Infertility: Management

Includes 2020 AUA/ASRM Guidelines on Infertility

Surgical Management

Surgical anatomy

• See Epididymis Anatomy
• Anatomy of the Excurrent Ducts
  • Sperm and testicular fluid exit the testes through efferent ducts. These ducts become convoluted when they exit the testes and form the caput of the epididymis. At that level, they freely anastomose with one another. They all coalesce at the distal caput to form a single epididymal tubule from the caput-corpus junction all the way to the vas deferens.
    • Clinical implication: puncture of a single tubule for sperm aspiration can be safely performed at the most proximal region of the head of the epididymis because there are multiple lobules at this level
      • Any injury to the epididymis distal to the caput will result in complete obstruction of the entire system on that side
  • Hydrocelectomy and orchiopexy for torsion can result in iatrogenic injury to the epididymis
• Ejaculatory Ducts
  • Obstruction of ejaculatory ducts can lead to azoospermia.
    • Transurethral resection (TUR) of the ejaculatory ducts (TURED) can relieve the obstruction.

Testicular Biopsy

• Fresh, unfixed tissue is examined for the presence of sperm with tails and possible motility; if sperm are not found initially, examination of multiple samples is recommended.
  • Optimal care requires the availability, at the time of biopsy, of an andrology laboratory capable of processing and cryopreserving any sperm found at the time of biopsy.

Approaches

• Open Testicular Biopsy: Microsurgical Technique
  • Open biopsy remains the gold standard
  • Technique
    • May be performed using either general, spinal, or local anesthetic.
• Percutaneous Testicular Biopsy
  • A blind procedure that could result in unintentional injury to either the epididymis or the testicular artery
  • The midsection of the testis has relatively fewer vessels compared with superior or inferior areas
  • Should not be used when previous surgery has resulted in scarring and obliteration of normal anatomy
• Percutaneous Testicular Aspiration
  • Technique
    • Performed with a 23-gauge needle or angiocath sheath
  • Less invasive and less painful than percutaneous biopsy
  • Usually yields few tubules with poorly preserved architecture

Adverse Events

• Most serious potential complication: inadvertent biopsy of the epididymis
  • If histologic evaluation of the biopsy material reveals epididymis with sperm within the epididymal tubule, obstruction of the epididymis at the site of the biopsy is certain.
    • If there are no sperm within the epididymal tubules, the patient is either obstructed above the level of the epididymal biopsy site or has primary seminiferous tubular failure and no harm has been done.
• Most common potential complication: hematoma

Surgical Sperm Extraction

Indications

1. Azoospermia (obstructive or non-obstructive)
2. Ejaculatory dysfunction

Approach

• Classified: Testicular vs. Epididymal
• Testicular sperm retrieval
  • Mainstay in the management of the man with non-obstructive azoospermia§
  • Techniques (3):
    1. Open Testicular Sperm Extraction (TESE)
       • A surgical procedure that involves wide opening of the tunica albuginea to allow examination of multiple regions of testicular tissue, each of which are oriented in a centrifugal pattern in parallel to the intratesticular blood supply, allowing extensive search of nearly all areas of the testis with limited risk of devascularization of tissue.[1]
         • Preferably done with an operating microscope (micro-TESE)
           • Conventional TESE has been associated with decreased postoperative testosterone levels, and many men with non-obstructive azoospermia have baseline testosterone deficiency levels.
           • Less effect on testosterone levels is seen after micro-TESE than with conventional TESE, but testosterone deficiency requiring testosterone replacement remains a risk, even after micro-TESE.
       • Contraindications
         • Sertoli-only cell syndrome
         • Spermatogenic arrest
       • Allows retrieval of the largest number of sperm with potential for cryopreservation
    2. Percutaneous core biopsy
       • Uses the same 14-gauge biopsy gun used for prostate biopsy
    3. Percutaneous aspiration (testicular sperm aspiration [TESA])
       • Done with a high-suction glass syringe and a 23-gauge needle.
       • Least invasive procedure but often requires 10 to 20 passes to obtain an adequate yield
• Epididymal sperm retrieval
  • Techniques (2):
    • Microsurgical Epididymal Sperm Aspiration (MESA)
    • Percutaneous Epididymal Sperm Aspiration (PESA)
• Selection of approach
  • If azoospermia due to obstruction, testicular or epididymal extraction★
    • Fertilization, pregnancy, and live birth rates similar for epididymal and testicular derived sperm in men with azoospermia due to obstruction
  • If non-obstructive azoospermia, microdissection testicular sperm extraction (TESE) should be performed.★
    1. Micro-TESE was observed to result in successful extraction 1.5 times more often than non-microsurgical testis sperm extraction

Vasography

• Absolute indications (must have all 3):
  1. Azoospermia
  2. Complete spermatogenesis with many mature spermatids on testis biopsy
  3. At least one palpable vas
• Relative indications:
  1. Severe oligospermia with normal testis biopsy
  2. High level of sperm-bound antibodies, which indicates unilateral, bilateral, or partial obstruction
  3. Low semen volume and very poor sperm motility (partial ejaculatory duct obstruction)
• The following diagnoses can be made with radiographic vasography
  • Inguinal vasal obstruction
  • Ejaculatory duct obstruction
  • Seminal vesicle agenesis
  • Partial agenesis of vasa deferentia
• If testis biopsy reveals normal spermatogenesis and the vasa are palpable, vasography, if necessary, should be performed only at the time of definitive repair of obstruction
  • There is no need to perform vasography at the time of testis biopsy for azoospermia unless immediate reconstruction is planned and the touch or wet prep biopsy reveals mature sperm with tails.
• Technique of Vasography and Interpretation of Findings
  • Any fluid exuding from the lumen is placed on a slide, mixed with a drop of saline, and sealed with a coverslip for microscopic examination.
  • If motile sperm are found in the vas, the testicular end should be gently barbotaged with 0.2 mL of human tubal fluid medium, and the fluid processed by the andrology laboratory for sperm cryopreservation for potential future use for IVF and ICSI.
    • Never inject fluid in direction of epididymis under pressure as it may rupture the epididymal tubules
    • Always sample vasal fluid first to allow cryopreservation of motile sperm if found; this should be done before injection with indigo carmine or x-ray contrast material  
      • Use indigo carmine instead of methylene blue to confirm patency; methylene blue kills sperm
      • Vasography with radiographic contrast media with intraoperative radiography is rarely indicated; formal vasography with x-ray contrast is needed only to locate obstructions proximal to the internal inguinal ring
        • Vasography may reveal the vas deferens ending blindly, far from the ejaculatory ducts. This finding indicates congenital partial absence of the vas deferens and warrants testing for cystic fibrosis mutations
  • If a large amount of fluid is found in the vasal lumen and microscopic examination reveals the presence of sperm, the obstruction is toward the seminal vesical end of the vas
  • If the vasal fluid is devoid of sperm with repeated sampling after milking the epididymis and convoluted vas, epididymal obstruction is present.
• Complications
  • Stricture
  • Injury to the vasal blood supply
  • Hematoma
  • Sperm granuloma

Varicocele Repair/Varicocelectomy

• See Varicocele Chapter Notes
• Indications★
  • Not recommend for males with non-palpable varicoceles detected solely by imaging
    • No demonstrable benefit of varicocele repair was observed in pregnancy or bulk seminal parameters with the exception of a possible small numerical effect on progressive sperm motility that is unlikely to be clinically important.
  • Should be considered in males attempting to conceive who have (3):
    1. Palpable varicocele(s) AND
    2. Infertility AND
    3. Abnormal semen parameters, except for azoospermic males
       • Meta-analyses demonstrate higher estimated pregnancy rates for men treated with any approach for repair of clinical varicocele compared to no treatment
       • For males with clinical varicocele and non-obstructive azoospermia, couples should be informed of the absence of definitive evidence supporting varicocele repair prior to ART.★
         • Varicocele repair defers treatment with ART for at least six months

Vasovasostomy/Vasoepididymostomy

• Microsurgical reconstruction is done by anastomosing the vas to the most distal site in continuity with the testis, documented by identifying sperm at this region of the reproductive tract. ★
• Higher patency and pregnancy rates after reconstruction are associated with ★
  • Bilateral vasovasostomy
  • More distal epididymal anastomoses (compared to epididymal anastomoses) for vasoepididymostomy
  • Presence of intact sperm at the site of reconstruction
  • Shorter obstructive interval
• Preoperative Evaluation
  • 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★
    • Limited data exist comparing outcomes for strategies for men interested in fertility after vasectomy.
    • Surgical sperm retrieval will require the use of ART/ICSI to achieve a pregnancy.
    • Microsurgical reconstruction of the male reproductive tract may be the preferable alternative to sperm retrieval and ICSI when the female partner has normal fertility potential
    • For couples with female factors that require ART, sperm retrieval and IVF is often the preferred option for management.
    • For couples interested in fertility who are farther out from vasectomy (e.g., over 25 years after vasectomy), microsurgical reconstruction with vasoepididymostomy may have lower success rates and sperm cryopreservation at the time of reconstruction should be considered.
  • Men with vasal or epididymal obstructive azoospermia should be counselled that microsurgical reconstruction may be successful in returning sperm to the ejaculate.★
  • Before attempted surgical reconstruction of the reproductive tract, adequate spermatogenesis should be documented. A prior history of natural fertility pre-vasectomy is usually adequate
  • Contraindications:
    • Non-obstructive azoospermia
  • Physical Examination
    • Testis: small or soft testes suggest impaired spermatogenesis and predict a poor outcome
    • Epididymis: an indurated irregular epididymis often predicts secondary epididymal obstruction, necessitating vasoepididymostomy
    • Sperm granuloma: suggests that sperm have been leaking at the vasectomy site.
      • Sperm are highly antigenic, and an intense inflammatory reaction occurs when sperm escape outside the reproductive epithelium.
      • The granuloma vents the high pressures away from the epididymis and is associated with a better prognosis for restored fertility
      • Rarely symptomatic
    • Hydrocele: the presence of a hydrocele in the presence of excurrent ductal system obstruction is often associated with secondary epididymal obstruction
    • Vasal gap: when a very destructive vasectomy has been performed, most of the scrotal straight vas may be absent or fibrotic and the patient should be advised that inguinal extension of the scrotal incision will be necessary to mobilize adequate length of vas to enable a tension-free anastomosis.
    • Scars from previous surgery: operative scars in the inguinal or scrotal region should alert surgeon to the possibility of iatrogenic inguinal obstruction (hernia repair) or vasal or epididymal obstruction (hydrocelectomy, orchiopexy)
  • Laboratory Tests
    • Semen analysis with centrifugation and examination of the pellet for sperm should be performed preoperatively.
      • Complete sperm with tails are found in 10% of preoperative pellets a mean of 10 years after vasectomy. Under these circumstances sperm are certain to be found in the vas on at least one side, indicating a favorable prognosis for restored fertility.
    • Serum anti-sperm antibody studies: the presence of serum anti-sperm antibodies corroborates the diagnosis of obstruction and the presence of active spermatogenesis
    • Serum FSH: men with small soft testes should have serum FSH measured; an elevated FSH predicts impaired spermatogenesis and a poorer prognosis
• Surgical Approaches
  • Scrotal Incision
    • Bilateral high vertical scrotal incisions provide the most direct access to the obstructed site in cases of vasectomy reversal
    • If the vasal gap is large or the vasectomy site is high, this incision can easily be extended toward the external ring
    • The testis should be delivered with the tunica vaginalis left intact
  • Inguinal Incision
    • An inguinal incision is the preferred approach in men when obstruction of the inguinal vas deferens from prior herniorrhaphy or orchiopexy is strongly suspected
• Maneuvers to gain vasal length what a large vasal gap is present (sequential):
  1. Separate the cord structures from the vas with blunt dissection using a gauze-wrapped index finger
  2. Dissect the entire convoluted vas free of its attachments (additional 4-6 cm of length) to the epididymal tunica, allowing the testis to drop upside down.
     • The convoluted vas should not be unraveled. This disturbs the blood supply at the anastomotic line
  3. Reroute vas under the floor of the inguinal canal by extending the incision to the internal inguinal ring and cutting the floor of the inguinal canal cut, as in a difficult orchiopexy
  4. Dissect the epididymis off the testis from the vasoepididymal (VE) junction to the caput epididymis (additional 4-6 cm of length)
     • See Epididymis Anatomy Notes
     • The epididymis can be intentionally dissected off the testis and mobilized to the caput, with the inferior and medial epididymal arteries intentionally ligated without adverse consequence. As long as the superior epididymal artery remains intact, the blood supply to the epididymis will be adequate
  5. With this combination of maneuvers, up to 10-cm gaps can be bridged

• When to Perform Vasoepididymostomy
  • A vasovasostomy is performed when:
    1. Copious, crystal clear, water-like fluid squirts out from the vas and no sperm are found in this fluid
    2. If microscopic examination of the vasal fluid reveals the presence of sperm with tails
  • If no fluid is found, a 24-gauge angiocatheter sheath is inserted into the lumen of the testicular end of the vas and barbotaged with 0.1 mL of saline while the convoluted vas is vigorously milked. The barbotage fluid is expressed onto a slide and examined
    • Men with large sperm granulomas often have virtually no dilation of the testicular end of the vas and little or no fluid initially; however, with barbotage and vigorous milking, invariably sperm can be found in this scant fluid and vasovasostomy is performed
    • If there is no sperm granuloma, and the vas is absolutely dry and spermless after multiple samples have been examined, vasoepididymostomy is indicated
    • If the fluid expressed from the vas is found to be thick, white, water insoluble, and toothpaste-like in quality, microscope examination rarely reveals sperm. Under these circumstances, the tunica vaginalis is opened and the epididymis inspected. If clear evidence of obstruction is found—that is, an epididymal sperm granuloma with dilated tubules above and collapsed tubules below—vasoepididymostomy is performed. When in doubt, or if not very experienced with vasoepididymostomy, vasovasostomy should be performed.
      • Vasoepididymostomy should only be performed on an epididymal tubule containing sperm
  • See Table 67-2 CW12th edition for relationship between gross apperance of vasal fluid and microscopic findings
    • UrologySchool.com Summary
      • Clear/thin, water vasal fluid: vasovasostomy
      • Thick/dry vasal fluid: vasoepididymostomy

• Multiple Vasal Obstructions
  • See section on arterial supply in Vas Deferens Anatomy Chapter Notes
  • Simultaneous vasovasostomies at two separate sites will usually lead to devascularization of the intervening segment with fibrosis and necrosis
• Varicocelectomy and Vasovasostomy
  • See Varicocelectomy Chapter Notes
  • When varicocelectomy is properly performed, all spermatic veins are ligated and the only remaining routes for testicular venous return are the (deferential) vasal veins
  • Varicocelectomy in men with a history of vasectomy with or without reversal requires careful preservation of the testicular artery as the primary remaining testicular blood supply as well as preservation of some avenue for venous return since the vasal arteries and veins are likely to be compromised from either the original vasectomy or the reversal itself
• Anastomotic Techniques: Keys to Success
  1. Mucosa-to-mucosa approximation
  2. Leakproof anastomosis
  3. Tension-free anastomosis
  4. Good blood supply
  5. Healthy mucosa and muscularis
  6. Good atraumatic anastomotic technique
• Microsurgical Multilayer Microdot Method
  • The microdot technique ensures precise suture placement by exact mapping of each planned suture.
  • Exactly 6 mucosal sutures are used for every anastomosis
• Crossed Vasovasostomy
  • Used to connect a healthy testicle to the contralateral unobstructed vas
  • Indications (2):
    • Unilateral obstruction of the inguinal vas deferens or ejaculatory duct associated with contralateral:
      1. Atrophic testis
      2. Epididymal obstruction
         • It is preferable to perform one anastomosis with a high probability of success (vasovasostomy) than two operations with a much lower chance of success (e.g., unilateral vasovasoepididymostomy and contralateral TURED
• Postoperative Management
  • Scrotal support at all times (except in the shower), even when sleeping, for 6 weeks postoperatively. Thereafter, scrotal support is worn during athletic activity until pregnancy is achieved.
  • Desk work is resumed in 3 days. No heavy work or sports are allowed for 3 weeks.
  • No intercourse or ejaculation is allowed for 3 weeks postoperatively.
  • Semen analyses are obtained at 1, 3, and 6 months postoperatively and every 6 months thereafter. If azoospermia persists at 6 months, a redo vasovasostomy or vasoepididymostomy will be necessary
• Postoperative Complications
  • The most common complication is hematoma
  • Progressive loss of motility followed by decreasing counts indicates stricture
    • Because of the risk of late stricture and obstruction, cryopreservation of semen specimens as soon as motile sperm appear in the ejaculate is strongly recommended

Surgery of the Epididymis

• The superior and middle epididymal branches of the testicular artery are medial to and separate from the main testicular artery and veins
  • Clinical implication: surgical procedures may be performed on the epididymis without compromise to testicular blood supply
• Vasoepididymostomy
  • Indications:
    • Testis biopsy reveals complete spermatogenesis and scrotal exploration reveals the absence of sperm in the vasal lumen with no vasal or ejaculatory duct obstruction
      • If microscopic examination of the vasal fluid sampled reveals the absence of sperm, the diagnosis of epididymal obstruction is confirmed and a vasoepididymostomy is performed.
  • Banking sperm both intraoperatively and as soon as they appear in the ejaculate postoperatively after vasoepididymostomy is recommended.

Ejaculatory Duct Obstruction

Causes

• Congenital (most common cause)
  • Aplastic segment at the terminal end of the vas
• Acquired
  • Occasionally results from chronic prostatitis or extrinsic compression of the ejaculatory ducts by prostate or seminal vesical duct cysts

Diagnosis and Evaluation

• Findings associated with ejaculatory duct obstruction:
  1. Azoospermic or severely oligospermic and/or asthenospermic men with at least one palpable vas deferens
  2. Low semen volume
  3. Acidic semen pH
  4. Negative, equivocal, or low semen fructose levels
  5. Normal serum levels of FSH
  6. Testis biopsy reveals normal spermatogenesis
• Transrectal US
  • A (müllerian duct) midline cystic lesion or dilated ejaculatory ducts and seminal vesicles can be visualized  
    • Suggestive if AP diameter of seminal vesicle >1.5cm
  • Microscopic examination of TRUS-guided aspiration of the cystic or dilated ejaculatory ducts or seminal vesicles can be performed.
    • If motile sperm are found, they are cryopreserved and 2 to 3 mL of indigo carmine diluted with water-soluble radiographic contrast is instilled. If a radiograph confirms a potentially resectable lesion, TURED is performed without the need for prior vasography
      • Transrectal sonography with aspiration should be performed immediately before anticipated [TURED] surgery and uses the same bowel preparation and antibiotic prophylaxis as for transrectal prostate biopsy.
    • If no sperm are found in the aspirate, vasography is necessary.
      • If no sperm are found in either vas when the vasotomy is made and vasography reveals ejaculatory duct obstruction, it is best to abandon attempts at reconstruction and simply perform microsurgical epididymal sperm aspiration and cryopreservation for future IVF and ICSI.
      • Performance of simultaneous vasoepididymostomy and TURED is unlikely to be successful.

Management

Options

• Surgical sperm extraction★
• Transurethral resection of ejaculatory ducts (TURED)★

Transurethral resection of ejaculatory ducts (TURED)

• Goal of the surgery is to resolve the obstruction to allow sperm to enter the ejaculate, which can be used for unassisted conception or ART
  • 63-83% of patients will have an improvement in semen parameters after the procedure
  • In addition to fertility, investigators have reported successful treatment with TURED for other symptoms including hematospermia, recurrent infection, or pain (i.e., scrotal, post-ejaculatory).
• Indications
  • May be offered if a seminal vesicle aspirate reveals the presence of sperm in an azoospermic male
• Technique
  • Resection of the verumontanum will often reveal the dilated ejaculatory duct orifice or cyst cavity. Resection should be carried out in this region with great care to preserve the bladder neck proximally, the striated sphincter distally, and the rectal mucosa posteriorly.
  • In men with EDO associated with Mullerian cysts, treatment involves unroofing of the cyst, resulting in decompression of the cyst and relief from extrinsic obstruction of the ejaculatory ducts.
• Adverse events (9):
  1. Restenosis
  2. Pain
  3. Epididymoorchitis
     1. Recurrent epididymitis often results in epididymal obstruction
        • Chronic low-dose antibacterial suppression, such as that used for vesicoureteral reflux, may be necessary until pregnancy is achieved
  4. Urinary retention
  5. Reflux of urine into the ejaculatory ducts and seminal vesicles or substantial defects in the prostatic fossa
     1. Leading to watery ejaculate and resulting in acute and chronic chemical and/or bacterial epididymitis
     2. can be assessed by voiding cystourethrography or measurement of semen creatinine levels
  6. Gross hematuria
  7. Incontinence
  8. Retrograde Ejaculation
     • Common after TUR, even when care has been taken to spare the bladder neck
  9. Urethral stricture

Ejaculatory Stimulation

Indications (1)

• Infertility due to ejaculatory dysfunction★
  • Neurologic conditions associated with abnormal or absent seminal emission due to impaired sympathetic outflow (4):
    1. Spinal cord injury
    2. Demyelinating neuropathies (multiple sclerosis)
    3. Diabetes
    4. Iatrogenic (retroperitoneal lymph node dissection, pelvic surgery)
  • With stimulation, motile sperm can be obtained for assisted reproduction techniques (IUI, IVF with ICSI).
    • Semen collected from men with spinal cord injury is often initially senescent and of poor quality with a low sperm count and reduced sperm motility but may improve with subsequent ejaculations

Technique

• Stimulation can be done with penile vibratory devices or electroejaculation
  • Approach depends on level of spinal cord lesion§
    • If lesion above T10, ejaculatory reflex arc will be intact so can stimulate with penile vibratory devices
    • If lesion T10 or below, consider electroejaculation
    • If these fail, sperm retrieval is performed
  • Ejaculatory stimulation for men with spinal cord injuries may result in autonomic dysreflexia
    • Autonomic dysreflexia
      • See 2019 CUA NLUTD Guideline Notes
      • An uninhibited sympathetic reflex accompanied by headache, diaphoresis, hypertension, bradycardia, and diaphoresis
      • More common with spinal cord injury at a level of T6 or above
      • Can be life-threatening.
      • Pretreatment, 15 minutes before the procedure, with 20 mg of sublingual nifedipine is used
      • Should have intravenous access and their blood pressure and pulse should be monitored every 2 minutes before, during, and for 20 minutes after ejaculatory stimulation.
      • In the event of a sympathetic outflow (autonomic dysreflexia), termination of the procedure should be sufficient to break the response; however, intravenous access allows for delivery of sympatholytic agents should they become necessary

Assisted Reproductive Technology

Indications

1. Surgically unreconstructable obstruction such as congenital absence of the vas deferens
2. Few viable sperm in the ejaculate
3. Azoospermia with varicoceles (half of these men will respond to varicocelectomy with return of enough sperm to ejaculate to achieve pregnancy using In-vitro Fertilization (IVF) with/out Intracytoplasmic Sperm Injection (ICSI)
4. Non-obstructive azoospermia

Options

• Intrauterine insemination (IUI)
• In-vitro Fertilization (IVF) with/out Intracytoplasmic Sperm Injection (ICSI)

Intrauterine insemination (IUI)

• Technique
  • Involves processing a semen specimen and placing the low volume washed semen into the uterine cavity at the time of ovulation
  • May be done with or without ovarian stimulation of the female partner to enhance oocyte production
    • Pregnancy rates with IUI are increased in couples with abnormal semen parameters if the woman undergoes ovulation induction.
      • In men with male factor infertility due to abnormal semen parameters, natural cycle intracervical or intrauterine insemination (IUI) is no better than timed vaginal intercourse.
        • Natural cycle refers to allowing the woman to ovulate on her own without pharmaceutical induced stimulation of the development of multiple follicles through ovulation induction.
        • Natural cycle IUI is useful in infertility caused by mechanical problems such as hypospadias, retrograde ejaculation, impotence, or pure cervical factor infertility.
• Males with low total motile sperm count (<5 million motile sperm after processing) are expected to have lower pregnancy rates after IUI than using sperm from men with normal total motile sperm counts.★
  • Since approximately 50% of sperm do not survive semen processing, a total motile count of at least 5 to 10 million sperm is usually required to allow for an adequate number of motile sperm for insemination.§

In-vitro Fertilization (IVF) with/out ICSI

• In IVF, the egg and sperm (of which there are multiple) are left in a petri dish to fertilize on their own. In ICSI, one sperm is directly injected into the egg.
• ICSI minimizes any adverse effects of sperm “quality” as measured by sperm concentration, motility, and morphology as long as viable sperm are present to inject into all oocytes
  • With IVF, abnormal sperm motility and morphology adversely affect fertilization rates. The application of ICSI during IVF treatment provided fertilization rates comparable to that observed with otherwise normal sperm
• Requires only a small number of motile sperm, compared to IUI§
• Involves limited medical risk to the female partner
• IVF treatment requires more than a week of ovarian stimulation, procedures for oocyte retrieval and intrauterine embryo transfer
• Couple may need to undergo several cycles of IVF treatment in order to achieve a pregnancy
  • Each attempt typically allows for a 33% live delivery rate per initiated IVF cycle
• Pregnancy and live birth results are closely related to female age, with progressively lower success with increased female age (over 35 years)
• Approximately 19% of all deliveries involve twins
• In men undergoing surgical sperm retrieval, either fresh or cryopreserved sperm may be used for ICSI★
  • A meta-analysis evaluating the use of sperm from men with NOA found no significant differences in fertilization, pregnancy, or live birth rates from ICSI in men for whom sperm was extracted and used with or without cryopreservation, as long as there were sperm of adequate number and survived cryopreservation and thawing.[2]

Orchiopexy in Adults

• When scrotal orchiopexy is performed for retractile or ectopic testis in adults, a dartos pouch operation should be performed.
  • Simple suture orchiopexy of the tunica albuginea of the testis to the dartos, as is performed sometimes to prevent torsion, will not prevent retraction of these testes into the groin. Creation of a dartos pouch will keep the testis well down in the scrotum and permanently prevent retraction. This is also the most reliable and safest technique for the prevention of testicular torsion

Non-surgical Management

Options

1. Selective estrogen receptor modulators (e.g. clomophene (clomid), tamoxifen)
2. Aromatase inhibitors (anastrazole or letrozole)
3. Gonadotropins (hCG, FSH)
4. Growth Hormone

Selective estrogen receptor modulators (e.g. clomophene (clomid), tamoxifen)

• MOA: acts as an agonist or antagonist on different estrogen receptors.
  • Agonists on receptors in bone, improving bone health
  • Antagonists on receptors on the hypothalamus and pituitary, resulting in increased GnRH.
    • In men normal binding of estrogen at these receptors functions as an indirect negative feedback mechanism of endogenous testosterone production to down-regulate GnRH and subsequently pituitary gonadotropin production.
• Benefits
  1. Increased testosterone
     • Treatment with SERMs results in increased GnRH, which then stimulates LH and FSH production by the pituitary gland; the increased LH production, in turn, stimulates Leydig cell production of testosterone§
     • Testosterone increase is more than that achieved with anastrazole
  2. Increased sperm counts
     • See Risk Calculator for expected changes for men with infertility who are given clomiphene citrate
• Indications
  • Not FDA-approved for use in males
    • Clomiphene citrate is the most commonly used SERM for treating hypogonadism when fertility must be maintained. However, this remains an off-label use.
      • Enclomiphene citrate, the functional stereoisomer of clomiphene citrate, is currently in commercial development. Its potential advantage is avoidance of the estrogenic side effects of its enantiomer zuclomiphene.
  • Consider in patients with low testosterone, borderline high/high FSH (lazy pituitary)
• Administration
  • Available orally
  • Typically dosing starts at 25 mg daily and can be increased up to 100 mg daily.
• Adverse events
  • No specific adverse effects attributed to clomiphene or enclomiphene citrate in males.
  • Same theoretical risk of testosterone replacement exists

Aromatase inhibitors (anastrazole or letrozole)

• MOA: inhibit the enzyme aromatase from converting testosterone to estradiol (E2)
  • Estradiol is an indirect mediator of testosterone feedback inhibition of the hypothalamus-pituitary-testis axis.
  • Aromatase inhibition can result in decreased estrogen levels and ultimately increased gonadotropin production
• May decrease estradiol and and LH and testosterone levels in patients with elevated estradiol (T/E ratios <10), such as those with obesity or Klinefelter syndrome (tend to have more adipose tissue)
• Limited data to improve sperm parameters
• Indications
  • May be considered for men with testosterone deficiency and elevated estradiol levels★
  • Not FDA-approved for use in males
• Administration
  • Available orally
• Adverse events
  • Theoretical risk of decreasing bone mineral density as they decrease E2.
  • Same theoretical risk of testosterone replacement exists

Gonadotropic related (hCG, FSH, GnRH)

Options

• hCG
• FSH
• GnRH

hCG

• MOA: stimulates testosterone production from Leydig cells by mimicking LH
  • hCG has the same structure as the beta unit for LH
• When used in conjunction with exogenous testosterone administration, may reverse azoospermia and maintain elevated intratesticular testosterone levels
  • By directly stimulating Leydig cells, intratesticular testosterone increases regardless of the extent of negative feedback on the HPG axis, improving spermatogenesis.
  • Greater effect seen in males with initial testes length >4cm
  • Effect improved with addition of FSH or hMG
    • Most experts treat with hCG alone for 3 to 6 months after which spermatogenesis induction occurs in some cases.
    • For patients without adequate spermatogenesis induction, treatment proceeds with the addition of FSH
• Indications
  • FDA approved for treatment of pituitary hypogonadism in males
  • Classically used to treat hypogonadotropic hypogonadism, such as Kallmann syndrome.

FSH

• When given alone or in combination with testosterone, has proven unsuccessful at inducing spermatogenesis or maintaining spermatogenesis in those previously induced with hCG/FSH, confirming the need for maintenance of elevated intratesticular testosterone.

• Indications
  • Infertility associated with hypogonadotropic hypogonadism★
  • Not FDA-approved for use in males★
  • Not used frequently due to cost
    • hCG is more expensive than clomiphene citrate and anastrozole, and requires multiple weekly subcutaneous injections.

• Adverse events
  • hCG is generally well tolerated but there are reports of gynecomastia in up to a third of the patients, which should be monitored.
    • If gynecomastia does occur, anastrazole would be the first line treatment option.
  • Same theoretical risk of testosterone replacement exists

GnRH

• Pulsatile GnRH is not currently approved in the US or Europe§

Growth Hormone (GH)

• Also known as somatotropin
• Single most important hormone for normal growth.
• Acts through its mediator, insulin-like growth factor-1 (IGF-1)
• GH and IGF-1 regulate gonadal steroidogenesis and spermatogenesis via receptors on pituitary gonadotrophs, Sertoli cells, Leydig cells and germ cells. GH and IGF1 also reduce SHBG levels, potentially increasing androgen bioavailability.
• GH for androgen replacement is off-label.

Supplements

• Benefits of supplements (e.g., vitamins, antioxidants, nutritional supplement formulations) are of questionable clinical utility§

Treatment Selection★

• Testosterone monotherapy should not be prescribed for the male interested in current or future fertility§
  • Exogenous testosterone administration provides negative feedback to the hypothalamus and pituitary gland, which can result in inhibition of gonadotropin secretion.
  • Depending on the degree of testosterone-induced suppression, spermatogenesis may decrease or cease altogether, resulting in azoospermia.
  • Although recovery of sperm to the ejaculate occurs in most men with cessation of testosterone therapy, the time course of recovery may be prolonged and can be months or rarely years.
    • In those that may want to pursue paternity in the more distant future, testosterone therapy may be offered, but the patient should be counseled about the effects on spermatogenesis and the time course required for resumption of spermatogenesis.
• Hyperprolactinemia
  • Etiology of hyperprolactinemia should be treated
• Secondary hypogonadism (hypogonadotropic hypogonadism)§
  • Patients with HH present with deficient LH and FSH secretion. In the absence of LH and FSH stimulation, the Leydig cells in the testes do not secrete testosterone, and spermatogenesis is disrupted.
  • Can be congenital (e.g. Kallman syndrome, associated with anosmia and the lack of endogenous GNRH secretion) or acquired (adult-onset)
  • Spermatogenesis can be initiated and pregnancies achieved in many of these idiopathic hypogonadotropic hypogonadism men when they are treated with exogenous gonadotropins (hCG, FSH) or GnRH.
    • Usual first-line drug for the treatment of IHH for restoration of testosterone and spermatogenesis is hCG
      • hCG is FDA-approved for use in men with HH
      • Degree of response correlates with the size of the testis prior to treatment
      • Initial treatment consists of hCG injections (1,500-2,500 IU, twice weekly)
        • Can be followed by FSH, when indicated, after testosterone levels are normalized on hCG
    • SERMs have been used off label as an alternative treatment to increase testosterone and sperm density in men with acquired hypogonadotropic hypogonadism.
  • Secondary causes of HH include pituitary or suprasellar tumors, pituitary infiltrative disorders (e.g., hemochromatosis, tuberculosis, sarcoidosis, histiocytosis), exogenous androgens, other medications (e.g., chronic narcotic exposure), hyperprolactinemia, prior head trauma, pituitary apoplexy, and severe chronic illness.
    • The first line treatment for secondary causes of hypogonadotropic hypogonadism is towards the underlying disorder. Once that has been accomplished, and the patient continues to have HH, a trial of the gonadotropin treatment regimen described above can be initiated.
      • SERM therapy will not be beneficial if the pathology is due to primary pituitary dysfunction, such as after surgical resection.
• Infertile men with low serum testosterone (and low or normal serum LH)
  • May use aromatase inhibitors (AIs), hCG, selective estrogen receptor modulators (SERMs), or a combination thereof
    • AIs, hCG, and SERMs act by different mechanisms to increase endogenous testosterone production. Each agent may be used separately or in combination in an effort to increase serum testosterone concentrations without impairing spermatogenesis.
      • If elevated estradiol levels: consider use of AIs
      • If low or normal serum LH: Either hCG or SERMs may be considered
      • If elevated LH, consistent with primary hypogonadism, may have a limited serum testosterone response to these medications due to inherent testicular dysfunction.
    • Although the goal of testosterone optimization in the infertile male may be symptom amelioration, symptomatic outcomes and benefits may not be comparable to those achieved using standard (exogenous) testosterone replacement therapy.
• Idiopathic infertility
  • Use of SERMs has limited benefits relative to results of ART
    • Any possible limited benefits of SERM administration, particularly in the patient population with idiopathic infertility, are small and, therefore, outweighed by the distinct advantages offered by other forms of medically-assisted reproduction (e.g., IVF), which include higher pregnancy rates and efficiencies with respect to the earlier timeframe of conception.
  • May consider treatment using an FSH analogue with the aim of improving sperm concentration, pregnancy rate, and live birth rate
• Non-obstructive Azoospermia
  • For any patient with NOA, it would be ideal to optimize spermatogenesis and hence the chances of sperm recovery at the time of attempted surgical sperm retrieval.§
  • Limited data supporting pharmacologic manipulation with SERMs, AIs, and gonadotropins prior to surgical intervention.

Questions

1. What are the different approaches to surgical sperm extraction? Which approach(es) can be used for obstructive azoospermia?
2. What are the different classes of medications used to treat infertility?

Answers

1. What are the different approaches to surgical sperm extraction? Which approach(es) can be used for obstructive azoospermia?
2. What are the different classes of medications used to treat infertility?

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 24
• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 25
• Schlegel, Peter N., et al. "Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I." The Journal of urology 205.1 (2021): 36-43.
• Khan MA, Pagani RL, Ohlander SJ. 2019 AUA Update: Exogenous Testosterone and Male Reproduction
• Gupta N, David M, Kohler TS. 2017 AUA Update: Treatment of Male Hypogonadism: Alternatives to Testosterone