Reproduction in Men with Klinefelter Syndrome: The Past, the Present, and the Future Darius A. Paduch, M.D., Ph.D., 1,2 Alexander Bolyakov, M.Sc., 1 Paula Cohen, Ph.D., 3 and Alexander Travis, V.M.D., Ph.D. 4 ABSTRACT Klinefelter syndrome (KS) is the most common chromosomal aberration in men. There are approximately 250,000 men with KS in the United States, and the prevalence of KS in male reproductive practices is 3 to 4%; however, most men are never diagnosed. KS has an effect on normal development, growth, social interactions, bone structure, and sexual and reproductive function, thus a multidisciplinary approach to men with KS is important in providing state of the art care to children and men with KS. Over the last 10 years, with advancements in artificial reproductive techniques and the successful delivery of healthy children from men with KS, the involvement of reproductive endocrinologists and urologists in the care of patients with KS is becoming commonplace. The new areas of intense research investigate optimal methods of hormonal manipulations, preservation of fertility in adolescents, and development of universal early screening programs for KS. This review provides the latest update in our understanding of the pathophysio- logy, natural history, and evolving paradigms of therapy in adolescents and men with KS. KEYWORDS: Klinefelter syndrome, meiosis, spermatogenesis Klinefelter syndrome (KS) is the most common numerical chromosomal aberration among men, with an estimated frequency of 1:500 to 1:1000 of live deliv- eries. 1 KS is characterized by X chromosome polysomy with X disomy being the most common variant (47,XXY). Ninety percent of men with KS have non- mosaic X chromosome polysomy. 2 Although classic description of men with KS emphasized tall eunuchoid body proportions, low testo- sterone, sparse facial and pubic hair, small, hard testicles, micropenis, sterility, and mild to moderate cognitive deficits, it is now well known that this original descrip- tion is not accurate and men with KS represent a broad spectrum of phenotype, professions, income, and socio- economic status. 1 Severe intellectual deficits are rare, and often auditory processing delay and language dysfunc- tion seen in men with KS are misdiagnosed as cognitive deficits. 2 Thus most if not all internists, pediatricians, urologists, and reproductive endocrinologies have seen men with KS who were not diagnosed appropriately. It is 1 Department of Urology and Reproductive Medicine, Weill Medical College of Cornell University, New York, New York; 2 Center for Biomedical Research, Population Council, New York, New York; 3 Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, New York; 4 Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York. Address for correspondence and reprint requests: Darius A. Paduch, M.D., Ph.D., Department of Urology, Weill Medical College of Cornell University, 525 East 68th St., F-924A, New York, NY 10065 (e-mail: darius.paduch@mac.com). Male Infertility in the Era of ART: Why Treat; How to Treat; Guest Editors, Marc Goldstein, M.D., and Zev Rosenwaks, M.D. Semin Reprod Med 2009;27:137–148. Copyright # 2009 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-0029-1202302. ISSN 1526-8004. 137