Previous studies demonstrated enhanced fetal adrenal cortisol biosynthesis following exposure to long-term hypoxia (LTH). The studies presented here were designed to determine the mechanism(s) regulating this important adaptive endocrine response. Ewes were maintained at high altitude (3,820 m) from approximately day 40 to 138-141 of gestation. Fetal adrenal glands were then collected from LTH and age matched normoxic controls. Dispersed fetal adrenal cortical cells (FACs) were untreated, treated with ACTH, treated in combination with ACTH precursors (POMC and 22-kDa pro-ACTH), or pre-treated with H-89 and or UO126 followed by ACTH treatment. Following ACTH treatment, cortisol biosynthesis increased in both groups but values were significantly higher in the LTH FACs. Neither basal nor ACTH-stimulated cAMP levels differed between groups. H-89 inhibition of PKA decreased cortisol to levels observed in the un-stimulated FACs in both groups. StAR protein was higher in the LTH group under un-stimulated and following ACTH treatment. ACTH precursors alone or in combination with ACTH did not affect cortisol synthesis in either group. StAR mRNA was not different between groups. Although UO126 inhibition of ERK decreased cortisol in both groups, the net decrease was greater in the LTH group in response to ACTH treatment. Basal ERK1/2, and pERK1/2 were not different between groups. In response to ACTH treatment pERK1/2 was higher in the LTH FACs, however, pERK1/2 declined significantly in normoxic control but not LTH FACs. Total ERK1/2 did not differ between groups or after ACTH treatment. UO126 significantly reduced pERK 10 to 20 fold in both groups similarly at all time points. Together with previous in vivo data, these data indicate that enhanced cortisol output in the LTH group is the result of increased adrenal ACTH sensitivity. This enhanced sensitivity is not due to differences in cAMP, PKA and or ACTH precursors. StAR, and the ERKs appear to play a key role in the enhanced cortisol response to ACTH following LTH. These adaptive responses to LTH are critical in maintaining normal fetal growth and development and these data may have important clinical implications.

LLU Discipline



Basic Sciences


School of Medicine

First Advisor

Ducsay, Charles A.

Degree Name

Doctor of Philosophy (PhD)

Degree Level


Year Degree Awarded

January 2010

Date (Title Page)




Library of Congress/MESH Subject Headings

Endocrinology; Endocrine glands;

Subject - Local

Fetal adrenal cortisol biosynthesis; Hypoxia; Adaptive endocrine response; Biosynthesis; Fetal physiology



Page Count

136 p.

Digital Format


Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.


Loma Linda University Electronic Theses & Dissertations

Collection Website



Loma Linda University. Del E. Webb Memorial Library. University Archives