ReviewAdrenal gland and bone
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.
References (88)
- et al.
Steroids
(2009) - et al.
Lancet
(2009) - et al.
Bone
(2000) - et al.
Bone
(2009) - et al.
Am. J. Clin. Nutr.
(2009) - et al.
Lancet
(2005) - et al.
Bone
(1996) Nat. Rev. Rheumatol.
(2010)- et al.
Mol. Endocrinol.
(2009) - et al.
J. Clin. Endocrinol. Metab.
(2000)
J. Endocrinol.
J. Clin. Endocrinol. Metab.
Rheumatol. Int.
Arch. Gynecol. Obstet.
J. Gerontol. A: Biol. Sci. Med. Sci.
J. Am. Geriatr. Soc.
Calcif. Tissue Int.
J. Clin. Endocrinol. Metab.
J. Clin. Endocrinol. Metab.
BMC Endocr. Disord.
Aging Cell
J. Clin. Endocrinol. Metab.
J. Clin. Endocrinol. Metab.
Clin. Endocrinol. (Oxf.)
Clin. Endocrinol. (Oxf.)
Eur. J. Endocrinol.
J. Clin. Endocrinol. Metab.
Endocr. J.
Osteoporos. Int.
Eur. J. Endocrinol.
J. Clin. Endocrinol. Metab.
J. Clin. Endocrinol. Metab.
Clin. Endocrinol. (Oxf.)
Osteoporos. Int.
Eur. J. Endocrinol.
World J. Surg.
Osteoporos. Int.
Clin. Endocrinol. (Oxf.)
J. Bone Miner. Res.
J. Bone Miner. Res.
Ann. Intern. Med.
Eur. J. Endocrinol.
Clin. Endocrinol. (Oxf.)
J. Clin. Endocrinol. Metab.
Cited by (32)
Bone mineral density and skeletal outcomes in congenital adrenal hyperplasia
2023, Genetic Steroid Disorders: Second EditionA transcriptome-wide association study to detect novel genes for volumetric bone mineral density
2021, BoneCitation Excerpt :Excess glucocorticoids can cause detrimental effects on bone physiology, which leads to osteoporosis and bone fracture. The cellular mechanisms by which glucocorticoids affects bone are complicated with a range of direct and indirect effects on the multiple cell types present in bone and on other tissues important in fracture protection [54]. The most important effects among them appear to be direct actions of glucocorticoids on osteoblasts to reduce their activities and cause their apoptosis and the stimulatory action on the activity of osteoclasts [55,56].
Unusual stress fracture post childbirth – Case-report and literature review
2021, Science and SportsReduced bone mineral density in glycogen storage disease type III: Evidence for a possible connection between metabolic imbalance and bone homeostasis
2016, BoneCitation Excerpt :Bone status is directly controlled by parathyroid hormone (PTH), calcitonin, osteocalcin (OC) and Vitamin D. However several other hormonal factors are known to interact to regulate bone metabolism: the GH-IGF-1 system [14], Insulin [15], thyroid hormones [16,17], sexual hormones [18,19] and adrenal hormones [20]. The effect of hyperlipidemia on bone resorption is also known [21,22].
Associations between hypothalamic-pituitary-adrenal axis function and peak bone mass at 20 years of age in a birth cohort
2016, BoneCitation Excerpt :It is well-recognized that glucocorticoid treatment is a risk factor for osteoporosis [1], and excessive endogenous cortisol production in Cushing's syndrome leads to significant reduction in bone mineral density (BMD) and increased fracture risk [2].
Targeting 11β-hydroxysteroid dehydrogenases: A novel approach to manipulating local glucocorticoid levels with implications for rheumatic disease
2013, Current Opinion in PharmacologyCitation Excerpt :Age-related osteoporosis is associated with a similar uncoupling of bone formation and resorption. However, the circulating level of cortisol, the active endogenous glucocorticoid in man, does not change appreciably with age ruling out systemic glucocorticoid excess as the cause [15]. We and others have demonstrated the presence of 11β-HSD1 within bone and bone cells with expression seen primarily in the osteoblast [7•,16].