Hypertension in Cushing’s Syndrome: Mechanisms and Implications

Cushing’s syndrome, a disorder caused by chronic exposure to high cortisol levels, is frequently associated with hypertension. Approximately 80% of patients with Cushing’s syndrome develop high blood pressure, underscoring its clinical significance. The pathogenesis of hypertension in this context is multifaceted, driven by cortisol’s diverse effects on fluid balance, vascular tone, and hormonal systems.

One critical factor is cortisol’s mineralocorticoid activity. While primarily involved in stress response and metabolism, cortisol can bind to mineralocorticoid receptors, mimicking aldosterone. This leads to increased sodium retention and water reabsorption in the kidneys, expanding blood volume and elevating blood pressure. Normally, cortisol’s effect is limited by the enzyme 11β-hydroxysteroid dehydrogenase type 2, which inactivates it. However, in Cushing’s syndrome, excessive cortisol overwhelms this system, amplifying its mineralocorticoid action.

Additionally, cortisol heightens vascular sensitivity to vasoconstrictors like catecholamines and angiotensin II. This results in pronounced vasoconstriction, raising peripheral vascular resistance. Simultaneously, cortisol inhibits vasodilators such as nitric oxide and prostacyclin, which ordinarily help maintain vascular relaxation. The diminished presence of these substances tips the balance further towards vasoconstriction, compounding the hypertensive effects.

Cortisol also activates the renin-angiotensin-aldosterone system (RAAS), a critical regulator of blood pressure. Through increased angiotensin II and aldosterone, the RAAS enhances vasoconstriction and promotes further sodium and water retention. Notably, even when plasma renin levels are suppressed in Cushing’s syndrome, cortisol's direct stimulation of aldosterone release sustains the hypertensive drive.

Recent studies emphasize the role of endothelial dysfunction in Cushing’s-related hypertension. Chronic exposure to high cortisol disrupts endothelial cell function, exacerbating vascular rigidity and resistance. Furthermore, the syndrome is associated with metabolic derangements, including hyperglycemia and dyslipidemia, which independently contribute to cardiovascular risk.

In conclusion, hypertension in Cushing’s syndrome arises from a complex interplay of mechanisms, including cortisol’s mineralocorticoid-like effects, vascular hyperreactivity, suppression of vasodilators, and RAAS activation. Understanding these pathways is crucial for effective management, as persistent hypertension significantly elevates the risk of cardiovascular complications in these patients.
Hypertension in Cushing’s Syndrome: Mechanisms and Implications

Flavonoids and hypertension

Plant compounds (polyphenols and flavonoids) have been reported to exert beneficial effects in the treatment of cardiovascular disease, including hypertension.

Flavonoids can be found in fruits, vegetables, nuts, seeds, in coffee, wine, or tea, with significant antioxidant effects. Flavonols, flavanols, and anthocyanidins are the main members of the group of natural phenolic compounds called flavonoids.

It is well known that nitric oxide (NO) from the endothelium plays a crucial role in regulating vascular tone and blood pressure. Nitric oxide causes vascular smooth muscle relaxation by activating soluble guanylate cyclase29 and by increasing cyclic guanosine 30 ,50-monophosphate (cGMP), which inactivates the release of intracellular calcium.

Flavones, a subgroup of luteolin-rich flavonoids, exert their antihypertensive effect by signaling and activating the cAMP/protein kinase A cascade, which will further activate NO synthase, the final result being the increased concentration of endothelial NO. Through this mechanism, vasodilation takes place, a process modulated by potassium and calcium channels.

A number of studies have shown that consumption of fruit, vegetables, wine and tea may protect against stroke, for which hypertension is the major risk factor.

Flavonoid’s antioxidant activity is well established, and epidemiologic studies have suggested associations between flavonoid intake and a lower risk of cardiovascular disease.
Flavonoids and hypertension

High blood pressure due to overweight

Overweight and obesity are caused by a number of factors including genetic, metabolic, psychological, sociocultural, and lifestyle.

Obesity is proven cause of hypertension. Although high blood pressure is a highly treatable, if left untreated its consequences are severe, and hypertension is a strong predictor of more severe CVD.

Nearly two-thirds of people who are obese are at risk of high blood pressure. The combination of obesity and hypertension is associated with an increased risk of cardiac failure due to thickening of the ventricular wall and increased heart volume.

Studies have been observed that both weight and weight gain are positively associated with the development of hypertension in adulthood. Obesity seems to lead to coronary artery disease is first to cause some of the other problems such as abnormal blood cholesterol levels or high blood pressure.

Raised blood pressure changes the structure of the arteries. As a result, risks of stroke, heart disease, kidney failure and other doses increase. There are several mechanisms through which obesity causes hypertension.

Hyperinsulinemia, which is common among overweight and obese individuals, can cause activation of the sympathetic nervous system, as well as cause sodium retention, thus increasing the risk of developing hypertension.

Obesity affects what is known as the renin-angiotensin-aldosterone (RAA) system. The RAA system is responsible for several factors involved in hypertension, including blood volume, control of the sympathetic nervous system, sodium levels, and the amount of water retained by the body.

All these factors have a significant role in blood pressure and since obesity disrupts each of them, the result can be high blood pressure.
High blood pressure due to overweight 

What is primary hypertension?

There are two main categories of hypertension: primary hypertension and secondary hypertension. Primary hypertension, also known as essential hypertension, is responsible for 90% to 95% of all hypertension. 

Secondary hypertension accounts for the remaining percentage.

The genesis of primary hypertension is multifactorial and complex. Primary hypertension usually begins insidiously as a benign disease, slowly progressing to malignant state.

A simplistic explanation of the pathogenesis is that there is specific mechanism appear to be involved in the development of primary hypertension: altered regulation of the sympathetic nervous system, abnormalities of the rennin-angiotensin- aldosterone system, salt sensitivity, as well as other vascular and hormonal factors. 

Carefully managed treatment, which may include lifestyle modification and drug therapy, improves the prognosis. Untreated, it carries a high mortality rate.

Risk factors associated with the development of primary hypertension include elevated blood lipid levels, smoking, diabetes, age older than 60 years, gender and family history of cardiovascular disease.

The majority of patients who developed primary hypertension do so between 20 to 50 years of age. 

Primary hypertension has a strong link with obesity and insulin resistance and it is greater in those patients with central obesity.

Obesity and the concomitant resultant hyperinsulinemia stimulate the sympathetic nervous system, thereby contributing to hypertension.
What is primary hypertension?