Functional hypothalamic amenorrhea (FHA) is characterized by a reversible reduction in GnRH drive and mild hypercortisolemia. The behavioral antecedents leading to the development of non-organic forms of chronic hypothalamic anovulation and amenorrhea are variable. Dieting and excessive exercise are often initiated to cope with subtle psychogenic challenges. It is accepted that what is deemed stressful is to a large extent idiosyncratic and individualistic. Further, women with FHA rarely report a single isolated stressor and FHA can develop in the absence of significant metabolic imbalance. We wondered, therefore, if metabolic and psychogenic stressors would be more deleterious to reproductive function when combined. We developed a monkey model to test the hypothesis that a combination of metabolic and psychosocial stressors would synergistically disrupt reproductive function. We recognized that the distinction between psychogenic and metabolic stress was, to some extent, artificial, because the corresponding increase in cortisol secretion that accompanies activation of the limbichypothalamic- pituitary-adrenal axis elicits obligatory metabolic adaptations regardless of initiating cause. However, therapeutic recommendations are often based on the notion that metabolic stressors are easier to identify and ameliorate than psychogenic ones, so it seemed important to try to determine the impact of metabolic versus psychosocial stressors alone and then in combination. To date, our monkey data suggest that mild metabolic imbalance heightens reactivity to subsequent psychogenic challenge. Other investigators have shown that psychogenic stress heightens the impact of metabolic (exercise) challenge. However, the neural concomitants that transduce either metabolic or psychogenic stress into altered neuroendocrine secretory patterns or heighten Abstract of the 8th Royan International Twin Congress, Tehran, Iran, 5-7 September 2007 46 Yakhteh Medical Journal, Vol 9, Sup 1, Summer 2007 reactivity to mildly stressful events remain poorly defined. Our work in female cynomolgus monkeys suggests that the serotonergic axis differs in stress-sensitive and stress-resistant monkeys. We found that cerebrospinal fluid levels of CRH were comparable in FHA and eumenorrheic women, but that, contrary to expectations, beta-endorphin levels were lower in women with established FHA. Interestingly, CSF levels of cortisol were higher in FHA. If the set point for inhibition of the HPA axis were comparable in FHA and eumenorrheic women, one would expect that CSF CRH levels would be lower in FHA than in eumenorrheic women. Thus, our data suggest that women with FHA display central resistance to the negative inhibitory feedback effects of cortisol. The physiological, cellular, or molecular basis of this stress sensitivity and limbic-hypothalamic-pituitary-adrenal feedback insensitivity in FHA has not been identified, but neurotransmitter systems such as serotonin and GABA remain as candidates. FHA is, in theory, reversible. Based on our understanding of the psychological and behavioral correlates of FHA, we developed a 16-session program of cognitive behavior therapy (CBT) for women with FHA. We did not instruct women to alter exercise or diet habits, but we did address attitudes that underlie stress sensitivity. Women with FHA were randomized to CBT or observation. Over 85% of women treated with CBT recovered either full or partial ovarian function as assessed by weekly estradiol and progesterone levels, whereas only 25% of those randomized to observation displayed reproductive recovery. Those who recovered did not gain weight. In aggregate, our data suggest that metabolic variables alone are rarely the primary cause of FHA and that psychological care has the potential to reverse FHA and thereby spare women with FHA the invasive, risky, and costly procedures of ovulation induction or assisted reproduction.