CUA: Azoospermia (2015)

Background

Infertility or subfertility affects 15% of couples in Canada; a male factor contributes to the problem in 50% of these couples
Of men presenting for fertility investigation, 20% are found to be azoospermic
Azoospermia can be categorized as (4):
1. Pre-testicular failure (2% of men with azoospermia); due to hypothalamic/pituitary abnormality (hypogonadotropic-hypogonadism)
2. Testicular failure (49%–93% of men with azoospermia)
3. Post-testicular (7%–51% of men with azoospermia)
4. Ejaculatory dysfunction

Diagnosis and Evaluation

After at least 2 semen analyses have confirmed azoospermia, men should be investigated with a thorough history and physical examination. Most men will also require laboratory and imaging studies.
History
- Infertility history
  - Duration of infertility
  - Whether the infertility is primary or secondary
  - Any treatments to date
  - Libido, sexual function, sexual activity
- General health of the man (diabetes, respiratory issues, recent illnesses)
  - If there has been a recent serious medical illness or injury or evidence of a recent reproductive tract infection, semen testing should be repeated at least 3 months following recovery from the illness
- Surgery of the reproductive tract: testis cancer, undescended testis, hydrocelectomies, spermatocelectomies, varicocelectomies, vasectomies
- Proven or suspected GU infections/inflammation: sexually transmitted infections, epididymo-orchitis, mumps orchitis
- Medications and therapies which might have an adverse impact on spermatogenesis
  1. Hormone/steroid therapy
  2. Antibiotics (sulphasalazine)
  3. Alpha-blockers
  4. 5-alpha-reductase inhibitors
  5. Chemotherapy
  6. Radiation
  7. Narcotics
  - If there has been exposure to any gonadotoxic agents, these medications should be stopped and semen should be retested in 3 to 6 months
- Environmental exposures (pesticides, excessive heat on the testicles)
- Recreational drugs (marijuana, excessive alcohol)
- History of any genetic abnormalities in the patient or the family
Physical exam
- Body habitus
  - Obese men have
    - Elevated estradiol; mechanism: adipose cells have aromatase which metabolizes testosterone to estradiol
    - Reduced serum testosterone and reduced SHBG (therefore, more bioavailable testosterone component of total testosterone)
- State of virilisation
- Abdominal examination
  - Scars indicative of previous inguinal surgery or treatment of undescended testis.
- Scrotal examination
  - Size and consistency of the testis (long axis length <4.6cm associated with impaired spermatogenesis, volume <20mL considered low); size correlates well with sperm production
  - Epididymis (engorgement may suggest obstruction)
- Phallus (meatal displacement)
- Prostate and seminal vesicles
- Vas deferens
  - Absence of the vas deferens is usually associated with absence of the seminal vesicles
  - Unilateral absence suggests complete lack of Wolffian duct development on that side, including renal agenesis.
  - Bilateral absence: consider investigation for CF gene mutation
  - Abdominal US to assess for renal agenesis is indicated in men with congenital bilateral or unilateral absence of the vas deferens who are not carriers of cystic fibrosis mutations since these men have a higher chance of having absence of one of their kidneys
    - 26% of men with unilateral congenital absence of the vas deferens (CAVD) and 11% of men with bilateral CAVD had an absent ipsilateral kidney; most of the bilateral CAVD patients with an absent ipsilateral kidney are in patients with no identifiable CF gene mutation. Semen is almost always of low volume and acidic in patients with bilateral CAVD due to hypoplasia or absence of the seminal vesicles, which provide alkalinity.
- Varicoceles
  - See Varicocelectomy Chapter Notes

Subsequent investigations are based on reduced volume (<1.5 mL) vs. normal volume azoospermia

Reduced semen volume (<1.5mL) azoospermia

Most of the semen comes from the seminal vesicles (largest contributor) and prostate (>90%)
Etiology (5) A Reduced Semen Volume Etiology Exercise:
1. Artifact: missed the container, difficulty providing specimen
2. Retrograde ejaculation
3. Seminal Vesicles obstruction or abnormality
4. Ejaculatory duct obstruction
5. Emission failure (psychogenic failure, diabetes, spinal cord injury, RPLND, etc.)
Diabetic men often have retrograde ejaculation or failure of emission
Investigations (sequential):
1. Rule out artifact (then)
2. Rule out retrograde ejaculation by testing the post-ejaculate urine for the presence of sperm (then)
  - Sperm in the post-ejaculation urine is diagnostic of retrograde ejaculation
3. Transrectal ultrasound (TRUS) to identify reproductive tract obstruction or abnormalities
  - Obstruction of the ejaculatory duct is usually detected by a TRUS and is usually accompanied by dilation of the seminal vesicles (typically >1.5 cm wide)
- Vasography is not required and should be discouraged for men with an ejaculatory duct obstruction

Normal semen volume azoospermia

Categorized based on the luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels, without the need for a testicular biopsy
- Pre-testicular failure: ↓LH and ↓ FSH levels and low or normal testosterone levels
- Testicular failure: ↑LH and ↑FSH and small testis bilaterally
  - Congenital causes of testicular failure DUNKY XX:
    - Down syndrome
    - Undescended testis
    - Noonan syndrome
    - Kleinfelter syndrome
    - Y-microdeletions
    - XX-male
Men with normal levels of FSH and LH [and normal semen volume] could have either testicular failure or [pre-ejaculatory duct] obstructive azoospermia. There is no non-invasive method to differentiate these and a testicular biopsy is usually required to provide a definitive diagnosis. However, a testis biopsy should only be offered to men in whom this diagnosis would alter management
- The biopsy could be performed either:
  - As a diagnostic procedure alone
  - As the initial part of the procedure where after the biopsy results are available for quick section, the surgery would proceed with a reconstruction and/or sperm retrieval
- A bilateral diagnostic testicular biopsy is generally not required. If there is a discrepancy in testicular size, the larger of the two testes should be biopsied
  - Men with congenital bilateral absence of the vas deferens typically have normal spermatogenesis and a diagnostic biopsy is usually not required to diagnose active spermatogenesis.

Genetic investigations for men with azoospermia

Pre-testicular failure (hypogonadotropic hypogonadism): refer for genetics counselling
- Almost all of the congenital abnormalities of the hypothalamus are due to a genetic alteration.
Testicular failure: karyotype and Y-micro-deletion testing
Post-testicular failure:
- CF testing: men with absence (epididymis, vas deferens, seminal vesicles, or ejaculatory duct) or obstruction (epididymal or ejaculatory obstruction, including ejaculatory duct cysts) of the reproductive tract ductal structures; not only the male, but also his partner, should be offered CF testing in this situation. Males with non-obstructive azoospermia do not require cystic fibrosis testing
- Patients with congenital unilateral absence of vas and normal contralateral vas are unlikely to have CF mutation but in presence of contralateral abnormality, CF risk higher§
If a genetic alteration is identified, then genetic counselling is suggested

Investigations in men with failure to ejaculate

In men with a clear neurological cause (e.g., spinal cord injury, RPLND), no further investigations are required prior to treatment
Men with idiopathic failure to ejaculate (particularly those with a failure to orgasm) should be seen by a sex therapist

Management

Pre-testicular azoospermia

FSH/LH or gonadotropin-releasing hormone (GnRH) analogues stimulate spermatogenesis
In > 90% of cases, spermatogenesis is induced and men have ejaculated sperm.
Treatment may take >6 months to be effective

Testicular failure

Testicular sperm extraction (TESE) may be used.
- Large sections of the seminiferous tubules of the testis are examined with an operating microscope.
  - Larger tubules are more likely to have spermatogenesis than smaller diameter tubules.

Failure to ejaculate

Men with a neurological cause for a failure to ejaculate should be offered either vibro-stimulation or electro-ejaculation.
- Both procedures may cause autonomic dysreflexia in men with high spinal cord injuries.

Retrograde ejaculation

Since retrograde ejaculation may be due to a failure of the bladder neck to close with orgasm, use of an alpha agonist (60 mg or other alpha agonist) [or SNRI such as imipramine] before ejaculation may close the bladder neck and convert retrograde into ante-grade ejaculation.
If this is not successful, it is often possible to retrieve sperm from the bladder (either using a post-ejaculatory voided or catheterized urine specimen). This sperm could then be used for one of the assisted reproductive technologies.

Obstructive azoospermia

Sperm retrieved from the reproductive tract
- The method of sperm retrieval used may be a percutaneous or an open microscopic aspiration of sperm from the epididymis or a percutaneous or open biopsy of the testis.
Bypass/repair of the obstructed area of the reproductive tract.
- The most common area of obstruction is the epididymis
- Men should be offered the option to cryo-bank sperm retrieved during the course of the operation in case the surgery is not successful
- Transurethral resection of the ejaculatory duct can be used to treat ejaculatory duct obstruction

Role of varicocelectomy in men with azoospermia

The role of varicocelectomy in men with azoospermia remains controversial.
Reasonable to offer a varicocele repair to men with palpable varicoceles and testicular failure; treating non-palpable varicoceles does not improve fertility
Men should be warned that there is a low probability that varicocelectomy will result in any improvement in semen parameters; most men still need ICSI to help conceive

Role of hormonal therapy for men with azoospermia

Apart from the management of men with hypogonadotropic hypogonadism, the use of hormones to treat men with azoospermia remains controversial
The use of androgens is contraindicated in men with azoospermia

Questions

How many semen analyses are required in the evaluation of azoospermia?
Take a history and describe the physical exam of a patient presenting with azoospermia.
List gonadotoxic medications
What are the indications for renal US in patients being investigated for infertility?
What is the grading of a varicocele?
List causes of reduced volume azoospermia
What investigations should be ordered in a patient with reduced vs. normal volume azoospermia:
What finding on TRUS is consistent with seminal vesicle obstruction?
What are the indications for genetic testing?
What are the indications for CF testing?
What are the management options?
After starting a patient with pre-testicular failure on hormonal therapy, how long should you wait before evaluating efficacy?
When should a varicocelectomy be considered in men with infertility?

Answers

How many semen analyses are required in the evaluation of azoospermia?
- 2
Take a history and describe the physical exam of a patient presenting with azoospermia.
- History: infertility history, PMHx (general health), PSHx (surgeries of the reproductive tract), any GU infection/inflammation, exposure to medications/treatments (chemo/rads), environmental exposure, recreational drugs, FHx (genetic conditions)
- Physical: body habitus, state of virilization, scrotal exam (vas deferences, varicoceles), phallus, prostate, abdominal exam (previous surgery scars)
List gonadotoxic medications
- Steroids, exogenous testosterone, estrogen, opioids, sulfasalazine, cimetidine, spironolactone, anti-androgens, HIV medications
What are the indications for renal US in patients being investigated for infertility?
- Unilateral or bilateral absence of vas
What is the grading of a varicocele?
- 0: not palpable, visible only by US
- I: palpable with Valsalva, not visible
- II: palpable at rest, not visible
- III: visible at rest
List causes of reduced volume azoospermia
- Artifact, retrograde ejaculation, semen vesicles obstruction or abnormality, ejaculatory duct obstruction, emission failure
What investigations should be ordered in a patient with reduced vs. normal volume azoospermia:
- Reduced volume azoospermia: rule out artifact, then post-ejaculate urinalysis, then TRUS
- Normal volume azoospermia: LH/FSH to categorize pre-testicular vs. testicular; if normal LH/FSH, cannot rule out obstruction vs. testicular failure and therefore consider biopsy
What finding on TRUS is consistent with seminal vesicle obstruction?
- Dilated seminal vesicle >1.5cm
What are the indications for genetic testing?
- Pre-testicular failure: all should be referred to genetic counselling
- Testicular failure: karyotype and Y micro-deletion
What are the indications for CF testing?
- Absence or obstruction of the reproductive tract structures
- Partner should also be tested
What are the management options?
- Pre-testicular: FSH/LH or gonadotropin-releasing hormone (GnRH) analogues
- Testicular: testicular sperm extraction
- Retrograde ejaculation: alpha agonist
- Obstruction: repair obstruction vs. obtain sperm from reproductive tract
After starting a patient with pre-testicular failure on hormonal therapy, how long should you wait before evaluating efficacy?
- 6 months
When should a varicocelectomy be considered in men with infertility?
- Palpable varicocele and testicular failure; however, low probability that this will result in any improvement in semen parameters