Detection and Management of Pediatric Conditions That may Affect Male Fertility

Geolani W. Dy, MD; Melissa Rust, MSPAC; Pamela Ellsworth, MD, FAAP, FACS

Disclosures

Urol Nurs. 2012;32(5):237-248. 

In This Article

Structural Anomalies

Varicocele

Approximately 30% to 50% of males with infertility have varicocele (Jarow, Coburn, & Sigman, 1996; Nashan, Behre, Grunert, & Nieschlag, 1990; Opitz, Shapiro, & Uehling, 1979). Varicocele is more common on the left than right. Although more commonly identified in adolescence, varicocele can occasionally be noted in pre-adolescent boys (Buch & Cromie, 1985; Saeczuk, Hensle, Burbige, & Nagler, 1993). In older adolescents, the reported incidence ranges from 12.4% to 17.8%, which is similar to that in adult males (Paduch & Skoog, 2001). The abnormal dilatation of the pampiniform plexus and internal spermatic vein often arises in puberty, when increased testicular blood flow exposes underlying anatomic abnormalities, such as faulty valvular venous return, venous collaterals, and increased venous pressure.

Evaluation. Patients may complain of scrotal discomfort or "heaviness," but more often, varicoceles are found on routine physical examination. Diagnosis and management of varicoceles depend heavily on physical findings, although various imaging modalities may be used as confirmation.

The patient should be examined in a warm room for a posterosuperior scrotal bulge while laying and standing. The standing patient should also be evaluated during a Valsalva maneuver, which may accentuate smaller varicoceles. Grading is subjective and based on examination. Subclinical varicoceles are nonpalpable but detectable with ultrasound or venography; Grade I varicoceles are small and palpable upon Valsalva; Grade II varicoceles are moderate and palpable without maneuvers; and Grade III varicoceles are large and visible from a distance. Varicoceles that are acute in onset, appear prior to puberty, do not reduce on supine examination, and/or are present on the right side should raise suspicion for an obstructing retroperitoneal mass.

When following a child with a varicocele, it is important that the same provider use the same tool to assess testicular size/volume consistently to minimize variation in measurements. In most males, the initial volume determination will serve as a comparator for future examinations. However, if a significant size discrepancy between the affected and normal contralateral testis is noted, it may dictate therapy.

Impact on Fertility. Numerous studies have shown a definite association between varicocele and male in fertility, although a direct cause-and-effect relationship has not been conclusively established (Zini & Boman, 2009). Many theories exist regarding the impact of varicocele on fertility, including hyperthermia, hypoxia, hyperperfusion injury, increased reactive oxygen species, and reflux of renal or adrenal metabolites. Effects on the testis include growth failure of the ipsilateral testis, decreased spermatogenesis, semen abnormalities, Leydig cell dysfunction and atrophy, and histologic changes, such as tubular thickening.

Determining who to Treat

The correlation between varicocele grade and testicular size, semen analysis, and fertility remains controversial in adults and children (Lyon, Marschall, & Scott, 1983; Paduch & Niedzielski, 1997; Sigman & Jarow, 1997; Vereecken & Boeckx, 1986). Lyon et al. (1983) found no correlation between varicocele grade and testicular size in 30 adolescents, whereas other researchers (Costabile, Skoog, & Radowich, 1992; Paduch & Niedzielski, 1997; Steeno et al., 1976) all independently noted that boys with severe varicocele had a smaller ipsilateral testis. Varicocele size, however, should not be used as the sole indication for varicocele treatment. Diamond and colleagues (2007) examined the relationship of varicocele grade and testicular hypotrophy to adolescent semen parameters, finding that volume differentials greater than 10% between normal and affected testes correlated with significantly reduced sperm concentration and total motile sperm count, while varicocele grade had no significant impact on semen analysis. Varicocele repair in the adolescent male with ipsilateral hypotrophy has been demonstrated to result in catch-up testicular growth in 80% (Kass & Belman, 1987).

Management. The presence of a varicocele in a child warrants continuous surveillance, although the ideal clinical follow-up protocol and surgical approach continue to be debated. Gargollo and Diamond (2009) recommend that adolescent patients with a varicocele be followed annually with physical examination, testicular ultrasound, and if Tanner Stage V, semen analysis. In the absence of testicular disproportion or symptoms, and with normal semen analysis, patients may be followed conservatively.

Recommendations vary as to what constitutes a significant size discrepancy justifying surgical correction. If serial evaluations demonstrate decreasing ipsilateral testicular size or 20% size differential consistently over one year, surgical management should be considered. Skoog, Roberts, Goldstein, and Pryor (1997) note that a size variation of more than 2 mL by ultrasound is currently the best indicator of testicular damage in the absence of a semen analysis and serves as the minimal requirement for surgical repair of the adolescent varicocele. Not every boy with a varicocele and testicular growth arrest will be infertile. A semen analysis remains the gold standard (Paduch & Skoog, 2001).

Undescended Testes

Cryptorchidism (often used interchangeably with undescended testes [UDT]) affects 3% to 5% of male newborns and is the most frequent congenital abnormality of male genitalia, encompassing undescended, atrophic, and ectopic testes (Scorer & Farrington, 1971). By 1 year of age, 75% of fullterm infants and 95% of premature infants with UDTs experience spontaneous descent of the testes (Berkowitz et al., 1993), and the incidence of UDT beyond 1 year of age decreases to 0.8%. Testes that remain undescended have an increased risk of infertility and malignancy; testicular cancer risk is 5 to 10 times normal (Pettersson, Richiardi, Nordenskjold, Kaijser, & Akre, 2007) and may be associated with higher rates of torsion, hernias, and anomalies of the testis and epididymis.

The etiology of UDT is presumed to be multifactorial with genetic and environmental components, but exact pathways have yet to be defined (Barthold, 2008). Premature newborns with a low birthweight, are small for gestational age, and are twins have increased incidence of cryptorchidism.

Evaluation. Testicular examination of the child with UDT should involve one hand on the abdomen starting at the level of the internal ring and "milking" the testis down to the external ring, and the other hand attempting to feel for the testis, distinguishing between palpable and nonpalpable testes. A palpable testis may be found along the normal pathway of descent from the internal inguinal ring toward external inguinal ring or outside of the normal path of testicular descent. Palpable testes outside of the scrotum can be categorized as retractile (not truly undescended), incompletely descended (within or just outside the inguinal canal), or ectopic (following a different line of descent). A nonpalpable testis is generally intra-abdominal, beneath the external oblique, or atrophic and absent (usually as a result of neonatal torsion).

Bilateral nonpalpable testes should be followed with chromosome and hormonal analysis to rule out disorders of sexual differentiation. Endocrine evaluation includes FSH, LH, testosterone, and human chorionic gonadotrophin (hCG) stimulation testing, with a failure to respond to hCG stimulation indicating atrophy or anorchia. An increase in testosterone in response to stimulation suggests the presence of at least one functioning testis (Davenport et al., 1995). The hCG stimulation test and other testis hormone markers can be useful in confirming bilateral anorchia after intraoperative diagnosis or for assuring completeness of gonadectomy after surgery to avoid malignant degeneration of residual tissue (McEachern, Houle, Garel, & Van Vliet, 2004).

Imaging is not traditionally used for evaluation of nonpalpable UDT in young males. Ultrasound does not reliably localize nonpalpable testes and does not rule out the presence of an intra-abdominal testis (Tasian & Copp, 2011). However, the authors have found that with overweight prepubertal and pubertal males with a normal size contralateral testis, it may be useful in detecting a testis within the inguinal region, which is not palpable due to the large amount of adipose tissue (Ellsworth & Cheuck, 2009).

Impact on Fertility. The effect of unilateral UDT on fertility and paternity has been debated – some studies conclude that there is minimal to no change in the likelihood of paternity, while others accept that the likelihood of paternity of a boy with bilateral descended testes decreases to two-thirds (Lee et al., 1997; Miller, Coughlin, & Lee, 2001). Semen analyses in men with untreated unilateral cryptorchidism show azoospermia or oligospermia in 50% to 70%. Bilateral UDT correspond to a marked decrease in paternity rates, estimated at one-third of the normal rate (Lee et al., 1997). The risk of infertility increases with the more abnormal the location of the testis, with an intraabdominal location having the greatest risk.

A variety of factors may result in infertility related to cryptorchidism. For the testis to produce viable sperm, the local environment must be 1.5 to 2 degrees C cooler than body temperature. The effect of cryptorchidism on fertility appears to begin before the onset of puberty, both hormonally and histologically. At 4 to 6 months of life, males undergo an androgen surge labeled "mini-puberty." Hadziselimovic, Emmons, and Buser (2004) concluded that there is impaired transformation of germ cells into adult dark (AD)-spermatogonia – thought to be stem cells for later spermatogenesis – during mini-puberty in UDT. Zivkovic and Hadziselimovic (2009) suggest that UDTs do not undergo the usual mini-pubertal increase of Sertoli cells either, leading to diminished numbers overall.

Hypogonadotropic hypogonadism appears to be an underlying mechanism in the impaired "mini-puberty" response. Infants and children with cryptorchidism have lower basal LH and testosterone, with a blunted response to GnRH stimulation (Job et al., 1987). Fibrosis of the interstitium has since been identified (Hadziselimovic, 1977), as well as progressive deterioration of germ cells visible after the first six months of life. Patient age and whether the cryptorchid testis is palpable have been predictive of severity of histologic changes on biopsy (Tasian, Hittelman, Kim, DiSandro, & Baskin, 2009). An argument for orchiopexy, particularly early orchiopexy, is that UDTs remaining undescended were associated with progressive loss of germ and Leydig cells; nonpalpable testes predicted severe germ cell loss.

Treatment. The goal for treatment of UDT is a testis within the scrotum without atrophy. Hormonal therapy involves hCG, gonad otrophin-releasing hormone (GnRH), and their synthetic analogues, shown in randomized control trials to have variable efficacy. In a multicenter study, overall success in inducing testis descent was 21%, 19%, and 4% for GnRH, hCG, and placebo, respectively (Christiansen et al., 1992).

Orchiopexy is recommended in the United States by 1 year of age (Korkorowski, Routh, Graham, & Nelson, 2010) if the UDT does not spontaneously descend before 6 to 12 months of life, with hopes of preserving spermatogonia and minimizing damage to seminiferous tubules. The European Association of Urology recommends that orchidopexy be performed at the latest by 12 to 18 months of age (Tekgül et al., 2011). The success rates of orchiopexy range from 85% to 95% (Thorup et al., 2007). Techniques include inguinal, laparoscopic, microsurgical, and transcrotal approaches. Staged orchidopexy (Fowler-Stephens procedure) can be performed when the spermatic cord or vessels are not long enough to properly mobilize the testis into the scrotum. Despite surgical treatment, long-term outcomes of impaired fertility and increased cancer risk are still higher than in boys without UDT.

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