Treatment of Endocrine Hypertension

Hypertension is a significant and prevalent cardiovascular risk factor that is amenable to treatment. When managed correctly, the risk for cardiovascular diseases, including stroke, ischemic heart disease, and heart failure, is lowered.¹ This entails accurate diagnosis and classification of hypertension and lifestyle modifications and pharmacotherapy to lower blood pressure to optimal levels.² Secondary hypertension can be effectively reversed or controlled to normotensive levels through early diagnosis and treatment of the underlying cause of high blood pressure. Endocrine hypertension, which is an uncommon form of secondary hypertension, is reversible in most cases when the cause is discovered and treated early. This requires expert evaluation of patients and specialist care. The most common endocrine pathology associated with hypertension is primary aldosteronism and less common endocrine causes are pheochromocytoma and Cushing’s syndrome.³ This article will briefly discuss current treatment options for endocrine causes of hypertension.

Primary Hyperaldosteronism

Hypertensive patients with primary hyperaldosteronism (PHA) experience higher rates of cardiovascular morbidity and mortality compared to patients with essential hypertension.⁴ Screening, early diagnosis and prompt treatment of PHA in hypertensive patients can thus improve clinical outcomes. The treatment is established after accurate identification of the cause of adrenal gland dysfunction through imaging and adrenal vein sampling. These causes include unilateral adrenal adenoma, unilateral/bilateral adrenal hyperplasia, familial hyperaldosteronism syndrome, and adrenocortical carcinoma.^3,5 Surgery is recommended in the case of unilateral PHA, whereas bilateral forms are treated with pharmacological therapy and lifestyle interventions.⁶ Unilateral adrenalectomy through a laparoscopic approach is the choice of surgical intervention.⁷ A mineralocorticoid receptor antagonist and potassium supplements are given to control hypertension and hypokalemia, respectively, before surgery and are discontinued after surgery.⁸ Most patients treated surgically for adrenal adenoma, hyperplasia or carcinoma have markedly improved blood pressure, plasma aldosterone-to-renin ratio, and potassium values.^3,8 Remission of hypertension after surgery depends on patient characteristics. Persistent high blood pressure may be observed in older patients, those with a  longer duration of hypertension, coexistent essential hypertension, or other risk factors for hypertension.^3,4,9

Lifelong pharmacological therapy with mineralocorticoid receptor antagonists (MRAs), usually spironolactone, is an alternative approach to PHA. It is recommended for patients with idiopathic PHA, bilateral adrenal hyperplasia, those who are unable or unwilling to undergo surgery, and when it is unclear whether PHA is unilateral or bilateral.^6,7 In addition, patients are advised to make lifestyle modifications to improve blood pressure, including minimizing sodium intake, avoiding tobacco use, and regular exercise.⁸ MRAs inhibit the actions of aldosterone by binding to the mineralocorticoid receptor, thus correcting sodium and water retention, hypokalemia, and hypertension.⁹ The use of spironolactone is limited by its side effects, like painful gynecomastia, erectile dysfunction, and dysmenorrhea.⁶ Eplerenone, although less potent, is an alternative MRA in patients who cannot tolerate spironolactone.^6,7 In some cases of bilateral PHA, resistant hypertension, and equivocal adrenal vein sampling, unilateral adrenalectomy may be considered to minimize the number of medications the patient requires to manage hyperaldosteronism and control blood pressure.³

Patient follow-up after medical or surgical treatment is necessary to monitor aldosterone and renin levels, blood pressure control, and potassium levels. Measurements of plasma renin activity can be used to monitor response to medical treatment.⁷ A risk for postoperative hyperkalemia exists and the patient’s serum potassium levels should be closely monitored after surgery.⁸ Evaluation of patients taking MRAs is recommended for the first two weeks to monitor tolerance and emergence of side effects.³

Pheochromocytomas

Localized adrenal and extra-adrenal pheochromocytomas, whether benign or malignant, are essentially treated with the same approach—surgical resection. ^10-12 Patient characteristics, such as suitability for surgery, and tumor characteristics, like tumor size, anatomical location, local invasion, and distant metastases, will guide the treatment approach.¹² Preoperative blood pressure control is necessary to prevent perioperative cardiovascular complications.¹⁰ Adrenergic receptor blockers are the first-line treatment for the clinical manifestations of pheochromocytomas and are given for at least 7–14 days before surgery.^11,12 An α-adrenoreceptor blocker, commonly phenoxybenzamine, is initially used to inhibit the actions of catecholamines and control blood pressure.^3,10 This is followed by a β-adrenoreceptor blocker, after achieving adequate α-blockade, if the patient experiences adverse effects such as tachycardia and postural hypotension.^10,11 The risk of postoperative hypotension caused by catecholamine-induced chronic vasoconstriction can be lowered by a high sodium diet, saline infusion or increased fluid intake to expand extracellular fluid volume before surgery.^11,12  

Laparoscopic surgery is the standard approach for the resection of abdominopelvic pheochromocytomas measuring less than 6 cm in diameter.^3,11 In contrast, open surgery may be more suitable for the resection of large tumors (>6 cm), invasive or malignant tumors, and paragangliomas.^10,11 Only a few cases of metastatic pheochromocytoma can be treated surgically; palliative care to reduce the disease burden is the choice of therapy when surgery is not possible.¹¹ Chemotherapy or radiotherapy can also be used for the treatment of aggressive metastatic tumors where surgical resection is impractical.⁶

Due to the uncertainty of recurrences and metastases, long-term clinical, biochemical and radiological monitoring is necessary.^9,10 Plasma or urine metanephrine measurements return to normal approximately within a week after surgery, indicating complete tumor resection.¹⁰ Measurements are obtained within the first month after surgery, again at six months, and at one year with imaging; thereafter, long-term annual follow-up is advised.¹¹ Ten-year follow-up is recommended in all patients, while those with hereditary pheochromocytoma require lifelong follow-up.¹² Monitoring is also important for assessing potential postoperative complications including tachyarrhythmias, renal impairment, hypoglycemia, and persistent hypotension.^3,10

Cushing’s syndrome

Hypertension is prevalent in patients with endogenous Cushing’s syndrome. Early diagnosis and prompt treatment of hypercortisolism will often lead to the resolution or alleviation of hypertension, among other comorbidities.^13,14 The therapeutic approach depends on a comprehensive diagnosis that distinctly identifies the underlying cause of the disease. Additionally, treatment will be based on the severity of hypercortisolism, medical history, current drug history, and patient perspectives and needs.¹⁴ Adrenocorticotropic hormone (ACTH)-producing pituitary adenomas are the most common cause of endogenous Cushing’s syndrome.¹³ Other causes are ACTH-producing ectopic tumors, cortisol-secreting adrenal tumors including unilateral adrenal adenoma and adrenocortical carcinoma, and micro- or macro-nodular adrenal hyperplasia.¹³

The treatment of choice for pituitary adenoma is conservative transsphenoidal surgical resection, with preservation of as much organ function as possible to avoid hormone replacement therapy.^9,14 If the initial surgery for pituitary adenoma is unsuccessful, a second surgery or radiation therapy may be attempted. Radiation therapy is indicated in the case of growing pituitary adenomas and post-surgical remnants.¹⁴ Surgical resection is also indicated as the first-choice treatment for other operable tumors. For instance, unilateral or bilateral adrenalectomy is used to treat adrenal adenomas, hyperplasia, and carcinoma.⁹ When surgery is not a therapeutic option, such as in the case of metastatic tumors, pharmacological therapy is the first-line treatment to reduce cortisol production. Pharmacotherapy can also be considered for disease control before surgery and adjuvant therapy after surgery or radiotherapy.¹⁴ Adrenal-directed drugs that inhibit steroidogenic enzymes (steroidogenesis inhibitors) and thus cortisol production and glucocorticoid receptor blockers are commonly used in Cushing’s syndrome. Pituitary-directed drugs, such as pasireotide and cabergoline, are less effective than steroidogenesis inhibitors but can be considered to block tumor secretion of ACTH and may lead to tumor shrinkage.¹⁴ Ketoconazole is the most common steroidogenesis inhibitor used⁹ while others include mitotane and metyrapone.^14,15 The glucocorticoid receptor antagonist mifepristone can also be used to control hypercortisolism.^14,15

In patients with complications of cortisol excess, symptomatic treatment, such as that of hypertension, is necessary before comprehensive diagnosis and definitive treatment of Cushing’s syndrome are completed.¹⁴ The treatment of hypertension is targeted at the underlying pathophysiological mechanisms and usually requires the use of more than one antihypertensive drug.¹⁶ Angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors may be initiated as first-line treatment since the renin-angiotensin system plays a major role in cortisol-induced hypertension.^13,14 Spironolactone can be used in hypokalemic hypertensive patients, alone or in combination,¹⁴ to target the mineralocorticoid receptor and block the aldosterone-like effects of excess cortisol.¹³ Calcium channel blockers or β-blockers may be used as adjuncts to improve blood pressure control.¹⁴

The complications of hypercortisolism, including hypertension, may sometimes persist despite surgical or pharmacological treatment for Cushing’s syndrome. Targeted treatment of persistent comorbidities is therefore recommended.^13,14 Follow-up of patients is also emphasized in those treated for ACTH- or cortisol-producing neoplasms due to the possibility of recurrences.¹⁴

Thyroid Disease

Conditions that cause thyroid dysfunction can be generally categorized as those that result in thyroid hormone deficiency (hypothyroidism) or excess (hyperthyroidism). Chronic autoimmune thyroid diseases are the most common causes of hypothyroidism in iodine-sufficient regions,¹⁷ with Hashimoto thyroiditis accounting for most cases.¹⁸ Other causes include iatrogenic thyroid injury after radioiodine or surgical treatment for hyperthyroidism, benign nodular thyroid disease or thyroid cancer, exposure to head and neck radiotherapy, and medications (e.g., amiodarone, lithium, and immune response modulators).^17,19 The most common causes of hyperthyroidism are autoimmune Graves’ disease and toxic multinodular goiter. Iodine-containing drugs, mainly amiodarone, excess levothyroxine therapy, and less frequently, subacute thyroiditis can also lead to hyperthyroidism. ^17,19 Disorders of the pituitary gland or hypothalamus can lead to secondary hypo/hyperthyroidism.¹⁹

The treatment of the underlying thyroid disease and restoration of euthyroidism in hypertensive patients will lead to the normalization of blood pressure in most cases. However, antihypertensive medications may be required after thyroid treatment to control blood pressure. β-adrenoreceptor blockers are used in hyperthyroidism, whereas vasodilators, such as calcium channel blockers, are the drugs of choice in hypothyroid patients.^20,21

Symptomatic primary hypothyroidism is usually treated with levothyroxine replacement therapy, a synthetic thyroxine hormone.^18,19 Treatment response is assessed by measuring the levels of thyroid-stimulating hormone (TSH) every three months until at least two similar measurements (three months apart) within the normal reference range are obtained, and then once a year. When TSH remains abnormal, additional testing of free thyroxine (T4) and/or tri-iodothyronine (T3) is required to guide further treatment decisions, after ruling out secondary causes.¹⁸ Other treatments for primary hypothyroidism include liothyronine (synthetic T3), as monotherapy or in combination with levothyroxine, and desiccated thyroid extract. Liothyronine is indicated when levothyroxine treatment fails whereas desiccated thyroid extract is currently not recommended by professional guidelines.^18,19

Antithyroid drugs (thionamides), usually carbimazole, are the first-line treatment for hyperthyroidism in Graves’ disease. However, long-term use is discouraged, and radioiodine ablation therapy or thyroidectomy may be indicated after thionamide therapy for definitive treatment.¹⁹ Radioiodine ablation of the thyroid gland is indicated when thionamide therapy fails, in recurrent Graves’ disease, and in patients who cannot tolerate thionamides.¹⁹ Thyroidectomy is preferred over radioiodine ablative therapy in patients with moderate-to-severe Graves’ orbitopathy; women who are planning to be pregnant within the next 6–12 months; large goiters with compressive symptoms or major retrosternal extension; when thyroid cancer is suspected; or when patients refuse radioiodine therapy.¹⁹

Primary Hyperparathyroidism

Parathyroidectomy is the first-line and only curative treatment for primary hyperparathyroidism (PHPT). It is indicated in all symptomatic patients without contraindications for surgery and asymptomatic patients with evidence of end-organ damage or risk of disease progression.^22,23 Normalization of calcium and parathyroid hormone levels is an indicator of PHPT cure after parathyroidectomy.²⁴ Surgical treatment improves many clinical manifestations of PHPT. However, resolution or amelioration of hypertension following parathyroidectomy has shown variable results, with some studies reporting no improvements and others showing improvements.²⁵

Monitoring is a safe and alternative approach for PHPT in patients who cannot undergo surgery.^22,23 It comprises annual evaluation of serum calcium, vitamin D, and renal function, bone mineral density evaluation every 1 to 2 years, and 24-hour biochemical renal stone evaluation with renal imaging if calcium stones are suspected.^23,24 Patients who are being monitored are advised to stay adequately hydrated and avoid restricting dietary calcium.²² Parathyroidectomy is recommended when signs of disease progression are observed in patients who are being monitored.²³ Medical therapy, with agents such as alendronate, denosumab, cinacalcet, vitamin D, or estrogen therapy, can also be when surgery is contraindicated, unsuccessful, or rejected by the patient.^22,23 Cinacalcet has been shown to reduce serum calcium and parathyroid hormone levels.^23,24 However, medical therapy is less effective than parathyroidectomy and is non-curative.²²

References

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