Detection and Management of Pediatric Conditions That may Affect Male Fertility

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


Urol Nurs. 2012;32(5):237-248. 

In This Article

Congenital/Chromosomal Abnormalities

Chromosomal causes of male infertility include Klinefelter syn drome, cystic fibrosis and its variants, trisomy, Y-chromosome microdeletions, Noonan syndrome, and Kallman's syndrome. Y-chromosome microdeletions are thought to be the most common genetic cause of azoospermia (Sadeghi-Nejad & Farrokhi, 2007). Noonan syndrome, sometimes called "male Turner's syndrome," is a relatively common autosomal dominant condition associated with bilateral undescended testes (UDT) (Elsawi, Pryor, Klufio, Barnes, & Patton, 1994). Kallman's syndrome, an X-linked disorder, typically presents with facial and renal abnormalities with UDT apparent at birth.

Klinefelter Syndrome

Klinefelter syndrome is the most common sex chromosome disorder causing azoospermia (overall incidence 1:500 males) (Lanfranco, Kamischke, Zitzmann, & Nieschlag, 2004), and it is characterized by hypogonadism and infertility. The most common chromosome complement is 47, XXY. In addition, a variety of mosaic complements are possible and contribute to the variable presentation of Klinefelter syndrome, though the mosaic most frequently found is 46,XY/47, XXY. While only 10% of men with Klinefelter syndrome are diagnosed before puberty (Bojesen, Juul, & Grayholt, 2003), new advancements in fertility preservation have made this a period of interest for investigation and possible initiation of treatment. Some children may be diagnosed prenatally, and subtle age-related clinical findings may prompt chromosomal evaluation in the in fant or child. Such clinical signs include 1) infants with hypospadias, small phallus, cryptorchidism, or developmental delay; 2) kindergarten-aged boys and elementary school-aged boys with developmental delay, learning disabilities, or behavioral problems; and 3) older boys and ad olescent males with eunuchoid body habitus, gynecomastia, or small testes (Radicioni et al., 2010; Ross et al., 2005; Visootsak & Graham, 2006).

Physical Findings. The classic triad of Klinefelter syndrome in cludes small firm testes, azoospermia, and gynecomastia in an adult male. The physiologically smaller prepubertal testis makes abnormality more difficult to discern, but testes volume less than 1.5 mL indicates loss of germ cells before puberty and should lead clinicians to perform cytogenetic evaluation (Paduch, Bolyakov, Cohen, & Travis, 2009). Historically, patients with Klinefelter syndrome have been described to exhibit delayed sexual maturation, increased height with exaggerated growth of lower extremities, decreased strength and facial hair growth, and mild to moderate cognitive impairment. It is now apparent that men with Klinefelter syndrome represent a variety of phenotypes and may only have impaired fertility, contributing to underdiagnosis of Klinefelter syndrome. The more specific findings of small testes at 5 to 7 mL (normal 12 to 30 mL) and low testosterone in postpubertal males should always prompt cytogenetic evaluation.

Laboratory Evaluation. Patients with Klinefelter syndrome tend to have a pattern of primary testicular failure, such as low to low-normal testosterone and elevated luteinizing hormone (LH), follicular stimulating hormone (FSH), and serum estradiol. Hormon al evaluation may also include prolactin, insulin-like growth factor-1 (IGF-1), and cortisol due to increasing evidence of adrenal steroidogenic deficiency in Klinefelter syndrome (Paduch et al., 2009). Peripheral blood cytogenetics are usually adequate for diagnosis, although mosaicism less than 10% may not be detected. The gold standard for postnatal diagnosis is karyotyping, but if unavailable, fluorescence in situ hybridization (FISH) and molecular techniques have been used. An optimal diagnostic test for Klinefelter syndrome would allow for screening at birth of groups at higher risk for nondisjunction – children born from older parents (Lorda-Sanchez, Binkert, Maechler, Robinson, & Schinzel, 1992) or through assisted reproductive technology (ART) (Aboulghar et al., 2001).

Fertility Preservation. Treatment options in adolescents and adults differ, especially in younger adolescents. Fertility preservation should be discussed with both the teen and his parents. The loss of spermatogonial cells in males with Klinefelter syndrome appears to occur progressively, and most boys are born with spermatogonia that undergo massive apoptosis most likely during early puberty (Lin, Huang, Lin, & Kup, 2004; Wikstrom et al., 2004; Yamamoto et al., 2002). It appears there is a period in early puberty when spermatogenesis begins and sperm are present in the ejaculate. This time frame presents an opportunity to obtain ejaculated sperm or sperm from testicular biopsy for cryopreservation. This is controversial. AlthoughWikstrom and colleagues (2004) found that apoptosis of spermatogonia occurs in the testes of men with Klinefelter syndrome at the onset of puberty, they also concluded that early puberty does not provide a unique window for increasing fertility potential of patients with Klinefelter syndrome because testicular germ cells of these patients show a maturational arrest and no meiotic cells on biopsy.

At present, it is recommended that fertility preservation in adolescents be performed at skilled centers because the team needs to address complex ethical, legal, and logistic issues that arise when a child with a genetic defect is being subjected to interventions. Benefits of these interventions, although likely, are not certain at this point in time (Paduch et al., 2009).

Prospective studies evaluating the use of aromatase inhibitors in adolescents with Klinefelter syndrome are ongoing; however, more data are needed before widespread use can be adopted. Aromatase inhibitors, such as anastrozole (Arimidex®), have been used offlabel to decrease intratesticular estradiol and increase testosterone production, and are thought to offer a physiologic treatment for Klinefelter syndrome (Paduch et al., 2009).

Testosterone replacement has been a mainstay of Klinefelter syndrome treatment, and is successful in correcting androgen deficiency symptoms but inadequate for improving infertility. More recently, testicular sperm extraction (TESE) and use of this sperm for in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have resulted in successful pregnancies from men with Klinefelter syndrome (Palermo et al., 1998).

A limitation of fertility preservation in such males is the lack of a recognized and well-accepted set of markers, which would allow one to determine the best timing for cryopreservation. Paduch and colleagues (2009) recommend monitoring adolescents with Klinefelter syndrome with FSH, LH, testosterone, inhibin B, and testicular volume measurements every six months, starting two years before predicted onset of puberty. Morning urine samples from two consecutive days are obtained, spun, and evaluated for the presence of sperm. Physical examination, including assessment of testicular volume, is performed every six months. When the FSH and LH start to increase, a discussion is held with the parents to determine the best method of sperm retrieval. If the child is comfortable with masturbation – typically around 12 years of age in the American Caucasian population (Kinsey, Pomeroy, & Martin, 2003) – a semen sample can be collected and evaluated for sperm. If sperm are found, anastrozole is administered for six months, and additional semen specimens are obtained and cryo preserved. If no sperm are found but the FSH continues to increase, the microsurgical testicular sperm retrieval is offered with cryopreservation if sperm are identified (Paduch et al., 2009).

Congenital Bilateral Absence of the Vas Deferens and Cystic Fibrosis

Absence of all or a portion of the vas deferens may indicate the presence of cystic fibrosis or variants. Patients with cystic fibrosis can have bilateral absence of the vas deferens (CBAVD) or unilateral absence of the vas deferens (CUAVD) with a normal or obstructed contralateral vas deferens. This may be associated with partial or complete agenesis of the epididymis and seminal vesicles. Cystic fibrosis is the most common autosomal recessive genetic disorder in the United States and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR mutations are more common in males with CBAVD (Casals et al., 2000). With severe CFTR mutations, cystic fibrosis presents in full form with fluid and electrolyte abnormalities, chronic lung obstruction and infection, and pancreatic insufficiency. Infertility is due to missing portions of the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts, leading to obstructive azoo spermia. A phenotype of isolated CBAVD and infertility occurs with a different spectrum or alternatively spliced mutations of CFTR genes (Cuppens & Cassiman, 2004). Spermato genesis in these patients is normal, and infertility is the result of obstruction. On physical examination, there is no palpable vas deferens bilaterally.

Screening for Cystic Fibrosis. Most states routinely screen all Caucasian newborns, the group with highest incidence of cystic fibrosis, which has led to better nutritional and pulmonary outcomes (Southern, Mérelle, Dankert-Roelse, & Nagelkerke, 2009). Recently, it has been suggested that community-tailored cystic fibrosis screening panels may benefit individuals from other ethnic groups who may carry different mutations (Comeau et al., 2007). The newborn screening test does not actually diagnose cystic fibrosis; if the results are abnormal, further tests, including a sweat test and genetic testing, can be performed. However, there have been reports of absence of the vas deferens as the first sign of the diagnosis of cystic fibrosis in infants, and less severe CFTR mutations may only be detected in the infertility evaluation of men with obstructive azoospermia, especially prior to ICSI (Mocanu et al., 2010).

One classic sign of cystic fibrosis is an excessively salty taste to the child's skin, which parents may taste when they kiss their child. Other signs and symptoms include persistent cough, wheezing, repeated pulmonary and sinus infections, foul-smelling greasy stools, poor weight gain and growth, distended abdomen and constipation, and intestinal obstruction, particularly in newborns (Egan, 2011).

Genetic Counseling. Male patients positive for CFTR mutations should undergo genetic counseling, and their female partners should also be screened to rule out carrier status.