Essence in brief:
The Cushing’s disease refers to the condition where there is an overproduction of adrenocorticotropic hormone (ACTH) in the pituitary gland, leading to excessive cortisol production. It is typically caused by a benign pituitary tumor.
Cushing’s syndrome, on the other hand, encompasses the signs and symptoms resulting from excessive cortisol in the body, regardless of the underlying cause. This can be due to various factors, such as adrenal tumors, long-term use of corticosteroid medications, or other endocrine disorders.
The symptoms of excessive cortisol levels can include weight gain, central obesity, moon face, muscle weakness, high blood pressure, skin changes, glucose intolerance, and mood disturbances.
Diagnosis involves measuring cortisol levels, performing imaging tests to locate the source of excess cortisol production, and differentiating between Cushing’s disease and other causes.
Treatment options depend on the underlying cause and may involve surgery to remove tumors, medication to suppress cortisol production, or managing the underlying condition causing the syndrome.
Postoperative follow-up is crucial to monitor cortisol levels, manage hormone replacement therapy, and address potential complications or recurrence of the condition. Regular monitoring and collaboration with healthcare professionals are essential for long-term management.
In Cushing’s disease, there is an overproduction of adrenocorticotropic hormone (ACTH) in the anterior pituitary gland or an increased production of corticotropin-releasing hormone (CRH) in the hypothalamus. CRH stimulates the production of ACTH in the pituitary gland. Cushing’s syndrome refers to the effects of excessive cortisol production. This can have causes other than Cushing’s disease, such as an adrenal adenoma, another corticosteroid-producing tumor (e.g., small cell lung carcinoma), or the use of corticosteroid medications.
Harvey Williams Cushing was an American neurosurgeon in Boston. He was a significant pioneer in pituitary surgery and reduced the mortality rate of the procedure from 90% to less than 6%.
ACTH stimulates the production of cortisol from the adrenal glands. The clinical symptoms are caused by elevated cortisol levels. Therefore, the clinical presentation of Cushing’s disease and Cushing’s syndrome is the same.
Short-term effects of cortisol and corticosteroids include increased blood pressure and a diabetic metabolic state due to increased gluconeogenesis (new sugar formation). Particularly in individuals with pre-existing metabolic syndrome, newly developed Cushing’s syndrome or corticosteroid treatment can lead to manifest hypertension and diabetes mellitus.
Long-term effects of cortisol and corticosteroids result in:
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Diagnosis:
The essence in brief:
A synthetic glucocorticoid called dexamethasone is taken orally. If the serum cortisol level falls below 3 µg/dL, Cushing’s syndrome or Cushing’s disease are ruled out.
In the case of an adrenal tumor or nodular adrenal hyperplasia, there will be low ACTH levels, cortisol will not be suppressed in the high-dose dexamethasone test, and there will be no increase in ACTH during the CRH test.
In patients with Morbus Cushing or Cushing’s syndrome, the initial diagnostic measure is a dexamethasone suppression test.
Dexamethasone suppression test: At 10:00 PM, a synthetic glucocorticoid called dexamethasone is taken orally at a dosage of 1 mg. The next morning, between 8:00 and 9:00 AM, a blood sample is taken to measure cortisol levels. By administering dexamethasone, the hypothalamic-pituitary feedback loop (CRH-ACTH-cortisol) is suppressed. If the serum cortisol level falls below 3 µg/dL, Cushing’s syndrome, including Cushing’s disease, is ruled out.
In overweight patients (> 80 kg), even in healthy individuals, cortisol levels may be elevated within the gray zone, so it is better to perform the dexamethasone suppression test with a dosage of 2 mg.
Alcoholics may also have elevated cortisol levels within the gray zone.
If cortisol is not suppressed in the dexamethasone suppression test, further diagnostics are required.
Dexamethasone long test:
The dexamethasone long test can be conducted in two different dosages.
In the low-dose dexamethasone long test over 2 days, patients take 0.5 mg of dexamethasone four times every 6 hours.
Day 1: 6 AM – 12 PM – 6 PM – 12 AM
Day 2: 6 AM – 12 PM – 6 PM – 12 AM
Day 3: 8 AM blood sample for cortisol and ACTH measurement.
If cortisol can be suppressed, Cushing’s syndrome is ruled out.
If cortisol is not suppressed, a high-dose dexamethasone long test is performed.
In the high-dose dexamethasone long test over 2 days, patients take 2 mg of dexamethasone four times every 6 hours.
Day 1: 6 AM – 12 PM – 6 PM – 12 AM
Day 2: 6 AM – 12 PM – 6 PM – 12 AM
Day 3: 8 AM blood sample for cortisol and ACTH measurement.
The execution of the dexamethasone tests may vary slightly and be conducted for slightly different durations.
To differentiate whether it is an adrenal tumor, Cushing’s disease, or ectopic ACTH production, a CRH test is conducted. In healthy individuals, ACTH is exclusively produced in the pituitary gland. Ectopic ACTH production refers to ACTH production outside the pituitary gland, for example, by a lung carcinoma.
During the CRH test, 100 µg of corticotropin-releasing hormone (CRH) is injected intravenously. Blood samples are taken at time points 0, 30, and 60 minutes, and ACTH and cortisol levels are measured. Cortisol should increase by at least 7.2 µg/L, and ACTH should rise by at least 50% from the baseline. If this increase occurs, insufficiency of the corticotropin axis is excluded. The interpretation of test results allows conclusions to be drawn about the cause of Cushing’s syndrome.
Adrenal tumor/nodular adrenal hyperplasia:
Cushing’s disease:
Ectopic ACTH synthesis:
After the laboratory diagnosis has been established, appropriate imaging procedures should be performed.
Adrenal tumor/nodular adrenal hyperplasia Ultrasound/MRI/CT of the adrenal glands
Morbus Cushing (Cushing’s disease): MRI of the pituitary gland
Ectopic ACTH synthesis: Abdominal ultrasound, MRI/CT of the thorax, abdomen, central nervous system (CNS), Octreotide scintigraphy, DOTATOC positron emission tomography (PET)
DOTADOC: Octreotide is a somatostatin analog that binds to receptors that may be present on ACTH-producing tumors. It is bound with a strong complexing agent and labeled with a short-lived radioisotope such as 111Indium. This allows for the detection of neuroendocrine tumors with somatostatin receptors.
DOTATOC-PET involves labeling the drug DOTA(0)-Phe(1)-Tyr(3))octreotide with 68Ga. With a tomograph, neuroendocrine tumors and small bronchial carcinomas that produce ACTH can be localized.
Cushing’s disease leads to unilateral or bilateral enlargement of the adrenal glands. Therefore, adrenal gland surgery should never be performed based solely on adrenal enlargement without prior functional diagnostic tests to confirm that it is not Cushing’s disease but rather an adrenal adenoma or nodular hyperplasia.
In some cases of Cushing’s disease, no pituitary adenoma can be visualized on MRI. In such cases, a bilateral catheterization of the inferior petrosal sinus is performed. The inferior petrosal sinus is a vascular system where venous drainage from the right and left lobes of the pituitary gland ends. During the procedure, a CRH test can be conducted. By examining each side separately, it can be determined whether the excessive production of ACTH in the pituitary gland occurs in the right or left lobe.
Treatment:
Cushing’s disease: In the presence of a pituitary adenoma, a transsphenoidal surgery is performed.
If the adenoma cannot be localized using imaging techniques and there is no difference found in the bilateral catheterization of the inferior petrosal sinus, bilateral adrenalectomy may be considered. Complete removal of the pituitary gland would not only cause insufficiency of the corticotropin axis but also lead to insufficiency of the thyrotropic axis (no TSH secretion), somatotropic axis (no growth hormone secretion), and gonadotropic axis (no LH and FSH secretion).
Adrenal adenoma: In cases of unilateral adrenal adenoma with definitive exclusion of Cushing’s disease, the adenoma is removed. Bilateral adrenalectomy may be necessary in cases of bilateral micronodular adrenal hyperplasia.
Ectopic ACTH syndrome: The primary goal is to locate and remove the primary tumor. Bilateral adrenalectomy is performed in cases of ectopic ACTH syndrome if tumor identification is not successful.
Osilodrostat (brand name Isturisa®) is an oral medication used to treat endogenous Cushing’s syndrome or Cushing’s disease in adults for whom pituitary surgery is not possible or has been unsuccessful.
(Sources: sciencedirect.com, drugbank.com, medscape.com)
Mechanism of Action
Osilodrostat inhibits the enzyme 11β-hydroxylase (CYP11B1) – and at higher doses, also aldosterone synthase (CYP11B2) – which are responsible for the final step in cortisol biosynthesis in the adrenal glands. This enzymatic blockade leads to reduced cortisol levels, thereby alleviating the symptoms of Cushing’s syndrome.
(Sources: wikipedia.org, drugbank.com, accessdata.fda.gov)
Usage & Dosage
Indication:
Standard dosing (per guidelines, e.g. Australian Prescriber):
Dose adjustments for organ impairment:
Monitoring & Side Effects
Monitoring:
Key Side Effects:
Practical Instructions
Summary
Osilodrostat is an innovative oral CYP11B1 inhibitor that effectively manages Cushing’s syndrome in patients who are not candidates for surgery. However, risks such as hypocortisolism, QTc prolongation, and electrolyte imbalances require close monitoring and individualized dose adjustments.
Postoperative follow-up:
After surgery of the pituitary gland or adrenal gland, it may take months or years for cortisol production to normalize. During and after the operation, treatment with hydrocortisone is administered. Higher doses are required during the operation and are given intravenously. After a few days, the treatment can be switched to oral administration, and the dose is gradually reduced.
Following the operation, 100 mg of intravenous hydrocortisone is given over 24 hours. If the posterior pituitary lobe is damaged during the operation, the patient may develop diabetes insipidus due to the loss of antidiuretic hormone (ADH). This is characterized by excessive fluid loss and electrolyte imbalances. These patients may require additional desmopressin therapy.
A cranial CT scan is performed on the first postoperative day to rule out any intracranial bleeding. If there is a deterioration in vision, an MRI may be necessary.
The switch to oral hydrocortisone is initiated on the first postoperative day, and the dose is gradually reduced according to the following schedule:
Postoperative day Hydrocortisone dosage (mg) orally
1 40-30-10
2 30-20-10
3 20-20-10
4 20-10-10
5 15-10-5
6 10-10-5
If cortisol levels were very high before the operation due to Cushing’s disease, there is a risk of glucocorticoid withdrawal syndrome. These patients may require higher hydrocortisone doses (30-50 mg per day) during the first few weeks. Glucocorticoid withdrawal syndrome manifests as muscle pain, joint discomfort, fatigue, depressive mood, and loss of appetite.
In approximately 50% of cases, recurrence may occur, necessitating a reoperation. Around 18% of cases develop anterior pituitary insufficiency, and 9% develop posterior pituitary insufficiency.
Patients with anterior pituitary insufficiency need hormone replacement therapy for the affected axes. Patients with posterior pituitary insufficiency require desmopressin.
In patients without clinical symptoms, hydrocortisone can be further reduced by 5 mg per week after four weeks until they are taking only 10 mg in the morning. A CRH test without the intake of hydrocortisone can then determine if ACTH and cortisol production is sufficient. The patients resume taking 10 mg of hydrocortisone immediately after the test until the results are available. If the hypothalamic-pituitary-adrenal regulation is intact, hydrocortisone can be discontinued.
The CRH test is combined with an LHRH and TRH test to exclude gonadotropin and thyroid axis insufficiency. Measurement of IGF-1 can exclude growth hormone deficiency.
Combined pituitary testing using CRH, LHRH, TRH test:
| Hormone measurement time | 0 min | 30 min | 60 min |
|---|---|---|---|
| ACTH | x | x | x |
| Cortisol | x | x | x |
| TSH | x | x | |
| Prolactin | x | x | |
| LH | x | x | |
| FSH | x | x | |
| fT3 | x | ||
| fT4 | x | ||
| Testosteron/Estradiol | x | ||
| DHEAS | x | ||
| IGF-1 | x |
The criteria for excluding pituitary insufficiency are described in the chapter on pituitary insufficiency. If the above tests do not provide a definite exclusion of pituitary insufficiency, an insulin hypoglycemia test may need to be performed (see chapter on pituitary insufficiency).
In cases of suspected posterior pituitary insufficiency (diabetes insipidus), a water deprivation test is conducted. Patients must not eat or drink anything after 10:00 p.m. The next morning, serum and urine osmolality, electrolytes, and copeptin are measured (see chapter on diabetes insipidus).
All patients suspected of or with existing adrenal insufficiency require an emergency card and should always carry it with them. This allows for the prompt initiation of necessary hydrocortisone therapy in the event of an Addisonian crisis. An Addisonian crisis occurs as a result of cortisol deficiency. Particularly in stressful situations, this deficiency can lead to weakness, fatigue, loss of appetite, abdominal pain, nausea, and low blood pressure. Severe circulatory disturbances can lead to a coma. Since the situation is life-threatening, immediate administration of corticosteroids is required.
If one adrenal gland has been surgically removed, the remaining adrenal gland may be suppressed due to excessive cortisol production. Through gradual reduction of hydrocortisone dosage while maintaining continuous ACTH stimulation, the adrenal gland is reactivated and resumes cortisol production. This is verified through a test called ACTH (Synacthen) test.
Histologically, it is often challenging to differentiate a cortisol-producing adrenal adenoma from a Cushing’s carcinoma. Therefore, patients who have undergone adrenal adenoma surgery should be monitored in the first few years to ensure that a Cushing’s carcinoma was not present.