Male Infertility

Male Infertility (Azospermia, Oligospermia, Aspermia, and Varicoceles)

1. What every clinician should know

Male infertility

Infertility is defined as the inability for a couple to achieve a pregnancy after 1 year of regular unprotected intercourse. Having said that, the following infertile couples should undergo a medical evaluation prior to 1 year. (1) male-specific risk factors (such as bilateral cryptorchidism), (2) female risk factors (such as age over 35 years), or (3) if the couple questions the male’s fertility potential.

There are two classes of male infertility: primary and secondary. In the case of primary infertility, the male was never fertile. This affects 15% of couples, with a work up demonstrating a male etiology approximately half the time. For the 50% of couples diagnosed with male infertility, 30% will have only a male-factor diagnosis, whereas the remaining 20% will have both male and female factors diagnosed.

For secondary infertility, the male was previously fertile, but is now unable to conceive. The most common factor for secondary infertility is a varicocele. Nonetheless, men with secondary infertility should be evaluated in the same way as men who have never initiated a pregnancy.

The chance of a “normal” couple conceiving is 20-25% per month, 75% by 6 months and 90% by 12 months. For both men and women fertility potential peaks at 24 years. Approximately 15% of couples are unable to conceive by one year. A fertility workup should be started right away when maternal age is over 35 years. Of infertile couples, 25% will conceive without treatment, and, on average, 1-3% will conceive each month. When a male factor is present, it is often identified (or classified) by an abnormal semen analysis. The standard is to review at least two semen analyses. (Table I)

Reference for sperm parameters (semen analysis).

WHO reference values

The reference values for a semen analysis continue to evolve. Traditionally, a committee working for the World Health Organization (WHO) would come to a consensus as to which semen-related parameters would predict a better chance for fertility. Historically, changes to the WHO reference values focused on the percentage of normal sperm shape as determined by strict Kruger morphology. The drop in percent normal morphology reflects the idea that a large proportion of sperm with normal shapes were becoming less and less important for normal fertility.

>50% normal morphology – WHO 1987 Criteria
>30% normal morphology – WHO 1992 Criteria
>14% normal morphology – WHO 1999 Criteria
>4% normal morphology – WHO 2010 Criteria

In 2010, the WHO published their latest update defining what a “normal” semen analysis looks like. The data is a based on semen parameters from 1,953 men from 14 different countries whose partners became pregnant within 12 months of discontinuing contraceptive use. This is divergent from prior tables from the WHO which focused on sperm parameters from fertility-challenged men. As with other laboratory reference ranges, the sperm parameters were divided into percentiles where 95% of the population was considered “normal.” The lower 5% (5th percentile) were considered the outlier (subfertile). In general, a patient can find their sperm parameters on the chart and determine what percentage of fertile men had a similar parameter.

Semen analysis classifications

Normospermia: all values are normal
Azoospermia: no sperm in ejaculate
Oligospermia: sperm concentration of less than 15 M/cc
Asthenospermia: impaired sperm motility
Teratospermia:abnromal sperm shape
Aspermia: no ejaculate, volume = 0

Risk factors for male factor infertility

(Table II)

Top 5 Diagnostic Categories for Male Infertility.

Varicocele
Cystic fibrosis
Congenital bilateral absence of the vas deferens
Ejaculatory disorders
Hormonal disorders
Prostatitis
Post-puberty mumps orchitis
Febrile illnesses
Thyroid disorders
Cirrhosis
Diabetes
Myotonic dystrophy
Young’s syndrome
Immotile cilia syndrome
Kartagener’s syndrome
Gonadotoxins

Hyperthermia (fever, varicocele)

Environmental exposure (pesticides, heavy metals, hyperthermia, cigarette smoke)

Therapeutics (radiation, chemotherapy, some antibiotics and other drugs)

Abused agents (cigarettes, marijuana, alcohol, steroids, opiates, cocaine, heroin/methadone)
Genetic abnormalities

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

Y chromosome microdeletion

Karyotype abnormality

2. Diagnosis and differential diagnosis

The full evaluation of an infertile male includes a complete reproductive and medical history, a physical exam, and at least two semen analyses. Based on the results of the full evaluation, other procedures and tests to elucidate the etiology of infertility may be recommended. These tests may include additional semen analyses, endocrine evaluation, post-ejaculatory urinalysis, ultrasonography, specialized tests on semen and sperm, and genetic screening.

History

Primary infertility

Undescended testes/cryptorchidism is associated with infertility especially if not corrected before two years of age. Watch for higher risk for testes cancer, including cancer in the contralateral (descended) testis. For delayed or early puberty, do hormonal workup including T/LH/FSH/Prolactin, or at a minimum T/FSH. Scrotal/testicular trauma may result in testis atrophy or disruption of the tunica albuginea. Disruption of the tunica albuginea may result in anti-sperm antibodies, which should be screened for on a semen analysis.

Post pubertal mumps orchitis, can reduce fertility. Pre-pubertal mumps do not generally impact subsequent fertility. Pre-pubertal mumps are not a problem. A history of sexually transmitted diseases can cause scaring, especially in the epididymis, which may cause post-testicular obstruction. In the case of erectile dysfunction, the man must be able to achieve penetration and antegrade ejaculation.

Lubricants are toxic to sperm motility. Examples include KY jelly, Surgilube, Lubrifax, Keri lotion, petroleum jelly, and saliva. Non-toxic lubricating agents are found in the kitchen, including raw egg whites and vegetable, peanut, and safflower oils. In the case of low libido, check testosterone/LH. Do not forget to inquire about depression/anxiety. Never treat low libido by exogenous testosterone products (gels, patches, injections). This will worsen spermatogenesis by down regulating the anterior pituitary release of LH and FSH—lowering both testicular testosterone production and spermatogenesis.

For anosmia (difficulty smelling), check LH/FSH/Prolactin, and order an MRI of the sella turcica to rule out a lesion of the pituitary such as Kallman’s syndrome. Respiratory infections may be a sign of Kartagener’s syndrome (immotile cilia), or, cystic fibrosis (CFTR mutation).

Exposure to gonadotoxins and radiation may also be a contributing factor. In addition, social factors such as use of tobacco, marijuana, excessive alcohol, steroids, cocaine, and opiates/heroin/methadone may play a role. The later lowers testosterone by an opioid induced androgen deficiency (OPIAD) syndrome. Chemotherapy, especially cyclophosphamide, nitrogen mustards, and chlorambucil, negatively impact male fertility.

Other medications, such as Cimetidine, Spironolactone, Allopurinol, Dilantin, Tricyclic antidepressants (increases prolactin), Colchicine, LHRH agonists (depresses gonadotropin secretion), Androgens (depresses gonadotropin secretion), and Sulfasalazine (lowers sperm motility and density) impact male fertility. Antibiotics can affect fertility. Tetracycline can lower testosterone by 20%, while ofloxacin, gentamycin, and erythromycin can depress spermatogenesis.

Environmental factors include exposure to excessive heat or fever, pesticides or agricultural agents such as DDT, methyl chloride, DBCP, and heavy metals.

Secondary infertility

Secondary infertility, defined as a preciously fertile male, now experiencing an inability to have another child, is most commonly caused by a varicocele.

Physical exam

Exam the general appearance for normal hair distribution, longer arms (Kleinfelter’s if extended arm length is greater than height), or breast development (may indicate excess estradiol or prolactin levels). Inspect the penis to rule out hypospadias. Severe hypospadias (peno-scrotal or proximal shaft locations) may preclude vaginal deposition of sperm. At birth, the combination of hypospadius and cryptorchid testes should prompt an intersex workup.

Testes need to be descended and of normal size (4 x 3 x 2 cm) and consistency. In the case of small, firm testes, test for Kleinfelter’s. Epididymis and vas deferens should be present bilaterally. A diagnosis of Congenital Absence of the Vas Deferens (CAVD) is made by physical exam. Spermatoceles may scar the involved epididymal tubule. A varicocele is the most common correctable cause for male infertility, especially secondary infertility.

Semen analysis

The specimen needs to be kept at body temperature (under a coat, or in a pant pocket) and submitted to the lab within one hour of ejaculation. This should occur three to five days after the previous ejaculation. The second semen analysis should occur at least one month after the first analysis. Evaluate no sooner than three months after a febrile illness or stressful event. It takes the sertoli cells (+/-) 74 days to recover from such an insult.

Fresh sperm is a pearly-white coagulum which liquefies within a few minutes. The liquefaction is catalyzed by prostate specific antigen (PSA). Check for anti-sperm antibodies if the semen specimen is reported to be viscous or has poor liquefaction. Sperm parameters include concentration, motility, and morphology (shape). There are no “normal” values.

Concentration

15 M/cc or better is the goal
5-15 M/cc – Oligospermia
0-5 M/cc – Severe Oligospermia (recommend genetic testing for these men. Karyotype cystic firbrosis, and Y-chromosome microdeletion testing)
0 M/cc – Azospermia (recommend genetic testing in addition to an evaluation for vasal obstruction physical exam, palpate bilateral vas deferens, trans-rectal ultrasound to rule out prostatic mullerian duct cyst
No ejaculate at all – Aspermia (evaluate for retrograde ejaculation (void after orgasm and check urine for sperm) and mullerian duct cyst via trans-rectal ultrasound)

Motility

40% or better is ideal motility. To improve, consider evaluation for varicoceles and a trial of antioxidants.

Morphology

Normal shape is more than 4% normal shape by strict Kruger morphology. Fertilization rates were lowest for patients with normal morphology scores of less than 4%. To improve, consider evaluation for varicoceles and trial of anti-oxidants. Strict morphology scores have not consistently predicted fertility and should not be used in isolation to make prognostic or therapeutic decisions.

Volume

Over 1.5 to 2 cc is ideal. If less than 1.5 cc with presence of vas deferens by physical exam, consider checking a post-ejaculate urine analysis for retrograde ejaculation. Patient “ejaculates” and then voids into a container with buffer solution. May also alkalinize the urine. Centrifuge the specimen and look at the resultant pellet for sperm. Collected sperm can be used for ICSI.

Classification of male infertility

This section describes the various classifications of the infertile male.

Pretesticular

(Figure 1)

This classification involves hormonal imbalance. Hypogonadotrophic hypogonadism is inadequate anterior pituitary LH/FSH levels to stimulate leydig and/or sertoli cells. Low testicular testosterone is caused by inadequate LH stimulation of otherwise normal leidig cells. If present early in life, T-dependent male development will be delayed. Such a patient will have undescended testes, micropenis, and an absence of puberty.

Etiology

Kallman’s syndrome (most common cause, X-linked mid-line defect with absence of GnRH secretion due to hypothalamus dysfunction)
Pituitary/Hypothalamic damage
Tumor
Trauma
Prior surgery
Prader-Willi Syndrome (Figure 2)

Absent GnRH secretion

Obese and short statured with small hands and feet

Developmentally disabled
Laurence-Moon-Bardet-Biedl Syndrome

Plydactyly, retinitis pigmentosa
Medications

LHRH agonist/antagonists

Exogenous androgens (testosterone replacement therapies)
Elevated prolactin will suppress LH/FSH secretion by the anterior pituitary

Prolactinoma: 25-100 ng/dl, usually benign, treat with bromocriptine or Cabergoline (less side effects than bromocriptine).
Renal failure
Stress
Hypothyroidism
Estrogens
Psychiatric drugs (especially phenothiazines)

Evaluate the hypothalamus-pituitary-gonadal axis. Start with testosterone and FSH. In hypogonadotrophic hypogonadism, total testosterone levels are less than 300 ng/dl and FSH is low. In this situation, also check serum LH (low), Prolactin (typically normal unless there is a prolactin secreting lesion), and TSH levels.

Testicular

This classification involves abnormal sperm production due to testicular hypofunction. Hypergonadotrophic hypogonadism is defined by elevated LH/FSH with suboptimal testicular response by leydig and/or sertoli cells.

Etiology

Kleinfelter’s Syndrome

(Figure 3)

In this syndrome, an individual gets an extra “X” from mom or dad: 47 XXY. This is the most common karyotype abnormality (66%) in infertile men. It also causes an increased risk for extra-gonadal germ cell tumors. Physically, find small firm testes with gynecomastia and azoospermia due to seminiferous tubule sclerosis. Sperm may be found in testes with biopsy. It is OK to use recovered sperm (with counselling) for assisted reproduction (ICSI).

Noonan Syndrome

(Figure 4)

This is Male Turner Syndrome (46 XY). Involves short stature, webbed neck, low set ears, cubitus valgus, undescended or absent testes, a person who has never developed, and Orchiectomy. Also may involve non-functioning testes, atrophy, torsion, cryptorchidism, Oligospermia (less than 10 M/cc) in 25% of unilateral and 50% of bilateral undescended testes. The higher in the abdomen the testis are, the more severe the dysfunction.

Sertoli-only syndrome

(Figure 5)

Sertoli and Leydig cells are present, but there is no organized sperm production. See smaller testes with azoospermia and elevated FSH (more than 2 times normal).

Maturation Arrest

Spermatogenesis is halted at a specific step in the maturation process. Early arrest is worse than late maturation arrest. With late maturation arrest, can often find sperm on testis biopsy (50-75%) for use with ICSI.

May be caused by testis infection, such as post-pubertal mumps orchitis, gonadotoxins, excessive heat or fever, pesticides or agricultural agents such as DDT, methyl chloride, DBCP, and heavy metals.

Varicoceles

Varicoceles are dilated veins that surround the testis. Varicoceles are typically demonstrated as veins measuring 3.5 mm or larger with reversal of blood flow with valsalva. The left side predominates (90% are on the left). An unilateral varicocele can cause bilateral testis damage. Varicoceles may cause testicular fibrosis, progressively worsening spermatogenesis, and testicular atrophy. This condition is rarely detected before the age of 10, and impacts 15% of the general population, 40% of infertile men, and 70% of men with secondary infertility. It is the most common cause of secondary infertility.

Varicoceles is graded by physical exam:

Grade I: palpable with valsalva
Grade II: palpable in standing position without valsalva, not visible through skin
Grade III: grossly visible through the scrotal skin
Subclinical: not palpable, noted only on scrotal ultrasound. Repair not recommended.

The effect on semen analysis parameters include decreased motility (90% of patients), less than 20 M/cc of sperm (65% of patients), and disrupted sperm shape/morphology. The etiology of a varicocele’s detrimental effect on sperm parameters is poorly understood. Possibilities include increased intrascrotal temperature, hypoxia, reflux of renal or adrenal metabolites from the renal veins, decreased blood flow, and oxidative stress/free radicals. In adolescents with a varicocele and ipsilateral testicular atrophy, a varicocelectomy will allow for testicular catch-up growth but may not prevent fertility problems. Finally, varicoceles may suppress testosterone levels. In retrospective analyses, varicocelectomy has demonstrated improved post-operative testosterone levels (mean increase of 109 ng/dL).

To check testicular function, evaluate testis size (should be 4 cm in length) and FSH. If FSH is more than twice the normal range, significant testicular failure is the cause. Recommend a testicular biopsy for both a diagnostic and therapeutic options. If sperm are recovered at the time of biopsy, they can be cryopreserved for future ICSI cycles. If semen analysis demonstrates azoospermia or severe oligosperma (<5 M/cc), obtain a Karyotype, cystic fibrosis mutations, and Y-chromosome microdeletion to rule out genetic causes. For recurrent pregnancy loss, check sperm for DNA damage.

Post Testicular

This is impaired delivery of sperm from the testes to the female.

Etiology

Ejaculatory duct obstruction

This may include a mullerian duct cyst (Figure 6), indicated by thin, watery ejaculate. Evaluate by trans-rectal ultrasound and look for wide ejaculatory ducts (normally less than 2.5 mm in AP diameter) and wide seminal vesicles (normally less than 1.5 cm in AP diameter), and treat by resecting verumontanum and thereby unroofing the mullerian duct cyst and related obstruction.

Congenital absence of the vas deferens

May see loss of ipsilateral wolffian duct structures. Use ultrasound to rule out ipsilateral renal agenesis, which can occur 25% of the time. Bilateral vasal absence is associated with cystic fibrosis. Rule out mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 10% will have unilateral renal loss. Screen partner so that offspring does not have full blown cystic fibrosis.

Other causes include vasectomy (the number one cause), epididymal obstruction (the number two cause), trauma, or infection.

An infertile male should be worked up with a history, physical exam, and at least two semen analyses. Findings on the semen analysis will guide additional work up recommendations, which may include a serum testosterone and FSH. Additional testing may include additional semen/sperm tests (such as fructose, anti-sperm antibodies, and DNA damage), endocrine evaluation of the hypothalamus-pituitary-gonadal axis, post-ejaculate urine analysis, and ultrasound evaluation of scrotum or prostate.

Look for obstruction of sperm from the vas deferens or epididymis. Testosterone and FSH will be normal. Check for presence of both vas deferentia on physical exam. Also, check for a mullerian duct cyst by digital rectal exam and trans-rectal ultrasound. On ultrasound, obstruction is likely if the seminal vesicle AP diameter is greater than 1.5 cm, the ampulla of vas AP diameter is greater than 2.5 mm, and a testis biopsy in this situation would demonstrate normal spermatogenesis.

Other conditions

Testis cancer

Cryptorchidism increases risk for testis cancer, and Oligospermia is noted in 60% or more of men with testis cancer or lymphoma.

Prolactin secreting tumor of the pituitary

Excess testosterone will suppress LH and FSH levels. Causes include Leydig cell tumor, exogenous anabolic steroids, and testosterone replacement.

Undiagnosed chromosome abnormalities

The most common abnormality in infertile men is Kleinfelter’s syndrome. Also rule out a Y-chromosome microdeletion. The father has no known phenotype characteristics. If the man’s sperm is used and produces a male offspring, that boy will also receive the Y-chromosome microdeletion. Girl offspring do not get the Y-chromosome and are thereby unaffected.

Intersex disorders

Androgen receptor dysfunction is often carried as a X-chromosome defect.

Other causes

Being a Cystic Fibrosis carrier may also be a cause of infertility. Check for missing vas on physical exam and for CFTR mutation and get a CF panel. Gynecomastia from excess prolactin production or a testosterone:estrogen imbalance may also be a factor. Neurological disorders may manifest as retrograde or an ejaculation.

Varicocele (right sided-only, or rapid onset) may indicate a renal tumor for which retroperitoneal imaging by ultrasound or cat scan is recommended.

3. Management

Expectant management

This option is OK for couples when the female partner is younger than 35 years old. The historical recommendation is to try natural conception techniques for at least 12 months and minimize both toxins such as tobacco, marijuana, and stress. Consider the use of antioxidants. Try timed intercourse. starting 14 days after the first day of period. Consider sexual activity at least every other day for 10 days starting on day 10-12 after first day of period. This ensures that viable sperm are present at all times when the oocyte could be fertilized. Sperm live for 48 hours, and the oocyte is capable of being fertilized within the fallopian tube for 12-24 hours. May also use temperature change and LH surge kits to more accurately predict ovulation.

Hormonal interventions

Do a hormonal workup if the sperm concentration is less than 15 M/cc or if there is erectile dysfunction or loss of libido. A minimum work up is testosterone and FSH, and if abnormal, add LH and prolactin. Primary testicular failure is predicted by smaller testis height (less than 4 cm) and FSH > 2-times normal.

When treating low testosterone, avoid exogenous testosterone replacement, as this will feedback inhibit LH/FSH from anterior pituitary. Lower LH levels will reduce intratesticular T-levels. This suppresses spermatogenesis. Avoid testosterone injections, patches, gels, and pellets. Consider clomid 50 mg every other day to start, then titrate to goal of 700-800 ng/dl.

When raising intravascular/intratesticular testosterone levels, follow these serum markers one to two months after starting medication:

Hematocrit: keep less than 52%. Over this level risks polycythemia and embolic events.
PSA: make sure there is no significant rise (less than 0.75 to 1.0 ng/dl in the first month on testosterone replacement.) If PSA rises significantly, stop clomid and consider a prostate biopsy to rule out cancer.
Testosterone level: titrate the dose of clomid to target a total testosterone of 700-800 ng/dl.

Consider testolactone/letrozole (2.5 mg daily) for obese men with higher estradiol levels (T:E ratio < 10:1). Inhibiting the conversion of testosterone into estradiol by aromatase in the adipose tissue indirectly increases testosterone levels and decreases estradiol feedback inhibition of LH/FSH from the anterior pituitary.

When treating low LH/FSH, anti-estrogens, such as clomid or Tamoxifen, will block estrogen’s feedback inhibition of the hypothalamus and anterior pituitary. This typically increases production of GnRH, LH, and FSH. The goal is a total testosterone of 800 ng/dl. Consider Clomid at 50 mg every other day, but the dosing schedule is controversial (low vs. high dose, and daily dose vs. dose withdrawal, i.e., three weeks of medication followed by one week of rest.) The current trend is to use clomid 50 mg daily.

Aromatase is an enzyme located in adipose cells that converts testosterone to estradiol. Estradiol can feedback inhibit hypothalamus/pituitary axis that reduces LH/FSH stimulation of the testes. If a patient has excess truncal obesity, check for elevated estradiol levels and consider an aromatase inhibitor such as anastrazole or letrozole.

If clomid or Letrozole do not work, may need to use recombinant LH/FSH/GnRH products. hMG is synthetic human menopausal gonadotropin, and hCG is synthetic human chorionic gonadotropin. Start with hCG, which will often improve both intratesticular testosterone in addition to sperm production. If testosterone normalizes but sperm production lags, add hMG to directly stimulate spermatogenesis from the Sertoli cells.

Non-hormonal therapies

Medications

This includes NSAIDS. Prostaglandins, blocked by NSAIDS, may inhibit both spermatogenesis and motility. Alpha blockers may reduce the sympathetic tone, which may improve spermatogenesis. In-vitro, Pentoxyphylline, a phosphodiesterase inhibitor, improves both sperm motility and acrosome reaction.

Nutritional supplements

A recent Cochrane review demonstrated that antioxidants and nutrient supplements were able to improve fertility rates. The review demonstrated 4.18-fold increased odds of pregnancy with antioxidants compared to controls and a 4.85-fold increased odds of live birth with anti-oxidants.

Nutritional supplementation includes:

L-carnitine fumarate
Acetyl-L-carnitine HCL
Fructose
Citric acid
Vitamin E
Vitamin C
Carotenoids
Ubiquinol
Folate
Zinc

Varicocelectomy

Surveillance

For children, follow with annual testis measurements for size. If normal, continue to follow. If testis size decreases, consider varicocele repair. For young adults, check semen analysis. If normal, repeat semen analysis annually. Repair varicocele if semen parameters decline.

Surgery

Techniques include open procedures (such as inguinal, subinguinal, or retroperitoneal) and laparoscopic (ligate retroperiotoneal spermatic vein) with or without arterial ligation, and percutaneous embolization. Results indicate that 70% of men will see improvements in sperm parameters. Give the testes 74+ days (three months) to recover prior to rechecking semen analysis. Microsurgical repair has the lowest recurrence rates. Embolization has the lowest hydrocele rates.

A study of those treated showed 70% of patients experienced improved motility, 51% improved concentration, and 44% improved morphology. Pregnancy rates trend higher after varicocelectomy. In a review of several studies, the average pregnancy rates included 33% of couples in varicocelectomy group and 16% of couples in the control (no surgery) group. A large WHO study reported pregnancy rates at one year to be 34.8% of couples in the varicocelectomy group and 16.7% of couples in the control (no surgery) group.

Vasovastostomy (VV)

The most important predictor of VV success is time since vasectomy. Less than 15 years is preferred. An even shorter interval of time predicts even better post-op success. After over 15 years of occlusion, less than 71% of men will have sperm in their ejaculation and less than 30% of these men will father a child. VV is most successful when there is more than 2.7 cm of vas retained as an epididymal vasal segment. This length acts to minimize back pressure and potential scarring of the epididymal tubule.

Presence of a sperm granuloma also decreased backpressure on the epididymis. Clear vasal fluid from the epdidymal vasal segment is best. Milky fluid is less good. Thick, toothpaste-like material is bad. If no sperm is noted at epididymal vasal tip, must consider a testicular/epdidymal exploration and vasoepididymostomy (VE).

Cryopreservation of sperm at the time of VV or VE should be considered. If there is not sperm in epididymis, sperm for cryopreservation can be obtained using a testicular biopsy. Post operatively, motile sperm are usually seen within six months after a VV. Motile sperm may take up to 15 months to appear after a VE.

Genetic screening

Before using sperm from a man with congenital bilateral absence of vas deferens (CBAVD), test both the patient and his partner for cystic fibrosis (CFTR mutations). Genetic counseling is indicated if CF carrier is present, definitely if both partners have the recessive trait. If there is an abnormal physical exam, such as hypospadias and history of undescended testes, do karyotype and rule out intersex.

For men with severe oligospermia (less than 5 M/cc) or azospermia, obtain karyotype CFTR (rule out cystic fibrosis) and Y-chromosome microdeletion (Figure 7), which is associated with 7% of males with severe oligospermia/azoospermia. When present, the individual has a normal phenotype and life expectancy. However, with use of this sperm for ICSI, male offspring will continue to have the Y-microdeletion. Deletions occur in non-overlapping regions of the long arm of the Y-chromosome.

There are three regions, labeled as azoospermia factor (AZF) a, b, and c. AZF a is the proximal portion of long arm. When present, no sperm found on testis biopsy.

AZF b is the middle portion. When present, no sperm found on testis biopsy. AZF c is the distal portion. When present, may find sperm on testis biopsy. This sperm can be used for ICSI. Male offspring will continue to have the Y-chromosome microdeletion (46 XY). Female offspring will not be affected (46 XX). The frequency of Karyotype abnormalities in infertile men is 10-15% for azoospermia, 5-7% for oligospermia, 1% for normospermia, and 7% for all infertile men.

Testis biopsy

(Figure 8)

The goal of a biopsy is two-fold. First, to obtain enough sperm to cryopreserve for future ICSI cycles. Secondly, some tissue can be preserved in Bouin’s, Zenker’s, or Conroy’s solution for pathological analysis. Formalin should be avoided as it distorts seminiferous architecture. Typical pathological diagnoses include normal spermatogenesis, sertoli-cell only, maturation arrest (early or late), and fibrosis. There are several options for attempted retrieval of sperm from the testicle or epididymis.

Open

MESA microsurgical epididymal sperm aspiration: requires surgical exposure to epididymis
Open testis biopsy: make a small incision through the skin, tunica vaginalis, and tunical albuginia

Needle aspirations

Consider a 27 gauge needle with use of local anesthesia for this procedure.

PESA percutaneous epididymal sperm aspiration
TESA percutaneous testicular sperm aspiration
TESE testicular sperm extraction (percutaneous or open approaches)

Core biopsy

Use a biopsy gun, the same device as used for prostate biopsies.

Microdissection

Bivalve the testis in the area where the equator would be, preserving the posterior/epididymal attachments. Microscopically, identify more plump seminiferous tubules and remove for identification of spermatozoa.

Results

In men with obstructive azoospermia, there is no difference in pregnancy rates by ICSI between frozen and fresh epididymal sperm. Open biopsy techniques retrieve more sperm than percutaneous techniques for sperm retrieval. For those with non-obstructive azoospermia, open surgical techniques retrieve sperm in a greater percentage of patients and yield a higher number of sperm than percutaneous techniques.

Intrauterine insemination (IUI)

In-vivo, fertilization occurs inside the fallopian tubes/uterus. This is indicated when there are cervical mucus abnormalities and other female factors, such as anatomical abnormalities or dyspareunia, and anatomic abnormalities, such as severe hypospadius or retrograde ejaculation. The female is often hyperstimulated, to release several eggs at time of insemination. Washed and prepared sperm (without seminal fluid) is inserted into the uterus via a trans-cervical cannula. Do not place raw sperm into the uterus.

Preferred sperm parameters include a > 4% normal morphology by strict Kruger criteria and at least 5 M sperm/cc is preferable. Pregnancy rates improve with increasing motile sperm counts up to 10-20 M/cc. Pregnancy rates plateau after 20 M/cc motile sperm counts.

Intracytoplasmic sperm injection (ICSI)

In-vitro fertilization occurs outside the maternal environment and uses maternal eggs and paternal sperm. The most important predictor of ICSI success is maternal age. This process involves the injection of a single sperm into the cytoplasm of a single egg. Do this for each egg retrieved from the ovaries after a period of ovarian hyperstimulation. Incubate for a few days and select most robust embryos for trans-cervical cannula deposit into the hormonally prepared uterus. Only 20-30% of transferred embryos will produce a clinical pregnancy. In 2011, the Centers for Disease Control (CDC) reported (using 2009 data) that 37.4% of women younger than 35 years of age realized a pregnancy, whereas 9.7% of women older than 40 years of age did the same.

Donor gametes

Donor sperm or eggs may be considered in the case of advanced maternal age with poor ovarian reserve and azoospermia with no sperm recovered with testis biopsy. (Table III) This is the case when AZF a and b are present, in many cases with sertoli only syndrome, and some cases with early maturation arrest.

Adoption

Adoption is an option for couples who are struggling with infertility.

4. Complications

Risks related to male infertility

Hypogonaotropic hypogonadism

Effects of chronic low testosterone:

Osteopenia

Lethargy

Loss of muscle mass

Depression

Erectile dysfunction

Cognitive impairment

Effects of elevated prolactin levels:

Benign prolactinoma

Prolactin/pituitary cancer

Cancer

Testis cancer can be picked up in 1% of infertile males. Leydig cell tumors are not generally palpable and should be ruled out in men with high serum testosterone or gynecomastia.

Undiagnosed genetic characteristics

Undiagnosed genetic characteristics (especially for those with azoospermia and oligospermia [< 10M/cc]) include Kleinfelter’s Syndrome, Cystic Fibrosis, Y-chromosome microdeletions, and others as described in the “classification of male infertility” section above.

Risks associated with assisted reproduction

Sperm retrieval

Scarring/blockage of epididymis
Infection, bleeding, hematoma, pain, spermatocele
Damage/atrophy of testis

Ovarian stimulation

Multiple gestations (15-30% of pregnancies)
Ectopic pregnancy
Spontaneous abortion
Increased risk for ovarian cancer
Ovarian hyperstimulation syndrome (OHSS)
Ascites with abdominal pain, nausea and vomiting, peritonitis, bleeding from follicle rupture, thrombosis, death

Oocyte retrieval

Bleeding
Infection
Cramping
Bowel injury

IUI

Uterine cramping
Pelvic infection (< 1% of patients)
Rare reactions to insemination media
Possible transmission of infectious diseases, such as HIV and Hepatitis
Multiple gestations (15-30% of pregnancies)

ICSI

Miscarriage (14% in women less than 35, 30% for those 40 or older)
Multiple gestations (25% of pregnancies)
Possible sex chromosome abnormalities, congenital malformations, and developmental delays

Surgery

Vasovasostomy

Ecchymosis and small hematomas are not uncommon. Secondary obstruction/scarring occur in 3-12% of cases.

Varicocelectomy

Hydrocele formation occurs in 3-39% of non-microsurgical cases. The recurrence of varicocele is 1-2% with the microsurgical approach, 9-16% without the use of the microscope, and 11-15% with the retroperitoneal approach.

(See Table IV, varicocele complication rates)

Testicular arterial injury is more likely the more distal (proximal to testis) the repair is attempted. However, testicular arterial ligation does not always result in testicular atrophy due to collateral circulation.

5. Prognosis and outcome

Prognosis

Watchful waiting

Of infertile couples, 25% will conceive without treatment. To improve chances, it is recommended that the couple cease tobacco use, avoid excess heat/saunas, avoid the use of lubricants, and consider using anti-oxidants/nutrient supplements.

Medical management

If circulating testosterone is low, optimize intratesticular testosterone by avoiding exogenous testosterone/steroids. For Hypogonadotropic Hypogonadism, rule out prolactin excess. Most respond to medical management with Bromocryptine, or with Cabergoline (less side effects). Replace GnRH, or, FSH (hCG) and LH (hMG) if needed. Many patients treated with these agents are able to conceive despite very low sperm densities. Results vary with the use of Clomid, and Anastrozole is for those men with a low testosterone and high BMI and or T:E ratio less than 10:1. Results vary.

Surgical management

Varicocele ligation is an option. Approximately 70% of men will realize an improvement in sperm concentration, motility, and/or morphology. DNA damage and oxidative stressors will also be reduced. For testis/epididymis biopsy or aspiration, a limited quantity of sperm will only allow for ICSI. There is less risk for genetic (DNA) damage if sperm is acquired from the testicle in contrast to the epididymis.

Outcome

Currently, there are no specific long term health impacts stemming from male factor infertility. However, there are several research premises, which include but are not limited to:

Are infertile men more prone to developing cancer due to a faulty DNA repair mechanism (gametes are turning over genetic material at a very fast pace)
Do older infertile men have a propensity for defective DNA, chromosome abnormalities, reduction in Y-chromosome integrity/prevalence?

Significant controversy surrounds the long-term safety of assisted reproduction. Areas being evaluated include an increase in sex chromosome abnormalities, delayed mental development, and congenital malformation rates.

6. What is the evidence for specific management and treatment recommendations?

Jarow, J, Sigman, M, Kolettis, PN. “The Optimal Evaluation of the Infertile Man: AUA Best Practice Statement”. 2010. (A current, authoritative, best practice guide from the AUA on Male Infertility.)

Howell, MG. “Cochrane Database of Systematic Reviews 2011”. vol. CD007411. (A Cochrane review of several studies, demonstrated improved fertility with the use of nutrient supplements.)

Wieder, JA. “Male Infertility”. Pocket Guide to Urology. 5th Edition. 2014. pp. 419-450. (Succinct, to the point, easy to read and understand overview of Male Infertility.)

Cooper, TG, Noonan, E, von Eckardstein, S, Auger, J, Baker, HWG. “World Health Organization reference values for human semen characteristics”. Human Reproduction Update. vol. 16. 2010. pp. 231-45. (The latest WHO guideline on sperm parameters. Uses fertile men as reference.)

Hsiao, W, Rosff, JS, Pale, JR, Goldstein, M. “Varicocelectomy is associated with increases in serum testosterone independent of clinical grade”. Urology. vol. 81. 2013. pp. 1213-7. (Among other insults, suggests varicoceles suppress testicular testosterone production.)

Spira, A. “Epidemiology of human reproduction”. Hum Reprod. vol. 1. 1986. pp. 111-5.

Ford, WC, North, K, Taylor, H. “Increasing paternal age is associated with delayed conception in a large population of fertile couples: Evidence for declining fecundity in older men. The ALSPAC Study Team (Avon Longitudinal Study of Pregnancy and Childhood)”. Hum Reprod. vol. 15. 2000. pp. 1703-8.

Collins, JA, Wrixon, W, Janes, LB, Wilson, EH. “Treatment-independent pregnancy among infertile couples”. N Engl J Med. vol. 309. 1983. pp. 1201-6.

Sigman, M, Jarow, JP, Wein, AJ, Kavoussi, LR, Novick, AC, Partin, AW, Peters, CA. “Male Infertility”. Campbell-Walsh Urology. 9th Edition. 2007. pp. 609-53.

Hoekstra, T, Witt, MA. “The correlation of internal spermatic vein palpability with ultrasonographic diameter and reversal of venous flow”. J Urol. vol. 153. 1995. pp. 82-4.

Zini, A, Boman, JM, Belzile, E. “Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis”. Hum Reprod.. vol. 23. 2008. pp. 2663

Carroll, PR, Whitmore, WF, Herr, HW. “Endocrine and exocrine profiles of men with testicular tumors before orchiectomy”. J Urol. vol. 137. 1987. pp. 420-3.

Schlegel, PN. “Is assisted reproduction the optimal treatment for varicocele-associated male infertility”. A cost-effectiveness analysis. Urology. vol. 49. 1997. pp. 83-90.

Hargreave, T. “Varicocele: Overview and commentary on the results of the World Health Organization Varicocele Trial”. Curr Adv Androl. 1997. pp. 31-44.

Belker, AM, Thomas, AJ. “Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group”. J Urol. vol. 145. 1991. pp. 505

Nicopoullos, JD, Gilling-Smith, C, Almeida, PA. “Use of surgical sperm retrieval in azoospermic men: A meta-analysis”. Fertil Steril. vol. 82. 2004. pp. 691-701.

Schlegel, PN. “Testicular sperm extraction: Microdissection improves sperm yield with minimal tissue excision”. Hum Reprod. vol. 14. 1999. pp. 131-5.

Berg, U, Brucker, C, Berg, FD. “Effect of motile sperm count after swim-up on outcome of intrauterine insemination”. Fertil Steril. vol. 67. 1997. pp. 747-50.

Horstman, WG, Haluszka, MM, Burkhard, TK. “Management of testicular masses incidentally discovered by ultrasound”. J Urol. vol. 151. 1994. pp. 1263-5.

Kolettis, PN, Thomas, AJ. “Vasoepididymostomy for vasectomy reversal: A critical assessment in the era of intracytoplasmic sperm injection”. J Urol. vol. 158. 1997. pp. 467-70.

Amelar, RD. “Early and late complications of inguinal varicocelectomy”. J Urol. vol. 170. 2003. pp. 366-9.

Burris, AS, Clark, RV, Vantman, DJ, Sherins, RJ. “A low sperm concentration does not preclude fertility in men with isolated hypogonadotropic hypogonadism after gonadotropin therapy”. Fertil. Steril. vol. 50. 1988. pp. 343-7.

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