CLINICAL STUDY Androgen receptor gene CAG and GGC repeat lengths in cryptorchidism Alberto Ferlin 1 , Andrea Garolla 1 , Andrea Bettella 1 , Lucia Bartoloni 1 , Cinzia Vinanzi 1 , Alberto Roverato 2 and Carlo Foresta 1 1 University of Padova, Department of Histology, Microbiology, and Medical Biotechnologies, Centre forMale Gamete Cryopreservation, 35121 Padova, Italy, 2 University of Modena and Reggio Emilia, Department of Social, Cognitive and Quantitative Sciences, 42100 Reggio Emilia, Italy (Correspondence should be addressed to C Foresta; Email: carlo.foresta@unipd.it) Abstract Objective: Cryptorchidism is the most common congenital birth defect in male children, and accumu- lating evidence suggests that genetic abnormalities may be associated with it. The androgen receptor has two polymorphic sites in exon 1, with different numbers of CAG and GGC repeats, resulting in variable lengths of polyglutamine and polyglycine stretches. Longer CAG repeats result in a reduced androgen receptor transcriptional activity, but the role of the GGC triplets is less clear. In this study we analysed CAG and GGC repeat lengths in men with a history of cryptorchidism, associated or not with impairment of sperm production, in comparison with normal fertile subjects. Methods: We analysed CAG and GGC repeat lengths in a group of 105 ex-cryptorchid men in compari- son with 115 fertile non-cryptorchid men. Results: No difference was found between patients and controls in the mean and median values, and in distribution of CAG and GGC, when considered separately. However, the analysis of the joint distri- bution of CAG and GGC showed that some combinations are significantly more frequent in men with bilateral cryptorchidism (who frequently presented severe testiculopathies), in a manner similar to that found in idiopathic infertile subjects. Conclusions: Although further studies are needed to elucidate the possible role of specific CAG/GGC combinations as a causative factor, these data suggest a possible association between androgen recep- tor gene polymorphisms and cryptorchidism. European Journal of Endocrinology 152 419–425 Introduction Cryptorchidism is the failure of the testes to descend into the scrotal sacs; it is the most common congenital birth defect in boys. Although its frequency may vary among different countries (1), a figure of 2–4% in full-term male births is generally accepted (2). The aetiology of cryptorchidism remains unknown for a large proportion of cases, reflecting our limited knowl- edge of the mechanisms regulating testicular descent from abdomen to scrotum during embryonic develop- ment. A growing body of evidence suggests that genetic abnormalities may be associated with cryptorchidism (3), such as mutations in the INSL3/LGR8 hormonal system (4 – 14). Mutations in the androgen receptor (AR) gene, causing the androgen insensitivity syn- drome, are known to be associated with variable devel- opment of the Wolffian duct and with micropenis, hypospadia and cryptorchidism (15, 16). However, screening for mutations in the AR gene in patients with isolated cryptorchidism failed to find any abnorm- ality (17, 18), even if clear conclusions cannot be drawn from the limited number of subjects studied. Nevertheless, androgens, together with Mullerian inhibiting substance (MIS) and INSL3, are thought to be important in testicular descent, inducing the involu- tion of the cranial suspensory ligament and the second migration step from the groin to the scrotum (trans- inguinal descent) (3). In fact, the critical role of andro- gens in testicular descent is supported by numerous clinical and animal evidence. The AR is a member of the steroid/nuclear receptor superfamily of ligand-acti- vated transactivation factors, and it is encoded by a gene located on chromosome Xq11-12 (19). The gene exhibits two polymorphic sites in exon 1, characterized by different numbers of CAG and GGC repeats, resulting in variable lengths of polyglutamine and polyglycine stretches in the N-terminal region of the AR protein. Longer CAG repeats result in reduced AR transcrip- tional activity (20, 21), and there is evidence that an inverse correlation between CAG number and andro- genicity exists. Consistent with this, expansion of the tract to . 40 CAG repeats results in Kennedy’s syn- drome, a rare motoneuron disorder also characterized European Journal of Endocrinology (2005) 152 419–425 ISSN 0804-4643 q 2005 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.01860 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 01/11/2022 02:40:37PM via Massachusetts Inst of Technology