Review
Adrenal gland and bone

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Abstract

The adrenal gland synthesizes steroid hormones from the adrenal cortex and catecholamines from the adrenal medulla. Both cortisol and adrenal androgens can have powerful effects on bone. The overproduction of cortisol in Cushing’s disease leads to a dramatic reduction in bone density and an increase risk of fracture. Overproduction of adrenal androgens in congenital adrenal hyperplasia (CAH) leads to marked changes in bone growth and development with early growth acceleration but ultimately a significant reduction in final adult height. The role of more physiological levels of glucocorticoids and androgens on bone metabolism is less clear. Cortisol levels measured in elderly individuals show a weak correlation with measures of bone density and change in bone density over time with a high cortisol level associated with lower bone density and more rapid bone loss. Cortisol levels and the dynamics of cortisol secretion change with age which could also explain some age related changes in bone physiology. It is also now clear that adrenal steroids can be metabolized within bone tissue itself. Local synthesis of cortisol within bone from its inactive precursor cortisone has been demonstrated and the amount of cortisol produced within osteoblasts appears to increase with age. With regard to adrenal androgens there is a dramatic reduction in levels with aging and several studies have examined the impact that restoration of these levels back to those seen in younger individuals has on bone health. Most of these studies show small positive effects in women, not men, but the skeletal sites where benefits are seen varies from study to study.

Introduction

The adrenal gland can influence bone through the production and action of a range of hormones. The action of adrenal steroids depends on the amount of steroids produced, the rhythm with which they are produced, how they are metabolized in the tissues, and the level of expression and affinity of the receptors for these hormones in the tissues. Adrenal hormones potentially impact on the growth and development of bone and on the maintenance of the mature skeletal. The adrenal gland produces steroid hormones from its cortex (cortisol, aldosterone and adrenal androgens) and catecholamines from its medulla (primarily adrenaline/epinephrine). Of these hormones, cortisol has the most dramatic impact on bone but there is also likely to be important effects of adrenal androgens, particularly in women (where the adrenal is the primary source of androgens).

Whether aldosterone or adrenaline play a physiological role in bone is less clear—there is currently little to suggest that either of these hormones plays an important role in bone physiology.

While cortisol and adrenal androgen synthesis may be of relevance to normal physiology they have their most dramatic effects in disease states, e.g. excess cortisol levels in Cushing’s disease, excess adrenal androgens in congenital adrenal hyperplasia (CAH),1 adrenal androgen deficiency in Addison’s disease and aging.

This article will review the actions of adrenal hormones on bone in normal physiology and during aging and disease. The effects of excess therapeutic glucocorticoids or androgens on bone will not be dealt with here as it is beyond the scope of this review and has been reviewed elsewhere [1], [2], [3].

Section snippets

Overview of hormone production by the adrenal gland

The adrenal glands are positioned above the upper pole of the kidney and are anatomically divided into a cortex and a medulla. The adrenal cortex is the site of synthesis of adrenal steroid hormones (Fig. 1). Steroid hormones are derived from cholesterol through a complex series of chemical modifications. Although the resulting steroid hormones vary only slightly structurally they have profoundly different specificities for steroid hormone receptors. The main adrenal steroids that enter the

Endogenous glucocorticoids—role in normal bone physiology

Excess endogenous and therapeutic glucocorticoids clearly cause detrimental effects on bone physiology leading to osteoporosis and bone fracture. The cellular mechanisms by which glucocorticoids exert their effects on bone are complex with a range of direct and indirect effects on the cell types present in bone (osteoblasts—the bone forming cells, osteocytes—the mechanosensing cells present within bone tissue, and osteoclasts—the bone resorbing cell) and on other tissues important in fracture

Excessive endogenous cortisol production—classical Cushing’s syndrome

Endogenous Cushing’s syndrome can be due to a pituitary adenoma which secretes excessive ACTH; an adrenal adenoma/carcinoma that secretes too much cortisol in an ACTH independent manner; or a peripheral neuroendocrine tumor, e.g. a carcinoid tumor, secreting excessive amounts of ACTH in an ectopic fashion. All of these states are associated with detrimental effects on bone resulting in a greatly increased risk of fractures and dramatic declines in BMD. The extent of the fracture risk has been

Excessive endogenous cortisol production—subclinical Cushing’s syndrome and adrenal incidentalomas

In addition to the well accepted deleterious effects of Cushing’s syndrome a role for more subtle excess secretion of cortisol from the adrenal gland has been proposed. Small tumors of the adrenal cortex are common in the population with an incidence of about 0.5–2% in patients undergoing abdominal CT scanning for unrelated reasons [36]. Given that these tumors are found incidentally they are referred to as adrenal incidentalomas. Incidentalomas most commonly are non-secretory but a minority of

Excessive endogenous cortisol production—the role of local glucocorticoid metabolism

In the previous sections the role of circulating glucocorticoids in bone physiology has been discussed. In recent years it has become appreciated that the circulating level of glucocorticoids may not reflect the levels found at a tissue level. Within interstitial fluid the level of cortisol is much lower than in the circulation since it is only free, unbound, cortisol that is normally found here [48]. This contrasts the situation in the circulation where the majority of cortisol is tightly

Adrenal androgens—role in bone development and physiology

Both the androgen and estrogen receptors are found in normal bone tissue, more prominently within osteoblasts [63], [64]. Until recent it was considered that androgens and estrogens had independent effects on bone and that estrogen effects were of most importance in women and androgen effects in men. The finding that men with mutations resulting in non-functioning of either the estrogen receptor or of the enzyme aromatase (an enzyme essential for the conversion of testosterone to estradiol) had

Decreased adrenal androgen production—potential role in age related bone loss and effects of treatment

As discussed above, there is a 40–70% decrease in adrenal androgen levels between the age of 20 and 80 [65]. This decline corresponds with many age related changes such as reduced bone density, reduced muscle mass and increased fatigue. These symptoms in other settings have responded to treatment with androgens. It has therefore been hypothesized that the decline in adrenal androgens might account for some of the features of aging and that replacement of these androgens could restore these

Excessive adrenal androgen production—congenital adrenal hyperplasia

Congenital adrenal hyperplasia is caused by an enzyme defect in adrenal steroidogenesis which leads to impaired synthesis of cortisol and sometimes aldosterone [76]. The lack of cortisol synthesis means that there is little negative feedback on ACTH secretion leading to high ACTH levels (Fig. 6). Sustained high ACTH secretion results in hypertrophy of the adrenal cortex which can partially overcome the enzyme defect through massive overproduction of cortisol precursors. Unfortunately, in

Role of other adrenal hormones in bone physiology and disease

The role of aldosterone and adrenaline (epinephrine) in bone physiology is much less certain. Mineralocorticoid receptors are present in bone tissue raising the possibility that bone could be selectively sensitive to aldosterone [88]. However, it is now established that the mineralocorticoid receptor is also able to bind cortisol with an affinity similar to that of aldosterone. Given that the concentration of cortisol is substantially higher than that of aldosterone is seems likely that

Conclusions

This review has highlighted the way in which hormones synthesised by the adrenal gland can affect bone. Ways that adrenal hormones either have, or potentially have, adverse or positive impacts on bone are summarized in Table 1. In several pathological situations the effects of adrenal hormones on bone are well established. Further investigation is needed to assess the role of physiological changes in either cortisol (at systemic or local levels) or adrenal androgens on bone during growth,

Acknowledgment

Mark Cooper is currently a recipient of an unrestricted GlaxoSmithKline Clinician Scientist Fellowship.

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