Morphological adrenarche in rhesus macaques: development of the zona reticularis is concurrent with fetal zone regression in the early neonatal period

Abstract

Human adrenarche is associated with the establishment of a functional zona reticularis (ZR) and increasing secretion of dehydroepiandrosterone (DHEA) in sulfated form (DS). Like most non-human primates, rhesus macaques are not believed to undergo adrenarche, though they clearly establish a functional ZR after birth. However, the origins of the rhesus ZR are not well defined. Therefore, we investigated the zonal development, steroidogenic enzyme expression and morphology of rhesus adrenals from 1 day to 14 months of age. Immunohistochemistry was conducted to determine expression profiles of the steroidogenic enzymes 17a-hydroxylase/17,20-lyase cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), cytochrome P450, family 21, subfamily A, polypeptide 2 (CYP21A2), hydroxy-D-5-steroid dehydrogenase, 3b-and steroid D-isomerase 2 (HSD3B2), the redox partner NADPH-cytochrome P450 oxidoreductase (CPR), as well as the accessory protein cytochrome b5 (b5), a marker of the primate ZR. The rhesus ZR is mature by 3 months of age based on differentiation of the innermost zone that lacks HSD3B2, but exhibits increased b5 expression during this period. Further, the ZR develops in neonates from a previously described dense band of cells which we show expresses b5, CYP17A1, CPR, and CYP21A2 throughout maturation. The fetal zone (FZ) is distinguished from the ZR by its lack of CYP21A2, and ZR development proceeded as the FZ regressed with two important implications: neither FZ regression nor ZR maturation can be monitored independently by circulating adrenal androgens, and these events must be induced by different factors in rhesus, and likely humans. Collectively these data demonstrate that ZR development begins before birth in the rhesus, proceeding concomitantly with FZ regression post-natally, suggesting that rhesus experiences morphological adrenarche during the first three months of life.

Adrenal androgen concentrations increase during infancy in male rhesus macaques (Macaca mulatta)

“…These are the first data to document a transient, prepubertal rise in adrenal androgen output in an Old World monkey, reflecting development and maturation of the ZR that have been defined previously histologically (43) and biochemically (42). Addition of endocrine to histological and biochemical data provides strong evidence that this event in the infant rhesus is akin to adrenarche in humans, which has not previously been considered to occur in any nonhuman primate, except some of the great apes.…”

“…In humans, the subsequent development of the ZR and associated increase in adrenal androgen concentrations are known as adrenarche (40,72), an event that occurs in early childhood (46,63). The rhesus macaque develops a ZR with the same steroidogenic phenotype (32), and differentiation takes place in infancy at 2 and 3 mo of age (43). During this same period in the rhesus monkey, there is a corresponding increase in androgen synthetic capacity of adrenal tissues (42), but whether this is reflected in circulating concentrations of androgens is unclear.…”

“…The evidence of ZR maturation in infancy (42,43), together with the prior observation of a transient increase in immunoreactive androgens in castrated male rhesus at this stage of development (54,56), prompted us to reinvestigate circulating adrenal androgens in castrated and testis-intact male rhesus infants, utilizing an opportunistic study design that capitalized on samples from ongoing experiments. Concentrations of DHEAS, DHEA, androstenedione, and cortisol were examined in monkeys sampled longitudinally from soon after birth through infancy, the interval during which ZR development and differentiation are completed (43).…”

“…Concentrations of DHEAS, DHEA, androstenedione, and cortisol were examined in monkeys sampled longitudinally from soon after birth through infancy, the interval during which ZR development and differentiation are completed (43). Gonadotropins were also measured, because luteinizing hormone (LH), in particular, may influence adrenal growth and steroidogenesis (5).…”

Plasticity of the zona reticularis in the adult marmoset adrenal cortex: voyages of discovery in the New World

“…Recent studies, nonetheless, suggest that the onset of adrenal ZR function in rhesus monkeys begins before FZ regression is complete. Demonstrating such development of the ZR simply through a rise in circulating DS in late fetal and early postnatal life is thus confounded by a still functional FZ which is also capable of contributing to circulating DS levels (Nguyen et al 2008).…”