Male Infertility Overview: Part II

TESTICULAR BIOPSY AND VASOGRAPHY

In azoospermic patients or selected cases of severe oligospermia with normal FSH levels, primary spermatogenic defects cannot be differentiated from obstructive lesions by hormonal investigation alone, and testicular biopsy and sometimes vasography should be considered. When patients have azoospermia or severe oligospermia in conjunction with markedly shrunken testes and serum FSH levels that are at least twice normal, testicular biopsy can be avoided as it will indicate untreatable testicular pathology and only provide a definitive diagnosis which allows the patient to investigate alternatives. The exception is the patient who has undergone chemotherapy in whom the elevated FSH level may normalize with return of spermatogenesis. Before biopsy, at least two semen analysis should reveal azoospermia and retrograde ejaculation should be ruled out by examining a post ejaculatory urine specimen. In men with acidic semen, i.e. pH of less than 7.0 and a volume of less than 1 cc, suspect ejaculatory duct obstruction or congenital absence of the seminal vesicles and vas deferens. For confirmation, seminal fructose levels should be determined. The presence of fructose rules out obstruction or atresia of the ejaculatory ducts but does not verify total ductal patency. Only when there is clinical suggestion of different pathologic conditions on each side are bilateral biopsies needed. The testicular tissue is always placed atraumatically into a container of Bouin's or Zenker's solution. Formalin should be avoided as it distorts the testicular architecture.

Vasography is used to rule out obstruction of the vas deferens, seminal vesicles, and ejaculatory ducts. Vasography should be performed only at the time of definitive reconstructive surgery. A vasotomy is generally performed at the junction of the straight and convoluted portions of the vas. Any fluid obtained from the vasotomy is evaluated for the presence of sperm. Patency of the ductal structures distal to this point is assessed by the injection of radio­opaque contrast solution. Injection of 3-5 cc of 50% Hypaque or Renografin-60 will provide adequate films of the vas, seminal vesicles and ejaculatory ducts. Methylene blue may also be instilled as the bladder is catheterized. The presence of blue or green urine documents patency distal to the instillation site. Retrograde injection of solution towards the testis makes images of the epididymal anatomy that are extremely difficult to interpret. There is also significant risk of causing epididymal injury and should be avoided.

Both clinical and laboratory investigations have provided convincing evidence that varicoceles are detrimental to spermatogenesis in some men. It has been shown that improvement in semen quality after varicocelectomy bares no relation to the palpable size of the varicocele. Because small but clinically significant varicoceles may be missed even on careful physical exam, several diagnostic techniques have been tried. The doppler pencil-probe stethoscope was one of the earliest techniques and is easily utilized in an office setting. If the clinician is still uncertain as to the presence of a varicocele, scrotal ultrasonography is a readily available non-invasive method.

Color flow duplex ultrasonography is a superior way to measure the diameters of the spermatic cord veins by imaging these vessels, at rest and during a Valsalva maneuver, as well as to quantify and qualify the flow of blood through these veins. It has been shown to be 85% sensitive in the detection of subclinical varicoceles when venography was used as the "gold standard". Duplex ultrasonography is certainly useful when there is a question on physical examination because it is an objective characterization of the pampiniform veins. Venography seems to be the most specific method of identification of varicoceles but it is invasive and associated with some morbidity. It is also expensive and so should be reserved for use in recurrent varicoceles for postoperative detection of aberrant veins. Transrectal ultrasonography is ideally suited now for evaluation of the prostate, seminal vesicles and ejaculatory ducts in patients with azoospermia or low ejaculate volumes. As discussed previously, the differential diagnoses of azoospermia included endocrinopathy, testicular failure, and obstruction. Differential diagnosis of low ejaculatory volume includes hypogonadism, retrograde ejaculation, failure of emission, seminal vesicle aplasia or hypoplasia and ejaculatory duct obstruction. Although vasography has been used to visualize the seminal vesicles and ejaculatory ducts, transrectal ultrasonography is accurate, inexpensive and relatively non-invasive. It can provide detailed images of the seminal vesicles and ejaculatory ducts. Vasography and testicular biopsy may be necessary to rule out testicular failure or proximal obstruction if the transrectal ultrasound study is normal in the azoospermic patient. It is easy to see that transrectal ultrasonography provides valuable information and may be used in place of vasography to identify obstruction or congenital anomalies of the ejaculatory ducts or seminal vesicles.

Varicocelectomy
The relationship between varicocele, altered spermatogenesis, and infertility is now so widely accepted that varicocelectomy is the most common surgical procedure for infertility in males. The term varicocelectomy as it is utilized here is actually a misnomer. The procedure should be termed internal spermatic vein ligation, as varicocelectomy implies that the veins are actually being removed and they are instead being ligated. This operation improves semen quality in about two-thirds of men and basically doubles the chance of conception. Ligation of varicoceles eliminates testicular venous reflux by interruption of the internal spermatic veins. The operation is usually performed through a small inguinal incision though modification of the older Palomo procedure, which is a retroperitoneal approach, is certainly acceptable. The scrotal approach is mentioned only for completeness though is not recommended because of the numerous small veins encountered as well as the possibility of arterial injury is greater. Percutaneous venographic occlusion is also an alternative to surgery but small veins outside the spermatic cord that are visualized during an open surgical procedure are not easily embolizable with the percutaneous approach. Laparoscopic techniques to treat varicoceles are also currently utilized and at this time have no clear cut advantage over a small inguinal incision. Complications following varicocelectomy include hydrocele formation, epididymitis, injury to the internal spermatic artery and persistent or recurrent scrotal varicoceles. Fortunately, this occurs in less than 3-5% of patients.

Vasovasostomy and Epididymovasostomy
The popularity of vasectomy as a form of male contraception, combined with high rates of divorce and remarriages, led to an increasing number of vasectomy reversals. With the application of microsurgical techniques along with the technical advances in magnification, high-intensity light production, and microvascular sutures and needles, I am firmly convinced that the results of microsurgical vasovasostomy are better than the results of vasovasostomy performed without microsurgical techniques. However, the surgeon's experience with vasovasostomy certainly is an important factor. Up to 8-10 years post vasectomy, the rate of successful reapproximation with sperm present in the ejaculate is 80-90% with a functional success rate/pregnancy rate of 50-60%. Intraoperative predictors of success revolve around the quality of the vasal fluid at the time of vasovasostomy. When clear copious fluid with motile sperm is found, the prognosis for postoperative pregnancy is in the 60-70% range. If no fluid is found or it is thick and "toothpasty", an epididymovasostomy should preferentially be performed. Unfortunately, epididymovasostomy success rates under these circumstances decrease the postoperative pregnancy rate to the 20-30% range. Failures of vasovasostomy may be attributed to anastomotic stenosis in about 10% of patients, antisperm antibodies, epididymal dysfunction, or an unrecognized epididymal tubule "blow-out" with subsequent obstruction. Even though antisperm antibodies can be found in the serum of almost 50% of men who have undergone vasectomy, their presence on sperm in the ejaculate postoperatively is considerably less. Unfortunately, it is not possible to use preoperative serum antisperm antibody results to predict the success of vasovasostomy for a given patient. There is general agreement that utilizing non-absorbable stents that are removed within the first week postoperatively seem to have an adverse effect on the results of vasovasostomy. Hollow absorbable stents have been utilized with some promise. Laser welding has been used both experimentally and clinically but it is necessary to perform some preliminary microsurgical suturing of the ends of the vas before the laser is used. Overall it appears to shorten the operating time but increases the expense.

Because sperm continues to be manufactured by the testes and attempt to travel through the epididymis, pressure-induced extravasation may occur at any point within the epididymal tubule. This results in a local inflammatory reaction that effectively blocks the movement of sperm. When this situation is recognized at the time of vasectomy reversal, an epididymovasostomy or vasoepididymostomy is required. This procedure is more technically demanding. Critical to the success of a vasoepididymal anastomosis is the ability to visualize the 0.2 to 0.4 mm lumen of the opened epididymal tubule exuding sperm, and to approximate it accurately to the vasal lumen. Epididymal obstruction can be the result of 1) congenital anatomical abnormalities of the vas/epididymis; 2) inflammatory process, and 3) vasal obstruction. It is apparent that the results of microsurgical reconstruction procedures indicate that sperm which traverse greater portions of the epididymis are functionally superior. Therefore, the greater the length of epididymis that the sperm traverse, the better the pregnancy rate. Patency rates have been reported to be between 50% and 70% with pregnancy rates varying between 15 and 30%.

Transurethral Resection of Ejaculatory Duct
Patients who present with azoospermia and even sometimes oligo-asthenospermia, normal sized testes, and a normal testicular biopsy in conjunction with transrectal ultrasound findings of dilated ejaculatory ducts are good candidates for transurethral resection of the ejaculatory ducts. The orifices of the ejaculatory ducts exit within the prostatic urethra just lateral to the verumontanum. Under anesthesia they are inspected endoscopically and then can be incised or unroofed. In select cases, transurethral resection of the ejaculatory ducts has resulted in marked improvement in semen parameters, and pregnancies have been achieved.

Microsurgical Epididymal Sperm Aspiration (MESA)
MESA is an alternative treatment method for obstructive azoospermia in order to obtain sperm from the epididymis with the use of an operating microscope. It is not a surgical technique to be used for 1) the non-obstructed system if ejaculation is normal; 2) the severely oligospermic patient with primary testicular dysfunction, or 3) the vasectomy patient who incorrectly views MESA as an easy alternative to a first-time vasectomy reversal. Its indications include all those obstructive disorders that are not surgically remedial. This includes congenital bilateral absence of the vas deferens, bilateral ejaculatory duct obstruction not corrected by transurethral surgery, obstructive azoospermia secondary to surgical removal of the vasal ampullae and seminal vesicles during cystoprostatectomy or radical prostatectomy, failed vasoepididymostomy where the prognosis for redo surgery is poor. In the past the only available therapy for these particular patients was the man-made reservoirs (artificial spermatoceles), which were used to collect sperm to be used for artificial insemination. The resultant pregnancy rates were dismal at less than 5%. This led to failure of the device to maintain epididymal patency and to the extremely poor motility of the collected sperm. MESA is performed in conjunction with either IVF or GIFT and/or assisted fertilization through gamete micromanipulation. When it comes to fertilization pregnancy rates, the level of sperm attainment, quality of that sperm, and female situation are all quite important factors. It is a complex event that requires the highest level of urologic, gynecologic and laboratory expertise to afford the couple the optimal chance for conception. Pregnancy rates from different groups vary widely ranging from O to 20% per attempt. As better techniques of sperm and egg manipulation are developed, the ultimate pregnancy rate will undoubtedly improve.

Ablation of Pituitary Adenomas
Therapeutic use of the dopamine agonist bromocriptine (Parlodel) or in selected cases, transphenoidal surgical ablation of pituitary micro or macroadenoma may be required in individuals with impotence and a spermatogenic defect associated with elevated Prolactin levels. Slight elevations in serum Prolactin levels without any concomitant suppression of gonadotropins does not require a particular medical therapy.

Prophylactic Surgical Measures
Few undescended testes descend spontaneously after nine months of age. Histological data has shown a progressive decrease in the number of spermatogonia per tubule beginning before age two.

Therefore orchidopexy is recommended prior to this age. If undescended testes have failed to respond to medical therapy with HCG injections or intranasal GnRH, then orchidopexy should be performed. It is certainly important to detorse a testicular torsion as soon as possible. A great deal of animal data, but few human studies, have shown a deleterious effect of an infarcted testis on the contralateral healthy testicle. This effect was thought to be immediated through an auto-immune process resulting from the breakdown of the intact blood-testis barrier. It has been recommended that the non-viable testicle be removed at the time of diagnosis of torsion.

Electroelaculation and Vibratory Stimulation
Ejaculatory dysfunction is a relatively uncommon occurrence in the general population. Ejaculatory dysfunction in fertility though is almost a universal sequelae of spinal cord injury to men. Ejaculatory dysfunction can result from either a spinal cord injury, retroperitoneal lymph node dissection and other types of retroperitoneal or pelvic surgery, diabetes mellitus, transverse myelitis, multiple sclerosis or psychogenic disorders. Electroejaculation had been used successfully for many years in animal husbandry and has since been adopted this past decade successfully for men with ejaculatory dysfunction. Through a rectal probe, an electrical current stimulates the post ganglionic sympathetic nerve endings that innervate the structures involved in seminal emission and ejaculation. The semen recovered has quite variable parameters. The specimens are processed and then utilized for either intrauterine insemination or in conjunction with the various assisted reproductive techniques. A multi-disciplinary approach is required for treating both the husband and the wife in order to optimize the outcome. Reported pregnancy rates approach 30-35%.

It is recommended that vibratory stimulation be attempted prior to enrolling a patient in an electroejaculation protocol. This technique involves the use of a high frequency vibrator placed along the glans penis for variable amounts of time ranging from a few minutes to 20 minutes until an ejaculate is produced. Just as in electroejaculation, any spinal cord injury patient with a complete lesion at or above the T6 level must be monitored for autonomic dysreflexia. Pre-treatment of the patient with a calcium channel blocker (Procardia) is recommended. One distinct advantage of vibratory stimulation is that should the sperm count and motility make it a reasonable consideration, it can easily be translated to home use coupled with an insemination program overseen by the physician.

MEDICAL MEASURES

Endocrine Therapy
Infertile men with hypogonadotropic hypogonadism (secondary hypogonadism) are the only appropriate candidates for exogenous gonadotropin therapy. For initiation of spermatogenesis, LH must be given to stimulate the Leydig cells to produce high intratesticular testosterone levels. hCG (Pregnyl or Profasi) 2,000 IU intramuscularly three times a week is usually effective in stimulating adequate production of testosterone for full virilization. Once the patient is fully virilized and 8-12 months of hCG therapy have not led to the production of sperm, then FSH therapy should be initiated. FSH is available as human menopausal gonadotropin (hMG). The commercial preparation Pergonal contains 75 IU of FSH and 75 IU of LH per vial. The usual dosage is 1/2 to 1 vial intramuscularly three times weekly. Since hCG and hMG are compatible in solution, the same syringe may be used. It takes months for sperm to appear in the ejaculate after initiation of FSH therapy. With the normal response, most patients achieve a sperm count of between 2 and 5 million sperm per ejaculate and then impregnation is possible. Once a pregnancy has occurred, the FSH therapy can be stopped. Spermatogenesis can be maintained with hCG alone. An alternative to exogenous gonadotropin usage is the use of GnRH to stimulate LH and FSH endogenously. GnRH must be given in a pulsatile manner as continuous administration down-regulates the pituitary. The initial dosage is 25-50 ng/kilogram every two hours by a small infusion pump. Both the gonadotropins and GnRH are expensive. Although GnRH achieves a more physiologic pattern of gonadotropin stimulation, its superiority has yet to be proved. Pituitary disease is not amenable to GnRH therapy, and combined treatment with hCG and hMG will be necessary. Individuals with the fertile eunuch syndrome (partial LH deficiency) may respond to hCG therapy alone.

Therapy for Immunoloqic Infertility
When detectable antisperm antibodies are clinically relevant, treatment is difficult. Formerly a common form of therapy was the use of immunosuppressive agents like corticosteroids to abort or modulate the production of antibodies. Results are still unclear as to whether any recommended regimen of steroid therapy really lessens either the production or the clinical effects of antisperm antibodies in the male. The risks of this therapy must be weighed against its benefits. Even though complications were generally mild and self-limited, aseptic necrosis of the femur was reported in several patients and was obviously a devastating consequence of yet-unproven therapy. Several innovative methods of semen manipulation have also been attempted. These have included immediate dilution and washing of the semen following ejaculation, use of sperm surface fragments as immuno-absorbants to remove "unbound" antibody, in-vitro cleavage of sperm-bound antibodies with proteases, and the absorption of sperm with bound antisperms on indifferent types of columns to allow separation and capture of the unbound sperm. Unfortunately most of these techniques have not proven to be routinely effective. Most patients end up-trying superovulation with sperm washing and intrauterine insemination. Despite the theoretical advantages of the above, intrauterine insemination pregnancies for antibodies have not exceeded 20%. Since these treatments have proven ineffectual, in-vitro factor infertility refractory to all other forms of treatment short of the assisted reproductive techniques. I am certainly very pro usage of donor sperm for my patients with severe male factor infertility.

As empirical medical treatment of male factor infertility has had limited success, semen processing and intrauterine insemination have become increasingly used to overcome the problems of reduced sperm number and motility. Semen processing is simply in-vitro manipulation of semen to enhance sperm function. It is done in an attempt to remove adverse seminal fluid factors and to extract a more normal and motile sperm population. Simple processing methods rely on dilution of the semen and centrifugation followed by resuspension of the sperm pellet in culture medium such as Ham's F10. More elaborate methods of sperm processing include swim-up procedures, centrifugation through Percoll density gradients, etc. On occasion, the patient's sperm may survive poorly in these procedures and it is desirable to test the semen in advance for the most appropriate preparative method. The above is followed by intrauterine insemination. Intrauterine inseminations principle indication was for cervical factor. It is logical that intrauterine insemination will bypass problems with the cervix or its secretion. The use of intrauterine insemination for male factor cases, immunological infertility, or unexplained infertility is widespread at this time, although the success rates are not optimal.

ASSISTED REPRODUCTIVE TECHNIQUES

In-vitro fertilization (IVF) was originally intended for individuals with tubal disease and female factor unexplained infertility. It has now been expanded to include couples with male factor infertility. Human ova can be fertilized using this technique with concentrations of 20,000 to 100,000 motile sperm. IVF alone aids many of the formidable obstacles to human sperm in the female reproductive tract. Although male factor patients have a lower fertilization rate compared to non-male factor groups, once fertilization has taken place in male factor couples, the pregnancy rate is as high as in non-male factor couples. Gamete intrafallopian transfer (GIFT) is a technique in which ova are retrieved in a manner similar to IVF but then the sperm are mixed together with the ova and injected directly into the fallopian tube for fertilization to occur. This technique has a theoretical advantage of allowing fertilization to occur in the fallopian tube. Knowledge of fertilization though is unknown unless a pregnancy ensues. Presently, several variations of IVF and GIFT have been born. These techniques include the names pronuclear stage tubal transfer (PROST), zygote intrafallopian transfer (ZIFT), tubal embryo transfer (TET) and tubal embryo stage transfer (TEST). They all involve the in-vitro fertilization of human eggs followed by transfer of the early-stage embryo back into the fallopian tube. Overall, the pregnancy rate for male factor patients has been reported to range from 10-35%.

Fertilization appears to be the best chance of conception in couples with documented antisperm antibodies.

Therapy for Retrograde Ejaculation
Antegrade ejaculation may be induced by treatment with alpha-adrenergic stimulation using sympathomimetic agents like Ornade, Sudafed or Tofranil. Alkalinization of the bladder urine with oral sodium bicarbonate or polycitra and retrieval of sperm from the bladder after ejaculation have been used successfully for artificial insemination.

Treatment of Infection
Individuals with symptomatic or documented genitourinary tract infection should be treated with the appropriate antibiotics. Tetracycline is often the first line drug of choice.

Empiric Therapy
Since up to 40% of infertile men fall into the category of idiopathic male infertility, many end up being treated empirically. A great number of these therapeutic modalities attest to the inability to find one or two that really work. Almost all patients wish to be treated even though the available therapy is nonspecific. Arginine, bromocriptine, corticosteroids and thyroid preparations should be relegated to the shelf as they have not had any effect on infertility when used empirically. Clomiphene citrate (Clomid or Serophene) is one of the most widely used drugs in male infertility. It is a weak anti-estrogen that interferes with the normal feedback of circulating estrogens and results in an increase in GnRH that stimulates androgenous gonadotropin secretion. The resulting elevation in LH and FSH increases intratesticular testosterone levels and in theory should improve spermatogenesis. Clomiphene citrate is given in a dose of 25-50 mg a day for 3-6 months. I usually start patients off at 25 mg per day and have then check back in four weeks to assess their current testosterone and FSH levels. This at least lets you know if the drug has " kicked in hormonally" and then you can make any adjustments on -the dosage at that time. There are many studies that show a positive effect of the drug on semen parameters, but there is no absolute evidence that it will substantially improve pregnancy rates.

ARTIFICIAL INSEMINATION

By definition, artificial insemination involves the use of the husband's sperm for insemination. It is particularly useful with low semen volumes or in cases where repeated post coital tests have shown cervical hostility. There really is no documented advantage in individuals with oligospermia or asthenospermia. The use of ultrasound to document enlarging follicles and urine testing to predict the timing of the LH surge and ovulation will increase the success rate. Therapeutic donor insemination is by far the most successful and cost effective form of therapy for couples with male infertility.

Micromanipulation
Despite the success that has been made available with IVF and GIFT, additional refinements have been necessary for patients whose concentration of functional sperm is extremely poor. Micromanipulation of gametes and assisted fertilization allows the surgical manipulation of sperm and ova. The methods of micromanipulation currently utilized include partial zone dissection (PZD), subzonal sperm injection (SZI) and intracytoplasmic sperm injection (ICSI). Overall, fertilization rates ranged from about 20-40%, with clinical pregnancy rates reported as high as 30% but averaging for severe male factor closer to 10%.