Molecular abnormalities of FSH and LH action

The identification of naturally occurring genetic mutations in individuals with disorders of reproductive function is the first logical step to therapy. To date, diagnostic investigations have been assisted by polymerase chain reaction and the development of an increasing number of effective screening techniques to scan genomic DNA (deoxyribonucleic acid) for causative mutations. The continued expansion of these technologies, coupled with high throughput gene sequencing, will ultimately result in automated DNA diagnosis for the practicing clinician at the point of care. At that time, the direct examination of a patient's DNA will be the definitive means of establishing the presence of specific genetic changes that cause or increase one's susceptibility to disease. This presentation selects important candidate genes in the human hypothalamic-pituitary-ovarian axis (HPG), reviews our knowledge of the spontaneously occurring human mutations that affect these genes, and reviews the biological implications of this information. To date, causative mutations in candidate genes have provided important insights into the transcription factors, receptors, and hormones that regulate the HPG axis at many levels. A major challenge in this field is that mutations in many of these genes and others remaining to be identified lead to infertility. The reduction in reproductive fitness due to these mutations limits the ability of investigators to use traditional genetic linkage and association studies to identify and clone important unidentified reproductive genes. Fortunately analysis of human gametes and new strategies that are being developed for the identification and mapping of complex human diseases will become increasingly important in continuing studies of idiopathic human infertility. At this time, it is helpful for the reader to become acquainted with some of the prototype mutations in candidate genes, their phenotypic consequences, and their prevalence. This presentation is designed to describe the known mutations in the gonadotropin genes and the genes encoding their respective receptors. The phenotypic effects of these mutations is compared, and evidence for causation is reviewed.