1 Department of Urology, 2 Department of Pathology, University of California San Francisco, 2330 Post Street, 6th Floor, San Francisco, CA 941151695 and 3 Department of Clinical Cytogenetics, Stanford University Medical Center, Stanford, California, USA
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Abstract |
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Key words: azoospermia/CBAVD/cytogenetic inversion/infertility
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Introduction |
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Men who have obstructive azoospermia due to congenital bilateral absence of the vas deferens (CBAVD) have a 64% chance for carrying at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) genes (Anguiano et al., 1992). In addition, men with CAVD have an increased chance of possessing a variant thymidine repeat sequence, the 5T allele, in intron 8 of this gene (Chillón et al., 1995
). This brings the likelihood of an identifiable genetic cause for CBAVD up to 80% (Jarvi et al., 1995
; Zielenski and Tsui, 1995
). However, it is generally assumed that CAVD is associated with normal spermatogenesis, and therefore men with CAVD are not at increased risk for the genetic factors that predispose to non-obstructive azoospermia.
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Case report |
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On physical examination, he had normal secondary sexual characteristics without evidence of gynaecomastia. Scrotal examination revealed descended testes with a bilateral testicular volume of 15 ml bilaterally by Prader orchidometer (ASSI, Westbury, NY, USA) and an abnormally soft testicular consistency. A grade II left varicocele was present. No scrotal vas deferens was palpated on either side. A small remnant of the caput epididymis was observed bilaterally. A rectal examination was unremarkable.
Laboratory investigation revealed a microscopically negative urinalysis and an ejaculate volume of 0.8 ml with no spermatozoa detected. Seminal fructose was absent. A serum follicle stimulating hormone concentration was 8.8 mIU/ml (normal range 114 mIU/ml). A renal ultrasound revealed normal kidneys bilaterally.
Because of the finding of testicular atrophy, diagnostic fine needle aspiration (FNA) mapping of both testicles was performed under local anaesthesia to confirm and localize spermatogenesis (Turek et al., 1997; Turek et al., 1999
). Testis FNA from 18 different sites revealed mature spermatozoa with tails at all sites, but in disproportionately low numbers relative to the abundant numbers of earlier germ cell forms (Figure 1
). This was consistent with a cytological diagnosis of late, incomplete maturation arrest of spermatogenesis.
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Discussion |
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Careful evaluation of this apparently `obstructed' patient led to a complete genetic evaluation for non-obstructive azoospermia, including analyses for cytogenetic abnormalities and Y chromosome microdeletions. The karyotypic finding of a structural rearrangement in a large chromosome has a recognized association with infertility (De Braekeleer and Dao, 1991). It has been postulated that pairing anomalies during prophase I of meiosis may lead to spermatogenic arrest and subsequent infertility (Gabriel-Robez and Rumpler, 1994
). The presence of the 5T thymidine variant within the CFTR gene may be a second contributing factor to abnormal spermatogenesis, as this allelic variant has been related to decreased spermatogenetic efficiency in CBAVD patients (Laribba et al., 1998
). Both or either of these distinct genetic defects could produce the maturation arrest pattern observed on testicular cytology in this patient.
The implications of the genetic findings in this case of obstructive and non-obstructive azoospermia are significant. This patient was advised that this karyotypic finding may be familial and that testing of other family members is indicated, especially if a sibling is being considered as a sperm donor. Concerning future pregnancy, the patient and his wife were advised that there is an increased risk for spontaneous abortions of karyotypically unbalanced embryos or fetuses (Kaiser, 1988). Additionally, there is an increased risk for liveborns with birth defects and mental retardation. Unfortunately, in this situation, potential fetal phenotypes are unknown, because structural rearrangements tend to be unique to families and therefore empirical data are quite limited. Lastly, the patient was informed that epididymal sperm aspiration would probably fail, and that testis sperm extraction would be needed to procure mature spermatozoa for IVF and ICSI, given that sperm production is lower than normal. In summary, compound genetic factors are possible in male infertility and have profound genetic implications for biological fatherhood, given the advances in assisted reproductive technology.
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Notes |
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References |
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Submitted on June 28, 1999; accepted on November 11, 1999.