Effects of Low Energy Availability on Reproductive Functions and Their Underlying Neuroendocrine Mechanisms

Abstract

It is known that metabolic disturbances suppress reproductive functions in females. The mechanisms underlying metabolic and nutritional effects on reproductive functions have been established based on a large body of clinical and experimental data. From the 1980s to 1990s, it was revealed that disrupted gonadotropin-releasing hormone (GnRH) secretion is the main cause of reproductive impairments in metabolic and nutritional disorders. From the late 1990s to early 2000s, it was demonstrated that, in addition to their primary functions, some appetite- or metabolism-regulating factors affect GnRH secretion. Furthermore, in the early 2000s, kisspeptin, which is a potent positive regulator of GnRH secretion, was newly discovered, and it has been revealed that kisspeptin integrates the effects of metabolic status on GnRH neurons. Recent studies have shown that kisspeptin mediates at least some of the effects of appetite- and metabolism-regulating factors on GnRH neurons. Thus, kisspeptin might be a useful clinical target for treatments aimed at restoring reproductive functions in individuals with metabolic or nutritional disturbances, such as those who exercise excessively, experience marked weight loss, or suffer from eating disorders. This paper presents a review of what is currently known about the effects of metabolic status on reproductive functions and their underlying mechanisms by summarizing the available evidence.

Keywords: AgRP; GnRH; NPY; kisspeptin; leptin; undernutrition.

Figure 1

The roles of central and peripheral factors in reproductive dysfunction under under-nourished and over-nourished conditions. In addition to their primary functions, appetite- and metabolism-regulating factors; i.e., orexigenic and anorexigenic factors, suppress or activate GnRH secretion. Changes in the levels of these factors promote feeding behavior, whereas they coordinately suppress GnRH secretion and induce reproductive dysfunction in the presence of a negative energy balance. In addition, kisspeptin neurons are sensitive to metabolic status, and their activities are suppressed in the presence of a negative energy balance. Such changes also adversely affect GnRH secretion. It has been revealed that the effects of appetite- and metabolism-regulating factors on GnRH are partially mediated by kisspeptin neurons. In addition, overnutrition induces central leptin resistance and this alteration directly and indirectly decrease kisspeptin action on GnRH, and consequently induce reproductive dysfunction.