Adrenal glands in older adults

Ageing gradually alters adrenal function in ways that are clinically relevant, transforming a gland designed to support homeostasis, the stress response and fluid and electrolyte balance into an organ that retains the ability to secrete essential hormones but does so within a profoundly changed physiological context. In older adults, the adrenal gland should not be regarded solely as the site of classical endocrine diseases, but also as a biological hub involved in frailty, cardiovascular vulnerability, the inflammatory response, bone metabolism and tolerance of acute stress. Ageing is associated with changes in the hypothalamic-pituitary-adrenal axis, aldosterone secretion and, above all, adrenal androgen production, while the frequency of incidental nodules, the burden of comorbidities and the risk of iatrogenic harm all increase.

From a clinical perspective, adrenal disorders in older adults are often difficult to recognise because they present with less specific symptoms than in younger people. Adrenal insufficiency may manifest as fatigue, hyponatraemia, falls, functional decline or confusion; mild hypercortisolism may mimic or aggravate diabetes, hypertension, osteoporosis, sarcopenia and depression; primary aldosteronism may remain hidden within cases of “difficult-to-treat” hypertension; pheochromocytoma may present with atypical cardiovascular phenotypes; and adrenal incidentalomas become much more common because of the extensive use of imaging. In this setting, the challenge is not merely to establish a correct endocrine diagnosis, but to determine when adrenal dysfunction is making a tangible contribution to the clinical frailty of an older person and when recognising it will genuinely change prognosis, independence and quality of life.

Ageing causes progressive changes in overall adrenal function, but these changes do not follow the same pattern in every cortical zone. The most evident alteration involves adrenal androgens, particularly DHEA and DHEAS, which decline substantially with age because of the progressive functional involution of the zona reticularis. This decline is one of the most characteristic endocrine signs of human ageing and has generated considerable interest because of its possible association with sarcopenia, frailty, reduced bone mass, immune changes and functional decline. However, a reduction in DHEA cannot automatically be interpreted as a “deficiency” requiring correction, because it also represents a physiological feature of later life and its clinical significance remains partly context-dependent.

The glucocorticoid compartment follows a different pattern. In older adults, total cortisol and mean daily cortisol tend to remain stable or increase modestly, often in association with reduced sensitivity to negative feedback and greater vulnerability to the metabolic and neurocognitive effects of chronic glucocorticoid exposure. This does not mean that older people physiologically develop pathological hypercortisolism, but rather that their hypothalamic-pituitary-adrenal axis operates at a set-point that is more susceptible to disturbances of circadian rhythm, chronic stress, inflammation and comorbidities. The result is a less flexible physiology in which the stress response may be simultaneously more persistent and less efficient.

Mineralocorticoid function also undergoes important changes. Ageing is associated with reduced renin activity and a tendency towards lower aldosterone secretion, factors that contribute to a reduced ability to retain sodium, respond to volume depletion and adapt rapidly to intercurrent illness, dehydration or diuretic treatment. This makes older adults more vulnerable to orthostatic hypotension, hyponatraemia, hyperkalaemia and deterioration of haemodynamic balance, particularly in the presence of chronic kidney disease or complex pharmacological therapy.

These endocrine changes do not act in isolation but are integrated into the systemic ageing process. The adrenal gland in older adults functions within an organism characterised by reduced physiological reserve, increased low-grade chronic inflammation, sleep disturbances, reduced muscle mass, polypharmacy and a higher frequency of acute events. In this context, even a modest adrenal alteration may have broader clinical consequences than in a younger adult because it affects a system that is already close to the limits of compensation. In other words, older adults tolerate a loss of endocrine reserve less effectively.

Adrenal ageing also has important implications for interpretation. An isolated low DHEAS level is insufficient to diagnose adrenal insufficiency, although it may form part of a broader picture of biological vulnerability. A relatively high cortisol level may be physiological or may reflect chronic illness, stress, depression, sleep disorders or medication use. A low aldosterone level may be part of the ageing process or an expression of a renin-dependent disorder, inhibitory therapy or adrenal insufficiency. For this reason, assessment of the adrenal glands in older adults must always distinguish between physiological senescence and true endocrinopathy.

In practice, advanced age transforms adrenal assessment from a purely endocrine exercise into an integrated interpretation of homeostasis, frailty and the ability to respond to stress. The adrenal glands of an older person may appear to function “within normal limits” while doing so with a reduced adaptive capacity, or they may harbour a mild hormonal disorder that is nevertheless sufficient to substantially worsen blood pressure, glycaemia, bone health, mood and physical function. Understanding physiological ageing is therefore an essential prerequisite both for avoiding the misclassification of normal ageing as disease and for ensuring that a treatable endocrine dysfunction is not mistakenly attributed to age.

Adrenal diagnosis in older adults is complicated by the fact that age, comorbidities and medications affect almost all major endocrine markers. The first practical principle is that no test should be interpreted outside its clinical context. An apparently abnormal hormone value may reflect kidney failure, malnutrition, stress, depression, chronic infection or treatment with diuretics, opioids, antifungals, glucocorticoids or inhibitors of the renin-angiotensin system. Conversely, a borderline result may be clinically significant in a frail patient with hypotension, weight loss, functional decline or metabolic decompensation.

When adrenal insufficiency is suspected, basal cortisol remains useful but has a broader grey zone, particularly in hospitalised older adults or those with multiple chronic diseases. Markedly low values in a compatible clinical setting are highly significant, but intermediate cases often require an ACTH stimulation test. Even in this setting, however, decisions cannot be mechanical: in a frail older person, delayed diagnosis may be more dangerous than promptly starting temporary replacement coverage when the clinical signs are strongly suggestive. Interpretation must integrate ACTH, electrolytes, blood glucose, blood pressure, medication history and the progression of symptoms.

Assessment of hypercortisolism is even more challenging. In older adults, visceral obesity, diabetes, hypertension, depression, sarcopenia and osteoporosis are common even in the absence of Cushing syndrome. This reduces the clinical specificity of traditional signs and makes biochemical testing central to diagnosis. However, tests such as post-dexamethasone cortisol or urinary free cortisol may also be affected by age, kidney failure, adherence to the protocol, sleep disorders and polypharmacy. In mild forms of autonomous secretion, the issue is not to demonstrate overt cortisol excess, but to determine whether a modest chronic secretion is making a clinically relevant contribution to the patient’s cardiovascular and metabolic profile.

In the renin-aldosterone system, advanced age further reduces the reliability of a simplified interpretation of the aldosterone-to-renin ratio. Renin tends to decline physiologically, but the overall picture is profoundly influenced by diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers and kidney failure. Consequently, screening for primary aldosteronism in older adults requires more careful preparation and more expert interpretation of the results, particularly when resistant hypertension, hypokalaemia or disproportionate cardiovascular disease are also present.

The laboratory diagnosis of pheochromocytoma and paraganglioma remains reliable when plasma or urinary metanephrines are used, although medications, acute stress and comorbidities may still generate borderline or false-positive results. In older adults, the problem is often more clinical than analytical: headache, palpitations, anxiety, blood pressure variability or syncope may be attributed to atrial fibrillation, dysautonomia, heart disease or medications, thereby delaying endocrine suspicion. The selection of patients for testing must therefore be accurate and guided by findings that are genuinely compatible with a catecholamine-related syndrome.

Imaging deserves specific consideration because the discovery of an adrenal mass is much more frequent in older adults, often during examinations performed for unrelated reasons. The higher prevalence of incidentalomas makes it essential to connect the radiological finding to a precise clinical question: is the lesion secreting, malignant, metastatic or simply benign and inactive? Without this framework, there is a risk of duplicating follow-up examinations, generating anxiety, initiating unnecessary diagnostic work-ups or, conversely, overlooking subclinical autonomous secretion capable of worsening frailty and cardiovascular risk.

In summary, the laboratory strategy in older adults should be restrained but rigorous. Tests should be ordered when there is a meaningful clinical question, prepared with careful consideration of medications and interpreted within a framework that includes age, kidney function, nutritional status, blood pressure, bone health, metabolism and comorbidities. In geriatric endocrinology, a technically correct result that is poorly contextualised may be less useful than a well-constructed clinical assessment.

Adrenal insufficiency is often underdiagnosed in older adults because it presents with less specific signs that are more readily attributed to age, multimorbidity or general frailty. Fatigue, anorexia, weight loss, nausea, orthostatic hypotension, hyponatraemia, recurrent falls, cognitive deterioration and reduced physical performance may be interpreted as manifestations of general geriatric decline, delaying recognition of an adrenocortical deficit that can instead be treated effectively. This delay is particularly dangerous because older adults have lower cardiovascular and renal reserve and tolerate progression towards adrenal crisis less effectively.

The causes may be primary, secondary or iatrogenic, but suppression of the axis by exogenous glucocorticoids is particularly important in older adults. Chronic systemic steroid treatment for rheumatological, respiratory, dermatological or oncological diseases is common, and inhaled steroids, intra-articular injections or high-dose topical preparations are frequently used at the same time. Problems arise when treatment is tapered or discontinued without assessing recovery of the axis, or when a patient who appears clinically stable develops an infection, undergoes surgery or sustains trauma without adequate stress-dose coverage.

Adrenal crisis in older adults may present dramatically but atypically. Acute confusion, dehydration, hypotension, hyponatraemia, acute kidney injury, fever without a clear cause, vomiting or circulatory collapse may initially be interpreted as sepsis, gastroenteritis, heart failure or a neurological event. Even when these possibilities are plausible, adrenal crisis should remain in the differential diagnosis when the medication or endocrine history supports it. In this setting, blood sampling for cortisol and ACTH must not delay treatment with hydrocortisone and volume replacement.

Long-term management requires appropriately dosed replacement therapy, but the balance is particularly delicate in older adults. Excessive doses promote hyperglycaemia, osteoporosis, sarcopenia, hypertension, oedema and skin fragility, whereas insufficient doses perpetuate fatigue, the risk of crisis and poor tolerance of acute stress. Dose titration must therefore be based not only on symptoms but also on blood pressure, electrolytes, weight, physical function, history of falls and cardiovascular comorbidities. In primary forms, the mineralocorticoid component must also be managed carefully, bearing in mind that older adults are more sensitive to fluctuations in blood volume and potassium disturbances.

Therapeutic education is crucial. Even at an advanced age, or through caregivers when patients are not independent, sick-day rules, the need to increase the dose temporarily during fever, infection, trauma or surgery, and the importance of having a written emergency plan must be clearly understood. In frail older adults, continuity of care is even more important than in younger people because the risk often arises not from the underlying disease itself, but from failure to recognise promptly when glucocorticoid coverage is no longer sufficient for the current stress.

In summary, adrenal insufficiency in older adults lies at the intersection of endocrinology, internal medicine and geriatrics. Recognising it requires a high degree of clinical suspicion, careful attention to medication history and awareness that apparently “geriatric” symptoms may conceal a potentially reversible hormonal deficit. In older people, correctly treating adrenal deficiency often improves not only survival but also haemodynamic stability, cognitive function and the ability to maintain everyday independence.

Hypercortisolism in older adults often has a different phenotype from that seen in younger patients. Overt forms of Cushing syndrome remain rare, but mild or moderate autonomous cortisol secretion becomes highly clinically relevant because it overlaps with conditions that are already common in later life, such as diabetes, hypertension, osteoporosis, visceral obesity, sarcopenia and depression. This creates a diagnostic problem: the clinical picture may appear “compatible with age”, when in reality chronic cortisol secretion is making a substantial contribution to the progression of cardiometabolic frailty.

In older adults, signs such as skin fragility, easy bruising, proximal weakness, vertebral fractures, rapid worsening of diabetes or hypertension, loss of muscle mass and recurrent infections have particular warning value. The problem is not merely the presence of excess cortisol, but the greater susceptibility of ageing tissues to its effects. Muscle, bone, the vascular system and glucose metabolism all have reduced reserve in later life, so even a modest but persistent hormonal excess may result in clinically relevant damage.

This is particularly evident in mild autonomous cortisol secretion associated with an incidentaloma. In these patients, the absence of a classical Cushingoid phenotype does not imply clinical irrelevance. Autonomous cortisol secretion may be associated with a higher prevalence of hypertension, diabetes, osteoporosis and cardiovascular events, and its significance must be assessed in the context of the patient’s overall burden of comorbidities. The correct question is not only “does the patient have Cushing syndrome?”, but also “is this secretion worsening the patient’s risk profile and frailty?”.

Diagnosis requires caution because many older adults take medications that interfere with the dexamethasone suppression test or have sleep disorders, depression, alcohol misuse or chronic diseases that alter the hypothalamic-pituitary-adrenal axis. Nevertheless, when the clinical picture is consistent, the diagnostic process should not be abandoned. Older adults are not patients in whom endocrine diagnosis becomes less important; on the contrary, attributing everything to age may prevent correction of a factor that accelerates sarcopenia, fractures and loss of independence.

Treatment must be individualised. In some cases, particularly in severe forms or clearly resectable lesions, surgery may offer substantial benefit. In other cases, the decision must take into account biological age, independence, comorbidities, operative risk and the likelihood that correcting the hormonal excess will genuinely improve clinical outcomes. This is the central principle of geriatric endocrinology: there are no automatic decisions based on chronological age, only an assessment of the relationship between the endocrine burden and the expected benefit of treatment.

Ultimately, hypercortisolism in older adults often presents not as a conspicuous endocrine syndrome, but as a silent accelerator of frailty. Recognising it requires a different interpretation of difficult-to-control diabetes, resistant hypertension, severe osteoporosis and progressive functional loss. In many patients, the value of diagnosis is not merely endocrine but prognostic, because it allows identification of a potentially correctable mechanism underlying clinical deterioration.

Arterial hypertension is extremely common in later life, and its very frequency makes secondary endocrine causes easy to overlook. Among these, primary aldosteronism deserves particular attention because it may also occur in older adults with a non-classical phenotype, without hypokalaemia and with a history that has been interpreted for years as simple essential hypertension. The clinical problem is that excess aldosterone does not merely increase blood pressure, but also exerts pro-inflammatory and profibrotic effects on the heart, blood vessels and kidneys, contributing to atrial fibrillation, stroke, nephropathy and cardiovascular damage that is disproportionate to blood pressure values.

In older adults, suspicion should arise in the presence of resistant hypertension, the need for multiple drug classes, spontaneous or diuretic-induced hypokalaemia, an incidentally discovered adrenal mass, atrial fibrillation without an adequate explanation or cardiovascular events that appear disproportionate to the degree of blood pressure control achieved. Diagnosis is complicated, however, by the fact that age reduces renin activity and that most patients take medications that alter the aldosterone-to-renin ratio. Screening therefore requires careful preparation and a contextualised, rather than automatic, interpretation.

The most important point is that older adults should not be excluded from diagnostic consideration solely because they have multiple comorbidities or a long history of hypertension. Indeed, in this age group, unrecognised primary aldosteronism may make a decisive contribution to accumulated target-organ damage. A distinction must therefore be made between the technical difficulty of diagnosis and its clinical irrelevance: the former is real, whereas the latter often is not.

The therapeutic strategy must be individualised. Adrenalectomy may be appropriate in some patients with lateralised disease and good functional reserve; in many others, particularly those of very advanced age or with a high operative risk, treatment with mineralocorticoid receptor antagonists represents the most pragmatic option. In both cases, the objective is not merely to lower blood pressure but to reduce the burden of inappropriately elevated aldosterone on the heart, kidneys and vascular system. This distinguishes the treatment of primary aldosteronism from simply intensifying nonspecific antihypertensive therapy.

Other forms of endocrine hypertension must also be considered in older adults. Pheochromocytoma may present with paroxysmal episodes or labile hypertension; hypercortisolism may cause a form of hypertension that appears primarily “metabolic”; and, more rarely, renin-secreting masses or other endocrine conditions may enter the differential diagnosis. In all these cases, the clinical priority is to prevent the label of “hypertension of old age” from prematurely ending the diagnostic process. When the blood pressure pattern is disproportionate, unstable or accompanied by atypical signs, investigation of an endocrine cause remains fully justified.

In essence, the endocrinology of hypertension in older adults requires careful selection but not diagnostic resignation. Advanced age increases the complexity of testing and decision-making, but it does not eliminate the value of identifying a specific cause. In many patients, recognising and treating adrenal hypertension can prevent cardiovascular events, reduce polypharmacy and improve clinical stability more effectively than merely pursuing blood pressure targets by empirically adding further medications.

The frequency of adrenal incidentalomas increases markedly with age because of the combined effects of a genuinely higher prevalence of adrenal nodules and the increasingly widespread use of CT and MRI for non-endocrine indications. The discovery of an adrenal mass is therefore common in older adults, but its interpretation requires balance. Most lesions are benign, nonfunctioning adenomas, although a clinically relevant proportion may exhibit mild autonomous secretion, represent a pheochromocytoma or metastasis or, more rarely, be an adrenocortical carcinoma.

The first clinical task is to determine whether the lesion is radiologically benign and whether it produces hormones to a clinically significant degree. This dual assessment is essential because malignancy is not always the principal concern in older adults. A radiologically benign mass associated with mild autonomous cortisol secretion may have a greater practical impact than a completely silent small lesion because it contributes to diabetes, hypertension, osteoporosis and frailty. Conversely, a nonfunctioning lesion with reassuring radiological characteristics may not require aggressive follow-up, particularly in very old individuals with limited life expectancy or a high burden of comorbidities.

The significance of imaging in older adults therefore differs from that in younger patients. The question is not only “what is the mass?”, but also “how much will it change this patient’s management?”. This approach avoids two opposing errors: on the one hand, excessive follow-up, investigations and surgery for lesions of little clinical relevance; on the other, underestimating masses that, because of hormonal secretion or structural characteristics, may significantly affect prognosis and cardiovascular risk. Modern guidelines emphasise precisely this integration of imaging, endocrinology and patient-centred clinical decision-making.

In older patients with cancer, the differential diagnosis also includes adrenal metastasis. In these cases, the oncological history profoundly alters radiological interpretation and the subsequent strategy. Even here, however, the approach should not be automatic: not every adrenal mass in a patient with cancer is a metastasis, and not every lesion requires the same intensity of diagnostic work-up. Integration with the radiological and hormonal profile remains essential to avoid misclassification.

The issue of surgery requires particular caution. Adrenalectomy may be appropriate in the presence of pheochromocytoma, a suspicious lesion or clinically relevant hormonal secretion, but in older adults the risk-benefit ratio depends heavily on independence, cardiopulmonary reserve, frailty, anaesthetic risk and expected benefit. Resection is the best treatment for some patients; for others, well-reasoned surveillance or medical management may offer a better balance. The guiding principle is that advanced age does not contraindicate treatment, but it does require a more realistic assessment of the clinical value of the diagnosis.

Ultimately, an adrenal incidentaloma in an older adult is a common but not trivial finding. Optimal management requires a careful distinction between what is benign and irrelevant and what, despite appearing clinically silent, contributes to metabolic, cardiovascular or oncological frailty. In this age group, the quality of the decision depends less on the number of examinations performed and more on the ability to connect the radiological finding to the patient’s actual clinical profile.

In older adults, adrenal medicine is closely intertwined with iatrogenic effects. Many endocrine or pseudo-endocrine abnormalities are caused by medications that interfere with the secretion, metabolism or interpretation of adrenal hormones. Exogenous glucocorticoids represent the principal problem, but they are not the only one: opioids, azole antifungals, certain antiepileptic drugs, spironolactone, eplerenone, ACE inhibitors, angiotensin receptor blockers, diuretics and beta-blockers may alter the clinical and biochemical adrenal profile, making a careful medication review necessary before attributing an abnormality to a primary endocrine disease.

Replacement treatment for adrenal insufficiency requires particular caution. Hydrocortisone remains the standard treatment, but doses must be adapted to the patient’s frailty, the presence of diabetes, osteoporosis, cognitive impairment and the risk of falls. Chronic glucocorticoid excess in an older person accelerates muscle loss, skin fragility, hyperglycaemia and fractures; insufficient replacement promotes fatigue, collapse, hyponatraemia and hospital admission. Therapeutic balance must therefore be pursued through regular reassessment and attention to apparently extra-endocrine objectives such as functional independence and blood pressure stability.

Treatment of primary aldosteronism or endocrine hypertension in older adults also requires clinical precision. Mineralocorticoid receptor antagonists can provide significant benefit but increase the risk of hyperkalaemia and deterioration of kidney function, particularly in the presence of chronic kidney disease or concomitant therapies acting on the renin-angiotensin system. Their use must therefore be accompanied by close monitoring and an integrated assessment of potassium, kidney function, blood pressure and tolerability, avoiding both undertreatment and excessive pharmacological aggressiveness.

In pheochromocytoma or paraganglioma, alpha-blockers and beta-blockers have the same rationale as in younger adults, but older patients are more vulnerable to orthostatic hypotension, syncope and haemodynamic instability. This requires more gradual titration, particularly careful perioperative preparation and close coordination with cardiologists, anaesthetists and internists. When deciding whether to operate on a secreting adrenal lesion, the medication profile and polypharmacy also become integral parts of the decision.

DHEA deserves separate consideration. The marked decline in DHEAS with age has for years fuelled the hypothesis of “anti-ageing” supplementation, but available evidence does not support the routine use of DHEA in older adults to improve strength, cognition or general well-being. The situation may differ in selected patients with adrenal insufficiency, but in general geriatric practice a supplement-centred approach lacks sufficiently robust evidence and risks oversimplifying problems that depend on sarcopenia, comorbidities, malnutrition or multisystem decline.

In summary, adrenal therapy in older adults should be guided by precision and restraint. Every intervention should address a defined clinical objective, reduce a tangible risk and take the burden of polypharmacy into account. In this age group, good endocrinology does not mean prescribing the greatest possible number of medications, but rather avoiding both undertreatment of genuine disease and the creation of new frailty through inappropriate treatment.

The clinical significance of adrenal diseases in older adults becomes clearest when they are viewed through the lens of frailty. At this stage of life, endocrine damage rarely presents as an isolated syndrome; more often, it acts as a multiplier of vulnerability by worsening bone health, muscle function, metabolism, fluid and electrolyte balance, blood pressure and cognitive function. Prognosis therefore depends not only on the accuracy of the diagnosis, but also on how rapidly the adrenal contribution to overall clinical decline is recognised.

Bone is one of the principal target organs. Excess endogenous or exogenous glucocorticoids accelerate bone loss and fracture risk, while relative hypogonadism, reduced adrenal androgen levels, low physical activity and malnutrition further aggravate the problem. In older adults, a vertebral or hip fracture is not merely an orthopaedic complication but a major prognostic event capable of causing loss of independence, repeated hospital admissions and increased mortality. In this context, recognising a hypercortisolaemic or iatrogenic component becomes essential for secondary prevention.

Muscle is another major target. Sarcopenia in older adults may be aggravated by hypercortisolism, excessive replacement therapy, inadequately treated adrenal insufficiency and hypokalaemia caused by primary aldosteronism. Proximal weakness, reduced walking speed, falls and loss of independence may consequently be interpreted as inevitable effects of age when they actually reflect a potentially reversible component of endocrine damage. This is one of the reasons why adrenal medicine in older adults must be closely integrated with geriatric functional assessment.

The cardiovascular dimension is equally important. Primary aldosteronism, hypercortisolism and pheochromocytoma increase the risk of atrial fibrillation, stroke, heart failure, nephropathy and mortality through different mechanisms. Unrecognised adrenal insufficiency also promotes haemodynamic instability, hospital admission and complications during infections or invasive procedures. In many older adults, the prognosis of an adrenal disorder depends less on the purely endocrine event than on the way in which it combines with heart disease, kidney disease, diabetes and pre-existing frailty.

Follow-up should therefore focus on meaningful outcomes: blood pressure control, prevention of adrenal crises, bone health, potassium stability, muscle function, fall prevention, treatment adherence and quality of life. In older adults, endocrine treatment is genuinely effective when it reduces hospital admissions, improves independence, stabilises the metabolic profile and enables a better response to acute stress. Simply normalising a hormone value without a tangible clinical benefit is much less meaningful than it would be in a younger patient.

In conclusion, the adrenal glands in older adults represent a field in which the physiology of ageing, clinical endocrinology and frailty medicine constantly overlap. The value of diagnosis lies not only in identifying a rare disease, but in understanding whether adrenal dysfunction is accelerating the decline of an already vulnerable organism. When this contribution is recognised and treated appropriately, the benefits can be highly tangible: fewer crises, fewer fractures, fewer falls, fewer hospital admissions and a greater ability to preserve functional independence.