Male Infertility Treatment & Management

Author: Jonathan Rubenstein, MD; Chief Editor: Edward David Kim, MD, FACS more...

Updated: Dec 16, 2011

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Medical Care
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Consultations
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Medical Care

Limited numbers of medical treatments are aimed at improving chances of conception for patients with known causes of infertility.

Endocrinopathies

A number of patients with hypogonadotropic hypogonadism respond to GnRH therapy or gonadotropin replacement.

HCG is an LH analogue that may be used alone or in combination with HMG for Leydig cell stimulation.

Clomiphene citrate and tamoxifen are antiestrogens that block the negative feedback loop at the pituitary level, allowing a potentially increased release of gonadotropins.

Patients with CAH may respond to therapy with glucocorticoids, while those with isolated testosterone deficiency may respond to testosterone replacement.

Exogenous testosterone decreases intratesticular testosterone production, thus inhibiting Sertoli cell function and spermatogenesis.

Treat patients with hyperprolactinemia with bromocriptine, a dopamine antagonist, or cabergoline.

Antisperm antibodies

Patients with antisperm antibody levels greater than 1:32 may respond to immunosuppression using cyclic steroids for 3-6 months. However, patients need to be aware of the potential side effects of steroids, including avascular necrosis of the hip, weight gain, and iatrogenic Cushing syndrome.

Retrograde ejaculation

Imipramine or alpha-sympathomimetics, such as pseudoephedrine, may help close the bladder neck to assist in antegrade ejaculation. However, these medicines are of limited efficacy, especially in patients with a fixed abnormality such as a bladder neck abnormality occurring after a surgical procedure.

Alternatively, sperm may be recovered from voided or catheterized postejaculatory urine to be used in assisted reproductive techniques. The urine should be alkalinized with a solution of sodium bicarbonate for optimal recovery.

More recently, the injection of collagen to the bladder neck has allowed antegrade ejaculation in a patient who had previously undergone a V-Y plasty of the bladder neck and for whom pseudoephedrine and intrauterine insemination had failed.^[16]

Semen processing

Patients with poor semen quality or numbers may benefit from having their semen washed and concentrated in preparation for intrauterine insemination.

Couples with an abnormal postcoital test result due to semen hyperviscosity may benefit from a precoital saline douche or semen processing with chymotrypsin.

Lifestyle

Patients should be encouraged to stop smoking cigarettes and marijuana and to limit environmental exposures to harmful substances and/or conditions.

Stress-relief therapy and consultation of other appropriate psychological and social professionals may be advised.

Infections should be treated with appropriate antimicrobial therapy.

Varicocelectomy

Various techniques for varicocelectomy have been proposed and used, each with advantages and disadvantages.

The retroperitoneal approach may be performed as an open procedure or laparoscopically.

The inguinal and subinguinal microscopic approach (see image below) allows for ligation of individual veins with decreased risk of inadvertent arterial damage. Collateral vessels entering the cord distally may also be directly addressed with this technique. Many therefore feel this is the safest and most effective technique.

Male infertility. Technique of microscopic varicocelectomy. The individual veins of the pampiniform plexus are isolated (top) and ligated, taking care to preserve the testicular artery (bottom) isolated using the intraoperative Doppler.

Successful varicocelectomy results in improvement in semen parameters in 60-70% of patients. The repair also typically halts further testicular damage and improves Leydig cell function.

Persistent dilatation after repair is not unusual and does not necessarily represent surgical failure. Rather, the veins may remain clinically apparent owing to chronic stretching or thrombosis, even if venous reflux is no longer present. Semen analysis may show improvement as early as the 3-month follow-up visit.^[17]

Results from a prospective, randomized controlled trial from Saudi Arabia compared subinguinal microsurgical varicocele repair to observation. Inclusion criteria included infertility lasting 1 year or longer, demonstration of a palpable varicocele, and presence of at least one impaired semen parameter (sperm concentration < 20 million/mL, progressive motility < 50%, or normal morphology < 30%). A total of 145 participants had follow-up within 1 year; spontaneous pregnancy was achieved in 13.9% of controls compared with 32.9% of treated men (odds ratio, 3.04). In treated men, the mean of all semen parameters significantly improved in follow-up compared with baseline (p < 0.0001). This study provided an evidence-based endorsement of the superiority of varicocelectomy over observation in infertile men with palpable varicoceles and impaired semen quality.^[18]

Vasovasostomy or vasoepididymostomy

These microsurgical techniques are performed in patients with known epididymal or vasal obstruction, both congenital and acquired (eg, due to surgery, trauma, infection). Improved surgical techniques and the use of the operating microscope have improved the outcomes in patients requiring vasectomy reversal or those with primary vas obstruction.^[19]In a study by Fenig et al, the timing of a reversal along with a sperm granuloma identified during the patient’s physical examination have been identified as predictors of the need for epididymovasostomy.^[20]

In addition, men with increased follicle-stimulating hormone levels of >10 U/l may have an increased likelihood of needing assisted reproduction to achieve pregnancy after vasectomy reversal according to a study by the Goldstein group of Weill Cornell Medical College.^[21]

After scrotal exploration, the patency of the duct system proximal to the proposed site of anastomosis is confirmed by examination of expressed fluid for the presence of sperm. If no fluid is expressed, a 24-gauge angiocatheter with 0.1 mL of saline should be used to gently barbotage the proximal vas. If no sperm are observed, inspect the vasal fluid aspirated.

A thickened, white, toothpaste-like fluid usually contains no sperm or nonviable sperm fragments and is likely merely from the vasal epithelium, whereas a watery thin fluid often implies proximal patency.^[22]If viable sperm are observed, send an additional sample for cryopreservation prior to vasovasostomy. These sperm may be used for IVF or ICSI if the man remains azoospermic after the repair.

The patency of the distal duct system is confirmed by injecting 10 mL of sterile saline through the vas; if no resistance is encountered, the system is deemed patent. Alternatively, radiographic vasography or chromogenic vasography with methylene blue can be performed, with radiographic contrast visualized passing into the bladder or blue coloration of the urine proving patency, respectively. A 2-0 nylon suture can be passed into the vasal lumen to check the distance to obstruction if the above tests reveal distal blockage.

A vasovasostomy is generally performed in 2 layers, the inner lining with interrupted 10-0 nylon suture and the outer layer with interrupted 9-0 nylon suture (see image below). Optimally, a tension-free, mucosa-to-mucosa, watertight anastomosis is created.

Male infertility. Technique of vasovasostomy: Upper left is confirmation of sperm from the proximal vas deferens, proving proximal patency. Upper right is the inner layer anastomosis using interrupted #10-0 Prolene. Lower left is the inner layer anastomosis completed. Lower right is the outer layer anastomosis using #9-0 Prolene completed.

A vasoepididymostomy is also closed in 2 layers (see image below). Factors that predict a more favorable outcome include a shorter time from the original injury/surgery, a vasovasostomy performed on one side rather than bilateral vasoepididymostomies, and reconstruction because of an infectious etiology rather than a surgical or idiopathic etiology.

Male infertility. Technique of vasoepididymostomy. Left upper is confirmation of mature sperm in epididymis. Right upper is the inner layer anastomosis of the end of the vas to the side of the epididymal tubule using interrupted #10-0 Prolene. Left lower is the inner layer completed. Right lower is the outer layer anastomosis using interrupted #9-0 Prolene completed.

When performing a vasoepididymostomy, an end-to-side technique is easier to perform and yields better outcomes than an end-to-end anastomosis. More recently, a triangular technique for vasoepididymostomy has been proposed.^[23]Although more motile sperm are present at the proximal epididymis in patients with ductal obstruction, the technique is easier and more successful if it is performed at the distal end.

A varicocelectomy and vasovasostomy should never be performed at the same time because of a risk of testicular atrophy.

Transurethral resection of the ejaculatory ducts

Patients with a known or suspected obstruction of the ejaculatory ducts may be eligible for transurethral resection of the ejaculatory ducts (TURED), which durably improves semen quality in patients with ejaculatory duct obstruction.

In the operating room, with patients under spinal or general anesthesia, the resectoscope with a 24F cutting loop is used to excise the verumontanum of the prostate. Using the O'Connor drape to enable placement of a finger in the rectum to elevate the prostate may be helpful.

Resection is performed with care to avoid injuring the bladder neck or external sphincter.

Risks with this procedure include watery (urine) ejaculate, chemical or bacterial epididymitis due to reflux, bleeding, and retrograde ejaculation.

Sperm retrieval techniques

Testicular sperm extraction (TESE) is performed at the time of testicular biopsy or as a separate procedure using the same technique.^[24]

Testicular sperm aspiration (TESA) is less invasive that TESE but yields fewer sperm and is suboptimal in cases of nonobstructive azoospermia.^[24]

Microsurgical epididymal sperm aspiration (MESA) involves directly retrieving sperm from the epididymis. Sperm in the epididymis are more mature than that in the testis. Using a microscope, the epididymis is uncovered and incised to express sperm. Epididymal fluid is aspirated into a tuberculin syringe primed with human tubal fluid (HTF).

Percutaneous epididymal sperm aspiration (PESA) involves direct sperm aspiration from the epididymis. This procedure can be performed under local anesthesia in the office setting. While effective in sperm retrieval, this does not allow sampling from multiple sites and is associated with an increased risk of epididymal and testicular injury and secondary epididymal obstruction.

An autogenous spermatocele can be created in patients with an unreconstructable ductal system. A buttonhole is created within the viscera, and repeated percutaneous aspirations of sperm can be performed using ultrasonographic guidance. An intact tunica vaginalis with no adhesions is needed, so it is ideal for use in patients with normal spermatogenesis and a congenital absence of the vas. This procedure is rarely used.

An alloplastic spermatocele uses an artificial silicone sperm reservoir in place of the tunica vaginalis for sperm storage and subsequent retrieval. This technique has been unsuccessful so far.

Electroejaculation

Under general anesthesia, an unlubricated Foley catheter is placed in the bladder and a buffer (ie, HTF) is instilled through the catheter. A rectal probe is inserted with its electrodes positioned against the posterior seminal vesicles. Electrical stimulation is begun at 3-5 volts and increased as necessary.

Electroejaculation achieves up to a 90% sperm retrieval rate.

The penile vibratory stimulator has been shown to be a useful alternative to electroejaculation in select patients. The US Food and Drug Administration (FDA) has recently approved this device for home use, using 2.2 mm at 100 Hz. This is associated with fewer adverse effects and lower morbidity costs less than electroejaculation. In addition, collection may occur at home instead of in the operating room.

Artificial insemination

Artificial insemination (AI) involves the placement of sperm directly into the cervix (ie, intracervical insemination [ICI]) or the uterus (ie, intrauterine insemination [IUI]). AI is most useful for couples in whom the postcoital test indicated no sperm, those who have very low sperm density or motility, or those who have unexplained infertility.

IUI allows the sperm to be placed past the inhospitable cervical mucus and increases the chance of natural fertilization. This results in a 4% pregnancy rate if used alone and a pregnancy rate of 8-17% if combined with superovulation. Both processes require semen processing.

Patients in whom IUI has failed 3-6 times should consider proceeding to IVF.

Assisted reproduction techniques

Patients with severe oligospermia, azoospermia, unexplained infertility, or known defects that preclude fertilization by other means are candidates for assisted reproduction techniques. Assisted reproduction techniques use donated or retrieved eggs that are fertilized by the male partner's sperm or donor sperm. The fertilized embryos are then replaced within the female reproductive tract. These techniques result in a 15-20% delivery rate per cycle and may eventually be successful in 50% of cases. However, the high cost and technical difficulty of the procedures generally preclude their routine use as first-line therapy.

In vitro fertilization

IVF involves fertilization of the egg outside the body and reimplantation of the fertilized embryo into the woman's uterus. Indications for IVF include previous failures with IUI and known conditions of the male or female precluding the use of less-demanding techniques.

IVF generally requires a minimum of 50,000-500,000 motile sperm. Harvesting eggs initially involves down-regulating the woman's pituitary with a GnRH agonist and then performing controlled ovarian hyperstimulation.

Follicular development is monitored by ultrasonographic examination and by checking serum levels of estrogen and progesterone. When the follicles are appropriately enlarged, a transvaginal follicular aspiration is performed.

A mean of 12 eggs are typically retrieved per cycle, and they are immediately placed in an agar of fallopian-tube medium. After an incubation period of 3-6 hours, the sperm are added to the medium using approximately 100,000 sperm per oocyte. After 48 hours, the embryos have usually reached the 3- to 8-cell stage. Two to 4 embryos are usually implanted in the uterus, while the remaining embryos are frozen for future use. Pregnancy rates are 10-45%.

Overall, IVF is a safe and useful procedure. Risks include multiple pregnancies and hyperstimulation syndrome. Additionally, an increased risk of hypospadias occurs in boys (1.5% vs 0.3%), probably because of the increased maternal progesterone used for egg harvesting.^[25]

Finally, the use of this technology has led to many ethical issues, such as the fate of embryos after divorce.

Gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT)

These procedures allow the placement of semen (GIFT) or a fertilized zygote (ZIFT) directly into the fallopian tube by laparoscopy or laparotomy. Success rates have been estimated to be 25-30% using these techniques. Unfortunately, these procedures require general anesthesia and have associated risks. Fertilization and implantation within the uterus are not guaranteed, and these procedures cannot be performed in patients with fallopian tube obstruction. GIFT and ZIFT are rarely used as a therapeutic option.

Intracytoplasmic sperm injection

ICSI involves the direct injection of a sperm into an egg under microscopy (see image below).

Male infertility. Technique of intracytoplasmic sperm injection (ICSI). A micropipette is used to inject a single sperm directly into an egg.

ICSI is indicated in patients who have failed more conservative therapies or those with severe abnormalities in which no other treatment would be effective, including patients with sperm extracted directly from the epididymis or testicle.

Oocytes are processed with hyaluronidase to remove the cumulus mass and corona radiata. A micropipette is used to hold the egg while a second micropipette injects the sperm. The oocyte is positioned with the polar body at the 6-o'clock or 12-o'clock position, and the sperm is injected at the 3-o'clock position to minimize the risk of chromosomal damage in the egg.

After incubation for 48 hours, the embryo is implanted in the woman. Van Steirteghem et al (1993) reported a 59% fertilization rate and a 35% pregnancy rate using ICSI in 1409 oocytes.^[26]

Fresh or cryopreserved sperm appear to have similar success rates.^[27]

The potential complications, ethical issues, and high costs of ICSI need to be considered and individualized.

Geneticist

A genetics consultation may be indicated in patients with a known or suspected genetic cause of infertility and in patients with nonobstructive azoospermia or severe oligospermia (< 5 million sperm/mL). In addition, in the era of IVF and ICSI, determining the risks of passing on chromosomal abnormalities to a potential offspring is important.

Use a peripheral karyotype and a PCR-based evaluation of the Y chromosome to evaluate for microdeletions. Patients with nonobstructive azoospermia have a 13-17% chance of genetic abnormalities, 4-16% of which are due to Klinefelter syndrome and 9% are due to a partial Y deletion.

Patients with CBAVD nearly uniformly have a mutation in the CFTR gene. An estimated 50-82% of men with CBAVD have a genital-only form of CF, which may manifest in patients with only one copy of the abnormal CF gene. In contrast, patients with clinical CF usually have 2 copies of the abnormal gene.

As for men who do have the digestive and pulmonary complications of CF, technology is allowing them to live longer. These men are now candidates for assisted reproductive techniques. The female partner must be evaluated for a CFTR gene mutation before attempted fertilization to determine the risk of producing offspring with CF, which is an autosomal recessive trait.

Endocrinologist

Patients with severe oligospermia or azoospermia should be evaluated with a hormonal evaluation.

Patients with unexplained hypogonadism or hyperprolactinemia should undergo a CT scan or MRI of the sella turcica to evaluate for a pituitary tumor.

Abnormalities may indicate the need for a formal endocrinology consultation.

A diet high in antioxidants such as vitamin C and vitamin E has been proposed to improve the quality of sperm by decreasing the number of free radicals that may cause membrane damage.
Additionally, the use of zinc, fish oil, and selenium has been shown to be of benefit in some studies.^[28]

Patients should limit the use of potentially spermatotoxic substances such as cigarettes, marijuana, and anabolic steroids. Environmental exposures to harmful substances and/or conditions should be minimized.
The optimal timing to perform intercourse for conception is every 2 days at mid cycle.
The use of spermatotoxic lubricants should be avoided.

Proceed to Medication

Contributor Information and Disclosures

Author

Jonathan Rubenstein, MD Staff Physician, Chesapeake Urology Associates, Towson, MD

Jonathan Rubenstein, MD is a member of the following medical societies: American Urological Association

Disclosure: Nothing to disclose.

Coauthor(s)

Robert E Brannigan, MD Associate Professor, Department of Urology, Northwestern University, Feinberg School of Medicine

Robert E Brannigan, MD is a member of the following medical societies: American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, Endocrine Society, Society for the Study of Male Reproduction, and Society for the Study of Reproduction

Disclosure: Nothing to disclose.

Specialty Editor Board

Daniel B Rukstalis, MD Director of Urological Services, Geisinger Medical Center, Geisinger Medical Group

Daniel B Rukstalis, MD is a member of the following medical societies: American Association for the Advancement of Science and American Urological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mark Jeffrey Noble, MD Consulting Staff, Urologic Institute, Cleveland Clinic Foundation

Mark Jeffrey Noble, MD is a member of the following medical societies: American College of Surgeons, American Medical Association, American Urological Association, Kansas Medical Society, Sigma Xi, Society of University Urologists, and Southwest Oncology Group

Disclosure: Nothing to disclose.

J Stuart Wolf Jr, MD, FACS The David A Bloom Professor of Urology, Director, Division of Endourology and Stone Disease, Department of Urology, University of Michigan Medical School

J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology

Disclosure: Nothing to disclose.

Chief Editor

Edward David Kim, MD, FACS Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center

Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, Sexual Medicine Society of North America, and Tennessee Medical Association

Disclosure: Lilly Consulting fee Advisor; Astellas Consulting fee Speaking and teaching; Watson Consulting fee Speaking and teaching; Allergan Consulting fee Speaking and teaching

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Male infertility. Hypothalamic-pituitary-gonadal axis stimulatory and inhibitory signals. Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. FSH stimulates the Sertoli cells to facilitate sperm production, while LH stimulates testosterone release from the Leydig cells. Feedback inhibition is from testosterone and inhibin.

Male infertility. Testicular histology magnified 500 times. Leydig cells reside in the interstitium. Spermatogonia and Sertoli cells lie on the basement membrane of the seminiferous tubules. Germ cells interdigitate with the Sertoli cells and undergo ordered maturation, migrating toward the lumen as they mature.

Male infertility. Normal male ductal anatomy.

Male infertility. Varicocele. A - Physical examination revealing the characteristic "bag of worms." B - Anatomy of the dilated pampiniform plexus of veins.

Male infertility. Technique of open vasography: The vas distal to the site of incision is determined to be patent if saline is injected without resistance. Alternatively, radiographic contrast dye is injected through the vas deferens and radiography is performed, or blue dye may be injected and visualized in the urine to confirm patency. A vasovasostomy or vasoepididymostomy may then be performed at this level.