Molecular and functional aspects of menstruation in the macaque.

Much of our understanding of the molecular control of menstruation arises from laboratory models that experimentally recapitulate some, but not all, aspects of uterine bleeding observed in women. These models include: in vitro culture of endometrial explants or isolated endometrial cells, transplantation of human endometrial tissue into immunodeficient mice and the induction of endometrial breakdown in appropriately pretreated mice. Each of these models has contributed to our understanding of molecular and cellular mechanisms of menstruation, but nonhuman primates, especially macaques, are the animal model of choice for evaluating therapies for menstrual disorders. In this chapter we review some basic aspects of menstruation, with special emphasis on the macaque model and its relevance to the clinical issues of irregular and heavy menstrual bleeding (HMB).

Lessons from experimental disruptions of the menstrual cycle in humans and monkeys.

Prospective studies in humans and monkeys have informed our understanding of the mechanism of exercise-associated menstrual disorders (EAMD). These studies have provided convincing evidence that a key causal factor in the development of EAMD is an imbalance between energy intake and energy expenditure. This imbalance is created by the increased energy cost of exercise in the face of inadequate supplementation of caloric intake. Although one prospective study in humans documents the impact of weight loss, studies in nonhuman primates (Macaca fasicularis) reveal that EAMD can occur with unobtrusive compensatory mechanisms indicative of energy conservation. The onset of EAMD is variable between individuals, but is abrupt, and with little forewarning with respect to recognizable symptoms. Future studies aimed at mechanisms should build upon the finding that key metabolic signals such as T3 are correlated with both the onset and reversal of EAMD, perhaps by focusing on concomitant metabolic changes that directly influence GnRH neurons. Translational studies examining the energetics of the reversal of EAMD by manipulating food intake and or exercise should build on the findings in the monkey model. Lastly, because EAMD is often associated with disordered eating, future prospective studies in humans should incorporate the potential interaction of disordered eating and psychosocial stress on EAMD.