some cases to a very marked delay in the pubertal development of reproductive capacity and the accompanying development of secondary sexual characteristics (Carpenter, 1994).

The primary site of disruption of the reproductive axis, with all forms of stress studied in detail to date, appears to be at the level of the GnRH neurons, which provide the central neural drive to the reproductive axis. Using animal models of various stresses, it has been shown that for at least some stresses GnRH secretion is impaired (I’Anson et al., 2000). However, more typically, it is inferred that GnRH secretion is impaired in stress conditions, when a suppression of pituitary gonadotropin secretion is measured. This is further supported by the finding that, in all conditions of stress-induced reproductive dysfunction studied to date, administration of exogenous GnRH can stimulate the function of the reproductive axis, indicating that stress is not acting to directly suppress pituitary or gonadal activity (Hotchkiss and Knobil, 1994). In some forms of acute stress a fall in gonadotropin secretion can be noted within minutes to hours. With more subtle stresses, impairment of gonadotropin secretion is generally noted when the stress is present on a chronic basis.

The mechanisms by which various forms of stress impair activity of the reproductive axis appear to have some common elements, but there also appear to be mechanisms specific to each type of stress. For example, many forms of stress can activate the hypothalamic-pituitary-adrenal axis (HPA), and experimental studies have shown several mechanisms by which activation of the HPA axis can impair the central neural drive to the reproductive axis. On the other hand, certain aspects of stress, such as decreased fuel availability, only occur with some forms of stress and are likely to impair the activity of the reproductive axis via relatively specific mechanisms.

Energetic Stresses

Much of what we know about the mechanisms by which nutritional status modulates activity of the reproductive axis comes from the clinical study of patients with the psychiatric disorder anorexia nervosa (Aono et al., 1975; Marshall and Kelch, 1979; Warren and Vande Wiele, 1973). This disorder involves an obsessive fear of being fat and leads to a profound decrease in food intake, which causes extreme weight loss and can become life-threatening. Nearly all females who develop anorexia nervosa show a loss of ovarian cyclicity and amenorrhea. Amenorrhea is often apparent for great lengths of time, with normal menstrual cycles sometimes returning when patients regain weight but often lasting long after weight recovery. Measurement of circulating levels of LH and FSH show that gonadotropin secretion during the weight loss phase of anorexia nervosa is very low and often nonpulsatile in nature or pulsatile only during the nighttime period,



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