A Direct Role for Thyroid Hormone in Development of the Adrenal Cortex

A relationship between thyroid and adrenal dysfunction has been recognized for some time. Certain human autoimmune conditions, for example, can destroy both the thyroid gland and adrenal cortex resulting in combined hormone deficiencies. Beyond autoimmune destruction, however, a relationship between thyroid and adrenocortical function is less clear. Glucocorticoid excess has been shown to suppress the central thyroid axis, whereas thyroid hormone has been suggested to regulate adrenocortical function through changes in hepatic glucocorticoid metabolism. Overall, these studies are limited in scope, and any real regulatory relationship between these glands still remains tenuous (Samuels and McDaniel [1], Johnson et al [2]). This is why the study of Huang et al (3) is both timely and novel. These investigators show for the first time that thyroid hormone, acting through one of its receptor isoforms (THRB1), has a direct role in adrenocortical development and function.

The adrenal cortex in mammals develops from intermediate mesoderm, whereas the adrenal medulla is derived from neuroectoderm (neural crest cells). The adrenal cortex first forms an immature zone, which is later replaced by mature cortical cell types. The immature or fetal zone in humans produces dehydroepiandrosterone sulfate, which is used by the placenta to produce estrogens. The definitive or adult zone in humans and other mammals, in contrast, produces mineralocorticoids and glucocorticoids.

In immature mice, an inner cortical zone has been described that expresses the steroid-metabolizing enzyme, 20-α-hydroxysteroid dehydrogenase (20αHSD). This is termed the x-zone and regresses in male but persists in female adult mice. Whether there is a developmental equivalent of this zone in higher mammals is unclear at the present time. Interestingly, gonadal factors, gonadotrophins, and thyroid hormone are known to modify the appearance of this zone (Huang et al). Huang et al show, using a β-galactosidase tagged Thrb1 locus, that THRB1 colocalizes with 20αHSD to the x-zone in mice. In addition, they demonstrate that T₃ treatment causes hypertrophy of this zone in wild-type but not Thrb^−/− mice. As the authors point out, thyroid extract has also been reported to induce hypertrophy of the adrenal cortex in other species, such as the rabbit and cat, that lack a definable x-zone, which suggests that this finding might be generalizable to other mammals including humans.

Armed with this knowledge, one might now wonder whether thyroid hormone deficiency per se can cause subtle or overt adrenocortical hormone deficiency by acting directly on the gland. The challenge here is to understand more fully the role of the fetal zone, which includes the x-zone, in adult adrenal cortical function. It appears that the definitive adult cortex develops from surface capsular cells that migrate into the gland, but the authors suggest that the x-zone might represent another source of cells involved in the stress response. Unfortunately, this hypothesis was not tested further in their study. One might predict, for instance, that hypothyroidism limits the acute stress response to ACTH or that thyroid hormone excess increases steroid hormone levels by expanding residual x-zone cells in the adult animal. Alternatively, the authors propose that thyroid hormone might regulate progesterone and 11-deoxycorticosterone levels via 20αHSD, which is known to catabolize both hormones, and this might alter adrenal function in some unknown way. Finally, given that thyroid hormone regulates adrenocortical cell development, it might also change cell surface antigens and be involved in some way in inducing adrenocortical autoimmunity. More work will need to be done to answer these questions.

A clear role for thyroid hormone receptors in the development of the cerebellum, retina, and cochlea has been shown using Thrb^−/− mice (Ortiga-Carvalho et al [4]), and many of these studies have been performed by the Forrest group. This study extends our knowledge of thyroid hormone to development of the adrenal cortex and provides a potential mechanism to explain unrecognized adrenocortical hormone deficiency in models of congenital hypothyroidism and adrenocortical hormone excess in states of thyroid hormone excess.