46,XX with male phenotype: No spermatogenesis, donor sperm/adoption
Primary ciliary dyskinesia (Kartagener syndrome): Immotile sperm; frequent respiratory infections; situs inversus
Globozoospermia (round-headed sperm): Severe teratospermia in which sperm lack acrosomes giving the heads a round appearance
• Posttesticular:
– Obstruction of epididymis or vas deferens: Congenital or acquired (eg, vasectomy)
– CBAVD: 80% have CFTR mutations—genetic testing must be performed for male and female
– Ejaculatory dysfunction:
Anejaculation: Caused by retroperitoneal surgery, neuropathic disorders, α-blockers and psychiatric medications
Retrograde ejaculation: Transurethral prostate and bladder neck procedures as well as the same causes of anejaculation (above)
– Ejaculatory duct obstruction (EDO): Low-volume azoospermia; causes include previous infection, iatrogenic trauma, and congenital
GENERAL PREVENTION
See “Risk Factors”
DIAGNOSIS
HISTORY
• Mnemonic TICS:
– Toxic: Varicocele, chemotherapy, radiation exposure, thermal exposure to testes, testicular injury, heavy alcohol use, recreational drugs (marijuana, cocaine), surgical history, medications, and other medical illnesses
– Infectious: Sexually transmitted disease, urinary tract infections, epididymitis, recent febrile illness, and postpubertal mumps
– Congenital: Bilateral cryptorchidism, testicular torsion, family history of difficulty conceiving or miscarriages, family history of cystic fibrosis
– Sexual: Length of time attempting to conceive, previous pregnancies with current or previous partner, frequency of intercourse, lubricant use, erectile dysfunction, age at puberty, libido, exogenous T use, energy level
PHYSICAL EXAM
• General: Degree of virilization, Tanner stage
• Penile exam: Location of urethral meatus, buried penis
• Scrotal exam:
– Measure testicles by long access length or orchidometer volume (nL ≥4 cm or 20 mL)
– Testicular consistency, including careful evaluation for testicular masses
– Epididymal exam—note presence of caput, corpus, and cauda as well as possible induration or fullness suggestive of obstruction
– Cord structures: Evaluate for varicocele in standing position, note presence or absence of vasa deferentia as well as continuity or malunion
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Semen analysis:
– Minimum of 2 specimens due to variability
– World Health Organization (WHO) 2010 5th edition reference values:
Volume >1.5 mL normal, if low, obtain post ejaculatory urinalysis to distinguish between retrograde ejaculation and EDO
Concentration >15 million/mL
Total sperm count >39 million/mL
Total Motility >40%
Morphology >4%
– Azoospermia:
Distinguish between obstructive and NOA
If FSH <7.6 mIU/mL and testicular long axis >4.6 cm then 96% probability of OA
If FSH ≥7.6 and testicle ≤4.6 cm then 89% probability of NOA (1)[B]
• Further specialized semen testing may aid decision-making but not routinely obtained
• Endocrine workup obtained if abnormal semen analysis, impaired sexual function or findings indicative of endocrine abnormality:
– Obtain T, sex hormone binding globulin (SHBG), albumin to calculate bioavailable T and FSH, LH estradiol for all patients needing workup
– Consider prolactin and others as indicated
• Genetic testing
– CBAVD: Patient and partner should have genetic counseling and CFTR mutation testing
– Karyotyping is indicated in patients with NOA or severe oligospermia (<5 million sperm/mL)
– Consider Y chromosome microdeletion testing if azoospermic
Imaging
• Transrectal ultrasound—use in azoospermic patients with palpable vasa and low-volume ejaculate. Seminal vesical dilatation (normal <2 cm) indicative of EDO
• Scrotal ultrasound—only used in patients with difficult or inadequate scrotal exams
• Renal ultrasound—recommended if unilateral absent vas or CBAVD with no CFTR mutations to evaluate for renal abnormalities
Diagnostic Procedures/Surgery
Testicular biopsy is typically unnecessary
Pathologic Findings
• Seminiferous tubules findings include:
– Normal spermatogenesis—indicative of OA
– Maturation arrest (∼20% of NOA)—can be “early” or “late”
– Sertoli-cell-only syndrome (∼60% of NOA)—germinal cell aplasia
– Hypospermatogenesis (∼20% of NOA) or germ cell hypoplasia
– Tubular hypoplasia—possible hypogonadotropic hypogonadism
– Seminiferous tubule sclerosis
– Testis cancer
DIFFERENTIAL DIAGNOSIS
See “Associated Conditions”
TREATMENT
GENERAL MEASURES
• The goal is to address the underlying problem to allow natural conception, if possible.
• Female evaluation by a reproductive specialist and coordinated care is crucial for optimal outcomes.
MEDICATION
First Line
• Clomiphene citrate 50 mg every other day: Used for hypoandrogenism. Stimulates GnRH resulting in increased T and spermatogenesis. Less than 10% of men with azoospermia and hypoandrogenism have return of sperm to ejaculate after T normalizes using clomiphene citrate (2)[B]. Note: Exogenous T decreases fertility
• Pseudoephedrine 60 mg 1–2 hr prior to sex: For retrograde ejaculation
• Anastrozole 1 mg daily: Men with abnormal semen parameters and low testosterone to estradiol ratio (<10:1)
Second Line
• hCG and/or recombinant FSH: If hypoandrogenism unsuccessfully treated with clomiphene citrate
• Alternatives for retrograde ejaculation: Imipramine 25 mg, ephedrine 25 mg
SURGERY/OTHER PROCEDURES
• MicroTESE: Performed for NOA, superior to other sperm-retrieval techniques with 20–30% improvement in yield up to 67%
• Vasectomy reversal: Time since vasectomy is the best predictor of success (3)[B]
• MicroTESE, vasovasostomy, or vasoepididymostomy should be performed by microsurgical specialist
• OA, if patient does not desire reconstruction or it is not possible: TESE, testicular sperm aspiration (TESA), percutaneous or microsurgical epididymal sperm aspiration (PESA or MESA)
• Varicocelectomy: Recommended for men with infertility, palpable varicocele, abnormal semen parameters, elevated FSH, and female partner with normal/potentially correctable infertility (4)[A]
• Transurethral resection of ejaculatory ducts: For EDO
• Neurostimulatory ejaculation: Men with spinal cord injury may be able to retrieve sperm via ejaculate with penile vibratory stimulation or, electroejaculation or via microTESE
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
Assisted Reproductive Technologies (ARTs), Intrauterine insemination (IUI), In Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI)
Complementary & Alternative Therapies
Coenzyme Q10 is used
ONGOING CARE
PROGNOSIS
• Pregnancy rates are highly dependent on the age of the female partner
• MicroTESE for NOA: 67% sperm-retrieval rate
• IUI: ∼15% pregnancy rate per cycle
• IVF: ∼30% pregnancy rate per cycle
• IVF with ICSI: ∼35–45% pregnancy/per cycle
COMPLICATIONS
• Scrotal surgery: Hematoma, bruising, pain
• ART: Multiple gestations, passing genetic defects to offspring
FOLLOW-UP
Patient Monitoring
Spermatogenesis takes approximately 64 days; semen analysis 3 mo after starting treatment
Patient Resources
• UrologyCare Foundation http://www.urologyhealth.org/urology/index.cfm?article=102
• Maledoc.com
REFERENCES
1. Schoor RA, Elhanbly S, Niederberger CS, et al. The role of testicular biopsy in the modern management of male infertility. J Urol. 2002;167:197–200.
2. 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(3 Pt B):E110–E114.
3. Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of 1469 microsurgical vasectomy reversals by the vasovasotomy study group. J Urol. 1991;145:505–511.
4. Agarwal A, Deepinder F, Cocuzza M, et al. Efficacy of varicocelectomy in improving semen parameters: New meta-analytical approach. Urology. 2007;70:532–538.
ADDITIONAL READING
Lipshultz LI, Howards SS, Niederberger CS. Infertility in the Male. 4th ed. New York, NY: Cambridge University Press; 2009.
See Also (Topic, Algorithm, Media)
• Assisted Reproductive Techniques (ARTs)
• Azoospermia, Oligospermia
• Ejaculatory Disturbances
• Infertility, Urologic Considerations Image 
• Semen Analysis, Abnormal Findings, and Terminology
• Semen Analysis, Technique, and Normal Values
• Varicocele
CODES
ICD9
• 606.1 Oligospermia
• 606.8 Infertility due to extratesticular causes
• 606.9 Male infertility, unspecified
ICD10
• N46.029 Azoospermia due to other extratesticular causes
• N46.129 Oligospermia due to other extratesticular causes
• N46.9 Male infertility, unspecified
CLINICAL/SURGICAL PEARLS
Testis biopsy is rarely indicated in the evaluation of male infertility.