Pituitary adenomas are tumors of the anterior pituitary. Most pituitary tumors are slow-growing and benign. They are classified based on size or cell of origin. Pituitary adenoma can be described as microadenoma, macroadenoma, and giant tumors based on size. Microadenoma is tumors less than 10 mm, while macroadenoma includes tumors larger than 10mm. Giant pituitary tumors are more 40 mm. There are functional pituitary adenomas in which the cell type that composes them causes increased secretion of one or multiple hormones of the anterior pituitary. Alternatively, there are nonfunctional adenomas that do not secrete hormones, but they can compress the surrounding areas of the anterior pituitary leading to hormonal deficiencies. Patients with pituitary adenoma need to be evaluated by a multidisciplinary team that includes both endocrinology and neurosurgery.
The pathogenesis of pituitary adenoma remains unknown. Most of the pituitary adenomas are sporadic. In a recent study from Iceland with 410 pituitary adenomas, 43% were non- functional adenoma, 40% prolactin-secreting adenoma, 11 % growth hormone (GH) secreting adenoma, and 6% Adrenocorticotropic hormone (ACTH) secreting adenoma. Genetic mutation is rarely a feature of pituitary adenoma. Familial cases of pituitary adenomas represent 5% of all pituitary tumors.  Mutation in the following genes has been found to play a role in the development of pituitary adenomas.
Multiple endocrine neoplasia type 1 (MEN1): MEN1 is a tumor suppressor gene. Loss of function mutation in this gene leads to tumor formation in the parathyroid, pancreatic, and pituitary glands.
Multiple endocrine neoplasia type 4 (MEN4): MEN 4 has a mutation in the cyclin-dependent kinase inhibitor 1 B gene (CDKN1B) presenting with pituitary tumors, hyperparathyroidism, testicular, and cervical neuroendocrine tumors.
Carney complex (CNC): In the Carney complex, there is a germline mutation of the tumor suppressor gene PRKAR1A leading to primary pigmented nodular adrenocortical disease (PPNAD), testicular tumors, thyroid nodules, spotty skin hyperpigmentation, and acromegaly.
Familial isolated pituitary adenomas (FIPA): Aryl hydrocarbon receptor-interacting protein (AIP) mutation is reported in adolescence or early adulthood in about 15% all FIPA. These tumors are usually aggressive and growth hormone-secreting adenoma.
Pituitary adenomas are mostly found incidentally on imaging modalities obtained for other reasons. Given the insidious nature of the pituitary adenomas, smaller size, and incidental diagnosis, it is challenging to accurately estimate the prevalence of pituitary adenomas in the general population. The estimated prevalence of pituitary adenomas is extrapolated from autopsy and radiological data. There is a wide range of prevalence among studies and the source of information. In a meta-analysis from 32 autopsy series, the pituitary adenomas frequency was 10.5%. Imaging studies, like MRI head, revealed 10% to 38% of pituitary incidentaloma. There are several population-based studies from different geographic areas spanned over many years to describe the epidemiology of pituitary adenoma. The most recent study from Iceland showed a prevalence of 115.57 per 100,000. A recent review article that included multiple community-based population studies showed the prevalence of pituitary adenoma ranges from 1 in 865 persons to 1 in 2688 persons.
Pituitary microadenoma is usually an incidental finding on MRI head. Patients are asymptomatic unless the tumor is hormonally active.
Pituitary macroadenoma presents with mass effects and hormonal deficiency or hormonal excess.
Pituitary apoplexy is a sudden hemorrhage into pituitary adenoma. It is very rare. It presents with symptoms of a mass effect that is sudden headaches, vision changes along with hormonal deficiency.
Gonadotropin deficiency presents as amenorrhea in females and erectile dysfunction in males.
Growth hormone (GH) deficiency in adults leads to fatigue and weight gain.
Thyroid-stimulating hormone (TSH) deficiency symptoms are weight gain, fatigue, cold intolerance, and constipation.
Adrenal corticotropic hormone (ACTH) deficiency presents as fatigue, arthralgia, weight loss, low blood pressure, dizziness, nausea, vomiting, and abdominal pain.
2. Functional adenoma: The clinical presentation depends on the hormone secreted as below:
Most pituitary adenomas are detected incidentally on routine CT imaging. An MRI with gadolinium is necessary for the distinction of a mass from an aneurysm and to assess for hemorrhage into the mass. Additionally, screening for hypopituitarism and assessing for hypersecretion is warranted. The Endocrine Society clinical practice guidelines recommend a complete biochemical assessment, even in asymptomatic patients. This evaluation includes the measurement of various hormones such as prolactin, TSH, free T4, follicle-stimulating hormone (FSH), IGF-1, GH, ACTH, estradiol, testosterone, BMP, and morning cortisol.
In patients with acromegaly, where the IGF-1 level is not high or equivocal, the serum GH level is assessable after a 75 gm oral glucose challenge test. A non-suppressed GH level of greater than 1 ng/dl with hyperglycemia confirms acromegaly.
In adults, isolated GH deficiency requires further evaluation with provocative testing like Insulin-induced hypoglycemia test, glucagon stimulation test, or the newly developed macimorelin stimulation test.
The screening tests for Cushing disease include late-night salivary cortisol, 24-hour urine cortisol, or dexamethasone suppression test (DST). Late-night salivary cortisol has a greater than 90% sensitivity and specificity if done accurately. DST includes checking early morning cortisol after taking 1 mg of dexamethasone at 11:00 PM. A cortisol level of 1.8 mcg/dl suggests hypercortisolemia. Urine free cortisol requires accurate 24-hour urine collection. Interpretation of the screening test for cortisol excess should proceed cautiously as many factors like exogenous steroids, depression, excess alcohol intake, and oral contraceptives can effects cortisol levels.
Once hypercortisolemia is confirmed biochemically, the next step is to find the etiology by checking ACTH. Hypercortisolemia with elevated ACTH suggests a corticotroph adenoma. ACTH producing adenomas is small, and an MRI of the head is normal in 50% of the patients. In the setting of normal MRI head or pituitary microadenoma less the 0.6 cm, inferior petrosal sinus sampling (IPSS) is recommended to differentiate between ectopic vs. pituitary Cushing. IPSS is an invasive procedure where catheters are inserted into the bilateral petrosal sinus. ACTH level measurement takes place before and after stimulation with the corticotropin-releasing hormone (CRH). A threefold increase in ACTH levels suggests a pituitary source.
Treatment of Non-Functioning Adenomas
Transsphenoidal resection is recommended in patients with macroadenoma and the following scenarios:
There is an improvement in visual symptoms and hormonal dysfunction in most patients after surgery. Radiotherapy is a consideration in patients with persistent residual or recurrence of the tumor.
In nonfunctional adenomas that do not require surgical management, annual follow up with endocrinology is important to assess for tumoral growth and development of hypopituitarism. MRI head is obtained annually for three years and thereafter less frequently.
Treatment of Individual Function Tumors
Dopamine agonists (DA) are the first-line treatment for prolactin-secreting tumors. The currently available DA is cabergoline and bromocriptine. Cabergoline is more than 90% effective in normalizing prolactin levels and decreasing tumor size. The adverse effects of DA are dizziness due to postural hypotension, valvular heart abnormalities, and the development of compulsive behavior/mood changes. DA could be discontinued after two years of treatment if the MRI head did not show a visible tumor. Monitoring serum prolactin levels annually is needed in these patients as there is some risk of recurrence or growth after stopping DA.
Transsphenoidal surgery is often reserved for prolactin-secreting tumors which are resistant to medical treatment, develop adverse effects to dopamine agonists and, in patients desiring pregnancy with tumor size of more than one centimeter.
Radiotherapy is seldom used in aggressive prolactinoma, where frequent surgeries and medical therapy had failed to control the size of adenoma.
Surgery: Trans-sphenoidal surgery is the first-line treatment for GH-secreting tumors. In the hands of an experienced surgeon, normalization of IGF-1 is achieved in 80% to 90% of patients with microadenomas and 40% to 60% of patients with macroadenomas.
Medical therapy: Medical treatment is considered in patients with persistently elevated IGF-1 and GH levels at three months after surgery or in non-surgical candidates with invasive tumors. Somatostatin analogs (SSA) are the first-line treatment for acromegaly. Current available SSAs are octreotide, lanreotide, and pasireotide. The adverse effects of SSA include gall bladder sludge and stones, abdominal cramps, flatulence, diarrhea, and alopecia. Pasireotide can lead to hyperglycemia in 50 to 70% of patients. DA, like cabergoline, is used for mildly elevated IGF-1 level post-surgery or as an adjunct therapy with SSA. If the GH remains elevated, pegvisomant, a GH receptor blocker, can be used in combination with SSA or alone for the treatment of acromegaly.
Radiotherapy: Radiation treatment is used as an adjunct in patients with elevated IGF-1 levels after surgery. It will take several years to be effective.
Surgery: Trans-sphenoidal surgery is the first-line treatment for Cushing disease. The cure rate is 70% to 90 % in the hands of an expert surgeon with initial and repeated surgeries.
Medical therapy: DA (cabergoline) and SSA (pasireotide, pasireotide LAR) are the drugs directed at the pituitary to decrease ACTH secretion. Ketoconazole, metyrapone, mitotane, and etomidate, all decreases adrenal cortisol production. Ketoconazole can lead to liver toxicity and prolongation of the QT interval. Metyrapone is 50 to 60% effective in reducing the cortisol level. Mitotane is an adrenolytic drug, mostly used in patients with adrenocortical cancer. Etomidate is given intravenously in critically ill severely hypercortisolemia patients as a bridge to work on other treatment interventions. The glucocorticoid receptor blocker, Mifepristone, can be used in selected patients with hypercortisolemia and diabetes.
Bilateral adrenalectomy can lead to an immediate cure of hypercortisolemia with resultant adrenal insufficiency requiring lifelong treatment. Nelson syndrome, which is radiological pituitary tumor enlargement, can occur in 50 % of patients after adrenalectomy.
Radiotherapy: Radiation treatment serves as an adjunct after surgery and medical therapy.
Differential diagnosis includes other sellar masses as:
The prognosis of pituitary adenoma depends if its function or non-functional. The non-functional adenomas and prolactinoma have an excellent prognosis if treated promptly with surgery and medical therapy. Functional adenoma like Cushing disease and acromegaly are associated with several other co-morbidities and complications. There is increased mortality especially in patients with Cushing disease with delay in medical or surgical treatment.
Pituitary adenomas are very common. They are usually benign. It can cause symptoms from mass effect and by effecting the level of the hormones.
Proper evaluation is needed by specialists, including an endocrinologist, neurosurgeon, and radiation oncologist, to take care of the pituitary disease.
Patient education is important with instruction of when to seek medical care with a diagnosis of pituitary adenoma.
Education on the adverse effects of medical therapy is important to prevent complications and mortalities.
Criteria defining Pituitary Centers of Excellence (PTCOE) were released in a statement by the Pituitary Society in 2017. In this, they described a structured approach with a "leading team" comprised of an endocrinologist and a neurosurgeon working together closely in the initial evaluation of the patient. They should be part of a center of excellence with supporting units of neuroradiology, neuropathology, radiation oncology, and neuro-ophthalmology.
Specialty care nurses monitor patients, provide patient and family education, and help coordinate care. Pharmacists review medication dosages, check for drug-drug interactions. If the tumor is not benign, a board-certified oncology pharmacist should consult with the oncology clinician team to assist with agent selection and other treatment factors.
With these interprofessional efforts, patient care will benefit, and outcomes will improve. [Level 5]
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