Acth-secreting Pituitary Adenoma
Disease Details
Family Health Simplified
- Description
- ACTH-secreting pituitary adenoma is a type of tumor in the pituitary gland that produces excess adrenocorticotropic hormone (ACTH), leading to overproduction of cortisol and resulting in Cushing's disease.
- Type
- ACTH-secreting pituitary adenomas are typically classified as benign tumors known as pituitary adenomas. These tumors arise from the anterior pituitary gland and secrete adrenocorticotropic hormone (ACTH), leading to conditions such as Cushing's disease. The majority of these adenomas are sporadic, meaning they occur without a clear hereditary pattern. However, a small percentage can be associated with genetic conditions such as Multiple Endocrine Neoplasia type 1 (MEN1) or Carney complex, which follow an autosomal dominant pattern of inheritance.
- Signs And Symptoms
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Symptoms include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity). Common signs include the growth of fat pads along the collarbone, on the back of the neck ("buffalo hump" or lipodystrophy), and on the face ("moon face"). Other symptoms include excess sweating, dilation of capillaries, thinning of the skin (which causes easy bruising and dryness, particularly the hands) and mucous membranes, purple or red striae (the weight gain in Cushing's syndrome stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs, or breasts, proximal muscle weakness (hips, shoulders), and hirsutism (facial male-pattern hair growth), baldness and/or extremely dry and brittle hair. In rare cases, Cushing's can cause hypocalcemia. The excess cortisol may also affect other endocrine systems and cause, for example, insomnia, inhibited aromatase, reduced libido, impotence in men, and amenorrhoea, oligomenorrhea and infertility in women due to elevations in androgens. Studies have also shown that the resultant amenorrhea is due to hypercortisolism, which feeds back onto the hypothalamus resulting in decreased levels of GnRH release.Many of the features of Cushing's are those seen in metabolic syndrome, including insulin resistance, hypertension, obesity, and elevated blood levels of triglycerides.Cognitive conditions, including memory and attention dysfunctions, as well as depression, are commonly associated with elevated cortisol, and may be early indicators of exogenous or endogenous Cushing's. Depression and anxiety disorders are also common.Other striking and distressing skin changes that may appear in Cushing's syndrome include facial acne, susceptibility to superficial fungus (dermatophyte and malassezia) infections, and the characteristic purplish, atrophic striae on the abdomen.: 500 Other signs include increased urination (and accompanying increased thirst), persistent high blood pressure (due to cortisol's enhancement of epinephrine's vasoconstrictive effect) and insulin resistance (especially common with ACTH production outside the pituitary), leading to high blood sugar and insulin resistance which can lead to diabetes mellitus. Insulin resistance is accompanied by skin changes such as acanthosis nigricans in the axilla and around the neck, as well as skin tags in the axilla. Untreated Cushing's syndrome can lead to heart disease and increased mortality. Cortisol can also exhibit mineralocorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia (common in ectopic ACTH secretion) and hypernatremia (increased Na+ ions concentration in plasma). Furthermore, excessive cortisol may lead to gastrointestinal disturbances, opportunistic infections, and impaired wound healing related to cortisol's suppression of the immune and inflammatory responses. Osteoporosis is also an issue in Cushing's syndrome since osteoblast activity is inhibited. Additionally, Cushing's syndrome may cause sore and aching joints, particularly in the hip, shoulders, and lower back.Brain changes such as cerebral atrophy may occur. This atrophy is associated with areas of high glucocorticoid receptor concentrations such as the hippocampus and correlates highly with psychopathological personality changes.
Rapid weight gain
Moodiness, irritability, or depression
Muscle and bone weakness
Memory and attention dysfunction
Osteoporosis
Diabetes mellitus
Hypertension
Immune suppression
Sleep disturbances
Menstrual disorders such as amenorrhea in women
Infertility in women
Impotence in men
Hirsutism
Baldness
Hypercholesterolemia - Prognosis
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The prognosis for an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma can vary depending on several factors, including the size and invasiveness of the tumor, as well as the success of treatment. These adenomas can lead to Cushing's disease, which, if left untreated, can cause serious health problems such as hypertension, diabetes, and osteoporosis.
Treatment typically involves surgical removal of the tumor, often through a procedure called transsphenoidal surgery. Success rates for this surgery are generally high, especially for microadenomas (tumors smaller than 10 mm), but the prognosis can be less favorable for larger or more invasive adenomas.
Following surgery, many patients experience a significant improvement in symptoms, but there is also a risk of tumor recurrence. Therefore, long-term follow-up with endocrinological assessments is essential.
In cases where surgery is not completely effective or feasible, additional treatments may include radiation therapy or medical management with medications that inhibit cortisol production.
Overall, with timely and effective treatment, the prognosis can be good, but careful monitoring and management are essential to address potential complications and reduce the risk of recurrence. - Onset
- The onset of an ACTH-secreting pituitary adenoma can occur at any age but is most commonly diagnosed in adults aged 20-50. The symptoms often develop gradually over time, making early detection challenging.
- Prevalence
- The estimated prevalence of ACTH-secreting pituitary adenomas, also known as Cushing's disease, is approximately 2-3 cases per million people per year. It often occurs more frequently in women than in men and typically presents in adults aged 20-50 years.
- Epidemiology
- Cushing's syndrome caused by treatment with corticosteroids is the most common form. Cushing's disease is rare; a Danish study found an incidence of less than one case per million people per year. However, asymptomatic microadenomas (less than 10 mm in size) of the pituitary are found in about one in six individuals.About 0.9 to 1% of those with Cushing's syndrome have a tendency to develop venous thrombosis. Other factors such as surgery and obesity also increase the chance of getting thrombosis.
- Intractability
- ACTH-secreting pituitary adenomas, also known as corticotroph adenomas, are not inherently intractable. They often cause Cushing's disease, which can be challenging but is usually manageable with appropriate treatment. Surgical removal of the adenoma is the primary treatment and is often successful. Additional treatments may include medications, radiation therapy, or bilateral adrenalectomy if surgery is not possible or fully effective. The prognosis largely depends on the tumor's size, location, and response to treatment.
- Disease Severity
- ACTH-secreting pituitary adenoma, also known as Cushing's disease, can vary significantly in severity. It is characterized by excessive production of adrenocorticotropic hormone (ACTH) from a benign tumor in the pituitary gland. This leads to overproduction of cortisol from the adrenal glands, causing symptoms ranging from weight gain and hypertension to osteoporosis, diabetes, and increased risk of infections. Severity depends on the size of the tumor and the degree of hormone imbalance. Early diagnosis and treatment are crucial for better outcomes.
- Healthcare Professionals
- Disease Ontology ID - DOID:7004
- Pathophysiology
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The hypothalamus is in the brain and the pituitary gland sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on CRH in the hypothalamus, which decreases the amount of ACTH released from the anterior pituitary gland.Strictly, Cushing's syndrome refers to excess cortisol of any etiology (as syndrome means a group of symptoms). One of the causes of Cushing's syndrome is a cortisol-secreting adenoma in the cortex of the adrenal gland (primary hypercortisolism/hypercorticism). The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low.Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotroph pituitary adenoma (secondary hypercortisolism/hypercorticism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism). This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because the tumor is unresponsive to negative feedback from high cortisol levels.When Cushing's syndrome is due to extra ACTH it is known as ectopic Cushing syndrome. This may be seen in a paraneoplastic syndrome.
When Cushing's syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offers equal detection rates. Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, cortisol levels >50 nmol/L (1.81 μg/dL) would be indicative of Cushing's syndrome because an ectopic source of cortisol or ACTH (such as adrenal adenoma) exists which is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late-night levels of salivary cortisol are high in cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm, causing typical bitemporal hemianopia.When any of these tests is positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Occasionally, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary. In many cases, the tumors causing Cushing's disease are less than 2 mm in size and difficult to detect using MRI or CT imaging. In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery.Plasma CRH levels are inadequate at diagnosis (with the possible exception of tumors secreting CRH) because of peripheral dilution and binding to CRHBP. - Carrier Status
- Carrier status is not applicable to ACTH-secreting pituitary adenoma. This condition is not inherited in a manner similar to genetic diseases that can have carriers. It is typically a sporadic condition caused by the growth of a benign tumor (adenoma) in the pituitary gland, which leads to overproduction of ACTH (adrenocorticotropic hormone).
- Mechanism
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An ACTH-secreting pituitary adenoma, also known as corticotroph adenoma, is a benign tumor of the pituitary gland that leads to the overproduction of adrenocorticotropic hormone (ACTH). Here are the details:
**Mechanism:**
1. **Overproduction of ACTH:** The adenoma results in excessive secretion of ACTH from the pituitary gland.
2. **Adrenal Cortex Stimulation:** Elevated ACTH levels stimulate the adrenal cortex, leading to increased production of cortisol.
3. **Cushing's Disease:** The excess cortisol causes a clinical syndrome known as Cushing's disease, characterized by symptoms such as weight gain, hypertension, diabetes, and osteoporosis.
**Molecular Mechanisms:**
1. **Mutations:** Genetic mutations, particularly in the USP8 gene, have been identified in some corticotroph adenomas. These mutations can lead to increased EGFR signaling, promoting adenoma growth and excessive ACTH production.
2. **POMC Gene Regulation:** The overproduction of ACTH is driven by the upregulation of the pro-opiomelanocortin (POMC) gene, which encodes the ACTH precursor.
3. **Signaling Pathways:** Dysregulation of intracellular signaling pathways, such as the cyclic AMP (cAMP) pathway, can enhance ACTH secretion from the adenoma cells.
4. **Microenvironment Factors:** Paracrine factors in the tumor microenvironment may also contribute to the growth and hormone secretion of corticotroph adenomas.
Understanding these mechanisms provides insight into potential therapeutic targets for treating ACTH-secreting pituitary adenomas and managing Cushing's disease. - Treatment
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Most cases of Cushingoid symptoms are caused by corticosteroid medications, such as those used for asthma, arthritis, eczema and other inflammatory conditions. Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms.If an adrenal adenoma is identified, it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Regardless of the adenoma's location, most patients require steroid replacement postoperatively at least in the interim, as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.In those patients not suited for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy. Mifepristone is a powerful glucocorticoid type II receptor antagonist and, since it does not interfere with normal cortisol homeostasis type I receptor transmission, may be especially useful for treating the cognitive effects of Cushing's syndrome. However, the medication faces considerable controversy due to its use as an abortifacient. In February 2012, the FDA approved mifepristone to control high blood sugar levels (hyperglycemia) in adult patients who are not candidates for surgery, or who did not respond to prior surgery, with the warning that mifepristone should never be used by pregnant women- although pregnancy is extremely rare during the course of Cushing's Syndrome In March 2020, Isturisa (osilodrostat) oral tablets a 11-beta-hydroxylase enzyme inhibitor was approved by FDA for treating those patients who cannot undergo pituitary surgery or for patients who underwent surgery but continue to have the disease.
Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome. - Compassionate Use Treatment
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ACTH-secreting pituitary adenomas, also known as corticotroph adenomas, are a type of pituitary tumor that overproduces adrenocorticotropic hormone (ACTH), leading to Cushing's disease. For patients who cannot undergo conventional treatments or for whom such treatments are ineffective, several options exist in the realms of compassionate use, off-label, and experimental treatments:
1. **Compassionate Use Treatments:**
- **Osilodrostat:** Though not widely available, it can sometimes be used under compassionate use programs to inhibit cortisol synthesis.
- **Mifepristone:** Used on a compassionate basis for patients with hypercortisolism when surgery is not an option.
2. **Off-label Treatments:**
- **Cabergoline:** Traditionally used for prolactinomas, cabergoline has shown some efficacy in reducing ACTH levels in corticotroph adenomas.
- **Pasireotide:** Though primarily indicated for acromegaly, pasireotide can reduce ACTH secretion in some patients with Cushing's disease.
- **Ketoconazole:** An antifungal with cortisol-lowering properties, used off-label to manage hypercortisolism in Cushing’s disease.
3. **Experimental Treatments:**
- **Temozolomide:** An alkylating agent tested in refractory or aggressive pituitary adenomas.
- **Retinoic Acid Derivatives:** Still under investigation, these aim to target the molecular pathways involved in ACTH secretion.
- **Gene Therapy:** Includes research into targeted therapy that addresses the genetic mutations associated with ACTH-secreting adenomas.
- **Immunotherapy:** Experimental use of immune checkpoint inhibitors to treat aggressive pituitary adenomas.
These treatments should be considered under the guidance of a specialized healthcare team with experience in managing pituitary disorders. - Lifestyle Recommendations
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Lifestyle recommendations for individuals with ACTH-secreting pituitary adenoma, also known as Cushing's disease, focus on managing symptoms and supporting overall health. Here are some key recommendations:
1. **Healthy Diet**:
- Focus on a balanced diet rich in fruits, vegetables, lean proteins, and whole grains.
- Limit intake of refined sugars and saturated fats to help manage weight gain and reduce cardiovascular risk.
2. **Regular Physical Activity**:
- Engage in regular, moderate exercise to help manage weight, improve mood, and maintain bone health.
- Consult with a healthcare provider before starting any new exercise regimen, especially if you have osteoporosis or muscle weakness.
3. **Stress Management**:
- Practice stress-reduction techniques such as meditation, yoga, and deep-breathing exercises to help manage the psychological impact of the disease.
4. **Adequate Sleep**:
- Ensure you get enough sleep to help the body recover and maintain energy levels.
5. **Regular Monitoring**:
- Attend regular check-ups with your endocrinologist or healthcare provider to monitor your condition and adjust treatment plans as necessary.
6. **Medication Adherence**:
- Adhere strictly to prescribed medications or postoperative care plans if surgery has been performed.
7. **Bone Health**:
- Consider calcium and vitamin D supplements if recommended by your healthcare provider to support bone health, as Cushing's disease can lead to osteoporosis.
8. **Avoid Smoking and Alcohol**:
- Avoid smoking and limit alcohol consumption to support overall health and reduce the risk of complications.
9. **Weight Management**:
- Work with a dietitian or healthcare provider to develop a weight management plan, as obesity is a common issue.
Adopting these lifestyle changes can help manage symptoms and improve quality of life for individuals with ACTH-secreting pituitary adenoma. - Medication
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Medication for ACTH-secreting pituitary adenoma primarily involves drugs that reduce cortisol production or inhibit its effects. Common medications include:
1. **Cabergoline and Bromocriptine**: These dopamine agonists can reduce ACTH production.
2. **Pasireotide**: A somatostatin analog that can decrease ACTH secretion.
3. **Ketoconazole, Metyrapone, and Mitotane**: Adrenal enzyme inhibitors that reduce cortisol synthesis.
4. **Mifepristone**: A glucocorticoid receptor antagonist that blocks cortisol's effects.
These medications may be used when surgery is not an option or as adjunctive treatment. Regular monitoring and dosage adjustments are essential. - Repurposable Drugs
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Repurposable drugs for ACTH-secreting pituitary adenoma, also known as Cushing's disease, include:
1. **Pasireotide**: A somatostatin analog that inhibits ACTH secretion.
2. **Cabergoline**: A dopamine agonist that has been shown to reduce ACTH production in some patients.
3. **Mifepristone**: A glucocorticoid receptor antagonist used to control hyperglycemia secondary to hypercortisolism.
These drugs may be considered when surgery or radiotherapy is not feasible or has not been fully effective. Always consult with a healthcare provider for personalized treatment options. - Metabolites
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For an ACTH-secreting pituitary adenoma, key metabolites of interest include:
1. **Cortisol**: Increased due to excessive ACTH stimulating the adrenal glands.
2. **ACTH (Adrenocorticotropic Hormone)**: Elevated levels due to overproduction by the adenoma.
These adenomas are associated with Cushing's disease, where the excessive ACTH leads to hypercortisolism. - Nutraceuticals
- There are no specific nutraceuticals that have been proven to effectively treat ACTH-secreting pituitary adenomas. Management typically involves medical, surgical, and sometimes radiotherapeutic approaches. Nutraceuticals may support overall health but should be discussed with a healthcare provider to ensure they don't interfere with primary treatments.
- Peptides
- Adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas are tumors of the pituitary gland that produce excessive amounts of ACTH. This leads to Cushing's disease, characterized by weight gain, hypertension, and glucose intolerance, among other symptoms. ACTH itself is a peptide hormone derived from the precursor molecule proopiomelanocortin (POMC). Upon processing, POMC also yields other peptides, including melanocyte-stimulating hormone (MSH) and beta-endorphin.