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What's New in Infertility

From Dr. Schlegel's What's New in Urology, JACS, October, 2001.

ADAM (Androgen deficiency in the aging male)

The study of androgen action and male reproductive dysfunction continues to expand significantly. Despite long-term discussion of similar syndromes in Europe, only recently has the definition of a disease state been associated with hormonal changes that occur in aging men. This syndrome, previously referred to as Andropause, has more recently been described as androgen decline in the aging male (ADAM; Morales et al., 2000.) The onset of ADAM is unpredictable and its manifestations are subtle and variable. It is associated with a decrease in testosterone, but also growth hormone, melatonin and dihydroepiandosterone. Clinical manifestations include fatigue, depression, decreased libido, erectile dysfunction as well as changes in cognition and mood. As the syndrome is better defined and understood, more specific treatment beyond androgen replacement is expected.

OTC Androgens

Popular over-the-counter androgenic agents such as androstenedione and dihydroepiandosterone (DHEA) have been used by an increasing proportion of the population. A study in JAMA (Leder et al., 2000) examined the effects of exogenous androstenedione on testosterone and other hormone levels in young healthy men. They found that oral androstenedione in high doses (300 mg/day) resulted in modest increases in serum testosterone levels and estradiol levels, whereas no change occurred in testosterone with lower doses. Knowledge of these changes is important in evaluation of men who are taking these medications.

Hormonal abnormalities in infertility

Other hormonal changes have been described for men with severe infertility. Pavlovich et al. (2001) reported on lower serum testosterone levels with high estradiol levels in men with infertility that was significantly different from a fertile reference group. Restoration of normal testosterone/estradiol levels was possible using treatment with oral aromatase inhibitors. An associated increase in sperm production and quality was also seen. Previously, it was thought that these men simply do not produce enough testosterone. These observations suggest that some men with severely dysfunctional testes may lose significant testosterone via aromatization to estrogens, an effect blocked by aromatase inhibitors. So, men with low testosterone levels are not always deficient in hormone production - they may actually have abnormal metabolism of the testosterone that is being produced.

Pathophysiology of testicular dysfunction

Recent observations have suggested that environmental effects on the developing testis may result in testicular dysfunction, hypospadias, undescended testes and a higher risk of testis cancer. Skakkebaek et al. (2001) referred to this condition as testicular dysgenesis syndrome. The causes are not yet clear. The mechanisms of sperm production in men with genetic disorders are also becoming more clear and leading to treatment possibilities for many individuals previously considered sterile. Blanco et al. (2001) demonstrated that many men with apparent non-mosaic Klinefelter syndrome may have subtle germ cell mosaicism, that allows production of a higher proportion of sperm with a normal genetic complement. Still, there remains a low but significant frequency of chromosome abnormalities in sperm from men with Klinefelter syndrome (Levron et al., 2000) so, genetic counseling is still required before treatment of these azoospermic men with sperm retrieval and intracytoplasmic sperm injection (ICSI). One common finding on ultrasound of testes of infertile men is a heterogeneous echo pattern of testicular parenchyma. This observation may reflect sclerotic seminiferous tubules within the testis. A study by Harris et al. (2000) noted that this finding was very common in men over age 50, and no further follow-up may be necessary for those individuals, whereas younger men at risk for testicular cancer may need additional studies.

Genetic factors and assisted reproduction

Although sperm production is dependent on hormone action, significant androgen receptor gene mutations in men with infertility are rare (<1%; Hiort et al., 2000.) Although Y chromosome partial deletions are known to cause infertility and they may be transmitted to sons produced with ICSI, they appear to occur only in the sons of fathers with non-mosaic patterns of Y partial deletions and not as common de novo events (Cram et al., 2000.) Application of assisted reproductive techniques in the United States is skyrocketing. CDC tracking suggests an increase in procedures of 11% per year in 1997, the last year for which results are available. Although this offers new options for couples, the overall average delivery rate per egg retrieval procedure was only 28%. The risk of multiple gestations (twins, higher order pregnancies) remains over 40% (SART, 2000.) For men who have had vasectomies and are interested in sperm retrieval and ICSI, there appears to be no effect of time since vasectomy (Sukcharoen et al., 2000) nor whether fresh or frozen sperm are used (Janzen et al., 2000) as long as the sperm used for ICSI are alive after freeze-thaw. The collection of sperm from men with anejaculation was reported using seminal collection devices, placed when the men are going to sleep, to allow retrieval of nocturnal emissions (Hovav et al., 1999.) Another approach is prostatic massage (Hovav et al., 2000.) The significance of microorganisms in seminal fluid continues to be debated. Cottell et al. (2000) reported that most semen cultures actually grow skin contaminants. Antibacterial skin preparation has been suggested before providing semen cultures to limit the risk of contamination (Kim & Goldstein, 1999.)

Vasectomy

Vasectomy is used by more than 10% of married couples in the United States for contraception. These procedures are usually performed under local anesthesia in an outpatient setting. Effectiveness is reflected by low pregnancy rates after the treatment. Although different follow-up schedules have been recommended, Badrakumar et al. (2000) suggested a single semen analysis 3 months after the procedure to confirm its effectiveness. Others have suggested at least 2 semen analyses with no sperm, beginning 6-8 weeks after the procedure. The complication rates reported after vasectomy are 1-6% (Schwingl & Guess, 2000.) A very rare complication of unknown etiology is persistent post-vasectomy pain, which was treated in a small series of 13 men by Nangia et al. (2000) using vasectomy reversal. This highly selected group of patients responded well to treatment.