PERSPECTIVE Genetic Causes of Human Reproductive Disease

Disorders of reproduction represent a significant social, medical, and economic burden for individuals and society. Approximately 1 in 10 couples in the United States are infertile, and each partner is equally likely to be affected (1). Although many causes of infertility can now be determined in both men and women, most couples still receive a diagnosis of idiopathic infertility. A subset of these patients is likely to have an underlying genetic disorder that is either inherited (germline) or acquired (somatic). Although the most severe genetic reproductive disorders cause dysgenetic gonads or abnormal hormonal profiles, milder phenotypes are being recognized with increasing frequency. Over the past decade, many genes have been identified that influence the development and function of the hypothalamic-pituitary-gonadal (HPG) axis. These genes encode an array of transcription factors, matrix proteins, hormones, receptors, and enzymes that are expressed at multiple levels of the HPG axis, and regulate the complex developmental, paracrine, and endocrine interactions that are necessary for spermatogenesis and ovulation. Identifying naturally occurring genetic mutations provides unique insight into the role that these factors play in the human HPG axis. In addition, defining the genetic basis of disease has significant benefits for the patients, as appropriate and educated counseling can be provided and treatment tailored to the individual. In this review, we focus on single gene mutations that affect the HPG axis in humans. Space limitations preclude discussion of the many chromosomal anomalies (e.g. XO, XXY), metabolic alterations (e.g. GALT), steroidogenic defects (e.g. CYP21), or activating mutations (e.g. Gs , LH-receptor) that also can disrupt human reproduction. Progress resulting from the human genome project, along with advances in genomics and proteomics, will undoubtedly enhance the rate at which human reproductive mutations are found. Capitalizing on these scientific advances to improve patient care will be a major opportunity of the next decade.