Насколько общим является гиперкортизолизм у пациентов с гипертензией? Факторы риска, эпидемиология и диагностика.

Introduction

Hypertension, both as a science and as a disease state, is undergoing a spirited revival, something of a modern renaissance. Our understanding of its nature is steadily deepening, and our therapeutic armamentarium continues to expand. The hormonal dimension of hypertension represents an essential thread within the broader fabric of the disease. Secondary endocrine disorders are among the most important and often overlooked causes of resistant hypertension.

Awareness of primary aldosteronism (PA), in particular, has grown substantially over the past decade. Its prevalence among individuals with hypertension is estimated to range from 10% to 30%, rising steadily as blood pressure (BP) rises into the more severe and resistant states of the disease. Contemporary guidelines now recommend broad screening, endorsed by endocrine societies and encouraged for most patients by cardiovascular guidelines [ 1 , 2 ].

By contrast, the true prevalence of hypercortisolism in hypertension remains uncertain. It has yet to find a clear place within standard screening recommendations, and therefore remains an unresolved gap in our current understanding. Approximately 10%–20% of hypertensive patients suffer from resistant hypertension, a condition that carries a markedly greater burden of cardiovascular (CV) morbidity and mortality [ 3 ]. Endogenous hypercortisolism (EHC) is defined by biochemical evidence of increased cortisol secretion, yet without the visible or classical signs of overt Cushing's syndrome. It unfolds quietly, absent the familiar catabolic characteristics, such as proximal muscle weakness, central redistribution of adipose tissue, skin fragility or unusual susceptibility to infection, that are hallmarks of the classic Cushing’s disease (CD). This condition has long been referred to as ‘subclinical Cushing's syndrome’, or ‘subclinical hypercortisolism’. Yet the term subclinical is, in many respects, a misnomer. Far from being benign, this state has been linked to hypertension, disturbances in glucose and lipid metabolism, increased cardiovascular risk, skeletal fragility and even premature mortality, that is similar to overt CD [ 4 , 5 ]. The term EHC will be used throughout this review to provide a unified framework and ensure conceptual consistency and clarity. As with hyperaldosteronism, the prevalence of EHC appears to be following a comparable trajectory, wherein advances in screening strategies and heightened clinical awareness are revealing a broader and previously underappreciated disease spectrum. The purpose of this review is to examine recent prevalence data on EHC in hypertension, initiating in the process a call to action for more attentive screening and more timely diagnosis at a moment when effective therapies are beginning to emerge within the clinical pipeline.

Shift From a Binary Disease Model to a Continuous Disease Spectrum

EHC, once regarded as a rare condition, is in fact a heterogeneous disorder, unfolding across a broad clinical and biochemical spectrum. Its manifestations, ranging from uncontrolled hypertension and diabetes to accelerated CV disease, arise from the sustained burden of excess cortisol activity. The European Society of Endocrinology employs the term autonomous cortisol secretion to describe a less severe but clinically meaningful excess of cortisol in patients with adrenal incidentalomas (AI) identified during imaging undertaken for unrelated reasons. CD, in its classically described form, is an extreme form of hypercortisolism arising from a pituitary origin. EHC, when presenting as uncontrolled hypertension in patients who lack the classical CD phenotype, has an adrenal origin in 85%–90% of cases [ 6 , 7 , 8 ].

We would like to focus on the fact that as our understanding of hyperaldosteronism has matured—from a rare disorder to a condition that unfolds along a continuum of autonomous aldosterone secretion ranging from quiet, normotensive states to severe resistant hypertension—so too must we reconsider hypercortisolism. It is no longer being seen as a singular or uniform disease, but rather as a spectrum, with imperceptible transitions. Hypercortisolism expresses itself across a wide range of clinical and biochemical severity, from subtle and easily overlooked disturbances to severe and unmistakable CD. These subtleties arise at the intersection of inherited genetic variations, epigenetic regulation and the finely balanced biochemical and enzymatic pathways that govern cortisol production.

A potential genetic basis can be identified in approximately 40% of patients with EHC, most commonly involving mutations in PRKARCA (5%), CTNNB1 (25%) and ARMC5 (11%). In the remaining individuals, the disturbance appears not to arise from altered genes alone, but from subtler forces that govern how genes are read and expressed. Among these epigenetic influences, DNA methylation stands as one of the most studied regulatory mechanisms [ 9 , 10 ]. In Cushing's syndrome, the excessive burden of circulating glucocorticoids overwhelms the inactivating capacity of the 11β‐hydroxysteroid dehydrogenase Type 2 (11β‐HSD2) enzyme, effectively rendering variations in 11β‐HSD1 and glucocorticoid receptor single‐nucleotide polymorphisms clinically inconsequential. In contrast, in milder hypercortisolism, these more subtle determinants of glucocorticoid exposure may assume a decisive role. This distinction is supported by observations in patients with AI, in whom 11β‐HSD2 activity is directly associated with cortisol secretion in those with mild hypercortisolism, but not in patients with overt Cushing's syndrome [ 4 , 11 ].

Pathophysiology of Hypertension in Hypercortisolism

EHC is a well‐recognised contributor to hypertension, yet until recently it has largely escaped careful study. In the proximal tubule, excess cortisol enhances the activity of the sodium–hydrogen exchanger 3, increasing sodium reabsorption at the proximal gateway. Farther downstream, cortisol may overwhelm the protective capacity of 11β‐HSD2, which ordinarily renders cortisol inactive by converting it to cortisone in the distal nephron [ 12 ]. When this safeguard fails, cortisol remains abundant and unopposed, binding the mineralocorticoid receptor with an affinity equal to that of aldosterone, and in concentrations that are often hundreds, even thousands, of times greater in plasma concentrations (Figure  1 ). This activation causes sodium and water retention, expanding plasma volume while at the same time increasing potassium loss, resulting in hypokalaemia, mirroring the physiologic imprint of PA [ 13 ]. Within the renin–angiotensin system, excess cortisol stimulates increased hepatic production of angiotensinogen, thereby enhancing angiotensin II receptor expression and favouring vasoconstriction. Beyond this peripheral effect, glucocorticoids also strengthen angiotensin II's role within the nervous system, increasing sympathetic overactivation, stimulating vasopressin release and dulling the protective arterial baroreceptor reflex. Furthermore, EHC increases circulating levels of potent vasoconstrictors such as endothelin‐1 and erythropoietin, while at the same time heightening the pressor response to β‐adrenergic stimulation, leading to sustained vasoconstriction and decreased vasodilation ability. With sustained exposure, cortisol further silences nitric oxide signalling by suppressing nitric oxide synthase, and diminishes the endothelial production of other protective vasodilators, including prostacyclin, prostaglandins and kallikreins, worsening endothelial dysfunction and resulting in vascular remodelling with sustained hypertension [ 14 , 15 ]. Angiogenic and growth influences, among them vascular endothelial growth factor (VEGF) and insulin, reshape the arterial wall, increasing medial thickness and narrowing the lumen. The vessel thus grows sturdier but less yielding, and this altered proportion between wall and passage is responsible for amplified small artery resistance [ 16 , 17 ].

Schematic diagram of the various pathways by which hypercortisolism causes hypertension. Created using Grok 4.3 Beta.

Cortisol also enhances the body's sensitivity to catecholamines. It is essential to the survival and maintenance of chromaffin cells, enabling them to generate epinephrine through the conversion of norepinephrine by phenylethanolamine N ‐methyltransferase, an enzyme whose transcription is glucocorticoid–dependent. In this manner, glucocorticoids regulate the synthesis of key neurotransmitters and the vascular response they elicit, thenceforth contributing to detrimental vascular injury [ 18 ]. Consistent with this view, several studies have shown an exaggerated pressor response to β‐adrenergic agonists, accompanied by impaired sympathetic autonomic modulation of the heart [ 18 , 19 ].

The loss of the normal nocturnal BP dipping, one of the earliest and most telling signs, appears inextricably linked to disruption of the cortisol circadian rhythm. This blunting of the night‐time fall is observed in more than half of affected individuals, whether normotensive or hypertensive, and is particularly pronounced in patients with adrenal etiologies. In Cushing's syndrome, BP variability is likewise abnormal, independently of BP elevation, resulting in an additional established CV risk factor [ 20 ].

Hypercortisolim–Induced Target–Organ Damage

Hypercortisolism carries a substantial burden of CV disease. It is associated with incident hypertension in up to 85% of patients with overt disease (CD phenotype), a more than fourfold increase in stroke risk, a doubling of myocardial infarction risk and a sixfold rise in the risk of heart failure [ 21 , 22 , 23 ]. The association between EHC and increased CV and all‐cause mortality is proportional to the degree of cortisol excess [ 24 , 25 ]. EHC is associated with moderately increased albuminuria in Type 2 diabetes mellitus and with increased all‐cause mortality in end‐stage renal disease [ 26 ].

In patients with cortisol excess, standard medical therapy offered little relief to BP control, whereas unilateral adrenalectomy brought about meaningful reductions in CV abnormalities. Among those with cortisol‐producing adrenal adenomas, 42.8% met criteria for metabolic syndrome, compared with 12.7% of patients with nonfunctioning adrenal adenomas; Type 2 diabetes mellitus was present in 19% versus 7%. Among patients with EHC, myocardial infarction occurred in 6.4%, compared with 1.5% in those without cortisol excess, while stroke was observed in 5.1% versus 1.5%. Uncorrected autonomous cortisol secretion henceforth conferred a markedly increased risk of subsequent CV events and CV mortality [ 27 ]. We turn next to the recent epidemiological evidence elucidating the relationship between EHC and hypertension specifically.

Beyond Weight Gain and Moon Facies: Rethinking the Epidemiology and Risk Landscape of Endogenous Hypercortisolism

Historically, hypercortisolism was acknowledged mostly in its most dramatic form. In the broader spectrum of Cushing’s syndrome, hypertension is present in 80%–85% of patients, surpassed only by weight gain and obesity as a defining feature [ 28 ]. The diagnosis was guided by what could be readily seen: easy bruising, facial plethora, proximal muscle weakness, the buffalo hump, supraclavicular fullness and hirsutism, all visible markers that left little room for doubt. Today, our understanding has grown more nuanced. We are learning to recognise hypercortisolism beyond these overt signs, and beyond the narrow confines of textbook description, in line with the continuous disease spectrum approach. In contrast to the striking appearances associated with classical CD, many individuals with cortisol excess who present with diabetes or hypertension bear no physical distinction from those without the disorder [ 29 , 30 , 31 ]. In this quieter yet seemingly common form of disease, suspicion must rest less on appearance and more on phenotype, namely resistant hypertension and difficult‐to‐control diabetes. Across the varied clinical expressions of EHC, these two phenotypes recur with particular regularity. Together with visceral obesity and early osteoporosis, they can be aptly described as the ‘big four’ of EHC.

In a prospective, single‐centre study of 423 patients with resistant hypertension, 26.5% demonstrated biochemical evidence of hypercortisolism on initial screening with the dexamethasone suppression testing (DST). When additional confirmatory testing with less sensitive modalities, such as late‐night salivary cortisol, was applied, the estimated prevalence decreased to approximately 8% (Table  1 ) [ 32 ]. A meta‐analysis of six studies in individuals with Type 2 diabetes found that the presence of hypertension was associated with a twofold increase in the likelihood of EHC [ 35 ]. Notwithstanding, hypertension stands as the most frequent companion of autonomous cortisol secretion, present in well over two‐thirds of patients at baseline. Among these individuals, approximately one in eight experience further deterioration of blood pressure control over time. More telling still, approximately 10% of patients develop new onset hypertension, after a mean follow‐up of nearly 5 years [ 36 ]. Recent large‐scale epidemiological studies of hypercortisolism are shedding new light on its true prevalence among patients with hypertension, as will be discussed in the next section.

TABLE 1 Prevalence of endogenous hypercortisolism in hypertensive patients based on current epidemiological data. Population studied Prevalence of hypercortisolism by DST
Prospective single–centre cohort
a


(423 patients)
Resistant hypertension 26.5%
CATALYST
b


(1057 patients)
Uncontrolled type II diabetes mellitus despite multiple antidiabetic drugs
23.8% in the overall population
Subpopulation of resistant hypertension:
36.6% prevalence

MOMENTUM
c


(1086 patients)
Resistant hypertension
27.3%
Subpopulation of uncontrolled diabetes mellitus: 32.6% prevalence

a
Martins et al. [ 32 ].
b
Buse et al. [ 33 ].
c
Bhatt [ 34 ].

Prevalence of endogenous hypercortisolism in hypertensive patients based on current epidemiological data.

Prospective single–centre cohort
a

(423 patients)

CATALYST
b

(1057 patients)

23.8% in the overall population

Subpopulation of resistant hypertension:

36.6% prevalence

MOMENTUM
c

(1086 patients)

27.3%

Subpopulation of uncontrolled diabetes mellitus: 32.6% prevalence

Martins et al. [ 32 ].

Buse et al. [ 33 ].

Bhatt [ 34 ].

CATALYST : The Winds of Change

The CATALYST study marked a turning point, revitalising the way we look at hypercortisolism in diabetes [ 33 ]. The study enrolled 1057 adults between 18 and 80 years of age with difficult–to–control Type 2 diabetes despite the use of multiple antidiabetic medications including insulin—what some may call ‘resistant diabetes’. The cohort's mean body mass index (BMI) was 33.5, mean HbA1c was 8.8%, 27.1% of patients were on ≥ 3 antihypertensive medications, BP averaged 127.6/75.3 mmHg, yet systolic blood pressure exceeded 130 mmHg in nearly 40% of patients. Individuals at risk for falsely positive DST were excluded. The prevalence of EHC was found to be 23.8% based on DST. The prevalence remained stable after 200 participants were recruited. Mean post–DST cortisol in patients with hypercortisolism was 3.49 μg/dL. Several factors emerged as independently associated with hypercortisolism, tracing a profile that is at once subtle and instructive. These included older age, a BMI below 30 kg/m 2 , a greater burden of antihypertensive therapy, and the use of specific metabolic agents, notably SGLT2 inhibitors, GLP‐1 receptor agonists at maximal doses, as well as fibrates and analgesics. The risk of EHC was more than twofold higher in patients on ≥ 3 antihypertensive drugs (OR = 2.28, 95% CI: 1.66–3.13, p  < 0.0001).

Most strikingly, in patients meeting certain criteria for resistant hypertension, the prevalence of hypercortisolism rose sharply to 36.6%. A higher proportion of patients with EHC were affected by hypertension compared with those without the condition (89% vs. 79%, p  < 0.001), and they more often required treatment with ≥ 3 antihypertensive medications (38% vs. 23%, p  < 0.001).

Adrenal abnormalities were identified in more than one third of patients, most commonly unilateral adrenal nodules. In the treatment phase of the CATALYST study, mifepristone, a competitive glucocorticoid receptor antagonist, was shown to markedly reduce HbA1c, while promoting significant weight loss and reducing the burden of antihyperglycemic therapy [ 37 ].

Henceforward, based on the CATALYST study, screening for hypercortisolism should be thoughtfully considered in individuals with difficult‐to‐treat Type 2 diabetes (multiple antidiabetic medications, inadequate control), particularly when accompanied by uncontrolled hypertension or elevated cardiovascular risk.

The MOMENTUM Is on

MOMENTUM represents the first robust, US–based investigation to focus on EHC specifically in patients with resistant hypertension, establishing a firm foundation for understanding this condition within a contemporary clinical context [ 38 ]. The study was conducted at 50 sites in the United States, the first participant enrolled in March 2025, and the last participant in December 2025. The study enrolled 1086 patients with resistant hypertension not optimally controlled on ≥ 3 antihypertensive drugs. Individuals at risk for falsely positive DST were excluded; these considerations are addressed in the following section. A post–dexamethasone cortisol threshold of > 1.8 μg/dL was used to define EHC, in conjunction with a dexamethasone level ≥ 140 ng/dL, based on the established reference range of the assay used by the central laboratory. Overall, 27.3% of these participants with resistant hypertension screened positive for EHC, with a mean post‐DST cortisol level of 4.2 μg/dL, and a mean serum dexamethasone concentration of 484.2 ng/dL. Notably, this prevalence closely mirrors that observed in the Brazilian cohort and aligns with findings from CATALYST, since the prevalence of EHC in MOMENTUM was found to be 32.6% among patients with uncontrolled diabetes mellitus [ 34 ].

Patients with EHC were outwardly indistinguishable from those without cortisol excess. In fact, they exhibited a slightly lower BMI and a smaller waist circumference. Use of antihypertensive medications was broadly similar between groups, though there was a tendency towards greater use of antihyperglycemic therapies among those with hypercortisolism. Notably, the prevalence of hypercortisolism was higher among patients with Stage IIIB chronic kidney disease, reaching over 40%. Overall renal function was poorer in this group, with lower estimated glomerular filtration rates and a greater degree of albuminuria.

Adrenal nodules were identified in approximately one quarter of patients with hypercortisolism. Moreover, individuals with hypercortisolism more frequently had a higher overall medication burden, and were more likely to require insulin and other antihyperglycemic therapies. They also carried a greater burden of cardiac comorbidities and demonstrated significantly more advanced chronic kidney disease [ 34 ].

Screening and Diagnosis of Endogenous Hypercortisolism

Based on the foregoing considerations, screening for EHC should be considered in patients with resistant hypertension, hypertension accompanied by hypokalaemia in the setting of a normal aldosterone‐renin axis, a non‐dipping BP profile, difficult‐to‐control Type 2 diabetes mellitus or the presence of adrenal incidentalomas.

DST remains the most sensitive screening tool for the detection of autonomous adrenal cortisol secretion, when compared to 24 h urinary cortisol (Table  2 ). The test consists of administering a single oral 1‐mg dose of dexamethasone at bedtime, typically around 11 PM, followed by a non‐fasting morning serum cortisol measurement obtained at approximately 8 AM the next day. Using a post‐DST serum cortisol threshold greater than 1.8 μg/dL yields a diagnostic sensitivity of roughly 95%. When this result is accompanied by an adequate serum dexamethasone concentration (≥ 140 ng/dL), accuracy approaches 100%, thereby substantially reducing the need for repeat testing and strengthening diagnostic confidence [ 8 , 40 , 41 ]. The degree of non‐suppression on dexamethasone testing appears to track along a spectrum of disease severity, ranging from mild EHC to overt Cushing’s syndrome. In the CATALYST study, 15.9% of patients demonstrated post‐DST cortisol levels between 1.9 and 3.0 μg/dL, 4.7% between 3.1 and 5.0 μg/dL, while 2.8% exceeded 5.0 μg/dL, illustrating a graded distribution rather than a single diagnostic threshold.

TABLE 2 Testing for hypercortisolism in Cushing’s disease: Strengths and limitations of available diagnostic tests. Sensitivity
a

Specificity
a

Limitations False positives Dexamethasone suppression testing 98% 81%
Requires 2 step testing (pill intake at 11 PM, testing at 8 AM next day)
Inconsistent use in clinical practise

Excessive alcohol consumption
Pregnancy and oral contraceptives
Advanced renal failure
Severe neuropsychiatric disease
Starvation/malnutrition
Night shift work
Severe untreated sleep apnea
24 h free urinary cortisol 91% 81%
Free cortisol does not appear in urine until serum cortisol levels are sufficiently high to saturate cortisol‐binding globulin
Frequently normal in early/less overt hypercortisolism
Substantial intra‐patient variability Late night salivary cortisol 97% 97% Salivary glands are rich in the enzyme 11β‐hydroxysteroid dehydrogenase Type 2 which converts active cortisol into inactive cortisone
Blood contamination of the sample (brushing, flossing teeth, use of toothpicks, oral injury)
Smoking or chewing tobacco Ingestion of licorice
Exposure to steroid‐containing inhalers, eye drops or lip balms
Night shift work

a
Hypercortisolism in general, not just adrenal hypercortisolism, from Fleseriu et al. [ 39 ]. Acute illness can cause false positives for all these tests.

Testing for hypercortisolism in Cushing’s disease: Strengths and limitations of available diagnostic tests.

Requires 2 step testing (pill intake at 11 PM, testing at 8 AM next day)

Inconsistent use in clinical practise

Excessive alcohol consumption

Pregnancy and oral contraceptives

Advanced renal failure

Severe neuropsychiatric disease

Starvation/malnutrition

Night shift work

Severe untreated sleep apnea

Free cortisol does not appear in urine until serum cortisol levels are sufficiently high to saturate cortisol‐binding globulin

Frequently normal in early/less overt hypercortisolism

Blood contamination of the sample (brushing, flossing teeth, use of toothpicks, oral injury)

Smoking or chewing tobacco Ingestion of licorice

Exposure to steroid‐containing inhalers, eye drops or lip balms

Night shift work

Hypercortisolism in general, not just adrenal hypercortisolism, from Fleseriu et al. [ 39 ]. Acute illness can cause false positives for all these tests.

Interpretation of the DST results requires careful attention to potential sources of false positivity. Conditions known to interfere with DST specificity include chronic alcoholism, pregnancy and intake of oral contraceptives containing estrogen, advanced chronic kidney disease and end‐stage renal disease, and exogenous glucocorticoid exposure. Severe neuropsychiatric disorders, particularly major depressive disorder with psychotic features, as well as starvation, malnutrition and anorexia nervosa may also produce false positives. Additional confounders include chronic intense exercise, prolonged intensive care unit stays, multiple sclerosis, severe medical or surgical illness, night‐shift work with wakefulness between 11 PM and 7 AM, and severe untreated obstructive sleep apnea.

Twenty‐four‐hour urinary free cortisol (UFC) has lower sensitivity than the DST for detecting milder forms of EHC. This limitation arises because free cortisol does not appear in the urine until serum cortisol levels are sufficiently high to saturate cortisol‐binding globulin. As a result, UFC measurements are frequently normal in patients with less overt or early hypercortisolism, which is more common in adrenal EHC. Further limiting its utility, UFC exhibits substantial intra‐patient variability and is therefore unreliable for subtle disease detection. Consequently, UFC testing is not so informative in patients with ACTH‐independent hypercortisolism, where milder elevations in cortisol are more common and easily overlooked [ 39 , 42 , 43 ].

Late‐night salivary cortisol (LNSC) is also less sensitive than the DST in the evaluation of EHC. This limitation reflects underlying physiology: the salivary glands are rich in the enzyme 11β‐HSD2, which converts active cortisol into inactive cortisone. As a result, LNSC levels are often normal in autonomous primary adrenal disease. Interpretation is further complicated by a broad range of potential false positives, including blood contamination of the sample, commonly from brushing or flossing teeth, use of toothpicks, or oral injury, as well as smoking or chewing tobacco, ingestion of licorice and exposure to steroid‐containing inhalers, eye drops or lip balms. Disruption of the normal sleep–wake cycle also undermines test reliability. False‐negative results may occur when an insufficient specimen volume is collected. Taken together, these limitations contribute to poorer specificity and make LNSC a relatively cumbersome and often unreliable tool in this clinical context [ 44 , 45 ]. When considering surgery, combining DST with LNSC can improve diagnostic accuracy while remaining mindful of the limitations and potential for false‐positive results associated with each modality. The development of more reliable screening approaches may further enhance diagnostic precision. Ongoing work in this area includes investigation of late‐night salivary cortisone and emerging wearable technologies designed to monitor circadian cortisol dynamics.

The next step is to measure plasma ACTH. A low ACTH level (< 10 pg/mL), together with a low DHEA‐S level (< 40 μg/dL), supports autonomous adrenal cortisol secretion. In this setting, adrenal imaging with CT scanning or magnetic resonance imaging (MRI) is indicated. If ACTH is elevated (> 20 pg/mL), a pituitary source should be considered, and the next diagnostic step would be pituitary MRI. Further inquiry may be needed to uncover the source of the disorder and to shape proper therapy, a task best undertaken in a tertiary referral centre with expertise in adrenal and pituitary endocrine surgery [ 42 ].

The co–Secretion of Aldosterone and Cortisol: A Common but Underrecognised Entity

Our understanding of the bond between aldosterone and cortisol is still taking shape, and with clearer sight comes a correction of old assumptions. What was once thought uncommon now appears more frequent: the co‐secretion of both hormones, acting in parallel and contributing to a complex clinical phenotype. This overlap has been tentatively described as a ‘Connshing syndrome’, though this term should be interpreted cautiously, as it remains a conceptual framework rather than a formally established entity. Studies suggest that nearly one‐quarter of patients with confirmed PA have some degree of autonomous cortisol secretion [ 46 ]. Even greater degrees of aldosterone/cortisol co‐secretion have been observed among patients with impaired glucose metabolism [ 47 ].

Several studies have identified somatic KCNJ5 mutations within adrenal tumours from these patients, findings that are thought to reflect adenomas capable of producing both aldosterone and cortisol. This dual secretory capacity may be explained, at least in part, by the shared expression of the steroidogenic enzymes CYP11B2 and CYP11B1 (11β‐hydroxylase) within KCNJ5‐mutated aldosterone‐producing adenomas. Such phenomena are most often observed in the presence of an adrenal nodule or hyperplasia, as sustained cortisol excess typically requires some degree of adrenal neoplastic change [ 48 , 49 ].

In MOMENTUM, biochemical markers suggestive of hyperaldosteronism were found in ~20% of the studied population. Among patients with hypercortisolism, the prevalence of hyperaldosteronism was similarly high at ~20%, while about 5% of the total study population exhibited combined cortisol–aldosterone co‐secretion. Notably, this study shows that the prevalence of hypercortisolism in individuals with resistant hypertension rivals that of hyperaldosteronism, a striking observation, given that hyperaldosteronism has long been regarded as the most common endocrine cause of resistant hypertension. Notwithstanding, these findings should be interpreted with caution, as the diagnosis of hyperaldosteronism was largely based on the serum aldosterone‐plasma renin activity ratio without confirmatory testing. Nonetheless, given the seemingly similar prevalence in resistant hypertension, clinicians should thoughtfully screen for both hyperaldosteronism and hypercortisolism when looking for endocrine causes of secondary and uncontrolled hypertension.

Evolving Paradigm and Future Directives

Hypertension is a complex disease that is not set by hard and fast rules, and that has many threads to unwind [ 50 ]. Among these, the hormonal pathway, shaped chiefly by aldosterone and cortisol, has, over the past 5 years, been steadily brought into clearer light. The management of hypertension in 2026 offers the exhilaration of a world experienced with both intensity and precision [ 51 ]. From this vantage point, a pattern begins to emerge. EHC seems to be a common phenotype, not based on appearance, but based on multimorbidity and medication burden. Patients burdened by uncontrolled hypertension, hyperglycaemia and visceral obesity bear a striking resemblance to the familiar contours of the metabolic syndrome. One is thus led to ask whether EHC may be the long‐sought connective thread, not merely accompanying these conditions, but binding together the very elements of the metabolic syndrome itself. The definitive answer to this question remains unsettled and the subject of thoughtful debate.

Recent guidelines call for screening for hypercortisolism in individuals with hypertension who are at heightened risk, including those with early‐onset hypertension, with sudden severe or worsening hypertension, and in those with resistant hypertension [ 28 , 52 ]. Clinical features that merit evaluation for endogenous hypercortisolism as a driver of hypertension include younger age at presentation (particularly under 40 years), resistant hypertension, acute or unexplained worsening of previously stable blood pressure, a non‐dipping nocturnal profile and disproportionate or extensive end‐organ damage. Additional indicators include incidental adrenal or pituitary lesions, hypokalaemia, early‐onset osteoporosis and poorly controlled diabetes mellitus [ 30 ].

Conclusion

Despite the growing recognition of the aldosterone pathway's central role in the pathogenesis of hypertension, systematic screening for hyperaldosteronism remains inconsistent in routine clinical practise. In response to this gap, professional medical societies are rightfully advocating for a broader and more proactive screening approach. Just as effective treatment of aldosterone excess requires aldosterone‐directed therapy to meaningfully reduce BP and CV risk [ 53 , 54 , 55 ], individuals with hypercortisolism require cortisol‐targeted treatment in addition to conventional antihypertensive agents. Lowering BP alone is insufficient to avert the cardiovascular consequences of cortisol excess.

Notably, among patients with hypercortisolism due to an adrenal adenoma, hypertension is the comorbidity most likely to improve following curative surgical intervention [ 56 ]. A  longitudinal study with up to 15 years of follow‐up in individuals with hypercortisolism demonstrated that, despite aggressive management of BP, glucose and lipid levels, patients who did not receive cortisol‐directed therapy experienced significantly higher rates of CV events and poorer long‐term survival than those who did receive targeted treatment. Adrenalectomy was effective in lowering blood pressure and improving cardiometabolic abnormalities [ 27 ].

To correct the burdens imposed by excess aldosterone or excess cortisol is to do far more than merely lower a number on the BP gauge. Such correction holds the promise of restoring balance across multiple systems of the body, with benefits that reach well beyond the vessels alone. Encouragingly, effective treatments are already within reach, and others are steadily taking shape [ 57 , 58 , 59 ]. A detailed discussion of therapies targeting hypercortisolism lies beyond the scope of this article and warrants a focused treatment of its own. We are amidst a decisive shift towards more individualised and precise care. Only by recognising the underlying phenotypes does the path to effective treatment become clear.

Funding

The authors have nothing to report.

Conflicts of Interest

Dr. Al Dhaybi reports serving as a consultant for Medtronic, Astrazeneca.

Dr. Bhatt discloses the following relationships—Advisory Board: Angiowave, Antlia Bioscience, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E‐Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Repair Biotechnologies, Stasys, SandboxAQ (stock options), Tourmaline Bio, Viatris; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Alnylam, Altimmune, Broadview Ventures, Corcept Therapeutics, Corsera, GlaxoSmithKline, Hims, Sanofi, SERB, SFJ, Summa Therapeutics, Worldwide Clinical Trials; Data Monitoring Committees: Acesion Pharma, Assistance Publique‐Hôpitaux de Paris, Baim Institute for Clinical Research, Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ABILITY‐DM trial, funded by Concept Medical; for ALLAY‐HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH‐funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org ; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol‐Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Duke Clinical Research Institute, Engage Health Media, HMP Global (Editor in Chief, Journal of Invasive Cardiology), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Philips (Becker's Webinar on AI), Population Health Research Institute, WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor, unpaid); Progress in Cardiovascular Diseases (Deputy Editor, unpaid); Added Health (Editorial Board; stock options); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Alnylam, Amarin, Amgen, AstraZeneca, Atricure, Bayer, Boehringer Ingelheim, Boston Scientific, CellProthera, Cereno Scientific, Chiesi, Cleerly, CSL Behring, Faraday Pharmaceuticals, Fractyl, Idorsia, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, MiRUS, Moderna, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co‐Investigator: Cleerly.