Hindawi Publishing Corporation Journal of Pregnancy Volume 2012, Article ID 681306, 9 pages doi:10.1155/2012/681306 Review Article Adrenocortical and Adipose Responses to High-Altitude-Induced, Long-Term Hypoxia in the Ovine Fetus Dean A. Myers1 and Charles A. Ducsay2 1 Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA 2 Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA Correspondence should be addressed to Dean A. Myers, dean-myers@ouhsc.edu Received 7 February 2012; Accepted 2 March 2012 Academic Editor: Timothy Regnault Copyright © 2012 D. A. Myers and C. A. Ducsay. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA) axis aids the fetus in responding to stress. Hypoxia represents a signiﬁcant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m), long-term hypoxia (LTH) in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN), anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramiﬁcations of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress. 1. Introduction Hypoxia represents a major threat to the developing fetus and often accompanies situations of preeclampsia, preterm labor, smoking, and high altitude. The impact that hypoxia has on the fetus depends on a variety of factors such as stage of gestation, severity of the hypoxic episode, duration of hypoxia, and the association with other confounders such as acidemia and hypercapnia. Severe hypoxic events can lead to fetal death or exert major deleterious impacts on develop- ment and function on fetal organs, including major damage of the CNS. However, fetuses are often and perhaps routinely exposed to less severe hypoxic episodes. While these hypoxic conditions may impact fetal growth, eﬀects on other organ systems are less clear. Due to its long gestational length, similarity of endocrine and physiological systems, and relative ease of fetal and maternal instrumentation, the sheep has emerged as a ma- jor animal model for studying the impact of hypoxia on the developing fetus. These studies have largely focused on so-called acute hypoxia in which a moderate-to-severe hypoxia (a decrease in fetal PO2 of 50% or greater) is induced for times ranging from minutes to several hours or chronic hypoxia in which the fetus is made hypoxic for one to several days. Experimentally, acute fetal hypoxia can be induced by maternal hypoxia [1–3], restricting blood ﬂow to the uterus and placenta on the maternal side [4], or reducing umbilical blood ﬂow by cord compression [5– 7]. More prolonged fetal hypoxemia can also be initiated by repeated umbilical cord compression [7–9], as well as placental embolization [10, 11] and restriction of uterine blood ﬂow [12]. These methods induce either a rather pure hypoxic episode or hypoxia accompanied with acidemia or hypoglycemia. Longer duration hypoxic situations (months) have been created in sheep by maternal carunclectomy, reducing the placentation area of the uterus [13]. However, the hypoxia in this model is secondary to nutrient restric- tion.