Role of Hormones, Genes, and Environment in Human Cryptorchidism Carlo Foresta, Daniela Zuccarello, Andrea Garolla, and Alberto Ferlin University of Padova, Department of Histology, Microbiology and Medical Biotechnologies, Section of Clinical Pathology, and Centre for Male Gamete Cryopreservation, 35121 Padova, Italy Cryptorchidism is the most frequent congenital birth defect in male children (2– 4% in full-term male births), and it has the potential to impact the health of the human male. In fact, although it is often considered a mild malformation, it rep- resents the best-characterized risk factor for reduced fertility and testicular cancer. Furthermore, some reports have high- lighted a significant increase in the prevalence of cryp- torchidism over the last few decades. Etiology of cryptorchid- ism remains for the most part unknown, and cryptorchidism itself might be considered a complex disease. Major regulators of testicular descent from intraabdominal location into the bottom of the scrotum are the Leydig-cell-derived hormones testosterone and insulin-like factor 3. Research on possible genetic causes of cryptorchidism has increased recently. Abundant animal evidence supports a genetic cause, whereas the genetic contribution to human cryptorchidism is being elucidated only recently. Mutations in the gene for insulin- like factor 3 and its receptor and in the androgen receptor gene have been recognized as causes of cryptorchidism in some cases, but some chromosomal alterations, above all the Klinefelter syndrome, are also frequently involved. Environ- mental factors acting as endocrine disruptors of testicular descent might also contribute to the etiology of cryptorchid- ism and its increased incidence in recent years. Furthermore, polymorphisms in different genes have recently been inves- tigated as contributing risk factors for cryptorchidism, alone or by influencing susceptibility to endocrine disruptors. Ob- viously, the interaction of environmental and genetic factors is fundamental, and many aspects have been clarified only recently. (Endocrine Reviews 29: 560 –580, 2008) I. Introduction II. Hormonal Regulation of Testicular Descent A. Normal descent of the testis B. Role of insulin-like factor 3 (INSL3) C. Role of androgens D. Role of anti-Mullerian hormone (AMH) E. Role of calcitonin gene-related peptide (CGRP) and genitofemoral nerve III. Genetic Causes and Polymorphisms Associated with Cryptorchidism A. Introduction B. INSL3 and INSL3 receptor genes C. The androgen receptor (AR) gene D. The Y chromosome E. The estrogen receptor (ER) genes F. Other genes G. Chromosomal alterations H. Syndromes and complex malformations IV. Endocrine Disruptors and Cryptorchidism V. Consequences of Cryptorchidism A. Infertility B. Testicular cancer VI. Conclusions I. Introduction T HE IMPORTANCE OF having both testes normally present in the scrotum was recognized centuries ago in the Middle Ages when “testiculos habet, et bene pendentes” (he has testicles, and they dangle nicely) was proclaimed to confirm, from a hole in the chair, that the cardinal elected as future Pope was a man. Cryptorchidism (from the Greek “hidden testicle”) or undescended testis is the failure of one or both testes to descend into the scrotal sac and is the most frequent congenital birth defect in male children. Although cryptorchidism is often considered a mild malformation, it represents the best-characterized risk factor for infertility and testicular cancer in adulthood. Failure of the testes to nor- mally descend occurs bilaterally in one third of cases and unilaterally in two thirds of cases. Cryptorchid testes are classified on the basis of their position along the normal route of descent (high/low abdominal, inguinal, suprascrotal, high scrotal) or as ectopic (1). In the clinical setting, however, a simple distinction between palpable and nonpalpable and between unilateral and bilateral is most often used (1). In some cases, cryptorchid patients are found to have an ab- sence of one or both testes, a condition better defined as anorchia or vanishing testis syndrome. Although the frequency of cryptorchidism may vary among different countries (2), a figure of 2– 4% in full-term male births is generally accepted (3). It is notable that the definition of cryptorchidism is still not uniform, and this might influence epidemiological studies reporting its prev- alence. For example, a high prevalence of cryptorchidism First Published Online April 24, 2008 Abbreviations: AIS, Androgen insensitivity syndrome; AMH, anti- Mullerian hormone; AR, androgen receptor; AZF, azoospermia factor; CAIS, complete AIS; CGRP, calcitonin gene-related peptide; CSL, cranial suspensory ligament; DES, diethylstilbestrol; GFN, genitofemoral nerve; hCG, human chorionic gonadotropin; HH, hypogonadotropic hypogo- nadism; hpg, natural hypogonadal; INSL3, insulin-like factor 3; LuRKO, LH receptor knockout; PAIS, partial AIS; TDS, testicular dysgenesis syndrome; tfm, testicular feminization. Endocrine Reviews is published by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community. 0163-769X/08/$20.00/0 Endocrine Reviews 29(5):560 –580 Printed in U.S.A. Copyright © 2008 by The Endocrine Society doi: 10.1210/er.2007-0042 560