6 levels were not altered and were not diﬀerent from control fetuses. This indicates that, while leptin may play a role in mediating the adaptive responses to LTH in CYP expression in the adrenal gland, clearly other mechanisms exist, such as NO production, that limit the ability to produce cortisol. The lack of eﬀect of the antagonist in the control fetuses would seemingly bring to question the role of leptin in regulating the HPA axis of the late gestation sheep fetus in a nonperturbed state. It should be noted that we have shown that the OB-Rb expression in the ovine fetal adrenal does decrease signiﬁcantly near term compared to younger animals at ∼120–130 days’ gestation [63]. Thus, leptin may play a role in regulating the HPA axis in less mature fetuses and this regulation is lost near term as the HPA axis rapidly matures in preparation for birth (Figure 2). 7. HPA Response to LTH: Adaptive versus Maladaptive As discussed previously, we have deﬁned changes in function of the fetal HPA axis in response to development under conditions of LTH as primarily adaptive, especially at the level of adrenal cortisol production. Indeed, these responses appear to support continued normal growth of the fetus in the face of the stress of sustained, moderate hypoxia. Con- sidering the essential role of maturation of the fetal HPA axis and the late gestation exponential rise in fetal plasma cortisol in initiating parturition in this species, this adaptation also allows the fetus to remain in utero for the normal length of gestation. This seems especially critical considering the lowered oxygen delivery to the fetus, thus allowing the max- imal opportunity for the fetal growth. As such, the observed response providing for the normal ontogenic maturation of adrenocortical function is critically adaptive in nature. However, the changes we have observed at the level of the hypothalamic PVN and anterior pituitary corticotrope may be viewed diﬀerently. Indeed, these changes might be argued as being maladaptive since they cumulatively result in enhanced processing of POMC to ACTH1−39 in the cor- ticotrope and enhanced release of ACTH1−39 into the circu- lation. Under situations where there is no additional (acute secondary) stress, the adrenal cortex, perhaps in concert with adipose derived leptin, has developed mechanisms to maintain “normal” function. But, when presented with an acute secondary stress resulting in greater ACTH release, cortisol production is actually greater than that of age matched normoxic fetal sheep. Although cortisol production in response to stress is part of the physiological homeostatic mechanism(s) helping the organism to survive the stressor, it could be argued that the excessive production of cortisol in response to the secondary stress in the LTH fetus is mal- adaptive. This would be especially true in situations where the LTH-compromised fetus is subjected to repeated episodes of acute secondary stress or perhaps greatly ampliﬁed when a longer-term secondary stress occurs. In the ﬁnal weeks of gestation, this capacity of the LTH fetus to produce a larger cortisol response to a secondary stress may serve as signal to terminate the pregnancy in this species indicative of a Journal of Pregnancy dangerously adverse intrauterine environment thus limiting the potential chance for fetal demise. Lastly, the changes in gene expression that we have noted in the perirenal adipose may also provide a means for the LTH newborn to survive in an adverse environment. Clearly, the increased production of leptin provides an essential brake to the adrenocortical response to LTH allowing the fetus to potentially remain in utero for a longer period. Perhaps more importantly however, the changes in gene expression in the adipose favor the brown fat phenotype that may aid the newborn LTH fetus in survival in the initial hours after birth. Similarly, the greater capacity for cortisol production in response to a secondary stressor, if retained post birth, would seem largely beneﬁcial in a harsh, low oxygen environment. 8. Conclusions Hypoxia, acute or sustained, is a major threat to the well- being of a fetus and is a relatively common insult during human pregnancy. During the ﬁnal third of gestation the ovine fetal HPA axis undergoes a maturational process in which the fetus not only develops the capacity to mount a cortisol response to physiological stressors but also under- goes an exponential rise in basal cortisol. As with most mammals, this parturient rise in cortisol is essential for maturation of fetal organ systems allowing for survival in the extrauterine environment, after birth [64–66]. However, sustained or repetitious fetal stressors can activate the hypothalamic-pituitary-adrenocortical (HPA) axis resulting in elevated cortisol production and premature maturation of the adrenal cortex contributing to fetal growth restriction [67–69]. Nonetheless, the capacity to mount an adrenocor- tical stress response during late gestation contributes to fetal survival in the face of the stressor, as happens with adults. We have established a model of altitude-induced long-term hypoxia where the ovine fetus develops under continuous moderate hypoxia. Despite this constant physiological stres- sor, the fetal HPA axis undergoes a remarkable adaptation in which the normal ontogenic rise in fetal plasma cortisol and HPA axis maturation is maintained while preserving the capacity to mount a stress response. Indeed, the cortisol response to a secondary stressor is ampliﬁed, undoubtedly to aid in helping the fetus survive in this hypoxic environment. We have identiﬁed both adaptive responses at the level of the hypothalamus and anterior pituitary as well as the adrenal cortex that contribute to this adaptation to LTH and have identiﬁed two mechanisms, one intraadrenal (NO produc- tion) and extra-adrenal (adipose-derived leptin) that play signiﬁcant roles in maintaining function of the fetal HPA axis at the level of the adrenal gland. It will be important to determine if these systems are a unique response to LTH or are invoked as a general adaptive response to other intrauterine stressors that aid in fetal survival. Acknowledgment Supported by National Institutes of Health Grants P01- HD31226, R01-HD51951, R01-HD33147.