I. Introduction II. Development A. Embryonic adrenal development B. Fetal adrenal development C. Neonatal adrenal development D. Growth E. Functional development 1. Ontogeny of steroidogenic activity 2. Functional zonation and ontogeny of steroidogenic enzyme expression 3. Responsiveness to ACTH III. Regulation A. The fetal pituitary and ACTH B. Growth factors 1. Basic fibroblast growth factor (bFGF) 2. Epidermal growth factor (EGF) 3. Insulin-like growth factors I and II (IGF-I and IGF-II) 4. Activin/inhibins 5. TGFβ C. Nuclear receptors/transcription factors D. Placental factors 1. Human CG (hCG) 2. Placental CRH and ACTH 3. Indirect effect of placental glucocorticoid metabolism 4. Placental estrogens IV. Physiology A. Placental estrogen formation B. Timing of parturition and fetal maturation V. Summary

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Developmental and functional biology of the primate fetal adrenal cortex.

To determine whether the well-documented hyperactivity of the hypothalamic-pituitary-adrenal axis in depressed patients includes adrenal gland hypertrophy, adrenal gland size was evaluated by computed tomography. Assessments consisted of (1) global ratings by two radiologists ignorant of the diagnostic identity of the subjects and (2) calculation of adrenal volume. Of the 38 patients with major depression, 12 were rated as exhibiting adrenal hypertrophy. Adrenal volumes in the depressed patients were significantly increased when compared with those of normal controls. Adrenal gland size was not correlated with dexamethasone suppression test results, patient age, duration of the depressive episode, or depression severity. These results are concordant with the hypothesis that chronic corticotropin hypersecretion in depression results in adrenocortical hypertrophy. Adrenal gland enlargement may be a measure of cumulative lifetime depression.

Adrenal Gland Enlargement in Major Depression: A Computed Tomographic Study

Background: Hyperactivity of the pituitary-adrenocortical axis is the most prominent neuroendocrine abnormality in major depression. It is state-related, returning to normal with resolution of the depressive episode. Adrenal gland enlargement also has been reported in patients with major depression and has been hypothesized as an index of cumulative lifetime depression. However, whether or not adrenal enlargement decreases with successful treatment of depression has not yet been studied, to our knowledge. We, therefore, determined adrenal gland volume in patients with major depression before and after treatment and in matched normal controls, and compared adrenal size with functional indexes of pituitary-adrenocortical activity. Methods: Adrenal volumes were measured by magnetic resonance imaging in nine adult and two-adolescent patients with major depression during their illness and during full remission when medication had been stopped for at least 1 month, and in nine adult and two adolescent normal control subjects individually matched to the patients. Basal, 4 to 7PMplasma corticotropin 1-39 and cortisol levels, and corticotropin 1-39 and cortisol responses to administration of ovine corticorelin and low-dose cosyntropin also were measured. Results: Mean adrenal gland volume was significantly larger, by about 70%, in the patients while depressed than after successful treatment, and it also was significantly larger, again by about 70%, than the mean adrenal gland volume of their matched controls. After treatment, the mean adrenal volume of the patients decreased and was no longer significantly different from that of their controls at baseline. The magnitude of the decrease was significantly positively correlated with the duration of the depressive episode. Basal, late-afternoon plasma corticotropin 1-39 levels were significantly lower in the patients while depressed than in their matched controls, but basal plasma cortisol levels did not differ significantly among the three groups, nor did the corticotropin 1-39 and cortisol responses to corticorelin or the cortisol response to cosyntropin. Correlations between adrenal gland volume and basal corticotropin and cortisol levels, and the corticotropin and cortisol responses to hormone challenge, were not consistently in the expected direction in any of the three groups of subjects. Conclusions: Adrenal gland enlargement occurring during an episode of major depression appears to be state-dependent, in that it reverts to the normal size range during remission after treatment. It thus does not appear to be an index of cumulative lifetime depression. The lack of a discernible relationship between adrenal volume and pituitary-adrenocortical activity remains to be explained and might be related to noncorticotropin influences on the adrenal gland, including other trophic hormones and/or neural mechanisms.

Adrenal Gland Volume in Major Depression Increase During the Depressive Episode and Decrease With Successful Treatment

Autoimmune polyendocrine syndrome type I (APS I) and idiopathic Addison's disease are both disorders with adrenal insufficiency but with differences in genetic background, clinical presentation, and extent of extraadrenal manifestations. In this study the major adrenal autoantigen identified with sera from patients with APS I was characterized by analyses using indirect immunofluorescence, Western blots of adrenal subcellular fractions and of recombinant proteins, immunoprecipitations of [35S]methionine-labeled lysates of a human steroid-producing cell line, and studies of enzymatic activity. Sera from patients with APS I, identifying cells in adrenal glands and testes involved in steroid synthesis, reacted in Western blots with a 53-kD antigen, which comigrated with the cytochrome P450 cholesterol side chain cleavage enzyme (SCC). The sera also immunoprecipitated this protein from lysates of radiolabeled adrenal cells. The enzymatic activity of SCC was inhibited by the APS I sera but not by control sera. Sera from patients with idiopathic Addison's disease did not react with the SCC. The results show that the autoimmune responses towards adrenal tissue in patients suffering from APS I and Addison's disease are remarkably selective and suggest that a determination of the antigen involved in a patient with autoimmune adrenal insufficiency will have diagnostic as well as prognostic implications.

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Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant product of the young adult human adrenal cortex and fetal adrenal gland.'-' DHEAS secretion shows a dramatic cycle of high and low points over the life span in humans, as discussed in several other articles in this volume. Secretion from the adrenal cortex is very high in the fetus, drops sharply after birth to very low levels in childhood, rises again before puberty, a phenomenon termed adrenarche, and reaches high levels once again in young adulthood. Thereafter, DHEAS secretion progressively declines, often reaching very low or negligible levels after age 70. Plasma DHEAS levels reflcct synthesis by the adrenal cortex, because the adrenal is normally the overwhelming source of DHEAS and the major contributor to unconjugated dehydroepiandrosterone (DHEA), which is present at much lower circulating levels and also is synthesized by the gonads. Synthesis of the adrenal androgens DHEA and DHEAS in adult humans and other primates presents several puzzles to the researcher. First, why do the adrenal glands synthesize large amounts of these steroids in young adulthood, after a period from birth to pre-puberty during which little or none of these steroids is synthesized? Second, why does the high rate of secretion in young adulthood show such a strong age-related decline? Third, is the age-related decline in the adrenal androgens equivalent to deprivation of an essential hormone, and, therefore, is there a role for replacement therapy of DHEA(S) in later life as has successfully been achieved with estrogens? The question of the function of DHEA(S) in young adulthood and approaches to the concept of replacement therapy in older individuals are thc subjects of several articles in this volume and will not be addressed here. Rather, the aim of this review is to account for the high rate of synthesis of DHEA(S) by the young adult adrenal gland at a cellular and molecular level, to examine the basis for the differences between humans and nonprimate species in DHEA(S) biosynthesis, and to offer some ideas for the mechanism of the age-rclatcd decline in secretion.

Biosynthesis of DHEAS by the Human Adrenal Cortex and Its Age‐Related Decline

Publisher Summary The regulation of the structure of the mammalian adrenal cortex is an intrinsic component of the regulation of the synthesis of its steroid hormones. The two important structural factors to be considered are (1) adrenocortical mass and (2) zonation. Adrenocortical structure is involved in the regulation of the synthesis of the mineralocorticoid, glucocorticoid, and androgenic steroids secreted by the adrenal under both normal and pathological conditions. The adrenal cortex exhibits a unique system of physiological regulation, incorporating three separately regulated systems of hormone synthesis—mineralocorticoid, glucocorticoid, and androgen—into the life history of a single cell type. The adrenal glands vary in shape from almost spherical, in fetal life and in the adult of some species, through somewhat flattened to more or less leaf-like, for example, in humans and cattle. Although the size of the gland varies with the size of the animal, the thickness of the cortex remains remarkably constant. The mass of the zona glomerulosa is a major factor in the long-term regulation of aldosterone synthesis, and the inner zone (zona reticularis or fetal zone) is of major importance for the regulation of adrenal androgen synthesis.

Peter J. Hornsby

Papers

The regulation of adrenocortical function by control of growth and structure