Metabolic fuel and clinical implications for female reproduction

Reproduction is a physiologically costly process that consumes significant amounts of energy. The physiological mechanisms controlling energy balance are closely linked to fertility. This close relationship ensures that pregnancy and lactation occur only in favourable conditions with respect to energy. The primary metabolic cue that modulates reproduction is the availability of oxidizable fuel. An organism's metabolic status is transmitted to the brain through metabolic fuel detectors. There are many of these detectors at both the peripheral (e.g., leptin, insulin, ghrelin) and central (e.g., neuropeptide Y, melanocortin, orexins) levels. When oxidizable fuel is scarce, the detectors function to inhibit the release of gonadotropin-releasing hormone and luteinizing hormone, thereby altering steroidogenesis, reproductive cyclicity, and sexual behaviour. Infertility can also result when resources are abundant but food intake fails to compensate for increased energy demands. Examples of these conditions in women include anorexia nervosa and exercise-induced amenorrhea. Infertility associated with obesity appears to be less related to an effect of oxidizable fuel on the hypothalamic-pituitary-ovarian axis. Impaired insulin sensitivity may play a role in the etiology of these conditions, but their specific etiology remains unresolved. Research into the metabolic regulation of reproductive function has implications for elucidating mechanisms of impaired pubertal development, nutritional amenorrhea, and obesity-related infertility. A better understanding of these etiologies has far-reaching implications for the prevention and management of reproductive dysfunction and its associated comorbidities.