Estrogen Regulation of Fetal Adrenal Cortical Zone-Specific Development in the Nonhuman Primate Impacts Adrenal Production of Androgen and Cortisol and Response to ACTH in Females in Adulthood

Abstract

We showed that the volume of the fetal zone of the fetal adrenal gland and serum dehydroepiandrosterone sulfate (DHAS) levels at term were increased in baboons in which estradiol levels were suppressed by treatment with aromatase inhibitor 4,4-[1,2,3-triazol-1yl-methylene] bis-benzonitrite (letrozole). The fetal zone remodels postnatally into the reticular zone and DHAS production, and serum levels decline with age. Therefore, we determined whether the trajectory of reticular zone DHAS secretion and response to ACTH were altered in offspring deprived of estrogen in utero. Female offspring were delivered to baboons untreated or treated daily throughout the second half of gestation with letrozole (estradiol reduced >95%) or letrozole plus estradiol and cortisol and DHAS determined in blood samples obtained bimonthly between 4 and 125 months and after iv bolus of ACTH. The slope/rate of decline in serum DHAS with advancing age was greater (P < .01) in letrozole-treated (-0.54 ± 0.005) than untreated (-0.32 ± 0.003) baboons and partially restored by letrozole-estradiol (-0.43 ± 0.004). Serum cortisol was similar and relatively constant in all offspring. Moreover, in letrozole-treated offspring, serum DHAS at 61-66, 67-95, and 96-125 months were lower (P < .05), and cortisol to DHAS ratio was greater (P < .05) than in untreated offspring. ACTH at high level increased cortisol and DHAS in untreated baboons and cortisol but not DHAS in letrozole-treated offspring. We propose that postnatal development of the primate adrenal cortex, including the decline in reticular zone DHAS production, response to ACTH and maintenance of cortisol to DHAS ratio with advancing age is modulated by exposure of the fetal adrenal to estradiol.

Insulin resistance elicited in postpubertal primate offspring deprived of estrogen in utero

“…Although it is well established that increased food intake/adiposity promotes insulin resistance [45], it is also unlikely that the latter are the cause of insulin resistance in letrozole-treated offspring as growth and body weights were comparable in the untreated and letrozole-treated offspring. Stress is also not likely to be a causative factor as we have recently shown that serum cortisol levels are comparable in offspring born to mothers untreated or treated in utero with letrozole [46]. Because maternal insulin sensitivity and glucose tolerance were normal in letrozole-treated baboons [1], it appears that the defect in insulin sensitivity in offspring of letrozole-treated baboons is also not the result of a change in maternal glucose metabolism.…”

Prenatal Testosterone Exposure Decreases Aldosterone Production but Maintains Normal Plasma Volume and Increases Blood Pressure in Adult Female Rats

“…Studies show that the androgen receptor is expressed in fetal adrenals [ 36 ], suggesting that androgens may have a direct effect on fetal adrenal development and function. Accordingly, treatment of pregnant rats with letrozole, an aromatase inhibitor, is shown to adversely affect fetal adrenal zone development [ 37 ]. In vitro studies show that androgens decrease the activity of many steroidogenic enzymes (e.g., 3β-hydroxysteroid dehydrogenase [3β-HSD] [ 38 ], 21-hydroxylase [ 39 ], and 11β-hydroxylase [ 40 ]).…”