Hyperpituitarism

Etiology

Hyperpituitarism is excessive production of any of the hormones secreted by the pituitary; therefore, the condition may have various causes. However, the most common cause of hyperpituitarism is pituitary adenomas. Two-thirds of pituitary tumors cause hormone hypersecretion.[5] Pituitary adenomas are classified as macroadenomas for tumors <10 mm or macroadenomas for tumors ≥10 mm. Determination of the underlying etiology is guided by the hormones found to be abnormally increased.[6] The most common types of pituitary adenomas include:

• Growth hormone-secreting tumors: Most cases of acromegaly and gigantism are secondary to pituitary adenomas that cause excessive production of growth hormone. The incidence of acromegaly is 5 cases per million per year, and the prevalence is 60 cases per million.[7] In less than 5% of cases, acromegaly results from excessive growth hormone-releasing hormone (GHRH) secretion from a hypothalamic or a neuroendocrine tumor. The ectopic production of GH is extremely rare.[8][5]

• Prolactinomas: These prolactin-secreting pituitary tumors are most commonly found in women, with an incidence 3 times higher than in men.[9] Prolactinomas are the most frequent secretory tumors of the pituitary gland, accounting for at least 40% of all pituitary tumors. Other causes of elevated prolactin include craniopharyngioma and other sellar or parasellar masses, infiltration of the hypothalamus, and some cases of head trauma. Nonsecretory pituitary tumors that compress the pituitary stalk and impair dopamine flow can result in hyperprolactinemia also.[9] Mild elevations in prolactin may also be seen in patients with hypothyroidism, renal or liver failure, pregnancy, and polycystic ovarian disease. Certain medications, such as antipsychotic agents, opioid analgesics, and antidepressants, may cause prolactin elevations also. Physiological causes of increased prolactin levels include stimulation of the nipple and sexual intercourse.[10][11][12]

• Adrenocorticotropic hormone–excreting tumors:  Pituitary adenomas that secrete ACTH, also referred to as Cushing disease, are the most common cause of hypercortisolism (ie, Cushing syndrome). The incidence of Cushing syndrome is 2.4 cases per million.[13] Pituitary adenomas causing hypercortisolism account for greater than 80% of cases. Other causes of hypercortisolism include neuroendocrine neoplasms ectopically producing ACTH or corticotropin-releasing hormone, adrenal adenomas or carcinomas resulting in cortisol levels elevated independently of ACTH, or exogenous glucocorticoids.[5] Only 10% to 20% of cases are secondary to ectopic production of ACTH. Cushing disease is more common in females than males, with a ratio of 3 to 1.[14][5]

• Thyrotropin hormone-secreting tumors: Pituitary adenomas that secrete thyroid-stimulating hormone (ie, TSHoma) represent <1% of functioning pituitary tumors, with the Swedish National Registry reporting an incidence rate of 0.15 cases in every 1 million patients annually.[15] Co-secretion of GH and prolactin is not uncommon as well.

• Gonadotrophin-secreting tumors: Typically, these pituitary adenomas are clinically nonfunctioning, discovered in 60% of surgical cases. Clinically functioning adenomas secreting excess of either FSH or LH are very rare and usually present with menstrual irregularities in premenopausal women, hypogonadism in men, and precocious puberty in children.[16]

• Multiple endocrine neoplasia (MEN) type 1 syndrome: The simultaneous presence of a pituitary adenoma with a pancreatic endocrine tumor and a parathyroid tumor is associated with this condition.

Epidemiology

The incidence of hyperpituitarism is usually reported with a specific condition associated with a particular pituitary hormone excess. Approximately two-thirds of pituitary adenomas may cause hormone overproduction. According to recent studies of pituitary adenomas, 32% to 66% were prolactinomas, 8% to 16% were growth hormone-secreting tumors, 2% to 6% were ACTH-secreting tumors, and less than 1% were thyrotropin-secreting tumors.[5] (Refer to the Etiology section for more information on the incidence of each related pituitary hormone excess).

Pathophysiology

The exact pathophysiology of pituitary adenomas has not been clearly defined.[5] Hypothalamic dysregulation may play a role in promoting tumor growth; some studies have also demonstrated intrinsic pituicyte genetic dysfunction playing a role in tumorigenesis. Due to the pituitary gland being responsible for producing various hormones, the pathophysiology can vary significantly.

• Cushing disease: Corticotropinomas occur in people of all ages, though with a female preponderance. A pituitary adenoma that produces excess adrenocorticotropic hormone (ACTH) leads to cortisol overproduction. Frequently, these adenomas are comparatively smaller than others. In adults, there is an absence of diurnal variation of plasma cortisol and ACTH; however, in children, these tumors present with weight gain and growth failure.[5]

• Gigantism: Somatotropinomas are adenomas of growth hormone-producing pituicytes, which may cause gigantism during childhood when the open epiphysial plates allow for excessive longitudinal growth. Aryl hydrocarbon receptor-interacting protein (AIP) mutations are associated with early-onset gigantism.[17]

• Prolactinoma: Prolactinomas are the most common pituitary adenoma found in childhood and originate from the same acidophilic cell lineage that thyrotropes and somatotropes are derived from. Because of this shared cell lineage, prolactinomas may also secrete growth hormone and TSH. Nonsecretory pituitary tumors that compress the pituitary stalk and impair dopamine flow can result in hyperprolactinemia also.[9]

• Thyrotropinoma: These adenomas secrete TSH mainly but may also secrete excess prolactin, growth hormone, and alpha subunit. Typically, these tumors are usually large and aggressive.

• Gonadotrophin-secreting adenomas: Clinically functioning gonadotrophin-secreting adenomas can present with varying levels of excess FSH or LH, normal or elevated levels of α-subunit and inhibin, elevated estrogen levels resulting in ovarian hyperstimulation syndrome, and elevated levels of testosterone causing enlarged testes.[18] Prolactin levels can also be elevated, usually secondary to pituitary stalk compression due to a macroadenoma.[19]

History and Physical

The clinical features associated with hyperpituitarism will depend on the hormone or hormones that are produced in excess, the presence of a mass pituitary lesion, and associated features of hypopituitarism. Local effects of a pituitary tumor, such as visual field disturbances and headache, may be present in the presence of a mass lesion. Additionally, clinicians should obtain a family history of endocrine tumors in patients suspected to have a hormonal excess or found to have an incidental pituitary adenoma on imaging.[20]

Excessive Production of Prolactin

Clinical features of prolactinomas may occur in isolation or with increased production of other hormones (eg, growth or thyroid). Because hyperprolactinemia suppresses the hypothalamic-pituitary-gonadal axis, decreased libido, infertility, and osteoporosis are common symptoms. Clinical features in females include galactorrhea, oligomenorrhea, and secondary amenorrhea. In males, impotence is common, and findings of macroadenomas with features of extension beyond the pituitary are frequent.[5]

Excessive Production of Growth Hormone

Growth hormone excess commonly also causes an elevation of insulin-like growth factor, resulting in acromegaly. Often, diagnosis of acromegaly is significantly delayed, and patients have advanced clinical features primarily involving the musculoskeletal and cardiovascular systems.[21] In adults, clinical features include:[4]

• Skeletal overgrowth of flat bones like the mandible (ie, prognathism), as well as the growth of bones in the feet with a resultant increase in shoe size
• Overgrowth of skin and subcutaneous tissue
• Increased presence of skin tags, macroglossia, cardiomyopathy, and peripheral neuropathy
• Carpal tunnel syndrome caused by compression of the median nerve due to increased soft-tissue growth
• Metabolic and cardiovascular disturbances that include diabetes mellitus, hypertension, dyslipidemia, and obstructive sleep apnea
• Osteoarthritis
• Excessive sweating

In children, before the fusion of epiphyseal plates in long bones (eg, femur and tibia), excessive GH production results in gigantism.

Excessive Production of Thyroid-Stimulating Hormone

Secondary hyperthyroidism is caused by increased secretion of TSH. Clinical features of thyroid hormone excess include weight loss, heat intolerance, anxiety, menstrual disturbances, and palpitations. Hyperthyroid symptoms with TSHomas are often mild to moderate. An enlarged goiter may also be present on physical exam. 

Excessive Production of Adrenocorticotropic Hormone

The characteristic clinical features of hypercortisolism (ie, Cushing syndrome) include central obesity, skeletal muscle wasting, the presence of a dorsocervical fat pad or "buffalo hump", striae, excessive bruising, menstrual abnormalities, increased blood pressure, glucose intolerance, depression, and psychosis.[4][5]

Excessive Production of Luteinizing Hormone and Follicle-Stimulating Hormone

In adult women, clinical features of gonadotrophin-secreting adenomas include irregular menstrual cycles (eg, amenorrhea or menorrhagia), ovarian hyperstimulation syndrome, and infertility. In adult males, common clinical findings are enlarged testes and hypogonadism. For children, clinical features associated with precocious puberty are frequently noted.[19]

Evaluation

Diagnostic Studies

The suspected excess hormone typically guides initial laboratory tests. Possible deficiencies of other pituitary hormones should also be considered, and relevant testing should be performed. Further pituitary imaging studies are usually recommended to assist with diagnosis unless a tumor is discovered incidentally when imaging studies have been done for other reasons. Using unenhanced or gadolinium-enhanced magnetic resonance imaging (MRI) is preferred to computerized tomography (CT) scans for visualization of pituitary adenomas. Adenomas are slow to take up gadolinium as opposed to the normal pituitary tissue; therefore, they tend to appear as hypoenhancing lesions.[22][23][24][25][26] The following diagnostic studies are recommended for the hormone abnormalities associated with hyperpituitarism.

Prolactin

In patients with clinical features of hyperprolactinemia or an incidental pituitary tumor, serum prolactin should be initially obtained. Basal levels of serum prolactin are useful as values of >200 ng/mL are associated with the presence of a prolactinoma. However, in patients with a prolactin level of <5 times the upper limit, a repeat serum prolactin should be obtained due to factors that may cause a transient elevation in prolactin (eg, stress, exercise, and alcohol consumption).[9] Because prolactin levels generally correspond with the tumor size, clinicians should consider differential diagnoses if this is not the case. Prolactin (PRL) may be increased due to other causes unrelated to pituitary disease; therefore, laboratory studies should also be performed to exclude these differential diagnoses (eg, TSH and creatinine).[9][5] (Refer to the Etiology section for more information on other causes of elevated prolactin levels).

Biologically inactive large-size prolactin variations (ie, big PRL) that may also be identified on serum testing can lead to assay interference. However, polyethylene glycol precipitation of big PRL can help differentiate between this and true hyperprolactinemia. Furthermore, macroprolactinomas >3 cm may cause extremely high PRL levels that inaccurately show a normal or mildly elevated result due to the antibody saturation of an assay. Therefore, specimens should be diluted to 1:100 in patients with macroprolactinomas to provide a reliable result.[9][5] Provocative tests are not indicated. Gadolinium-enhanced MRI brain imaging is recommended to confirm a prolactinoma diagnosis in patients with elevated PRL levels. Follow-up MRIs every 3 to 6 months are often performed for treatment monitoring.[9][4]

Growth Hormone

Random GH levels are usually not recommended due to the diurnal and pulsatile nature of secretion that occurs during the day. Instead, insulin-like growth factor (IGF-1) is recommended as the initial screening test for a growth hormone-secreting pituitary adenoma, as increased IGF-1 accompanies excessive GH production. IGF-1 measurement does not require a fasting sample or suppression testing; a random sample adequately reflects the influence of GH excess or deficiency. Relevant age and sex-matched reference intervals should be used to interpret IGF-1 results. Furthermore, comorbid conditions can affect IGF-1 interpretation. For instance, under the action of GH, the liver produces IGF-1; therefore, significant liver disease may result in decreased IGF-1 production. Other conditions affecting IGF-1 results include renal failure, hypothyroidism, poorly controlled diabetes mellitus, and severe malnutrition. When appropriately interpreted, however, an elevated IGF-1 level is 90% specific for a growth hormone excess secondary to a pituitary adenoma.[5] For presentations with diagnostic uncertainty (eg, mildly elevated IGF-1 and equivocal symptoms), dynamic function (ie, suppression testing) with an oral glucose tolerance test is the primary laboratory investigation performed for possible growth hormone excess. The oral glucose suppression test involves an intake of 75 gm of glucose with measurement of growth hormone levels at 0, 60, and 120 minutes; a growth hormone level of <1 μg/L usually excludes the diagnosis of acromegaly.[27][5] Around 30% of patients with acromegaly can have increased prolactin levels. 

Additional diagnostic studies are frequently performed in patients with acromegaly to evaluate the comorbid conditions associated with this disorder. Patients with acromegaly have an increased risk of thyroid nodules or cancer and cardiac valve abnormalities; therefore, a thyroid ultrasound and echocardiogram should performed as clinically indicated. Furthermore, a colonoscopy is typically recommended to exclude colon cancer and polyps, which are also associated with elevated growth hormones.[5]

Adrenocorticotropic Hormone 

Cushing syndrome commonly has a delayed diagnosis due to clinicians being unfamiliar with the condition and the complicated testing modalities. After excluding exogenous steroid use, the diagnostic laboratory studies recommended for Cushing syndrome consist of confirming an abnormally elevated corticosteroid level and determining the underlying pathology (eg, ACTH-independent cortisol elevation, Cushing disease, or ectopic oversecretion). When confirming the presence of hypercortisolism, more than one laboratory test is typically performed. Following this confirmation, the etiology must be determined as this guides treatment decisions.[5][28]

• Tests for hypercortisolism confirmation
  • The midnight serum or salivary cortisol test is considered to have the highest specificity and sensitivity compared to other laboratory studies. A serum cortisol of >5 μg/dL or salivary cortisol >.15 μg/dL supports a diagnosis of Cushing syndrome. Cushing syndrome is associated with the loss of circadian rhythm cortisol production. Consequently, the expected nadir of cortisol at midnight is absent.[5]
  •  A 24-hour urine collection for free cortisol measures unbound cortisol excreted in the urine. The unbound fraction is the active fraction in serum and comprises 5% to 10% of the total circulating cortisol. Typically, a collection is repeated 2 or 3 times to increase the reliability of the results. Potential issues with this test are that patients must be able to provide an accurate urine collection and that this modality is not recommended in some patients (eg, those with significant renal impairment).[28]
  • An overnight dexamethasone suppression test (ODST) consists of dexamethasone 1 mg orally between 11 pm and midnight. A serum cortisol is measured the following day between 8 and 9 am. In individuals with normal findings, the cortisol is suppressed <1.8 μg/dL. An ODST has a high sensitivity, but the specificity is comparatively low. Medications affecting the absorption and metabolism of dexamethasone in the liver may affect results. For instance, phenytoin and phenobarbital therapy, which enhance the clearance of dexamethasone, can result in false-positive results. Additionally, false positives for the ODST may occur with some conditions, including obesity, depression, alcoholism, and high estrogen states, which can be etiologies for pseudo-Cushing syndrome. Retesting and monitoring patients for clinical improvement after treating these pseudo-Cushing syndrome conditions are strategies clinicians should consider to prevent inappropriate treatment.[28]
  • A low-dose dexamethasone suppression test (LDDST) is another option. With this test, dexamethasone 0.5 mg is taken orally at 9 am on day 0 and then every 6 hours for 48 hours. The serum cortisol is measured between 8 and 9 am at 24 and 48 hours. Clinicians may consider this testing modality to help differentiate an ACTH-dependent etiology and pseudo-Cushing syndrome.[28]
• Determination of hypercortisolism etiology
  • ACTH and cortisol measurement: After confirming the presence of hypercortisolism, a corticotrophin-releasing hormone (CRH) stimulation test is commonly used to measure ACTH and cortisol response to help determine the etiology of an individual's hypercortisolism. Normally, CRH is produced by the hypothalamus and stimulates the production of ACTH by the pituitary. This test administers CRH intravenously, and ACTH and cortisol are measured at baseline and short intervals after that. A rise in ACTH of greater than 40% and cortisol levels of greater than 20% indicate an ACTH-dependent cause, most likely Cushing's disease, because ectopic sources of ACTH are not usually responsive to CRH stimulation. A high-dose dexamethasone suppression test is not as accurate but can also be used. With this test, either dexamethasone 2 mg is administered every 6 hours for 48 hours or dexamethasone 8 mg is given once. Eighty percent of patients with Cushing disease will suppress cortisol to <50% of baseline levels.[28][29]
  • Diagnostic imaging: Findings of an ACTH level >15 to 20 ng/L indicate an ACTH-dependent Cushing syndrome etiology. Patients with ectopic ACTH production also usually have higher levels of ACTH than patients with Cushing disease.[29] A pituitary MRI should be performed in these patients to determine if an adenoma is present. However, low ACTH levels indicate an adrenal etiology, and an adrenal MRI or CT should be performed.[28]
  • Further diagnostic testing: A bilateral inferior petrosal sinus sampling (BIPSS) to confirm the presence of a pituitary lesion can also be considered when imaging is equivocal. During this invasive procedure, the inferior petrosal sinuses, into which the pituitary venous blood drains, are catheterized by a radiologist. ACTH is measured at baseline and following stimulation with 100 mcg of CRH from each inferior petrosal sinus (IPS) and peripheral veins. Prolactin measurements are also performed to confirm the catheter is in the correct position. A ratio of IPS to peripheral ACTH of 2:1 before CRH stimulation and 3:1 after stimulation is consistent with Cushing disease. Although the test is highly accurate in diagnosing a pituitary adenoma, some experts do not recommend utilizing it to locate which pituitary lobe is involved.[28]

Thyroid-Stimulating Hormone

Findings consistent with secondary hyperthyroidism include increased or unsuppressed TSH levels and elevated levels of free and total T4 and T3.[4][30] However, this picture is more commonly seen in the presence of laboratory interference and thyroid hormone resistance, which are more frequently encountered than TSH-producing pituitary tumors. Since glycoprotein hormones have α and β subunits, tumors can produce an excess of α subunits in TSHoma. If available, thyroid-releasing hormone (TRH) can be used for a stimulation test to verify if the TSH is of pituitary origin. With this testing method, TRH is given, and following TRH administration, TSH is measured. Patients with a TSH-producing tumor demonstrate an impaired response.

Gonadotropin Hormones

FSH, LH, estradiol, and testosterone levels may help ascertain the deficiency of these hormones secondary to a pituitary tumor. Rarely elevated FSH and LH may be associated with a gonadotropin-secreting adenoma; if suspected, further workup is required to assess the reproductive system. Women may present with enlarged ovaries and ovarian hyperstimulation syndrome, while men may present with enlarged testes and infertility. In children, there are often signs of precocious puberty.[18]

Treatment / Management

The management of hyperpituitarism depends on the underlying cause and the hormones affected.[4] Refer to separate specialized topics in Statpearls for further details on the specific treatments for each condition (eg, acromegaly, Cushing syndrome).

Pharmacological Therapy

Prolactinomas are the only pituitary adenomas in which long-term pharmacological therapy (eg, bromocriptine and cabergoline) is satisfactory. Unless there is an acute threat, pharmacologic management should always be preferred to surgical intervention. Dopamine agonists suppress prolactin effectively and decrease serum prolactin levels. Furthermore, they reduce galactorrhea, recover the gonadal function, and have also been found to cause tumor shrinkage. Medications can also include the use of somatostatin analogs and competitive receptor antagonists.[4] 

Pharmacologic management has only an adjunctive role for Cushing disease as the cornerstone of management is surgical intervention. The medications used are adrenal enzyme inhibitors (eg, metyrapone, aminoglutethimide, and ketoconazole).[4] Somatostatin analogs have been effectively used in patients with excessive growth hormone. Octreotide reduces circulating levels of growth hormone and IGF-1. Long-acting octreotide and lanreotide suppress growth hormone and IGF-1 more consistently.[31][8](A1)

Surgical Management

Transsphenoidal resection is the initial treatment recommended for most pituitary adenomas other than prolactinomas.[28] Resection of the pituitary gland and any tumor is technically challenging because of the anatomical location. Minimally invasive procedures are increasingly utilized, including transsphenoidal surgery for acromegaly, macroprolactinomas, and Cushing disease. However, as many patients with pituitary tumors often present late with large tumors, complete resection is usually not possible.[32] (B3)

In patients with microadenomas causing acromegaly, neurosurgeons can achieve clinical improvement in 80% to 90% of cases, and in patients with macroadenomas, 40% to 60% of cases are successful. For ACTH-secreting pituitary adenomas, neurosurgeons are typically successful in achieving clinical improvement in 80% to 90% of patients. Approximately 2% to 8% of growth hormone-secreting pituitary adenomas reoccur within 5 years; therefore, clinicians should repeat IGF-1 and growth hormone levels along with an oral glucose tolerance test around 12 weeks after surgery. An MRI should also be repeated to evaluate any tumor changes.[28](B3)

Radiotherapy

Conventional radiotherapy may be used to reduce tumor size and hormone levels in addition to surgery and pharmacologic therapy; however, pituitary damage and resultant hypopituitarism may occur.[28](B3)

Differential Diagnosis

Differential diagnoses of hyperpituitarism depend on the type of hormone involved. The following are some differentials that should be considered for each hormone.

Hyperprolactinemia

• Prolactinomas
• Destruction of hypothalamus
• Nipple stimulation
• Chest wall stimulation
• Pregnancy
• Drugs, such as antipsychotics

Hypercortisolism

• Corticotropinomas
• Primary adrenal tumors
• Ectopic ACTH-producing tumors
• Bronchial or thymic carcinoids

Elevated Growth Hormone

• Somatotropinomas
• GHRH-secreting tumors
• Bronchial carcinomas
• Carcinoids
• MEN type-1
• Tuberous sclerosis 

Elevated Gonadotrophins

• Primary Hypogonadism
• Testicular tumors
• Ovarian tumors
• Polycystic ovary syndrome
• Ovarian hyperstimulation syndrome

Prognosis

The prognosis for hyperpituitarism secondary to pituitary tumors depends on the size of the tumors and the underlying excess hormone.[16][33] The prognosis is typically excellent with complete tumor resection or only minimal tissue remains and is controlled with medications.[34][35][36] Both medical therapy and transsphenoidal surgery are treatment options for the various tumor types with reportedly good clinical outcomes.

Complications

Complications of hyperpituitarism depend on the specific hormonal effect as well as the pituitary tumor size. Individuals with macroadenomas may present with visual problems or other neurological manifestations when the tumor expands in other areas of the brain surrounding the pituitary gland. Patients with acromegaly frequently have comorbid conditions, including heart failure, gastrointestinal problems, cancer, and diabetes.[37] 

Patients with Cushing disease may suffer from hypertension, diabetes, heart issues, and osteoporosis.[36] Individuals with elevated TSH levels due to pituitary tumors can have arrhythmias and osteoporosis, while those with gonadotrophin-secreting adenomas may have infertility issues, especially when not diagnosed or managed promptly.[16]