The presentation of pituitary adenoma depends on tumor size and functional status.[1][2]

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.

1. Symptoms from Mass Effect:

• Visual impairments: Visual impairment is reported in approximated 40% to 60% of patients. Suprasellar extension of the pituitary adenoma compresses the optic chiasm leading to visual field defects. Bitemporal defects are the most prevalent pattern, followed by homonymous defects. The involvement of the oculomotor nerve can lead to diplopia, while the fourth, fifth, and sixth cranial nerves may also be involved with invasive tumors.[6][7] 
• Headaches: Headache is commonly reported in pituitary adenoma; however, it is a non-specific symptom.[7]
• Hormonal deficiency: One or more anterior pituitary hormonal deficiency is observed in patients with pituitary macroadenoma.

      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:

• Prolactin-secreting adenoma: Elevated prolactin suppresses the gonadotrophin levels leading to infertility, decrease libido, and osteoporosis in both sexes. Females present with amenorrhea and galactorrhea while men with erectile dysfunction and gynecomastia.
• GH secreting adenomas (acromegaly) presentation includes headaches, vision changes, an increase in ring or shoe size, arthritis, carpal tunnel syndrome, and excessive sweating. Clinically patients have coarse facial features, frontal bossing, enlarged nose, prognathism, enlarged tongue, and skin tags. Other comorbidities like hypertension, cardiomyopathy, obstructive sleep apnea, and multiple colonic polyps are usually present at the time of diagnosis.
• ACTH-secreting adenomas (Cushing disease) present with weight gain, muscle weakness, mood disorders, easy bruising, and multiple fractures. Clinical features include a round face, facial plethora, supra-clavicular fat, ecchymoses, and purple striae on abdomen and armpits.
• TSH secreting adenomas have symptoms of palpitation, arrhythmias, and weight loss. On exam, the patient may have tremors and goiter.

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.[1][2][6][8]

• Prolactin: The prolactin level usually correlates with the size of adenoma. Serum prolactin level of less than 200 ng/ml present in microadenoma, due to the "stalk effect " in macroadenoma or medications. A serum prolactin level of greater than 200 ng/ml suggests prolactin-secreting macroadenoma. Prolactin becomes elevated in pregnancy, breastfeeding, nipple stimulation, chest wall trauma, hypothyroidism, renal failure, and medications, including antipsychotics,  anti-depressants, opiates, and antiemetics. Macroprolactin, also known as "big -prolactin," is the inactive form of prolactin. It is essential to diagnose macroprolactin to avoid unnecessary medical treatment. The diagnosis of macroprolactin involves precipitation of the serum with polyethylene glycol (PEG). The presence of free prolactin over 60% confirms prolactinoma.

• IGF-1/GH: Serum IGF-1 is a screening test for the diagnosis of acromegaly and GH deficiency. Conditions like poorly controlled diabetes, malnutrition,  sepsis, hypothyroidism, hepatic, and renal failure can impact the IGF-1 and GH levels.

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. 

• Cortisol: Early morning cortisol can be useful in assessing the hypothalamic-pituitary-adrenal (HPA) insufficiency. AM cortisol level of greater than 15 mcg/dl is suggestive of normal HPA. If morning cortisol is equivocal or low, the clinician should obtain a cosyntropin stim test. Morning or random cortisol does help in identifying patients with cortisol excess.

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.

• TSH/FreeT4: Low free T4 with normal or low TSH stipulates secondary hypothyroidism. TSH producing adenoma will have elevated T4 and T3 with inappropriately normal or elevated TSH. 

• Gonadotropin levels (LH/FSH): Low estradiol or testosterone levels with normal or low LH/FSH levels suggest hypogonadotropic hypogonadism. The sex hormones can not be interpreted accurately in females if they are on oral contraceptives. Post-menopausal females will have elevated FSH levels.

The management of pituitary adenomas involves an endocrinologist and neurosurgeon to work closely together and develop an "individualized patient-centric" approach.[1][2][9][10][6][11][8]

Treatment of Non-Functioning Adenomas

Transsphenoidal resection is recommended in patients with macroadenoma and the following scenarios:

• Visual field deficit due to tumor
• Other visual abnormalities as ophthalmoplegia 
• The lesion is compressing the optic nerves or chiasm on imaging
• Pituitary apoplexy with visual disturbance
• Loss of endocrine function
• Significant growth of pituitary tumor over time.

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

• Prolactin-Secreting Adenoma:  The goal of treatment is to restore gonadal function and decrease tumor size. Observation with periodic monitoring of prolactin levels can be an option in patients who are asymptomatic with microadenoma.  

Medical Therapy

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.

Surgery

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.

Radiation Therapy

Radiotherapy is seldom used in aggressive prolactinoma, where frequent surgeries and medical therapy had failed to control the size of adenoma. 

• GH Secreting adenoma: The goal is to decrease growth hormone levels to less than 1ug/L and IGF-1 levels to the normal age-adjusted range.

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.

• ACTH secreting adenoma: The goal of treatment is to decrease cortisol levels rapidly and to reduce the associated complications and mortality.

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. 

•  TSH secreting adenoma: Trans-sphenoidal surgery is the initial preferred treatment option leading to a cure in 50% to 90% of patients. It is crucial to control hyperthyroidism before surgery to avoid thyroid storm. Presurgical euthyroidism is achieved by using anti-thyroidal medical therapy like methimazole or SSA. Patients who are not cured by surgery can be treated with SSA to decrease TSH levels and tumor size and or with radiation treatment. 

Differential diagnosis includes other sellar masses as:

• Arachnoid cysts
• Basilar artery thrombosis
• Brainstem gliomas
• Cavernous sinus syndromes
• Cerebral venous thrombosis
• Craniopharyngiomas
• Dermoid cysts
• Ependymoma
• Glioblastoma multiforme
• Leptomeningeal carcinomatosis
• Low-grade astrocytoma
• Meningioma
• Primary CNS lymphoma
• Rathke cleft cysts
• Tuberculous meningitis

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.[12]

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]