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Editorial |
Department of Obstetrics and Gynecology Baylor College of Medicine Houston, Texas 77030
Address all correspondence and requests for reprints to: Alexander I. Agoulnik, Ph.D., Department of Obstetrics and Gynecology, Baylor College of Medicine, 6550 Fannin Street, Suite 861, Houston, Texas 77030. E-mail: agoulnik{at}bcm.tmc.edu.
Cryptorchidism (which in Greek means "hidden gonad") in the vast majority of cases is caused by a failure of the testis to descend from its embryonic retroperitoneal position into the scrotum (1, 2). Such an abnormality is distinct from a retractile testis, wherein the testis retracts intermittently from the normal scrotal location to an extrascrotal position, usually into the inguinal canal. Cryptorchidism is the most common congenital abnormality in newborn boys, with an incidence of 1–4% in the full-term newborn (3). It is a major risk factor for male infertility and for testicular malignancy in adulthood. Based mainly on the laboratory studies of the rodent models, several hormonal and genetic pathways have been shown to be involved in testicular descent; however, data on humans are less compelling (4).
During mammalian development, the differential development of two mesenteric ligaments, the cranial suspensory ligament (CSL) and the caudal ligament (or gubernaculum), is responsible for a sexual dimorphic position of the testis and ovary. In females, the development and persistence of the CSL coupled with the gubernacular regression results in high abdominal position of the ovaries. In males, regression of the CSL, along with the outgrowth of the gubernaculum and its migration to the scrotum, results in the extraabdominal position of the testis. The two-phase model of testicular descent proposed by Hutson et al. (1) found its proof in the studies of genetic and hormonal control of normal testicular descent. During the first, or transabdominal, phase of descent (in humans, 10–23 wk gestation; in mice, embryonic d 14.5–18), the CSL regresses while the gubernaculum shortens and develops its caudal segment into the gubernacular bulb. The crucial role at this stage belongs to insulin-like 3 signaling (5, 6). Genetic disruption of the Insl3 gene or its receptor (Lgr8) in mice has led to the high intraabdominal cryptorchidism in males (5), whereas all other known cryptorchid mouse mutants have testes located at the bladder level. Moreover, it was shown that transgenic Insl3 overexpression alone caused gubernacular differentiation and descent of the ovaries to the low abdominal position in female mice (7). During the second, or inguinoscrotal, phase, normally completed by the 35th week (in mice by 20 d after birth), the gubernaculum extends caudally into the scrotum and involutes, following the passage of the testis through the inguinal canal. Mouse mutants with a deficiency of the hypothalamus pituitary gonadal axis, genes involved in androgen signaling, and several transcription factors such as Hoxa10, Hoxa11, and Desrt cause disruption of the second stage of descent (1, 4).
Mutation analysis of the human homologs of INSL3, LGR8, or HOXA10 genes in patients with cryptorchidism found only occasional mutations or unique alleles with single nucleotide polymorphism (SNP) (6, 8, 9). Thus, the genetic basis of cryptorchidism to the disease in humans remains unclear. Several reports have documented the deleterious effects of uterine exposure to environmental endocrine disruptors (EEDs) on male reproductive tract development in embryos (3, 10). EEDs, broadly defined as exogenous substances with an ability to disrupt normal endocrine homeostasis and reproduction, include xenoestrogens (industrial chemicals), synthetic and natural hormones, phyto- and mycoestrogens, and other substances affecting endocrine signaling (10). In laboratory animals, the male progeny of pregnant females treated with various EEDs develop cryptorchidism. Testicular descent is significantly inhibited by estradiol or the nonsteroidal estrogenic substance diethylstilbestrol (3, 10). The estrogen effect might be mediated through suppression of fetal Leydig cell development (11), with resulting decrease of androgen and INSL3 production. Alternatively, estrogens could directly target development of the CSL and the gubernaculum, which express ESR1 (our unpublished data). The failure of the gonadotropin and testosterone injections to reverse estrogen-induced cryptorchidism in fetal mice (12) suggests that the second scenario may be true. In humans, the population studies of farming communities exposed to EEDs indicated an increase risk of cryptorchidism (13). In industrialized countries, there is a secular trend toward increased incidence of cryptorchidism (3, 10).
In this issue of the JCEM, Yoshida et al. (14) report an association of cryptorchidism with a specific haplotype of the estrogen receptor 1 gene. In this case-control study of 63 Japanese patients and 47 control males, five DNA markers (SNPs) encompassing a contiguous region of the 3' region of ESR1 were found to be overrepresented in patients in comparison to controls (34.0 vs. 21.3%). Most remarkably, the homozygosity for this variant was found only among patients with undescended testes (10 of 63 vs. 0 of 47). Mutational analysis of other usual suspects such as the androgen receptor gene, 5
-reductase-2, or INSL3 did not reveal any abnormalities in the same group of patients. The authors also excluded karyotype abnormalities, the presence of Y chromosomal deletions, and an increased frequency of Val89Leu polymorphism at exon 1 of SRD5A2, previously linked to the reduction of 5-reductase-2 activity (15). Significantly, no deviations from the normal range of basal serum gonadotropin and testosterone were detected. Based on these results, the authors suggested that a specific ESR1 allele might be responsible for cryptorchidism in humans and thus may be the first genetic factor with a high degree of association for this abnormality. Such a specific allele is postulated to confer susceptibility to EEDs, resulting in testicular maldescent.
SNP analysis of disease gene association with various clinical abnormalities has been the tool of choice in recent years (16). The idea is based on defining the linkage disequilibrium of the mutation responsible for the abnormality and polymorphic genomic DNA marker. SNPs are best suited for such an analysis due to a high degree of genetic variation (SNPs are detected every 200–300 bp in genomic DNA) and the availability of the high-throughput methods of SNP detection. More importantly, the power of analysis increases when multiple SNPs are used to define the haplotype associated with the disease. Depending on the structure of the human population and the way the linkage disequilibrium (LD) is measured, the extent of the LD can vary significantly (17). The larger and more outbred populations have an LD of minimal size (
10 kb), whereas the more isolated and smaller ones are predicted to have a bigger LD (<100 kb). The size of the ESR1 haplotype (AGATA) associated with cryptorchidism was defined to be around 50 kb at the region surrounding the sixth exon (of eight) of ESR1 (14). SNP15, located in the last exon of ESR1, was not linked to the haplotype. One marker (SNP12), located in intron 6, was 100% associated with the disease haplotype and was found in the homozygous condition only in affected patients. Thus, it is logical to suggest that the genetic abnormality is localized somewhere at the 3' end of the gene.
What is the nature of the mutation? Direct sequencing of the ESR1 exons containing the AGATA haplotype did not reveal any differences in the protein-coding sequence, indicating that gene regulation might be involved (14). Although not common, several examples of the transcription 3' localized enhancers are known (18). An increased production of ESR1 could provide a phenotype more sensitive to EEDs and, thus, more prone to testicular maldescent. It should be noted, however, that the posttranscriptional control of gene expression might also be affected. The cryptorchidism-associated mutation could change the proper Ers1 mRNA splicing or context-specific regulation of the stability of mRNA transcripts (19). The result of such alternative splicing can be receptor variants with more sensitivity to the EEDs or acquired dominant-negative properties. Finally, it is also possible that the mutation alters a transcriptional regulator of the neighboring genes, located in the vicinity of ESR1. It is important to note that the effects of the AGATA haplotype are fully recessive; hence, both control and patient groups contained almost an equal number of heterozygotes (42.5 and 36.5%, respectively). Molecular analysis of ESR signaling in cultured cells in vitro or investigation of estrogen stimulation in the Esr1 transgenic mice could determine the exact mechanism by which mutation in the ESR1 allele results in cryptorchidism.
This is the first study describing such a high association of a particular gene with idiopathic cryptorchidism. Further analysis of other patient and control groups in Japan, genetically related populations, and populations in other countries may be necessary to confirm the detected association. Such analysis would not only confirm the finding in this first study but could also be useful in refining the exact genomic region associated with cryptorchidism. The postulated involvement of a genetic factor in EED susceptibility provides an opportunity for hereditary analysis. An identification of the AGATA haplotype in patients with a family history of cryptorchidism and subsequent analysis of the segregation pattern of the ESR1 variants within such families could provide a strong conformation of these findings. Regardless of specific mechanisms underlying AGATA ESR1 action, the genetic diagnostics could now establish genotypes susceptible to cryptorchidism.
We do not know whether the EED exposure have anything to do with AGATA ESR1 haplotype. Could it be that ESR1 confers an increased sensitivity not to exogenous stimuli, but to endogenous estrogen signaling? The sensitization of estrogen response in mutants can provide a basis for a predisposition to the disease even within the normal range of estrogen fluctuation during pregnancy. One argument in favor of this suggestion is that no homozygous AGATA individuals were found in the control group. If EEDs were involved in the etiology of cryptorchidism, one would expect a variability in actual exposure levels within the population; and, as a result, some of the AGATA/AGATA individuals with low levels or no exposure to EEDs would have a normal phenotype. Nonetheless, all 10 homozygotes in this study had cryptorchidism, despite the fact that genotype distribution by locus was in agreement with Hardy-Weinberg expectations in the combined population of patients and controls. Future studies will define whether the AGATA homozygosity is compatible with normal testicular descent.
Footnotes
Abbreviations: CSL, Cranial suspensory ligament; EED, environmental endocrine disruptor; LD, linkage disequilibrium; SNP, single nucleotide polymorphism.
Received June 15, 2005.
Accepted June 22, 2005.
References
. Endocrinology 146:2454–2461 gene: implication for the susceptibility to estrogenic environmental endocrine disruptors. J Clin Endocrinol Metab 90:4716–4721-reductase type II. Pharmacogenetics 10:407–413[CrossRef][Medline]
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