Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: Implications for growth and remodeling

After 10-15 weeks of gestation, the human fetal adrenal cortex undergoes ra pid growth due to enlargement of a specialized cortical compartment known a s the fetal zone (FZ). Soon after birth, the FZ regresses and the adult zon ation pattern develops at least in part from cells derived from the persist ent definitive zone (DZ), a thin layer of tightly packed cells surrounding the FZ. We postulated that growth of the fetal adrenal cortex involves zone -specific cellular hyperplasia, whereas the postnatal involution of the FZ is due to apoptosis. Therefore, we investigated the pattern of cellular pro liferation and death in the FZ and DZ of the human fetal and postnatal adre nal cortex using immunohistochemical staining for proliferating cell nuclea r antigen as a marker of mitosis and in situ detection of DNA fragmentation as a marker of apoptosis. Between 10-14 weeks' gestation, the mitotic inde xes (percentage of proliferating cell nuclear antigen-positive cells) in th e DZ (26.46 +/- 2.95%) and in the FZ (21.26 +/- 2.57%) were not significant ly different. Between 15-20 weeks gestation, the mitotic index increased si gnificantly (P < 0.05) in both zones (FZ, 33.84 +/- 5.21%; DZ, 67.45 +/- 7. 58%) relative to levels before 15 weeks: This increase persisted between 21 -24 weeks gestation (FZ, 39.5 +/- 4.22%; DZ, 58.63 +/- 6.83%). Interestingl y, after 14 weeks, the mitotic index of the DZ was significantly greater (P < 0.05) than that of the FZ. In adrenal specimens obtained from infants bo rn prematurely and treated in utero with glucocorticoid, the mitotic indexe s in the FZ and DZ were significantly decreased. At all stages of gestation , no apoptotic nuclei were detected in the DZ. However, scattered apoptotic nuclei were detected in the central portions of the FZ. The number of apop totic nuclei in the inner FZ increased with advancing gestation and was max imal during the first postnatal month. To identify factors that may regulat e apoptosis, primary cultures of midgestation FZ cells were treated with ac tivin A and transforming growth factor-beta (TGF beta). Activin A and TGF b eta both induced apoptotic cell death, as assessed by internucleosomal DNA cleavage (DNA laddering). Induction of apoptosis by activin A was prevented by concomitant addition of follistatin, an activin-binding protein. Taken together, these data indicate that 1) growth of the human fetal adrenal cor tex involves cellular hyperplasia, mainly in the DZ and to a lesser extent in the FZ, which is probably dependent on ACTH; and 2) apoptosis occurs pre dominantly in the inner cortical compartment and may be responsible for the rapid regression of the FZ after birth, a process that may be regulated by activin A and/or TGF beta.