Treatment -medical, empirical, surgical, alternative, adoption, donor, psychological

Infertility affects approximately 10-15% of all reproductive-age couples and a male factor is present in 40-50% of those couples. Specific interventions to treat an abnormality in the male partner is not possible for some affected couples. Fortunately, assisted reproductive techniques (ART) can help bypass the abnormality in many patients without problems amenable to specific treatment.

Current treatment of male factor infertility
The key to treatment of male factor infertility is identification of a specific cause of abnormal fertility.

Medical treatment
Specific treatment of males with hormonal abnormalities is frequently effective. For men without production of gonadotropin releasing hormone (GnRH), and the subsequent lack of pituitary release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), puberty is not achieved until exogenous LH, FSH or testosterone is given. Initial treatment with testosterone injections (in oil) will activate the onset of puberty and the development of secondary sexual characteristics. When the man is interested in fertility, sperm production may be stimulated by intramuscular replacement of the pituitary hormones LH (in the form of human chorionic gonadotropin, hCG) and FSH (as human menopausal gonadotropin, hMG; or recombinant human FSH). Replacement of deficient hypothalamic hormones may also be provided with pulsatile subcutaneous GnRH given by a small portable pump, but this treatment is awkward since the patient must carry around the pump at all times. Abnormal production of prolactin by a pituitary tumor can also result in a lack of production of LH and FSH by the pituitary with a subsequent drop in testosterone production in the testicle and loss of sperm production. Bromocriptine suppression of a prolactin-producing tumor is highly successful in restoring both normal hormone levels and sperm production. An initial dose of 5 mg per day is gradually increased until side effects occur or there is normalization of gonadotropins and testosterone. Exogenous gonadotropin may still need to be used in these cases because the tumor, or treatment of the tumor with surgery or radiation therapy, can cause destruction of the pituitary itself. Finally, other effective specific medical treatments include eradication of infection with antibiotics and decreasing antisperm antibodies with corticosteroids. Although treating antisperm antibodies with corticosteroids is treatment for a specific problem, it needs to be emphasized that this treatment is controversial because the effectiveness is sporadi, and the steroids themselves can have serious side effects (e.g., aseptic hip necrosis).

Empiric medical therapy involves administration of an agent that somehow supports the normal processes of sperm production in a man who is infertile, but who has normal hormone levels. Approaches used include estrogen receptor blockers (e.g., tamoxifen, clomiphene citrate) to stimulate the pituitary to increase LH and FSH release, with a resultant increase in intratesticular testosterone production. Chemicals known to artificially improve sperm motility or appearance in vitro, such as the protease kallikrein or the phosphodiesterase inhibitor pentoxifylline, have been given systemically in an attempt to improve sperm function. However, it must be stressed that empiric therapies are, in general, not successful in improving male fertility when evaluated in controlled trials. A semen analysis may be abnormal for many reasons and, in addition, sperm quality is highly variable in serial semen analyses from a single man over time. An apparent improvement in sperm production temporally related to an empiric intervention is more often due to natural variability than to an actual effect of the treatment on the man's fertility.

Surgical intervention
Surgical intervention will allow correction of obstructions of the reproductive tract or of structural abnormalities that can affect sperm production, such as a varicocele. A varicocele results from enlarged testicular veins that are thought to occur because of reflux of blood from the left renal vein down into the left internal spermatic vein (Fig.1). The reflux manifests clinically as enlargement of the scrotal testicular veins (Fig.2), which may be easily seen from across the room for a man with a large varicocele in a standing position. The enlarged veins are corrected by a direct surgical dissec- tion of the vessels of the spermatic cord with division of the internal spermatic veins which prevents reflux of blood in the testicular veins; outflow of blood from the testis can then occur via the external spermatic veins and vasal veins. Alternatively, the veins can be obstructed angiographically via the inferior vena cava by retrograde sclerosis. Overall, there is an improvement in the semen analysis in two-thirds of patients after treatment of a varicocele.

Obstructions in the epididymis or vas deferens can be microsurgically corrected. An operating microscope is helpful to accurately identify and reconstruct these structures that are only a fraction of a millimeter in luminal diameter. Obstructions of the epididymis or vas may be congenital, due to infection, or due to iatrogenic intervention, such as a prior inguinal hernia repair. Reversal of a vasectomy is typically very successful if a second blockage or "blowout'' has not occurred in the epididymis. Vasal reanastomosis (i.e., vasovasostomy) under an operating microscope will yield patency rates above 90% (and subsequent pregnancy rates of 50-70%) in experienced hands, when sperm are present in the testicular side of the vas deferens. Pregnancy is not achieved by all couples that have undergone a successful vasectomy reversal because of antisperm antibodies, female factor infertility, restricture of the vas deferens and other poorly understood factors.

Obstruction of the ejaculatory duct may also occur from congenital, infectious or iatrogenic reasons. Resection of a small area of the prostate and ejaculatory duct can relieve these obstructions. Highly successful results are possible when a specific obstruction or obstructions of the male reproductive tract can be identified and corrected.

Bypassing abnormal sperm quality: assisted reproduction
After all factors affecting male fertility have been corrected and pregnancy has not occurred, it is appropriate to use assisted reproductive techniques (ART), which include intrauterine insemination (IUI), in vitro fertilization (IVF), IVF with micromanipulation of sperm etc., in an attempt to improve interaction between sperm and egg and, thus, increase the chance of pregnancy. In selected cases, where the female partner has an abnormality that will require ART, it may be appropriate to proceed directly to these techniques. For example, if the female partner of a man with abnormal sperm quality has obstructed fallopian tubes and IVF will be necessary, it may be indicated to proceed directly to IVF without correcting the primary cause of abnormal male fertility. On the other hand, treating a correctable male problem can result in improved semen quality and better results at the time of IVF. In general, these interventions in male and female partners must be closely coordinated to optimize chances of achieving pregnancy with a minimum of treatments.

Intrauterine insemination involves processing sperm into a small volume and placement of the washed, concentrated sperm specimen directly into the female partner's uterus, timed to the woman's ovulation. After 3-4 cycles (attempts) at IUI, pregnancy is rarely achieved. The overall results with IUI are little better than natural intercourse alone for male factor infertility. Specific success rates with IUI are also dependent on sperm quality. If very poor sperm motility is present, pregnancy rates are usually less than 10% over a total of three or four cycles. With only minor impairment of semen parameters, pregnancy rates approach 50%. These numbers differ by less than 5-10% from expected pregnancy rates for natural intercourse over 10-12 natural cycles. IVF involves stimulation of egg production in the female partner, followed by transvaginal ultrasound-guided egg retrieval from the ovaries. Eggs and sperm are then brought together outside of the body. Up to four fertilized eggs (embryos) are returned to the uterus after 2-3 days of incubation in vitro. Overall pregnancy rates of 10-15% are achieved nationwide per attempt with IVF. Optimal pregnancy rates (up to 50% per attempt) can be achieved at a select number of centers in which injection of a single sperm into the egg is performed as part of IVF, an involved and expensive process referred to as intracytoplasmic sperm injection (ICSI).

Substitutive treatments
In some cases, a couple will elect to use sperm provided by an anonymous donor or to proceed with adoption instead of having children that are genetically their own. This is a difficult decision to make, as one's sense of gender and identity sometimes are closely related to the ability to have children. In other cases, the extremely high cost of assisted reproductive techniques and male infertility treatment are not covered by insurance, and the only option for having children is to use donor sperm or proceed with adoption. The use of donor sperm is applied in those cases where male factor infertility cannot be treated to allow for pregnancy to occur, and/or assisted reproduction is unsuccessful or not an alternative for the couple. Sperm is provided anonymously from donors who are carefully screened by history for the presence of genetic and infectious diseases. Donated sperm are frozen for a quarantine period of at least 6 months to allow serial testing of the donor for the presence of HIV antibodies. The donor is also tested for hepatitis and other sexually transmissible diseases. The donor is usually identifiable by religious, ethnic and physical characteristics, as desired by the recipient couple. In some centers sperm from a designated donor can be used. However, donation by a known donor is often discouraged because of the potential legal paternity liability that could later occur.

Psychological Counselling
Male infertility is often a psychologically disruptive situation, as fertility is assumed to be natural and essentially automatic. In addition, any disturbance in male sexual or fertility functions is likely to deeply affect a man's sense of gender identity. Although men are unlikely to immediately verbally express their psychological difficulty with the identification of a male fertility problem, jokes, denial and other seemingly inappropriate behavior are common. In other cases, depression may occur without an apparent cause. Any suspicion that the man may be psychologically affected by the identification of male infertility is an indication for referral for psychological evaluation. In addition, any couple considering IUI with donor sperm should consider psychological counselling. The issues of masculine identity for an infertile man, and lack of genetic parenthood may arise after the "donor child'' is born and cause psychological difficulty for the father if not addressed prior to donor insemination. An additional problem for the couple who chooses substitutive treatments for infertility is what to tell friends, family and the child him/herself. All of these issues should be explored and discussed openly prior to the initiation of pregnancy. Summary
Male infertility is a common problem and can be addressed successfully with a number of interventions. Direct treatment of the male problem, assisted reproduction, donor insemination, and adoption are all alternatives for management of this situation. Modern technological advances, including ICSI and microsurgical correction of obstructive problems, allow many couples who were not previously treatable to successfully have children. Future developments in diagnosing and treating subtle endocrinopathies, better methods of treating antisperm antibodies, and identification of environmental causes of infertility are expected and await the next generation of andrologists.

Suggested Reading

Pryor JL, Howards SS. Varicocele. Urol Clin North Am 1987;14:499-513.

Van Steirteghem AC, Nagy Z, Joris H, et al. Higher success rate by intracytoplasmic sperm injection than by subzonal insemination. Report of a second series of 300 consecutive treatment cycles. Hum Reprod 1993;8:1061.

Lipshultz LI, Howards SS, Buch JP. Male infertility. In: Gillenwater JY, Grayhack JT, Howards SS, Duckett JW, eds. Adult & Pediatric Urology, 2nd edition. St. Louis, MO: Mosby-Year Book; 1991.