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The role for long-term use of dehydroepiandrosterone in adrenal insufficiency (2022)
Gillian Bennett, Leanne Cussen, and Michael W. O'Reilly
Purpose of review
Dehydroepiandrosterone (DHEA) is an androgen produced by the zona reticularis of the adrenal gland. Patients with adrenal insufficiency will have a deficiency of DHEA. Unlike glucocorticoid and mineralocorticoid replacement, DHEA supplementation is not considered essential for life and is therefore not routinely replaced in adrenal failure. DHEA deficiency is associated with morbidity, including adverse impacts on metabolic function, quality of life, and sexuality in multiple studies. The role of replacement, however, remains unclear.
Recent findings
The benefits of DHEA supplementation have been definitively demonstrated in a number of historical studies of patients with primary and secondary adrenal insufficiency. Beneficial impacts on quality of life, body composition, bone health, and metabolic markers have been demonstrated. However, published data are inconsistent; controversies persist around the exact role of DHEA replacement and around which patient cohorts are most likely to benefit. There is also a paucity of recent randomized controlled trials in the medical literature to inform on the optimal dose and duration of DHEA replacement in adrenal failure.
Summary
Here, we review the evidence for DHEA supplementation in patients with adrenal insufficiency. We highlight knowledge gaps in the medical literature and areas that should be prioritized for future research endeavors.
INTRODUCTION
The adrenal cortex is responsible for producing glucocorticoids, mineralocorticoids, and adrenal androgens, including dehydroepiandrosterone (DHEA). Glucocorticoid and androgen generation is predominantly under the control of adrenocorticotropic hormone (ACTH) secretion from corticotroph cells of the pituitary gland. Adrenal insufficiency can be classified as primary, secondary, or tertiary. Primary adrenal insufficiency (PAI) is commonly due to autoimmune-mediated destruction of the adrenal cortex also known as Addison’s disease but is also caused by other processes such as mycobacterial infection, infiltrative disorders, bilateral adrenalectomy, and bilateral hemorrhage [1]. Secondary adrenal insufficiency (SAI) occurs in the context of pituitary dysfunction wherein ACTH release is impaired; this may be seen with tumors of the sella or as a consequence of their treatment. Tertiary adrenal insufficiency (TAI) occurs when there is decreased production of corticotrophin-releasing hormone (CRH) and vasopressin by the hypothalamus, which has a downstream effect on ACTH release; TAI is commonly caused by long-term exogenous administration of glucocorticoids [2]. PAI results in glucocorticoid, mineralocorticoid, and adrenal androgen deficiency, whereas mineralocorticoid deficiency is not a feature of SAI and TAI due to the preservation of the renin-angiotensin-aldosterone system. Glucocorticoid and mineralocorticoid replacement is therefore essential in PAI, while glucocorticoid replacement in isolation is appropriate in SAI and TAI. DHEA replacement is not routine in adrenal insufficiency despite being a central biochemical feature of both PAI and SAI.
DHEA is produced primarily by the zona reticularis of the adrenal cortex; it is converted to DHEA sulfate (DHEAS), its inactive sulfated ester, in the liver and adrenal glands [3]. They are bound to albumin and together form the most abundant steroid hormones in human circulation [4]; DHEA secretion increases with adrenarche and peaks by the end of the third decade [5], after which serum concentrations begin to decline. It has been postulated that low circulating levels of DHEA may be associated with cardiovascular disease (CVD), reduced bone mineral density (BMD), and increased all-cause mortality; this has resulted in a debate surrounding the potential role of DHEA replacement in the setting of PAI or SAI [6]. The objective of this review is to investigate the evidence for DHEA supplementation in patients with adrenal insufficiency.
*PHYSIOLOGY OF ADRENAL ANDROGEN SECRETION
*IMPACT OF DEHDROEPIANDROSTERONE SUPPLEMENTATION ON HEALTH OUTCOMES IN ADRENAL INSUFFICIENCY
-Pharmacokinetics and safety profile
-Quality of life
-Bone health
-Lipid metabolism
-Insulin sensitivity and body composition
-Sexual function
*ROLE OF DEHDROEPIANDROSTERONE IN FERTILITY
CONCLUSION
Low levels of circulating DHEA may be associated with CVD, T2DM, and reduced QoL in patients with and without adrenal insufficiency. It is not clear whether long-term exogenous DHEA mitigates the risk of these complications in adrenal failure. Relatively few studies involving patients with PAI and SAI have been carried out in humans, most with a relatively short follow-up period and small patient numbers, and relatively few randomized controlled trials have been conducted since 2012. As such, it is difficult to draw conclusions about long-term health benefits. Shorter-term studies cannot definitively confirm long-term impacts on these physiological parameters, and adequately powered trials over longer periods of time are needed to assess this further. In fact, the Endocrine Society and several other medical societies appointed a task force to investigate the safety and possible clinical uses of DHEA replacement, the consensus recommendation being that currently there is not enough evidence to support the routine use of DHEA in women with adrenal insufficiency [67]. In summary, the evidence for DHEA replacement in adrenal insufficiency is weak, and larger randomized control trials with longer follow-up and adequate sample sizes are warranted to support claims regarding long-term health benefits.
Gillian Bennett, Leanne Cussen, and Michael W. O'Reilly
Purpose of review
Dehydroepiandrosterone (DHEA) is an androgen produced by the zona reticularis of the adrenal gland. Patients with adrenal insufficiency will have a deficiency of DHEA. Unlike glucocorticoid and mineralocorticoid replacement, DHEA supplementation is not considered essential for life and is therefore not routinely replaced in adrenal failure. DHEA deficiency is associated with morbidity, including adverse impacts on metabolic function, quality of life, and sexuality in multiple studies. The role of replacement, however, remains unclear.
Recent findings
The benefits of DHEA supplementation have been definitively demonstrated in a number of historical studies of patients with primary and secondary adrenal insufficiency. Beneficial impacts on quality of life, body composition, bone health, and metabolic markers have been demonstrated. However, published data are inconsistent; controversies persist around the exact role of DHEA replacement and around which patient cohorts are most likely to benefit. There is also a paucity of recent randomized controlled trials in the medical literature to inform on the optimal dose and duration of DHEA replacement in adrenal failure.
Summary
Here, we review the evidence for DHEA supplementation in patients with adrenal insufficiency. We highlight knowledge gaps in the medical literature and areas that should be prioritized for future research endeavors.
INTRODUCTION
The adrenal cortex is responsible for producing glucocorticoids, mineralocorticoids, and adrenal androgens, including dehydroepiandrosterone (DHEA). Glucocorticoid and androgen generation is predominantly under the control of adrenocorticotropic hormone (ACTH) secretion from corticotroph cells of the pituitary gland. Adrenal insufficiency can be classified as primary, secondary, or tertiary. Primary adrenal insufficiency (PAI) is commonly due to autoimmune-mediated destruction of the adrenal cortex also known as Addison’s disease but is also caused by other processes such as mycobacterial infection, infiltrative disorders, bilateral adrenalectomy, and bilateral hemorrhage [1]. Secondary adrenal insufficiency (SAI) occurs in the context of pituitary dysfunction wherein ACTH release is impaired; this may be seen with tumors of the sella or as a consequence of their treatment. Tertiary adrenal insufficiency (TAI) occurs when there is decreased production of corticotrophin-releasing hormone (CRH) and vasopressin by the hypothalamus, which has a downstream effect on ACTH release; TAI is commonly caused by long-term exogenous administration of glucocorticoids [2]. PAI results in glucocorticoid, mineralocorticoid, and adrenal androgen deficiency, whereas mineralocorticoid deficiency is not a feature of SAI and TAI due to the preservation of the renin-angiotensin-aldosterone system. Glucocorticoid and mineralocorticoid replacement is therefore essential in PAI, while glucocorticoid replacement in isolation is appropriate in SAI and TAI. DHEA replacement is not routine in adrenal insufficiency despite being a central biochemical feature of both PAI and SAI.
DHEA is produced primarily by the zona reticularis of the adrenal cortex; it is converted to DHEA sulfate (DHEAS), its inactive sulfated ester, in the liver and adrenal glands [3]. They are bound to albumin and together form the most abundant steroid hormones in human circulation [4]; DHEA secretion increases with adrenarche and peaks by the end of the third decade [5], after which serum concentrations begin to decline. It has been postulated that low circulating levels of DHEA may be associated with cardiovascular disease (CVD), reduced bone mineral density (BMD), and increased all-cause mortality; this has resulted in a debate surrounding the potential role of DHEA replacement in the setting of PAI or SAI [6]. The objective of this review is to investigate the evidence for DHEA supplementation in patients with adrenal insufficiency.
*PHYSIOLOGY OF ADRENAL ANDROGEN SECRETION
*IMPACT OF DEHDROEPIANDROSTERONE SUPPLEMENTATION ON HEALTH OUTCOMES IN ADRENAL INSUFFICIENCY
-Pharmacokinetics and safety profile
-Quality of life
-Bone health
-Lipid metabolism
-Insulin sensitivity and body composition
-Sexual function
*ROLE OF DEHDROEPIANDROSTERONE IN FERTILITY
CONCLUSION
Low levels of circulating DHEA may be associated with CVD, T2DM, and reduced QoL in patients with and without adrenal insufficiency. It is not clear whether long-term exogenous DHEA mitigates the risk of these complications in adrenal failure. Relatively few studies involving patients with PAI and SAI have been carried out in humans, most with a relatively short follow-up period and small patient numbers, and relatively few randomized controlled trials have been conducted since 2012. As such, it is difficult to draw conclusions about long-term health benefits. Shorter-term studies cannot definitively confirm long-term impacts on these physiological parameters, and adequately powered trials over longer periods of time are needed to assess this further. In fact, the Endocrine Society and several other medical societies appointed a task force to investigate the safety and possible clinical uses of DHEA replacement, the consensus recommendation being that currently there is not enough evidence to support the routine use of DHEA in women with adrenal insufficiency [67]. In summary, the evidence for DHEA replacement in adrenal insufficiency is weak, and larger randomized control trials with longer follow-up and adequate sample sizes are warranted to support claims regarding long-term health benefits.
