Objectives: Upon completion of this CE activity, the APRN will be able to:
- Describe the statistical data regarding adrenal disorders in the US, including prevalence and significance
- Discuss the pathophysiology, risk factors, clinical presentation, diagnostic workup, evidence-based management, and potential complications of adrenal insufficiency, as in Addison’s disease
- Explore the pathophysiology, risk factors, clinical presentation, diagnostic workup, evidence-based management, and potential complications of hypercortisolism, otherwise known as Cushing’s syndrome
The purpose of this module is to provide the APRN with an overview of the pathophysiology, risk factors, clinical presentation, diagnostic workup, evidence-based management guidelines, and potential complications of primary endocrine disorders affecting the adrenal gland and leading to either an excess or deficiency in adrenal hormones. Please see the first part of this endocrine series for a review of the anatomy and physiology of the endocrine system (Figure 1).
There are many disorders of the endocrine system, and an imbalance or disorder of one part of the endocrine system can lead to disorders in other parts. Identifying the primary etiology of the disorder is vital for determining the optimal treatment. Primary endocrine disorders originate within the gland, while secondary endocrine disorders are caused by problems outside of the glands, typically within the feedback mechanism. External problems may occur in response to trauma, surgery, infection, tumors, or certain drugs. Causes of endocrine disorders vary but typically involve either an excess or deficiency in hormone secretion or insensitivity of the target tissue to the hormone (Hopper, 2015; Ignatavicius et al., 2018).
The adrenal glands (Figure 2) make essential hormones for various body functions. The cortex creates three types of steroids: corticosteroids (e.g., mineralocorticoids, glucocorticoids) and sex hormones. These hormones regulate metabolism, the immune system, blood pressure (BP), and responses to stress or other essential functions. When the adrenal glands do not produce enough hormones, it can lead to adrenal insufficiency, which is also known as Addison's disease (Johns Hopkins Medicine, n.d.). The adrenal gland is regulated by a negative feedback system involving the hypothalamus, which secretes corticotropin-releasing hormone (CRH), triggering the corticotrophs in the anterior pituitary to secrete adrenocorticotrophic hormone (ACTH). Increasing levels of adrenal hormones in circulation inhibit the secretion of both CRH and ACTH, completing the hypothalamus-pituitary-adrenal (HPA) axis (El Sayed et al., 2020).
Understanding normal cortisol physiology is important to appreciate adrenal dysfunction. Cortisol is among the key hormones produced by the cortex; it helps control the body's use of fats, proteins, and carbohydrates, suppresses inflammation, regulates BP via vascular tone (a decrease in cortisol production is associated with a decrease in BP), increases blood glucose (BG), and may decrease the formation of bone tissue. Cortisol impacts the body’s response to stress and stressful situations as one of the fight-or-flight hormones. Increased cortisol is needed to cope with acutely stressful situations such as surgery. An inadequate release of cortisol in these situations can be fatal. Cortisol also regulates the sleep/wake cycle and provides a boost of energy during periods of increased stress. Varying amounts of cortisol are secreted throughout the day, with the lowest levels at midnight and the highest levels early in the morning. Aldosterone is a mineralocorticoid hormone that regulates BP as well as sodium and potassium levels. Aldosterone signals the kidneys to retain sodium and excrete potassium into the urine, also helping regulate the pH of the blood. Dehydroepiandrosterone (DHEA) and androgenic steroids are precursor hormones that are produced by the cortex and converted in the ovaries of females to estrogens and in the testes of males to androgens (Johns Hopkins Medicine, n.d.; University of California Los Angeles [UCLA] Health, n.d.).
Adrenal insufficiency is rare and may be either primary (due to adrenal gland dysfunction) or secondary (due to a lack of CRH, ACTH, or both). Even in patients with hypopituitarism, ACTH is less likely to be affected than growth hormone (GH), luteinizing hormone, and follicle-stimulating hormone (Snyder, 2020a).
Primary adrenal insufficiency most commonly results from autoimmune adrenalitis, which is also known as Addison’s disease. It may also occur due to fungal or other infections (tuberculosis [TB]), genetic causes, or cancer. Autoimmune Addison’s disease is more common in females and children and typically affects adults between the ages of 30 and 50 years. It does not appear to have a racial predilection (Griffing, 2020). Secondary adrenal insufficiency may be due to any of the previously mentioned pathologies that often affect the hypothalamus or pituitary, but the most common cause of ACTH deficiency is prolonged glucocorticoid therapy (Nieman, 2019a; Snyder, 2020a). If the condition is mild and chronic, patients with adrenal insufficiency may present with vague symptoms, such as hypotension (especially postural), tachycardia, lassitude, fatigue, anorexia, weight loss, decreased libido, hypoglycemia, and eosinophilia. In primary adrenal insufficiency, cortisol deficiency is accompanied by aldosterone deficiency, and patients typically present with salt-wasting leading to hyponatremia, volume contraction, and hyperkalemia plus hyperpigmentation of the skin. Furthermore, a reduced circulating cortisol level triggers an increase in the secretion of antidiuretic hormone (ADH) by the posterior pituitary, worsening the hyponatremia (Snyder, 2020a). Adrenal insufficiency symptoms typically increase during times of stress and may also include:
- nausea, vomiting, or diarrhea;
- amenorrhea or irregular menstrual periods;
- bluish-black coloring around the nipples, mouth, rectum, scrotum, or vagina (primary disease only); and
- abdominal pain (Johns Hopkins Medicine, n.d.).
Adrenal insufficiency characteristically develops over time. When the condition manifests suddenly, it is referred to as acute adrenal failure or an adrenal crisis. The symptoms resemble those listed above but may be accompanied by severe abdominal pain, extreme weakness, kidney failure, life-threatening shock, seizures, and coma (Johns Hopkins, n.d.). An adrenal crisis in patients with untreated Addison's disease typically involves hypovolemia, hypotension, hyperkalemia, and hyponatremia. Those with secondary adrenal insufficiency will typically present without hypovolemia and hyperkalemia, but with decreased vascular tone leading to hypotension and hyponatremia as well as hypoglycemia (Nieman, 2020b). An international survey of patients with known Addison’s disease found a roughly 8% prevalence of annual hospitalization for an adrenal crisis event, and an increased risk seen among patients with gastrointestinal infections, diabetes, or asthma (Griffing, 2020).
Similar to adults, central adrenal insufficiency in children is often caused by suppression of the HPA axis due to prolonged glucocorticoid therapy. The most common cause of primary adrenal insufficiency in children and infants is congenital adrenal hyperplasia (CAH), which is a genetic disorder that results in a deficiency in 21-hydroxylase, an enzyme required for cortisol synthesis. Infants with CAH often develop salt wasting and may present with dehydration, weight loss, lethargy, hyponatremia, hypoglycemia, hyperkalemia, or failure to thrive at just 2 weeks old, especially if they also have concurrent GH deficiency. In some cases, CAH can remain undiagnosed for years. Older children with adrenal insufficiency usually present with nausea, vomiting, diarrhea, abdominal pain, weight loss, reduced growth velocity, and salt cravings. Pediatric patients with primary adrenal insufficiency also develop hyperpigmentation of the skin (especially the mucous membranes and creases) due to elevated ACTH levels, as well as hyponatremia, hyperkalemia, and metabolic acidosis due to aldosterone deficiency. These findings will not occur if the child also has concurrent vomiting or central adrenal insufficiency. If they have an excess of androgen, male characteristics may occur in females, and precocious puberty may occur in boys; more severe cases may present with ambiguous genitalia (Bowden & Henry, 2018; Johns Hopkins, n.d.).
A thorough history and physical should be completed with a focus on the primary symptoms of adrenal insufficiency. The potential differential diagnoses for suspected adrenal insufficiency include:
- adrenal hemorrhage
- C-17 hydroxylase deficiency
- tuberculosis (TB; Griffing, 2020)
Serum cortisol is the first-line test for diagnosing central or primary adrenal insufficiency. It should be measured at 8-9 a.m., as random cortisol levels are not valid for diagnostic purposes. A cortisol level under 3 μg/dL indicates adrenal insufficiency, but anything less than 15-18 μg/dL warrants a repeat test (reference range 10-20 μg/dL or 276-552 nmol/L). A serum ACTH (reference range 20-52 pg/mL or 4.5-11 pmol/L) should be performed if the cortisol level is confirmed to be below 18 μg/dL. An elevated ACTH in combination with a decreased cortisol level indicates primary adrenal insufficiency, and aldosterone (typically decreased) and renin levels (typically increased) should be subsequently assessed. A decreased cortisol level in combination with a normal or reduced serum ACTH indicates secondary adrenal insufficiency, and ACTH reserve should be assessed. A cortisol level above 18 μg/dL (497 nmol/L) rules out adrenal insufficiency (Nieman, 2019a; Snyder, 2020b).
An ACTH (corticotropin) stimulation test may be indicated when morning cortisol values are between 3 and 18 μg/dL (indeterminate). This uses cosyntropin (Cortrosyn, Tetracosactide) or metyrapone (Metopirone) to assess the ACTH reserve. The cosyntropin (Cortrosyn) stimulation test is recommended by the Endocrine Society, primarily due to its ease of administration and the relative availability. Cosyntropin (Cortrosyn) is a synthetic form of ACTH 1-24. The medication is administered (0.25 mg IM or IV), and a serum cortisol level is checked 30 and 60 minutes later. If the cortisol level is above 18 μg/dL, the results are considered normal (negative). A cortisol level below 18 μg/dL may indicate adrenal atrophy due to ACTH deficiency. Critics maintain this test is less useful than the metyrapone (Metopirone) reserve test, as patients with partial ACTH deficiency may present with falsely normal results. The procedure and dosing for pediatrics mirror those for adults, with the exception that neonates with central adrenal insufficiency may present with falsely negative results, which should prompt repeat testing at 3 to 4 weeks of age. A lower-dose version of cosyntropin (Cortrosyn) testing (using 1 mcg IV with serum cortisol checks at 20 and 30 minutes) may increase the sensitivity and reduce the risk of false negatives, especially for patients with secondary adrenal insufficiency. Metyrapone (Metopirone) blocks the conversion of deoxycortisol to cortisol. It is administered every 4 hours for 24 hours orally, with serum cortisol and 11-deoxycortisol levels drawn the next morning at 0800. A healthy patient—based on a negative test—will have a cortisol level below 7 μg/dL but an elevated 11-deoxycortisol above 10 μg/dL, which indicates intact ACTH production. Impaired ACTH secretion is indicated by a cortisol level below 7 μg/dL but a reduced 11-deoxycortisol level (below 10 μg/dL). A single 100-mg dose of intravenous hydrocortisone (Solu-Cortef) is given after labs are drawn to reverse the effect of the metyrapone (Metopirone). The patient should be monitored closely, especially for BP and HR in the lying and standing positions prior to each dose of metyrapone. If postural hypotension develops, the test should be discontinued, and hydrocortisone (Solu-Cortef) should be administered (Bowden & Henry, 2018; Nieman, 2019a; Snyder, 2020b).
A third option is an insulin stress test. During this procedure, 0.1 u/kg of insulin is administered as an insulin bolus, causing a drop in BG and an increase in ACTH and cortisol in response. Serum cortisol and BG are assessed prior to the administration of insulin, and again at 15- to 30-minute intervals for 2 hours. As the patient’s BG is reduced below 50 mg/dL, their cortisol level should increase to a level above 18 μg/dL. There are significant risks associated with the administration of an insulin bolus, and the patient should be monitored closely, especially during the first hour, with IV glucose on hand if needed. This test is especially risky for older patients or those with a history of cardiovascular disease, cerebrovascular disease, or seizures. It is not recommended for pediatric patients. A significant advantage of the insulin stress test is that it can simultaneously diagnose a GH deficiency in patients with suspected hypopituitarism affecting multiple hormones. A glucose stress test may be done to assess for GH deficiency, but providers should be aware that this is more difficult to interpret and carries an increased risk of false-positive results (decreased specificity). Ancillary diagnostic assessments might include an antibody test for autoimmune adrenalitis, as well as advanced imaging studies to assess the adrenal glands, pituitary, and hypothalamus for structural abnormalities and/or secondary causes (Bowden & Henry, 2018; Nieman, 2019a; Snyder, 2020b).
Emergent treatment for an adrenal crisis includes the rapid infusion of one to three liters of 0.9% NS or D5 in 0.9% NS initially to maintain BP. Glucose may be added to the IV solution to manage hypoglycemia. Diagnostic labs should be drawn immediately to determine the underlying cause of the patient’s condition, including blood chemistries, cortisol, ACTH, renin, and aldosterone, but the treatment should proceed without waiting for definitive results. An initial dose of 100 mg of hydrocortisone (Solu-Cortef) IV push should be given, followed by 200 mg over the next 24 hours via continuous infusion or four 50 mg doses every 6 hours, then 100 mg over the following 24 hours. When the patient can tolerate medications by mouth, the IV hydrocortisone (Solu-Cortef) infusion is tapered off over 1-3 days. Fludrocortisone (Florinef) should be added to the regime in those with primary insufficiency. Prednisone (Deltasone), prednisolone (Millipred), or dexamethasone (Decadron) may be substituted for hydrocortisone as alternatives (Griffing, 2020; Nieman, 2020b). Pediatric patients presenting with an adrenal crisis should receive 100 mg/m2 IV hydrocortisone (Solu-Cortef) as well as D5 in 0.9% NS for 2-3 days. These crises in pediatric patients are typically triggered by trauma or illness, so the underlying cause should be identified and corrected whenever possible (Bowden & Henry, 2018).
Chronic adrenal insufficiency is treated with oral hormone replacement. Oral corticosteroids such as hydrocortisone (Cortef) divided BID/TID or an equivalent are typically the first-line treatment of choice to replace adrenal corticosteroid. Adrenal function must be assessed, and treatment should be initiated prior to or concurrently with treatment to correct GH or thyroid deficiency to avoid triggering an adrenal crisis. Most recommendations target between 15 and 25 mg/day, with higher doses in the morning to mirror the natural endogenous hormone fluctuations. Many experts advocate for dosing based on body surface area, suggesting 10-12 mg/m2 per day divided BID/TID. This is especially prudent for pediatric patients. If non-compliance is an issue, the medication can be dosed once daily. Dose adjustments should be made based on physical signs and symptoms, and no specific laboratory monitoring is required. The dose should be decreased if the patient presents with weight gain, facial plethora (dusky, cyanosed, and covered with a fine growth of hair), or other signs/symptoms of Cushing’s syndrome. A slightly higher range (12-20 mg/m2/day) is typically required for pediatric patients with CAH, along with 1-2 mg/day of salt supplementation in infants under 12 months of age. Liquid preparations are not recommended for pediatric patients, although compounded suspensions are acceptable. The dosing may fluctuate with stress, such as physical illness, surgery, or mental and emotional stress. Upper respiratory infections are typically treated based on the “3x3” rule, which indicates two to three times the patient’s standard dose for up to 3 days. Minor surgeries are typically treated with 25 mg hydrocortisone (Cortef) on the surgery day only, while moderate surgeries (cholecystectomy, joint replacement) are typically treated with 50-75 mg hydrocortisone (Solu-Cortef) IV on the surgery day as well as the first postoperative day. Major surgeries, such as cardiac bypass procedures, are typically treated with 100-150 mg of hydrocortisone (Solu-Cortef) IV in divided doses for 3 days. In pediatric patients, moderate stress doses should be treated with 30-50 mg/m2/day, and severe stress doses may be as high as 100 mg/m2/day for 2-3 days, followed by a taper to typical dosing levels. The increase in BP caused by hydrocortisone (Cortef) treatment may boost renal blood flow and decrease ADH secretion from the posterior pituitary, causing polyuria and unmasking mild DI. Cortisol is replaced less often using 5 mg prednisone (Deltasone) daily or 0.5 mg dexamethasone (Decadron) daily, but this is not recommended for pediatric patients. In primary adrenal insufficiency, aldosterone replacement may be required via 0.1 mg fludrocortisone (Florinef) daily to balance sodium and fluids. Similarly, pediatric dosing of fludrocortisone (Florinef) may vary between 0.05 and 0.2 mg daily divided BID while monitoring the child’s growth, weight gain, BP, electrolytes, and renin levels. Patients with secondary adrenal insufficiency should have sufficient endogenous aldosterone and do not require this. If the patient’s BP increases, they should be advised to decrease their sodium intake, and the dose of fludrocortisone (Florinef) should be reduced instead of adding diuretics or spironolactone (Aldactone). Pediatric patients may also present with hypervolemia, hypertension (HTN), and edema, indicating the need for reduced fludrocortisone (Florinef) dosing. Patients with panhypopituitarism, especially women, may also benefit from androgen replacement with DHEA to improve their mood and quality of life. Common side effects include hirsutism (extra hair growth on the face, chin, or body), oily skin, acne, and increased sweating/odor. The replacement of GH or thyroid hormone in a patient with adrenal insufficiency may trigger an adrenal crisis, so adrenal insufficiency should always be corrected while or prior to treating either GH deficiency or central hypothyroidism (Bowden & Henry, 2018; Griffing, 2020; Nieman, 2020b; Snyder, 2019). Of note, pharmaceutical companies are currently attempting to develop an SQ formula of hydrocortisone, although this is not currently available in the US commercially, as well as various sustained- or modified-release formulations like Infacort granules/sprinkles, which may allow for more flexible/convenient dosing in the future (Bowden & Henry, 2018).
An individual with adrenal insufficiency who becomes pregnant should continue with pre-pregnancy doses of all medications. However, if nausea and vomiting from early pregnancy make oral medication intake difficult, corticosteroid injections may be needed. Medication doses may be increased during the third trimester slightly, as well as during delivery. Typically, patients are given 25 mg hydrocortisone (Solu-Cortef) IV every 6 hours during labor, then 100 mg every 6 hours during delivery. Doses should be decreased over several days after delivery to pre-pregnancy doses (Nieman, 2020b).
Patient education for adrenal insufficiency should include the following items:
- A high-sodium diet may be beneficial for those with low aldosterone.
- The importance of compliance with follow-up appointments with the entire health care team—which should include a dietician, endocrinologist, and primary health care provider—should be clearly stated.
- The importance of routine monitoring of hormone levels to maintain therapeutic levels and avoid excess or inadequate replacement should be emphasized.
- The patient should be instructed to wear a medical alert bracelet to alert caregivers of their diagnosis and treatment.
- The patient should be instructed to increase (typically double or triple) their steroid replacement doses during periods of stress, such as illness, surgical procedures, and pregnancy.
- Signs and symptoms of acute adrenal insufficiency should be reviewed regularly, such as:
- extreme weakness,
- mental confusion,
- abdominal pain,
- nausea or vomiting,
- sudden pain in the lower back or legs, and
- loss of appetite.
- The patient should be instructed to keep a vial of 100 mg of hydrocortisone (Solu-Cortef) and a syringe at home and carry them when traveling for acute adrenal insufficiency.
- The patient and at least one family member should be instructed on the correct administration of parenteral hydrocortisone (Solu-Cortef) via IM or SQ injection during situations such as blood loss (greater than 1 cup), fracture, or severe nausea/vomiting with an inability to tolerate oral medications, or if the patient is found unresponsive to ensure adequate levels (Gounden & Jialal, 2020; Griffing, 2020; Nieman, 2020b).
Corticosteroids may lead to osteoporosis, so an increase in dietary calcium and vitamin D are crucial, and dietary supplements may be advised. Providers should also attempt to prescribe the lowest effective dose of glucocorticoids necessary to limit this risk. Most often, morbidity and mortality related to Addison’s disease are secondary to a delay in diagnosis or inadequate replacement of glucocorticoids and mineralocorticoids. Mortality among patients with Addison’s disease is increased two-fold due to cardiovascular, malignant, or infectious disease risk. Females with autoimmune Addison’s disease are more than twice as likely to develop ischemic heart disease as compared to controls (Griffing, 2020).
Hypercortisolism (Cushing’s syndrome, or CS) is defined as excess cortisol in the peripheral circulation. This condition affects approximately 10-15 people per million annually. It may be exogenous (i.e., caused by the intake of corticosteroids) or endogenous (i.e., caused by an excess in ACTH or cortisol secretion). Exogenous CS occurs more commonly due to the widespread use of corticosteroids. Endogenous CS most often results from Cushing's disease, a pituitary condition that accounts for approximately 65-70% of all cases of endogenous CS. It most commonly affects those from 20-50 years of age, with women accounting for more than 70% of all cases (Albani et al., 2018; Nieman, 2019b).
Exogenous CS is typically related to a corticosteroid medication such as hydrocortisone (Cortef), prednisone (Deltasone), hydrocortisone skin ointments (Cortaid, Deltacort), inhaled corticosteroids for asthma (Flovent), or joint injections such as dexamethasone (Decadron). Endogenous Cushing’s disease is characterized by a pituitary tumor, most often a microadenoma, which causes an increased and unregulated secretion of ACTH. Alternative causes of endogenous CS can include:
- tumors/nodules of the adrenal glands (approximately 20% of cases of CS);
- ectopic ACTH production related to tumors elsewhere in the body secreting ACTH, which then stimulates the adrenal glands to make excess cortisol; and
- physiologic hypercortisolism due to pregnancy, severe obesity, significant stress (e.g., psychological stress, illness, or surgery), severe major depressive disorder, anorexia nervosa, uncontrolled diabetes, obstructive sleep apnea, or chronic alcohol use disorder (Albani et al., 2018; Nieman, 2020a).
Since Cushing's disease and CS are both associated with increased cortisol levels, their signs and symptoms align, as shown in Figure 3.
If the origin of CS involves a pituitary macroadenoma, the patient will experience severe hormonal effects such as vision loss, hypopituitarism, hypogonadism, or hyperprolactinemia (UCLA Health, n.d.). Less common signs and symptoms of CS include atherosclerosis, electrocardiogram (ECG) abnormalities, edema, back pain, abdominal pain, and hair loss, especially female balding (Nieman, 2020a).
Early Cushing's disease is difficult to recognize as it typically develops slowly. The hormone changes may be cyclic or periodic. During pregnancy, Cushing's disease symptoms typically worsen. During the history and physical, it is important to establish symptoms that would indicate excess cortisol. Excess cortisol intake (exogenous CS) should always be ruled out first, followed by physiologic hypercortisolism (UCLA Health, n.d.). Findings that should increase the provider’s suspicion for endogenous CS include HTN or osteoporosis in young adults, facial plethora, proximal myopathy/weakness, striae (red/purple and greater than 1 cm in width), easy bruising/ecchymoses, resistant HTN or severe osteoporosis at any age, and the presence of adrenal incidentalomas. If the index of suspicion is low, a single first-line test is recommended. For patients with a high index of suspicion, two or three of the following tests are strongly recommended to establish the diagnosis (Nieman, 2020a). The primary first-line tests recommended by the Endocrine Society for the diagnosis of CS include:
- A late-night/evening salivary cortisol measurement, which includes two separate saliva samples collected by the patient at home in the late evening before bedtime. This test is especially helpful in cyclic/intermittent CS and is noninvasive. It can be done using a serum sample in specialized centers, but this is not routinely used in clinical practice due to a lack of convenience.
- A 24-hour urinary free cortisol (UFC) excretion should be done using two full 24-hour samples and tested via a reliable reference laboratory to maintain accuracy. A result greater than three times the expected normal value is diagnostic for CS. A result that is elevated but under three times the expected value may indicate physiologic hypercortisolism or excess fluid intake, prompting a repeat of the test. It is not recommended for patients with renal failure.
- A low-dose oral dexamethasone (Decadron) suppression test may be done using 1 mg (performed overnight) or 2 mg/day (performed over 2 days). If the HPA axis is healthy and intact, exogenous dexamethasone (Decadron) should cause a reduction in the patient’s ACTH secretion and, consequently, their cortisol level. Patients on oral contraceptives should stop this prescription 6 weeks prior to the test to avoid a false-positive result. The test is considered unreliable in pregnant patients. The overnight test consists of 1 mg of dexamethasone (Decadron, 0.3 mg/m2 in children) given between 23 and 2400, followed by a serum cortisol level drawn at 0800. The 2-day test consists of eight doses of 0.5 mg of dexamethasone (Decadron) given every 6 hours, followed by a serum cortisol level drawn either 2 or 6 hours after the last dose. In both tests, the recommended cutoff is 1.8 µg/dL (50 nmol/L) to optimize sensitivity over specificity. The 2-day test offers superior accuracy but is less convenient. If the results are abnormal (serum cortisol level greater than 1.8 µg/dL), the overnight test should be followed by another screening test to confirm the diagnosis due to its decreased specificity. Concurrently measuring plasma ACTH during these suppression tests may help establish the underlying pathology of CS, as elevated ACTH levels often occur in ectopic ACTH syndrome, normal or slightly elevated levels in pituitary Cushing’s disease, and low or undetectable levels in primary adrenal CS (Nieman, 2020a).
Any abnormal test results should prompt referral to an endocrinologist for additional testing. Once CS has been established, if no obvious cause (e.g., physiologic, medication-based) is apparent, an MRI of the pituitary may be indicated to rule out Cushing’s disease if the serum ACTH is normal or slightly elevated. A CT scan of the adrenal gland to rule out an adrenal tumor may be indicated if the serum ACTH level is low or undetectable (Nieman, 2020a). If no tumor is found, further testing may include inferior petrosal sinus sampling (UCLA Health, n.d.).
For CS caused by the long-term use or overuse of corticosteroid therapy, the dosage may be decreased over time; this will require an alternative therapy for the condition being treated, such as asthma or arthritis. Non-steroidal medications may be used, but the corticosteroids must be tapered slowly to avoid an adrenal crisis (Mayo Clinic, 2019).
The primary goal of treatment for endogenous CS is to reduce cortisol secretion, thereby reducing the signs and symptoms of CS. This may involve eradicating any life-threatening tumors and avoiding hormone deficiency and the need for permanent dependence on medications. Treatment options vary depending on the diagnostic findings. For patients with Cushing’s disease, the ideal treatment plan begins with transsphenoidal microadenomectomy, a pituitary surgery to remove the tumor and decrease ACTH production. This procedure has a 75-90% initial cure rate, a 5-20% chance of recurrence, and a 60-70% final cure rate in adults; the same rates in pediatric patients are 70-90%, 20-40%, and 45-50%, respectively. This can be repeated for a recurrent tumor that is visible on MRI scanning, with a 50-70% cure rate. Radiation therapy and steroidogenesis inhibitors (85-100% cure rate) may be used in the case of nonresectable recurrence. Radiation therapy is an initial treatment option for patients under the age of 18 years or women seeking fertility for whom surgical resection was ineffective or in whom a tumor was not found. Subtotal resection (85-90%) of the pituitary gland may be indicated for some patients if future fertility is not desired, although this carries a risk of hypopituitarism (Nieman, 2019b).
Patients who cannot undergo or are currently awaiting surgery may be candidates for pharmacologic therapy. An adrenal enzyme inhibitor is most commonly prescribed, such as ketoconazole (Nizoral; off-label), osilodrostat (Isturisa), metyrapone (Metopirone), or etomidate (Amidate). Corticotrope-directed pharmacological therapy with pasireotide (Signifor) or cabergoline (Dostinex) may be indicated for those with mild hypercortisolism following initial transsphenoidal resection of a pituitary adenoma. Pasireotide (Signifor) acts as a somatostatin analog, binding to somatostatin receptors and inhibiting ACTH secretion. It is administered as a twice-daily injection. This option is not effective for patients with primary (adrenal) CS. Cabergoline (Dostinex), which was previously discussed as a dopamine agonist used in the treatment of hyperprolactinemia, may be used to target a corticotroph tumor. These two medications result in remission in 20-40% of cases. Mifepristone (Mifeprex, Korlym) is a glucocorticoid and a progesterone antagonist that is FDA approved for the treatment of impaired glucose tolerance in patients who are not surgical candidates. Some patients may be prescribed mitotane (Lisodren) as an adrenocorticolytic, although its use for CS is off label (Nieman, 2019b).
Adrenalectomy, which is the surgical removal of the adrenal gland, may also be considered. Most cases of primary adrenal disease can be treated with unilateral adrenalectomy. Bilateral adrenalectomy, which has a 100% cure rate but will require lifelong hormone replacement, is reserved for the secondary treatment of severe hypercortisolism, women seeking pregnancy, bilateral micronodular adrenal tumors, and most cases of macronodular adrenal hyperplasia. Patients with ectopic ACTH-producing tumors are typically treated using surgical excision; a pharmacologic adrenal enzyme inhibitor may be prescribed if the tumor is nonresectable or if the resection is ineffective (Nieman, 2019b).
Patient education should include the following details:
- Patients should increase activity slowly due to weakened muscles.
- A balanced diet with reduced sodium and increased calcium and vitamin D is recommended. Refer the patient to a dietician as appropriate.
- Educate the patient and their family on the signs and symptoms of depression and encourage them to seek help. Refer the patient as needed for mental health services.
- Offer alternative methods to soothe muscle aches and pains such as hot baths, massages, and low-impact exercises like water aerobics.
- Encourage support groups for CS and recovery (Mayo Clinic, 2019).
Patients with hypercortisolism previously had a roughly 50% mortality rate within 5 years of developing symptoms, but medical advances have made the prognosis significantly better. Cushing’s disease is generally curable. Potential complications are perioperative, cardiovascular, thromboembolic, or hypertensive. Hypercortisolism increases a patient’s coagulability, which may increase the risk of deep vein thrombosis, pulmonary edema, and myocardial infarction. Severe CS also places the patient at risk for opportunistic infections such as pneumocystis carinii pneumonia, cryptococcosis, aspergillosis, or nocardiosis (Nieman, 2019b).
For learners who are eager to access additional content related to the endocrine system and endocrine disorders, please see the following NursingCE courses:
- Endocrine and Hormonal Disorders Part 1: Anatomy and Physiology
- Endocrine and Hormonal Disorders Part 2: Hypopituitarism and Other Hormone Deficiencies
- Endocrine and Hormonal Disorders Part 3: Syndromes of Excessive Hormone Secretion
- Thyroid Dysfunction
- Sexual Dysfunction
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