Altered hypothalamic-pituitary-ovarian axis function in young female athletes: implications and recommendations for management.

Young women have become increasingly active in athletics during the 20th century. Those involved in sports that emphasize lean body type are at high risk for the development of menstrual dysfunction, including amenorrhea. This is mediated by an alteration in function of the hypothalamic-pituitary-ovarian (HPO) axis, with loss of normal secretion of luteinizing hormone, and subsequent lack of estrogen production. Disruption of the HPO axis appears to be dependent on the body's recognition of an energy imbalance, which may be due to a lack of compensatory caloric intake in the face of significant energy expenditure. Other pituitary hormones, such as triiodothyronine, growth hormone, and insulin-like growth factor-1 may also be affected. These metabolic changes have an impact on bone mineralization during a critical period in the development of bone mass. Recognition by physicians of the so-called 'female athlete triad', consisting of disordered eating, amenorrhea, and osteoporosis, may allow therapeutic intervention. Diagnosis of eating disorders and decreased bone mineral density can have significant impact on the health of the young athlete. Treatment is aimed at restoring normal menstrual function by increasing caloric intake to balance the increased energy demands of athletic participation. Concurrent treatment of the hypoestrogenemic state using estrogen replacement is controversial, but may aid in alleviating further loss of bone mass.

Identification of a discrete promoter region of the human GnRH gene that is sufficient for directing neuron-specific expression: a role for POU homeodomain transcription factors.

The human GnRH (hGnRH) gene is expressed, and the GnRH decapeptide produced, primarily in the GnRH neurons of the diencephalon. The molecular elements important for the cell-specific expression and regulation of the hGnRH gene are not well established at this time; therefore, we have used a transgenic mouse model to isolate cis-regulatory elements important for directing gene expression to GnRH neurons in the hypothalamus. Gene constructs consisting of various promoter deletion fragments of the hGnRH gene fused to the luciferase (LUC) reporter gene have been used to create transgenic mouse lines. Cell-specific expression, with the criterion being luciferase expression directed to GnRH neurons of the hypothalamus, was observed when 992 bp, but not 795 bp, of the hGnRH gene promoter were used. Tissue-specific expression was also observed when a deletion construct containing the region from -992 to -763 was fused to a minimal 48-bp promoter fragment fused to LUC. These data indicate that the region between -992 and -795 contains elements both essential and sufficient for targeting gene expression to GnRH neurons. This promoter region was found to contain two DNA-binding sites for the POU class of transcription factors, each of which specifically interacted with the POU homeodomain proteins Brn-2 and Oct-1. Functional studies demonstrated that Brn-2 increased promoter activity of the human and mouse GnRH genes.