Male Infertility Treatment & Management

A limited number of medical treatments are available for improving chances of conception in men with certain causes of infertility.

Endocrinopathies

A number of patients with hypogonadotropic hypogonadism respond to gonadotropin-releasing hormone (GnRH) therapy or gonadotropin replacement. Pulsatile GnRH therapy can be used in those with intact pituitary function. Gonadotropin replacement can be effective in patients with hypothalamic and pituitary dysfunction.

Human chorionic gonadotropin (hCG) is a luteinizing hormone (LH) analogue that may be used alone or in combination with human menopausal gonadotropin (hMG) for Leydig cell stimulation. hCG is biologically similar to LH, but has a longer half life and is less costly than LH. hMG is a purified combination of follicle-stimulating hormone (FSH) and LH. When using hCG in combination with hMG or FSH, one should use hCG first, as it increases testosterone levels, which is essential for spermatogenesis and thus may better augment the overall effect of the therapy. ^[50] FSH alone is not effective in inducing spermatogenesis, although recent studies suggest otherwise. ^[51]

Estrogen modulators can also be of use. Aromatase inhibitors (eg, anastrozole) block the conversion of testosterone to estrogen, thus increasing the serum testosterone concentration.They are especially useful in improving semen parameters in patients with decreased testosterone:estradiol ratios. ^[52]

Clomiphene citrate is a weak estrogen-receptor antagonist that works by blocking the negative feedback inhibition of estrogen on the anterior pituitary, thus increasing the release of FSH and LH. This will then result in increased testosterone production, ultimately augmenting spermatogenesis. Clomiphene citrate is effective in improving the semen parameters in patients with hypogonadotropic hypogonadism. ^[53] Tamoxifen is another estrogen-receptor antagonist that, in combination with clomiphene, can increase sperm concentration, sperm motility, and pregnancy rates in males with idiopathic infertility. ^[54]

Patients with congenital adrenal hyperplasia (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. Consequently, it is not recommended for use in treatment of infertile males who desire parenthood.

Treatment of hyperprolactinemia is with dopamine antagonists, such as bromocriptine or cabergoline. In certain patients with prolactinomas, transsphenoidal surgery is indicated, but generally medically management is advocated first.

Antisperm antibodies

Use of steroids in patients with antisperm antibodies is controversial, with some studies showing improvement in spermatozoal quality and conception rates and others showing no benefit in rates of conception. ^{[55, 56]} Patients with antisperm antibody levels greater than 1:32 may respond to immunosuppression using low-dose steroids for 3-6 months. However, patients need to be aware of the potential adverse 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 secondary to 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. ^[57]

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 with other appropriate psychological and social professionals may be advised.

Infections should be treated with appropriate antimicrobial therapy.

Dietary supplements and vitamins

Oxidative stress causes suboptimal levels of fertility in men; therefore, the idea of antioxidant supplementation to improve male subfertility has theoretical merit. Smoking is one cause of oxidative stress; this would explain the findings typically seen in smokers, such as lower semen volume and lower sperm count and motion than in nonsmokers. ^[58]  

In a single-blinded clinical trial from Iran, both qualitative and quantitative sperm parameters in infertile male smokers improved with the use of an experimental antioxidant supplement mixture. The study population comprised 50 oligospermic and asthenospermic male smokers with at least a 1-year history of infertility and with no history of genitourinary surgery. Additionally, the participants could not have had any history of chronic physical conditions; consumed any alcohol, illicit drugs, or vitamin supplements within the past 2 months; or been exposed to radiation during work or routine activities. ^[58]

The experimental supplement mixture contained 30 mg of coenzyme Q10, 8 mg of zinc, 100 mg of vitamin C, 12 mg of vitamin E, and 400 µg of folic acid; this was taken once a day, along with 200 mg of selenium every other day after lunch. ^[58] After 3 months of supplement use, comparison of the mean sperm parameters with baseline measurements demonstrated the following:

• Sperm volume increased from 3.48 ± 1.44 to 3.71 ± 1.42
• Sperm motion increased from 27.22 ± 13.69 to 31.85 ± 5.82
• Sperm morphology changed from 23.22 ± 23.28 to 33.60 ± 20.01
• Sperm count rose from 21.76 ± 23.02 to 23.22 ± 23.28
• Progressive motility increased from 9.82 ± 9.10 to 11.57 ± 10.18

The improvements in total and progressive motility, morphology, and count were statistically significant (P ≥ 0.005). ^[58]  In the 14 participants who had an abnormal seminal fluid pH (5) on baseline testing, all 14 had a return to a normal seminal fluid pH range (≥7.2). In the two subjects whose initial sperm concentration had been above normal, sperm concentration returned to normal. The authors concluded that consuming 30 mg of coenzyme Q10, 8 mg of zinc, 100 mg of vitamin C, 12 mg of vitamin E, 400 µg of folic acid once a day and 200 mg of selenium every other day had an ameliorative affect on sperm concentration, pH, volume, total and progressive motility, morphology, and count. ^[58]  

Safarinejad et al published a prospective, double-blind, randomized controlled trial assessing the effects of coenzyme Q10 (ubiquinol) 200 mg po daily (n = 114 men) compared with placebo (n = 114 men) over 26 weeks. The authors found a statistically significant increase in sperm concentration, motility, and strict morphology in subjects who received ubiquinol compared with those who received placebo, and these effects gradually returned to baseline levels during the off-drug time period. While pregnancy rates were not tracked or reported, the improvement in semen parameters does appear to support the use of ubiquinol in men trying to achieve a pregnancy. ^[59]

Additional research needs to be done with larger subject pools, in a controlled setting, with direct evaluation of pregnancy outcomes, as well as on the specific mechanisms of action of these potentially therapeutic supplements. Although there are not enough data for formal recommendations, the existing data indicate an opportunity for further research.

Varicocelectomy

Various techniques for varicocelectomy have been proposed and used, including retroperitoneal, inguinal, and subinguinal approaches. Each has advantages and disadvantages.

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

The inguinal approach (see image below) allows for ligation of individual veins with decreased risk of inadvertent arterial damage. A 3-5 cm incision is made over the inguinal canal and the spermatic cord is identified and elevated. The external veins parallel to the cord are ligated, followed by microscopic ligation of the spermatic veins Collateral vessels entering the cord distally may also be directly addressed with this technique. This is in contrast to the subinguinal approach, in which a greater number of arteries and veins are exposed and the dissection may be more difficult. ^[60]

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. Preoperative factors that predict success with these repairs include the following ^{[61, 62]} :

• Younger patient age
• Greater sperm density
• Larger varicoceles
• High testosterone and lower FSH levels

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. ^[63]

Results from a prospective, randomized, controlled trial from Saudi Arabia provide an evidence-based endorsement of the superiority of subinguinal microsurgical varicocele repair over observation in infertile men with palpable varicoceles and impaired semen quality. ^[64] 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 32.9% of treated men compared with 13.9% of controls (odds ratio, 3.04). In treated men, the mean of all semen parameters significantly improved on follow-up compared with baseline (P < 0.0001).

A meta-analysis that compared the various varicocelectomy approaches found that pregnancy rates increased in inguinal, subinguinal, open inguinal, and laparoscopic approaches. However, the subinguinal and inguinal groups had the lowest recurrence rates, highest pregnancy rates, greatest increases in sperm parameters, and lowest rate of hydrocele formation. ^[65]  

Interest in the use of robotic surgery has been growing across various medical fields, including varicocelectomy. The potential advantages of robotic-assisted microsurgery include the following ^{[66, 67]} :

• Elimination of tremor
• Improved stability
• Surgeon ergonomics
• Scalability of motion
• Multi-input visual interphases with multiple visual views
• Enhanced magnifications
• Ability to manipulate multiple instruments and cameras simultaneously

Robot-assisted subinguinal varicocelectomy has been shown to be safe and efficacious, with one group reporting improved sperm parameters in 76% of patients. ^[68] Operative times are similar to those with microscopic inguinal varicocelectomy, although the robotic technique does have a learning curve. ^[69]

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. ^[70] 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. ^[71]

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. ^[72]

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. ^[73] If viable sperm are observed, send an additional sample for cryopreservation prior to vasovasostomy. These sperm may be used for in vitro fertilization (IVF) or intracytoplasmic sperm injection (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.

A vasoepididymostomy is also closed in 2 layers (see image below). Factors that predict a more favorable outcome include the following:

• Shorter time from the original injury/surgery
• Vasovasostomy performed on one side rather than bilateral vasoepididymostomies
• Reconstruction because of an infectious etiology rather than a surgical or idiopathic etiology

For vasoepididymostomy, an end-to-side technique is easier to perform and yields better outcomes than an end-to-end anastomosis. In 1998, a triangulation end-to-side technique for vasoepididymostomy was described, which has since been broadly implemented. ^[74] The two-stitch longitudinal intussception technique described by Marc Goldstein is also popular with many microsurgeons due to its simplicity and high patency rates. ^{[75, 76, 77]} 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.

Robotic vasovasostomy has been shown to yield similar patency rates as the microsurgical approach, but no difference in pregnancy rates (~60%). The mean operating times for robotic vasovasostomy and vasoepididymostomy have also been shown to be comparable to the microsurgical approaches. ^[66]

Robotic assistance also permits microsurgical procedures to be used in areas that are normally difficult to access. For example, in patients who have a vasal obstruction as a result of a prior inguinal hernia repair, robotic-assisted intra-abdominal vasovasostomy has been effectively employed. ^[69] It provides an advantage to these patients because it requires very small inguinal incisions to mobilize the external vas and it allows for tension-free anastomosis because the testicular vas is brought into the pelvis for the procedure. ^[68]

Varicocele embolization

Percutaneous embolization is a procedure in which interventional radiologists occlude the veins that drain blood from the testes, using a variety of methods. This procedure is most commonly performed in the left spermatic vein for left-sided varicoceles. Occluding the left spermatic vein reduces retrograde blood flow, which reduces hydrostatic pressure in the testicles and, consequently, reduces the potential for testicular damage and atrophy.

Originally, the femoral approach was used to access and occlude the left spermatic veins. The femoral approach goes in through the right femoral vein to occlude the contralateral varicocele. This approach is still used but it can only be used for a unilateral left-sided varicocele, whereas the newer transjugular approach allows for the possibility of bilateral access. Once accessed, the spermatic veins can be occluded with sclerosing agents, balloon occlusion, or coil embolization. ^[78]

Percutaneous embolization is the preferred treatment for some cases of varicocele as it is the least invasive. One of the major advantages is that it is done under spermatic venography, which allows more precise identification of the internal spermatic veins and thus decreases the risk of injuring the testicular artery. ^[78]

Additionally, the procedure can be performed using local anesthesia and intravenous sedation as opposed to general anesthesia. The radiation exposure is then mitigated by fluoroscopy, which is especially important in younger males. Furthermore, percutaneous intervention requires no scrotal incisions.

All patients need a follow-up Doppler ultrasound 3 months post embolization, and patients who are actively attempting conception also need a semen analysis 4 to 6 months post embolization. The procedure is considered successful if there is no evidence of retrograde flow. With left-sided varicocele repairs, failure is very rare; however, multiple studies have illustrated that technical failure rates for right-sided varicoceles with the percutaneous approach are as high as 49%. ^[78] Nonetheless, a meta-analysis that included 315 patients revealed that the overall failure rate, on either left or right side, was 13.05%. ^[78]

The success of this procedure depends on various factors, including anatomy, vascular access, and intraoperative factors such as the material used to embolize the vein and vasospasm ^[78] . Thus, it is important to select patients for each procedure very carefully.

Additionally, even though the recovery may be quicker and seemingly easier for patients, there is a high degree of variability.  The recurrence rate varies substantially from 0%-24% with this technique versus the low and consistent recurrence rate of 0%-3% observed with microsurgical varicocelectomy. ^[78] Due to this variability, microsurgical varicocelectomy still tends to be the preferred treatment for most cases. Another major prohibitive factor to this approach is the significantly higher cost compared with surgical approaches.

Alternatively, this approach seems to be a very good choice for patients who have initially undergone a microsurgical varicocelectomy and later have a recurrence. The precision can be very useful when the anatomy is disrupted from the previous procedure or in certain cases where a patient may not want to undergo a second operation. Many cases of recurrence tend to be due to an incompetent gonadal vein that is most commonly caused by an anatomical duplication of the gonadal vein itself. ^[78] In these cases, the success rate was near-perfect, once the anatomical differences in these patients were correctly identified via retrograde venography and subsequently treated with embolization. ^[78]

Complications from percutaneous embolization include vascular perforation, coil migration, and thrombosis of the pampiniform venous plexus. ^[78] Further, the variability of outcomes indicates that radiological techniques in treating varicoceles are much more heavily dependent on the expertise, skill, and experience of the clinician. When the surgical candidate is appropriately identified, this technique may be the best option. 

Treatment of subclinical varicocele

The presence of a varicocele and resulting oxidative stress can have a deleterious effect on fertility over time.  Performing a prophylactic varicocelectomy in patients with subclinical varicoceles has been proposed as a way to ensure future fertility. However, this is still a highly debated topic among surgeons. Evidence is lacking that the potential risks and benefits of the procedures outweigh having no intervention at all; thus, it is not a recommended option.

A prospective study by Contaro and colleagues demonstrated a benefit of percutaneous embolization in infertile men with left-sided subclinical varicocele and one or more abnormal semen parameters. Six months post-procedure, significant improvement from pre-procedure values were noted in mean sperm concentration, total motility, and follicle-stimulating hormone levels in the 218 patients who underwent varicocele embolization, as compared with the 119 patients in the observation group. After 39.4 ± 6.5 months, pregnancy rates were 46.3% for the treated group and 11.8% for the control group (P = 0.011). These authors concluded that in infertile men, small varicoceles, even subclinical ones, should be identified and treated. ^[79]

Pasqualotto et al reported that repair of a subclinical varicocele in the right testicle results in significant seminal improvement in patients who have  a grade II-III varicocele in the left testicle. In this study, patients were divided into two groups: Group I underwent unilateral varicocelectomy and Group II underwent bilateral varicocelectomy. Group I (21.01 ± 19.1) had a higher mean sperm concentration before treatment than Group II (5.7 ± 10.7) (P = 0.04). Volume increased in the left testicle in Group I (17 ± 7.9 vs. 22.81 ± 8.2; p = 0.04)  and in the right testicle in Group II (18.4 ± 6.2 vs. 22.3 ± 6.5; P = 0.04). Additionally, postoperative mean sperm concentration increased significantly in Group II (30.32 ± 9.8; P = 0.03) compared with Group I (25.7 ± 22.8), in whom it increased only slightly. Group II exhibited higher pregnancy rates (66.7%) compared with Group I (33.3%). ^[80]

Pasqualotto et al concluded that “even a small, subclinical unrepaired varicocele continues to have a detrimental effect on bilateral testis function in a patient with grade II–III left varicocele." Further, they hypothesized that, “even though the surgery was performed in infertile adult men, the varicocelectomy procedure may increase the testicle size and this fact, in turn, may be the reason for the surgery’s leading to an improvement in semen analysis." ^[80]

Although the current data are controversial, acting early and establishing a long-term plan for subclinical varicoceles seems to be beneficial. Perhaps surgeons can weigh the risks and benefits on an individual basis to see whether serial monitoring or intervention may help increase fertility. Deciding if and when to treat is especially important with adolescent varicoceles. Many of these cases are subclinical; therefore, deciding on a plan based on individual patient factors and intervening at the appropriate time can have a significant effect on long-term outcomes of fertility.

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 the patient under spinal or general anesthesia, the resectoscope with a 24F cutting loop is used to excise the verumontanum of the prostate. A video example of this has been provided by Savio et al. ^[81] 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-contaminated) 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. ^[82] In a study spanning 15 years, TESE from men with azoospermia followed by cryopreservation was more effective at fertilization than fresh sperm from biopsies (62% vs 47% for all diagnoses). ^{[83, 84]}

Microscopic TESE (microTESE) has been shown to improve sperm retrieval rates with minimal tissue excision.During microdissection, the surgeon can identify sperm-producing areas in the testicles, which is not possible with standard TESE. ^[85] Robotic-assisted TESE (ROTESE) has been employed in select studies and has been shown to be safe and feasible for sperm retrieval. An advantage of ROTESE over microTESE is that ROTESE can provide surgeons with multiple imaging modalities to use during the procedure, which may assist in identifying tubules that contain sperm. ^[66]

Testicular sperm aspiration (TESA) is less invasive than TESE but yields fewer sperm and is suboptimal in cases of nonobstructive azoospermia. ^[82]

Microsurgical epididymal sperm aspiration (MESA) involves directly retrieving sperm from the epididymis. Sperm in the epididymis are more mature than those 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. ^[86] While effective in sperm retrieval, PESA 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

With the patient under general anesthesia, an unlubricated Foley catheter is placed in the bladder and a buffer (ie, HTF medium) 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. ^[87] Patients must have an intact lumbosacral spinal cord segment. The US Food and Drug Administration (FDA) has approved this device for home use, using 2.2 mm at 100 Hz. This is associated with fewer adverse effects and lower cost than electroejaculation. In addition, collection may take place 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.

Older age in the man has been associated with lower pregnancy rates and higher rates of subsequent spontaneous abortions in patients undergoing IUI. ^{[88, 89]} 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, as well as a slightly higher rate of major birth defects. ^[90] 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. ^[91]

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

Sperm samples are collected either via masturbation or surgically. Surgical extraction may be more useful in cases of persistent necrozoospermia, due to the high DNA fragmentation rates in ejaculated sperm. Sperm can then be evaluated microscopically for motility, morphology, DNA quality, and/or the ability to bind a hyaluronic acid assay. ^[92] The embryologist then chooses the most adequate sperm for the procedure.

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 reported a 59% fertilization rate and a 35% pregnancy rate with the use of ICSI in 1409 oocytes. ^[93] Fresh sperm and cryopreserved sperm appear to have similar success rates. ^[94] In female partners of men with infertility who are undergoing ICSI, diminished ovarian reserve may adversely affect the success of TESE (ie, reduce the clinical pregnancy rate). ^{[83, 84]} Some studies also suggest that a direct correlation exists between endometrial thickness and pregnancy rates after ICSI. ^[95]

The potential complications, ethical issues, and high costs of ICSI must 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%, 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 two copies of the abnormal gene.

In 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.

See the list below:

• 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. ^[96]

See the list below:

• 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.