Pituitary Microadenomas

Updated: Nov 07, 2022
Author: Andre E Manov, MD, MSHM, FACP, CPE; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

By definition, a microadenoma (seen in the image below) is a tumor less than 10 mm in diameter. Pituitary adenomas may secrete hormones, but most are clinically inactive. Many pituitary lesions are discovered while investigating other neurologic problems; these lesions are called incidentalomas. With the use of magnetic resonance imaging (MRI) increasing, the discovery of incidental microadenomas has become relatively common. Nonsecreting pituitary microadenomas do not need to be surgically resected.[1, 2]  Secretory microadenomas, however, require further medical or surgical care.

MRI showing a nonenhancing area in the pituitary c MRI showing a nonenhancing area in the pituitary consistent with a microadenoma, in a patient with hyperprolactinemia.

The microadenoma may be discovered during an investigation for the cause of a clinically diagnosed hypersecretory syndrome such as hyperprolactinemia, acromegaly, or Cushing syndrome. In more than 90% of cases, a nonsecreting microadenoma is a nonfunctioning pituitary adenoma, although a variety of other cystic, vascular, neoplastic, hyperplastic, or inflammatory processes may present in a similar manner.

Signs and symptoms of pituitary microadenomas

Patients with prolactin-secreting adenomas may present with galactorrhea/menstrual disorders.

Growth hormone–secreting adenomas cause acromegaly, with coarsening of facial features and increased width of the hands and feet. Progressive bony proliferation of the mandible both lengthens and thickens it, resulting in separation of the lower teeth and an underbite. Skin thickness is increased compared with age- and sex-matched controls (>2 mm in reproductive-aged women, >3 mm in men). The clinical changes may be subtle or absent at the time of presentation.

Corticotropin-secreting adenomas cause Cushing disease, characterized by weight gain, primarily in the facial, nuchal, truncal, and girdle areas (ie, centripetal, or "buffalo," obesity). Protein breakdown leads to thin, friable skin that bruises easily; this breakdown may form wide striae that are often purple. In addition, this protein breakdown often causes muscle weakness (in proximal muscles more than distal ones), wasting, and osteopenia with fragility fractures. Women frequently develop hirsutism and menstrual changes. In children, growth is arrested. Depression/anxiety is common.

Workup in pituitary microadenomas

Individualizing the evaluation of microadenomas with an evidence-based approach while considering signs, symptoms, the size of the lesion, imaging characteristics, and patient factors is key. Endocrine Society clinical practice guidelines recommend a complete biochemical assessment, even in asymptomatic patients.[1]

Because the excess secretion of growth hormone does not always produce the above-described clinical phenotype, especially early in the course of the disorder, a serum insulinlike growth factor-1 (IGF-1) level is recommended in all cases.[1] Hormonal hypersecretion in the setting of a sellar mass is typically caused by a pituitary adenoma, and prolactin-secreting microadenomas are the most frequent secretory microadenomas.. Screening for Cushing syndrome is advised, using an overnight dexamethasone suppression test

Magnetic resonance imaging (MRI) studies have shown a sensitivity and specificity of about 90% for secretory tumors. Enhancement with gadolinium and enhanced dynamic images improve the detection rate. However, the sensitivity for detection of corticotropin-secreting adenomas is much lower (60-75%); in contrast, the incidental finding of nonsecreting microadenomas is sufficiently common that the diagnosis of a corticotropin-secreting adenoma after positive clinical and biochemical testing may then require specialized tests such as petrosal sinus sampling to confirm the anatomic diagnosis. Cystic lesions, such as Rathke cleft cysts, typically have a low-intensity signal on T1-weighted images, whereas on T2-weighted images, cystic lesions may have a high-intensity signal.[3] Pituitary hemorrhage results in a high-intensity signal on T1- and T2-weighted images.

Management of pituitary microadenomas

For prolactinomas, therapy with a dopaminergic drug is the treatment of choice (see Hyperprolactinemia). The most common are bromocriptine and cabergoline.

For prolactin-secreting microadenomas, surgical removal is followed by recurrence in 10-50% of patients. Therefore, medical therapy is preferred. Secretory tumors are best removed by the transsphenoidal approach.

Nonsecreting pituitary microadenomas rarely grow to produce mass symptoms and rarely become clinically secretory, so they are best merely observed. Observational studies show that some enlargement of nonsecreting pituitary adenomas may occur in 10% of patients, whereas reduction in size occurs in 6%.[2]

Pathophysiology

Most pituitary tumors are sporadic. Some are part of genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1), McCune-Albright syndrome, or Carney complex. Clonal analysis shows almost all are monoclonal in origin from a genetically mutated single cell. The cause of sporadic tumors is unknown. Familial pituitary tumors are described, and some have been found to result from germline mutations, such as aryl hydrocarbon receptor–interacting protein (AIP).[4]  The role of genetic mutations was highlighted in a report suggesting that patients with pituitary tumors from four Irish families shared a common mutation with a patient from the 18th century who had pituitary tumor–mediated gigantism.[5]

Of the secretory tumors, the most common are prolactinomas.[1] Other secretory tumors may secrete (1) corticotropin, causing Cushing disease; (2) growth hormone, causing acromegaly; (3) gonadotropins with clinical presentations reflective of severity and sex (rare); (4) or thyroid-stimulating hormone (TSH), causing hyperthyroidism (rare). Most clinically nonsecreting adenomas are gonadotropin in origin and secrete fragments of beta or alpha subunits of gonadotropin peptide. Such clinically inactive microadenomas are of little clinical consequence.[1, 2]

 

Epidemiology

Frequency

United States

Autopsy studies find pituitary adenomas, almost all being microadenomas, in 10-14% of cases. They occur in persons of all ages, with no sex predisposition or geographic variation. In the largest meta-analysis of autopsy studies, in which 18,902 pituitaries were examined in 32 reports, pituitary microadenomas were found in 10.7% of autopsies, while macroadenomas were found in less than 1%.[6]

In a surgical series of 1120 sellar masses, 91% were noted to be pituitary adenomas. Of these, 42% were non-functioning pituitary adenomas. Nineteen percent of secretory lesions were found to be prolactinomas, while 15% were growth hormone secretory, and 14% were corticotropin secretory.[1]

The use of MRI now may identify previously unsuspected presumed pituitary microadenomas. MRI studies in unselected populations have reported presumed microadenomas in 10-38% of individuals.[7]

The frequency of microadenomas and the scarcity of macroadenomas at autopsy indicate that microadenomas only rarely progress to macroadenomas and that most macroadenomas clinically present during life.

Mortality/Morbidity

Microadenomas do not cause excess mortality. These tumors generally are too small to cause pain, diplopia, or pressure on the optic chiasm. Otherwise-normal anterior and posterior pituitary function remains intact. Any morbidity is caused by excessive hormone secretion or patient anxiety.

Secretory microadenomas are typically treated medically or surgically.

Nonsecreting microadenomas are best clinically followed without treatment. Their natural history is that tumor enlargement is uncommon and is rarely clinically significant. There is tumor enlargement in 10% of patients, decreased size in 6%, and no change in about 83%.[1, 2] Acute changes from hemorrhage may rarely occur, but this is less common than with macroadenomas.

A population-based, retrospective, open-cohort study by Toulis et al indicated that prolactinomas in males, but not females, increase their risk of incident cardiovascular disease (CVD). The investigators found that males in the study had an incident CVD rate of 14.8 per 1000 person-years, compared with 1.8 per 1000 person-years for females.[8]  However, the majority of the men in this report likely had macroadenomas, and thus, many probably had some degree of hypopituitarism, which is associated with increased cardiovascular morbidity. This may not apply to patients with microadenomas and has not been noticed in clinical practice.

A retrospective study by Machado et al found that in patients with Cushing disease, those with microadenomas had a higher cortisol/adrenocorticotropic hormone (ACTH) ratio than did those with macroadenomas. The study also found that hirsutism, facial plethora, and muscular weakness and atrophy occurred more often in the patients with microadenomas, while nephrolithiasis, osteopenia, hyperprolactinemia, and galactorrhea occurred at a higher rate in those with macroadenomas.[9]

A study by Harbeck et al indicated that in patients with hypothalamic-pituitary disorders, those with microadenomas suffer from headache and depression more frequently than do those with macroadenomas.[10]  This is not appreciated in clinical practice, however, and the report's results may have arisen from incidental findings of microadenomas occurring when patients with headache and depression have had MRI studies.

A study by Nakhleh et al indicated that in patients with pituitary apoplexy, those with pituitary microadenomas have a better prognosis than do patients with pituitary macroadenomas. The investigators reported that in patients with macroadenomas, 30%, 44.4%, and 22.2% had hyponatremia, a random cortisol level below 200 nmol/L, and secondary hypothyroidism, respectively, on admission compared with 20%, 40%, and 16.7%, respectively, of those with microadenomas. At median 3-year follow-up, the rate of corticotropic deficiency and secondary hypothyroidism was 14.3% in patients with microadenomas, and 65% in those with macroadenomas.[11]

Race

No race predilection exists.

Sex

Microadenomas may occur in either sex. Prolactinomas, the most common secretory microadenoma, are diagnosed more frequently in women, possibly because of the more striking presenting features such as amenorrhea and/or galactorrhea.

Age

Microadenomas may occur at any age, as shown by autopsy studies, but the clinical prevalence appears to increase with advancing age.

 

Presentation

History

Types of pituitary microadenomas

Nonsecreting incidentalomas usually have no associated symptoms. They are ordinarily found in people who have radiologic studies for other reasons (eg, headaches). Unlike macroadenomas, incidentalomas are too small to cause pressure-related symptoms such as headache, diplopia, or visual-field loss. Moreover, they are not associated with hypopituitarism.[1, 2]

Prolactinomas may be asymptomatic if prolactin levels are only slightly elevated. In women, hyperprolactinemia may cause galactorrhea, oligomenorrhea/amenorrhea, decreased libido, or infertility. In men, hypogonadism, erectile dysfunction, and decreased libido may ensue. Galactorrhea is uncommon in men.

Corticotropin-secreting adenomas cause Cushing disease.

Growth hormone–secreting adenomas cause acromegaly.

Thyroid-stimulating hormone (TSH)–secreting adenomas are a very rare cause of hyperthyroidism, and the patient has a nonsuppressed serum TSH level. This biochemical pattern needs to be differentiated from thyroid hormone resistance.

Gonadotropin-secreting adenomas have been reported. The frequency is rare. Women may present with amenorrhea and a mismatch between estrogen and gonadotropin levels (eg, elevated gonadotropin levels despite normal or elevated levels estrogen levels without suppression of gonadotropins).[12] They may be misdiagnosed as having ovarian failure.

Physical

Any physical abnormalities are caused by excessive hormone secretion (eg, galactorrhea due to hyperprolactinemia, acromegaly due to excessive growth hormone, corticotropin-mediated Cushing disease). Most microadenomas found incidentally on CT scan or MRI are clinically inactive and neurologically silent.

Patients with prolactin-secreting adenomas may present with galactorrhea/menstrual disorders. Other causes of galactorrhea need to be excluded, such as hypothyroidism, chest wall lesions, and medications.

Growth hormone–secreting adenomas cause acromegaly, with coarsening of facial features and increased width of the hands and feet. Progressive bony proliferation of the mandible both lengthens and thickens it, resulting in separation of the lower teeth and an underbite. Skin thickness is increased compared with age- and sex-matched controls (>2 mm in reproductive-aged women, >3 mm in men).The clinical changes may be subtle or even not noticeable at the time of presentation.

Corticotropin-secreting adenomas cause Cushing disease, characterized by weight gain, primarily in the facial, nuchal, truncal, and girdle areas (ie, centripetal or "buffalo" obesity). Protein breakdown leads to thin, friable skin (2 mm in reproductive-aged women, < 3 mm in men) that bruises easily; this breakdown may form wide striae that are often purple. The protein breakdown often causes muscle weakness (proximal muscles more than distal muscles), wasting, and osteopenia with fragility fractures. Women often develop hirsutism. In children, growth is arrested. Depression/anxiety is common.

Causes

As with adenomas elsewhere, the likely cause of pituitary microadenomas is a local mutation leading to autonomous growth and/or secretion. A variety of tumor suppressor genes and oncogenes have been described in sporadic pituitary tumorigenesis.[13, 4]

 

DDx

Diagnostic Considerations

Sellar masses other than adenomas should be considered based on the radiologic appearance, concomitant symptoms, and biochemical testing. Sellar lesions can be cystic, benign, malignant, vascular, or inflammatory.

Differentials include:

  • Pituitary hyperplasia (lactotroph hyperplasia during pregnancy)
  • Rathke cyst
  • Dermoid cyst
  • Meningioma
  • Craniopharyngioma
  • Primary central nervous system (CNS) lymphoma
  • Germ cell tumor

Differential Diagnoses

 

Workup

Laboratory Studies

Individualizing the evaluation of microadenomas with an evidence-based approach while considering signs, symptoms, size of the lesion, imaging characteristics, and patient factors is key. Endocrine Society clinical practice guidelines recommend a complete biochemical assessment even in asymptomatic patients.[1]

Autonomous secretion by a tumor usually leads to an inappropriate relationship between the level of the hormone secreted by the peripheral gland (thyroid, adrenal, gonadal) and the amount of stimulating pituitary hormone (TSH, corticotropin, gonadotropin). That is, the normal decrease or suppression of the stimulating hormones found in conjunction with the rise of the peripheral gland hormones would not be demonstrated.

Hormonal hypersecretion in the setting of a sellar mass is typically caused by a pituitary adenoma, with the most frequent secretory microadenomas being the prolactin-secreting form.[3]  The prolactin level may correlate with the size of the adenoma;[3]  prolactin concentrations of more than 250 ng/mL are usually associated with macroadenomas and would warrant further imaging follow-up. The prolactin level can also be elevated as a result of factors such as pregnancy, breastfeeding, renal failure, cirrhosis of the liver, and primary hypothyroidism and with certain concomitant medications (antipsychotics/neuroleptics, antidepressants, antiemetics); elevation can also result from the stalk effect, in which a non-functioning adenoma compresses the pituitary stalk, leading to hyperprolactinemia. The prolactin level in the above instances is usually less than 100 ng/mL. However, certain medications, including risperidone and metoclopramide, can elevate the level above 200 ng/mL. 

A thorough history and a review of ongoing medication use are very important. Because excess secretion of growth hormone does not always produce the expected clinical phenotype, especially early on, evaluation of the serum IGF-1 level, age and gender adjusted, is recommended in all cases. Equivocal values warrant further serum growth hormone level measurement after an oral glucose load test.

A patient with Cushing disease may have an elevated or normal (non-suppressed) corticotropin level. Screening for Cushing syndrome with an overnight dexamethasone suppression test is advised. If positive, increased midnight salivary cortisol, the test for which needs to be repeated on a separate day, confirms the diagnosis of Cushing syndrome. Another possibility for the confirmation of Cushing syndrome is a grossly abnormal 24-hour urinary free cortisol test, which also needs to be repeated for confirmation on a separate day. This test usually becomes positive in more advanced cases of Cushing syndrome.

ACTH-secreting tumors can be as small as 5 mm or less in diameter.[14] The incidental finding of nonsecreting microadenomas is sufficiently common that the diagnosis of a corticotropin-secreting adenoma after positive clinical and biochemical testing may require specialized tests such as petrosal sinus sampling to confirm the Cushing disease diagnosis. This is especially appropriate if the microadenoma is less than 6 mm.

Thyrotroph adenomas characteristically lead to elevated serum free thyroxin (T4) and triiodothyronine (T3), with an inappropriately normal or elevated serum TSH level. Such patients may have hyperthyroidism without TSH suppression; however, it is necessary in these cases to differentiate between the presence a thyrotroph adenoma and thyroid hormone resistance.

Evaluation for hormonal hyposecretion is generally conducted in the presence of macroadenomas, since these larger tumors can destroy the hypophyseal gland, leading to the hyposecretion.

Imaging Studies

Microadenomas are generally confined to the pituitary gland/sella, and, given its high sensitivity and specificity, MRI is the imaging modality of choice for workup of these lesions. 

On MRI scans, normal pituitary tissue and pituitary adenomas have a signal that is similar to or slightly greater in intensity than that of CNS tissue. Enhancement with gadolinium improves the detection rate for pituitary adenomas. Microadenomas are isointense to the normal pituitary gland tissue on T1- and T2-weighted images. With contrast, however, these growths enhance at a slower rate than normal pituitary tissue does; dynamic enhanced images can detect this early enhancement difference and confer higher sensitivity for microadenoma detection. Rapid sequential images obtained during the first-pass arterial phase help to detect a microadenoma as a region of non-enhancing tissue, in contrast to the normally enhancing pituitary tissue surrounding it. These enhancement differences can be useful when adenomas are suspected (especially ACTH-secreting tumors) but conventional imaging is negative.[15]

Cystic lesions, such as Rathke cleft cysts, typically have a low-intensity signal on T1-weighted images but may have a high-intensity signal on T2-weighted images.[16]  Pituitary hemorrhage results in a high-intensity signal on both T1- and T2-weighted images.

Meningiomas typically have a brighter and more homogeneous signal than pituitary adenomas. They also have a suprasellar, rather than a sellar, epicenter and a dural-based attachment best seen after contrast enhancement 

Computed tomography (CT) scans are not very specific or sensitive for microadenomas. High-resolution CT scanning is complementary and may be used primarily if MRI is contraindicated. For best spatial resolution, CT scanning can be performed with 1-mm axial thin slices with contrast.

MRI showing a nonenhancing area in the pituitary c MRI showing a nonenhancing area in the pituitary consistent with a microadenoma, in a patient with hyperprolactinemia.

 

Other Tests

Other tests are dictated by the clinical picture of hormonal excess or, very rarely, hormonal deficiency. In contrast to macroadenomas, pituitary function testing is generally not needed for microadenomas. In addition, unlike pituitary macroadenomas, microadenomas rarely cause visual-field defects, and if there is no involvement of the optic chiasm on MRI, there is no need to perform the associated test.

Histologic Findings

If the tumor is removed surgically, immunohistochemical staining for secretory granules is advisable. If the test is negative and if it is clinically indicated, transcription factor immunostaining may identify the cell of origin for the adenoma.[17]

Staging

Staging is determined primarily by the size of the microadenoma. By definition, all are less than 10 mm and are likely to be confined to the sella.

 

Treatment

Medical Care

Microprolactinomas

For symptomatic microprolactinomas, therapy with a dopamine agonist (D2-receptor agonist) is the treatment of choice (see Hyperprolactinemia). The goal is to restore prolactin levels to normal, with return to a eugonadal state, and to reduce the tumor size, preserve pituitary function, improve bone mineral density, stop galactorrhea, and prevent disease progression and recurrence. Only 7-10% of microprolactinomas will progress to macroadenomas.

The most common dopamine agonists are bromocriptine (2.5-15 mg taken at night or given in divided doses up to three times a day) and cabergoline (0.25-3 mg weekly dose/0.125-1.5 mg given twice weekly). Cabergoline is the primary dopamine agonist used. It is also employed in cases of bromocriptine intolerance or resistance (although if there is intolerance to oral bromocriptine in a female patient, a transvaginal formulation is available).

The reasons for the preferential use of cabergoline over bromocriptine are better patient compliance (twice weekly versus three times a day dosing for bromocriptine), a longer half-life, a better side-effect profile, a higher affinity to D2 receptors on microprolactinomas, lesser resistance, and higher potency and efficacy. Cabergoline normalizes prolactin levels in patients with microprolactinomas in 80-90% of cases, shrinks the tumor in 80%, leads to resolution of amenorrhea and restoration of fertility in 72%, and results in resolution of galactorrhea in 86% of patients.[18, 19, 20] In patients taking bromocriptine, tumor shrinkage is achieved in 60% of patients. 

In prolactinomas that are resistant to bromocriptine, switching to cabergoline is frequently effective in overcoming the resistance, with prolactin levels decreasing to normal in 70-80% of patients.[20]  Resistance to bromocriptine is defined as failure of a 15 mg per day dose of the drug over at least 3 months to decrease the size of the microprolactinoma by over half and the prolactin level by more than 50%. Bromocriptine resistance is also defined as a failure to restore fertility and eugonadism.[21, 22, 23, 24, 25, 26, 19, 27, 28, 29, 20]

It is recommended, if the dose of cabergoline is higher than 2 mg per week, that echocardiograms be performed periodically to monitor for heart valve abnormalities.[30]

In post-menopausal women with microprolactinomas, treatment is not necessary. Similarly, in patients with microprolactinomas who are not seeking fertility and in the absence of hypogonadism and galactorrhea, treatment with a dopamine agonist is not indicated. In these instances, however, it is necessary to continue to follow up with the patient clinically and biochemically and to perform MRI of the hypophyseal area periodically. In pre-menopausal women with microprolactinomas and amenorrhea who do not desire pregnancy, consider treatment with oral contraceptives as an alternative to dopamine agonists. During pregnancy, dopamine agonists should be discontinued; the incidence of growth of microprolactinomas during pregnancy is very low, at approximately 2.4%.[31, 32]

For men with microprolactinomas and hypogonadism who do not seek fertility, testosterone administration without dopamine agonists will usually suffice.[21, 22, 26, 19, 27, 29, 31]

Acromegaly

Acromegaly due to microadenoma may be controlled medically with long-acting injectable somatostatin receptor ligands (iSRLs), dopamine agonists such as cabergoline, growth hormone receptor antagonists, or selective estrogen receptor modulators (SERM). However, medical treatment for acromegaly is usually considered second-line therapy. The primary treatment for the disease is transsphenoidal surgery (TSS) of the microadenoma.[33, 34, 35, 36]

Medical therapy for acromegaly is administered if the disease persists after TSS. Patients with persistent disease will demonstrate elevated IGF-1, random growth hormone levels of more than 1 mcg/L, or post–oral glucose tolerance test growth hormone levels of more than 1 mcg/L. Medical treatment is also used on patients who are poor surgical candidates. In addition, due to the delayed effect of stereotactic radiosurgery, medical therapy can be employed as adjunctive treatment to the procedure.

The success of the medical therapy depends on the tumor size, pretreatment IGF-1 level, and random growth hormone level, as well as the growth hormone granularity of the microadenoma.[36]  Research found that iSRLs controlled acromegaly in around 50% of patients, as measured by normal IGF-1, and in 60% of patients when assessed by a random growth hormone level of less than 2.5 mcg/L.[37]  Both a normal IGF-1 level and a random growth hormone level of less than 2.5 mcg/L were achieved in 40% of patients in this study using octreotide long-acting release (LAR) and lanreotide autogel.

The response to the iSRLs octreotide LAR and lanreotide autogel, as well as to oral octreotide, has been found to be better in tumors containing dense intra-tumoral growth hormone granules.[36] Such tumors possess more somatostatin receptor-2 (SST2) granules.[36, 37]  

The action of the iSRL pasireotide was found to be better in growth hormone microadenomas that are less densely granulated and contain more somatostatin receptor-5 (SST5) granules, achieving a better growth hormone response than octreotide LAR.[36]  However, tumors lacking SST5 granules but containing SST2 granules were seen usually to be resistant to pasireotide but, as stated, sensitive to octreotide LAR and lanreotide autogel. In addition, pasireotide leads to higher degree of glycemic dysregulation than those other therapies.[36]

ISRLs have been reported to reduce microadenoma volume in 59% of patients with acromegaly.[36, 38, 39]

In a meta-analysis conducted by Sandret et al, the D2-receptor agonist cabergoline normalized IGF-1 in 34% of patients with acromegaly; however, the response was less than that seen with iSRLs.[40]  The use of cabergoline is reserved for milder forms of acromegaly. In the same meta-analysis, adding cabergoline to iSRLs was able to normalize IGF-1 in 52% of patients with acromegaly[40] .

The growth hormone–receptor antagonist pegvisomant at 20 mg subcutaneously (SC) once daily normalized IGF-1 in 90% of patients with acromegaly. However, it is necessary with the use of this drug to monitor the size of growth hormone–secreting microadenomas, since pegvisomant was associated with enlargement of these lesions in 2.2% of patients.[38, 41]  Moreover, close monitoring of aspartate transaminase (AST) and alanine transaminase (ALT) was found to be necessary on a monthly basis in the first 6 months and periodically thereafter, with 1.2% of patients having demonstrated elevations of these enzymes to over three times the normal level.[38]  Used together, pegvisomant, with doses of up to 160 mg SC once a week, and iSRLs, administered once monthly, normalized the IGF-1 level in 95% of patients with acromegaly.[38]

In one study, the SERM raloxifene decreased growth hormone response in the liver and normalized IGF-1, in 45% of patients.[36] . Similar results were seen with another SERM, clomiphene. Rarely, SERM might help as an add-on drug, usually in some cases of acromegaly due to microadenomas of the hypophyseal gland.[38]

Cushing disease

Cushing disease is best treated with surgical resection of the microadenoma. If there is recurrent disease, a second TSS is recommended if possible.[38, 32, 42, 43] .

Medical management of Cushing disease is considered second-line treatment, usually occurring after surgical failure.[38, 44]  It includes the use of a long-acting iSRL like pasireotide and the dopamine agonist cabergoline. Both drugs act on pituitary microadenomas to decrease ACTH oversecretion. Other drugs used are the glucocorticoid receptor antagonist mifepristone and adrenal steroidogenesis inhibitors such as ketoconazole and the 11-beta-hydroxylase blockers (such as osilodrostat and metyrapone). Glucocorticoid replacement therapy is needed after successful surgery for ACTH-secreting microadenomas, until the hypophyseal adrenal axis recovers

Medical therapy for Cushing disease can be initiated even before treatment with TSS, in patients with severe metabolic derangement as well as in those with Cushing disease who are waiting for pituitary radiotherapy to take effect. It also can be started in patients in whom surgery and/or radiotherapy have failed as well as in individuals with no visible pituitary lesion who decline inferior petrosal sinus sampling, radiotherapy, or exploratory hemi-hypophysectomy (the latter two serving as temporizing measures until the lesion appears).[45]

Research found that in cases of Cushing disease, adrenally directed medical therapy with ketoconazole normalized urinary free cortisol in 50% of patients; with metyrapone, in 43% of patients; and with osilodrostat, in 46% of patients, after 6-8 months of treatment.[46, 47, 48, 49]

Mifepristone was reported to improve hemoglobin A1c (HbA1c) by 1% or more in 60% of patients with endogenous Cushing syndrome associated with type 2 diabetes mellitus/impaired glucose tolerance.[50]  Combination therapy with ketoconazole and metyrapone was very effective against Cushing disease, in one study normalizing urinary free cortisol in 70-80% of patients.[51, 52]

Hyperthyroidism

Microadenomas secreting excessive amounts of TSH and presenting with a clinical picture of hyperthyroidism are initially treated with iSRLs. Such therapy can be used before surgery for faster control of hyperthyroidism. ISRLs were reported to normalize free T4 (FT4) in 96% of patients, decrease TSH by more than 50% in over 90% of patients, and shrink TSH-secreting microadenomas by 46%.[38]  Research also found that approximately 4% of patients required methimazole or propylthiouracil (PTU), in addition to iSRLs, to control their hyperthyroidism before surgery.[53]  Some patients with TSH-secreting microadenomas may prefer to avoid TSS. In such instances, their disease can be controlled by iSRLs and close follow-up with repeat MRI, assessment of the clinical picture, and thyroid function tests.[53]

If the tumor enlarges or hyperthyroidism persists, then TSS is required.[38, 53]  For persistent hyperthyroidism after tumor removal with TSS, iSRLs are used. If there is incomplete tumor removal with TSS, without hyperthyroidism, then stereotactic radiosurgery can be utilized. If there is incomplete tumor removal after TSS and hyperthyroidism persists, then both radiosurgery and iSRLs are employed.

Nonsecreting pituitary microadenomas

Nonsecreting pituitary microadenomas are usually detected incidentally (incidentalomas).[38, 54]  They rarely grow to produce mass symptoms or cause visual field defects and are best merely observed. Observational studies showed that enlargement of nonsecreting pituitary microadenomas occurred in 10% of patients, whereas size reduction occurred in 6% of individuals, with lesion size in 83% of patients remaining unchanged.[38]

Usually, it is recommended that nonsecreting pituitary microadenomas be followed with MRI of the hypophyseal area at 1, 3, and 5 years.[38]  If the tumor does not change, no further studies are needed. If there is tumor growth or the occurrence of abnormal visual fields (which is extremely rare with non-functioning pituitary microadenomas), then TSS is recommended.

Additionally, follow-up is not routinely recommended for hormonal hypersecretion unless symptoms arise. Some nonsecreting pituitary microadenomas are clinically silent while revealing growth hormone, prolactin, ACTH, or TSH on immunostaining.[54]  If, in what had been a nonsecreting lesion, hypersecretion with symptoms occurs, the appropriate management, as described above, needs to be undertaken.

Surgical Care

Microprolactinomas

Prolactin-secreting microadenomas are best removed by TSS, which can be performed via an endoscopic endonasal approach. Most patients with microprolactinomas experience postoperative normalization of prolactin levels, but the success rate of surgery has nonetheless been found to be lower than that achieved with medical treatment with dopamine agonists.

The operative success rate is determined by the extent of the surgeon's experience and correlates inversely with the prolactinoma's size and the serum prolactin concentration. In a compilation of results from 31 published surgical series, serum prolactin normalized in 71% of 1224 patients with microprolactinomas. However, up to 100% cure rates for microprolactinomas have been reported by high-volume surgeons. Overall, the recurrence rate is less than 30%.[36, 38]

Although the results of medical therapy for microprolactinomas are superior to those attained through surgery, there remains a role for the operative approach. Surgery for microprolactinomas is indicated in symptomatic patients who are not responsive to dopamine agonist therapy, who are unable to tolerate an effective dose of cabergoline, or who have a rare cerebrospinal leak while undergoing dopamine agonist therapy, as well as in patients who have other, co-secreting hormones and those in whom long-term medical therapy is not feasible.

Surgical complications include anterior hypopituitarism, diabetes insipidus, cerebrospinal leak, epistaxis, tumor bed hemorrhage, and infection.

A study by Mattogno et al indicated that in the treatment of pituitary microadenomas, the microsurgical sublabial approach is more effective than the endoscopic endonasal technique[55] .

A study by Fraioli et al found that in patients with prolactin-secreting microadenomas who, following dopamine agonist treatment, underwent TSS, better postoperative results were achieved in individuals who had been on dopamine agonist therapy for less than a year than in those who had been treated with a dopamine agonist for over a year. The former group had a hormonal remission rate of 84%, with the overall rate of prolactinemia improvement with no need for medical treatment reaching 92%. In the group treated for more than a year, the hormonal remission rate was 33.3%, with the overall rate of prolactinemia improvement with the possibility of medical treatment discontinuation reaching 49.9%.[56, 57, 58]

Acromegaly

TSS is the primary treatment for acromegaly caused by a pituitary microadenoma, unless there is severe pharyngeal thickness or high cardiac output heart failure. Surgical cure rates for acromegaly due to a growth hormone–secreting microadenoma vary between 75% and 91%. If initial surgery is not successful and there is residual intrasellar tumor, a second surgery is recommended. The experience of the surgeon as well as the size and location of the microadenoma are the most important features determining the TSS success rate.[33, 34, 35, 36]

Cushing disease

For Cushing disease resulting from a microadenoma secreting an excessive amount of ACTH, the recommended first-line treatment is TSS of the hypophyseal tumor.[32]  Initial remission can be achieved in up to 80% of patients. Research found predictors of remission to be microadenoma of the hypophyseal area versus macroadenoma (83% vs 68%, respectively), imaging characteristics such as clear visibility of the pituitary adenoma on MRI (81% vs 69%), confirmed adenoma on histopathology (87% vs 45%), postoperative morning (a.m.) serum cortisol nadir of less than 2 mcg/dL, and lower preoperative 24-hour urine free cortisol.[38, 44]  A study determined the remission rate after a second TSS for recurrent disease to be 58%.[59]  Recurrence rates after primary and revision TSS have been reported as 18% and 28%, respectively, but recurrence rates of up to 50% after TSS have been found.[38, 59]  

The success of TSS is predicted by morning (a.m.) serum cortisol the day after surgery; levels of less than 5 mcg/dL correlate with successful resection, with levels of less than 2 mcg/dL increasing specificity.[44]  Occasionally, 72 hours of serum cortisol follow-up, with measurements taken every 6 hours, is needed to prove post-TSS remission.[44]

Bilateral adrenalectomy

Bilateral adrenalectomy is performed very rarely, being carried out in patients with Cushing disease due to pituitary microadenoma that is not controlled with TSS, radiation, and medications.[38, 32]

THS-secreting microadenomas

If patients with TSH-secreting microadenomas are euthyroid, then TSS is the treatment of choice, with a 90-100% success rate. It should be remembered that 70-90% of TSH-secreting adenomas are macroadenomas and that 30% of them cosecrete growth hormone or prolactin.[53]  

Nonsecreting pituitary microadenomas

Nonsecreting pituitary microadenomas do not typically need surgical resection. However, when tumor growth occurs, which can be the case in up to 10% of non-functioning pituitary microadenomas, or when tumors cause visual field defects, TSS is recommended. Surgery has a high success rate, with up to 95% of procedures resulting in complete tumor removal.[54]  If there is a post-TSS remnant of pituitary microadenoma (which is rare), the dopamine agonist cabergoline may prevent tumor recurrence, with nonsecreting pituitary microadenomas having D2 receptors and shrinking in response to the drug.[54]  Additionally, stereotactic radiosurgery can be used to prevent recurrent tumor growth of nonsecreting pituitary microadenomas.[38]

Consultations

Endocrinologic consultation is advisable if clinical evidence of hormone secretion or deficiency exists.

Diet

Diet depends on the disease activity and complications of hormone-secreting microadenomas.

Activity

Activity depends on the disease activity and complications of hormone-secreting microadenomas.

Complications

Major complications of microprolactinomas include tumor growth in 7-10% of patients, infertility, hypogonadism, and bone loss.

The major complications of untreated acromegaly due to microadenoma include progressive tumor growth in up to 10% patients, cardiovascular morbidity and mortality, secondary diabetes mellitus, gastrointestinal adenomas or cancers, and respiratory problems.

Major complications of untreated Cushing disease include increased cardiovascular morbidity and mortality, development of secondary diabetes mellitus, psychiatric problems, dyslipidemia, osteoporosis, venous thromboembolism, and hypertension..

Major complications of untreated TSH-secreting microadenomas are related to hyperthyroidism, such as cardiovascular and gastrointestinal complications; neurologic complications can also occur.[53]

Complications of nonsecreting pituitary microadenomas can arise from progressive tumor growth (in 10% of cases); very rarely, visual field defects occur. Furthermore, these tumors occasionally become secretory, in which case appropriate management, as previously described, should be initiated.[38, 54]

Patients on iSRLs need to be monitored for side effects of these drugs.

Due to an increased risk of venous thromboembolism after surgery, especially in patients with Cushing disease, appropriate deep venous thrombosis (DVT) prophylaxis must be instituted.

Long-Term Monitoring

Screening for bone loss using a bone density (DEXA) scan and monitoring for growth hormone excess by checking IGF-1 levels are warranted in microprolactinoma. Consider prolactin-level monitoring 1 month after starting medical therapy with dopamine agonists in symptomatic patients.[21, 22, 32] .

Monitoring microprolactinoma growth with MRI of the hypophyseal region at 1, 3, and 5 years is prudent. Consider stopping dopamine agonists after the microprolactinoma has been treated for at least 2 years, if the prolactin level is normal and there is no tumor remnant on MRI. After dopamine agonists are no longer being administered, check the prolactin level every 3 months at least for 1 year and then periodically after that. In patients who have undergone stereotactic radiosurgery, periodically monitor the prolactin level and levels of other pituitary hormones to exclude hypopituitarism.[38]

If the cabergoline dose is higher than 2 mg per week, periodic echocardiograms are recommended to monitor for any heart valve abnormalities.[30]

In patients with acromegaly due to pituitary microadenoma, check IGF-1 and random growth hormone levels 12 weeks after TSS. Achievement of surgical control can be assumed if random growth hormone levels are less than 1 mcg/L; it can be assumed that remission has occurred if growth hormone levels are less than 0.14 mcg/L. If random growth hormone levels are above 1 mcg/L, consider using an oral glucose tolerance test to assess surgical control of the disease. MRI is done at baseline and if there are clinical and biochemical signs of recurrence.[33, 34]

In patients treated with the growth hormone receptor antagonist pegvisomant, monitor the size of the growth hormone–secreting microadenoma with MRI, since progressive enlargement of the tumor was reported in 2.2% of patients receiving this therapy. Additionally, use of this drug requires monitoring of AST and ALT monthly over the first 6 months and periodically thereafter; elevations over three times the upper limit of AST/ALT were seen in 1.2 % of patients.[38]  Using IGF-1 levels, rather than random growth hormone concentrations, to monitor for the effect of treatment with pegvisomant is recommended because growth hormone levels can also increase with this drug.

In patients who have received stereotactic radiosurgery for acromegaly, IGF-1 levels, random growth hormone concentrations, and other pituitary hormone levels should periodically be monitored to exclude hypopituitarism.[60, 38]

In Cushing disease, use the morning cortisol level to monitor for successful TSS outcome. The goal is less than 5 mcg/dL, with increasing specificity if it is less than 2 mcg/dL.[44]  Normalization of a.m. cortisol after successful TSS usually is demonstrated within 24 hours, although occasionally it can take up to 72 hours post surgery.[44]  Monitoring for recurrent disease is done primarily by checking midnight salivary cortisol at 1, 3, 6 and 12 months post TSS and annually thereafter. If Cushing disease does recur, MRI of the hypophyseal area is recommended. If MRI is not conclusive with regard to recurrence, then inferior petrosal sinus sampling should be performed before proceeding with repeat TSS.[51, 42, 45]

To assess recovery of the hypophyseal adrenal axis in patients receiving replacement doses of glucocorticoids post TSS for Cushing disease, monitoring of morning serum cortisol or serum cortisol response to the ACTH stimulation test is warranted before discontinuing the glucocorticoids. [45]

Close monitoring of blood pressure in patients receiving a 11-beta-hydroxylase blocker (osilodrostat or metyrapone) is recommended. Avoid these medications in patients with uncontrolled hypertension, since they increase aldosterone precursors and worsen hypertension.[47, 52]

Using liver function tests, closely monitor patients taking ketoconazole, as this drug is hepatotoxic; avoid administering ketoconazole in patients with known liver disease.[32]  Additionally, monitor for QT prolongation, and avoid using ketoconazole, pasireotide, and osilodrostat in patients with underlying QT prolongation. Also, patients taking mifepristone need to be monitored for hypokalemia.

In patients with TSH-secreting microadenomas who refuse surgery and prefer treatment with iSRLs, methimazole, or PTU, periodically monitor microadenoma growth with MRI of the hypophyseal area. Also, thyroid function testing is needed to monitor for adequate control of hyperthyroidism.[53]

Nonsecreting pituitary microadenomas are usually detected incidentally (incidentalomas). Observational studies show that for these lesions, enlargement may occur in up to 10% of patients, whereas size reduction occurs in 6% of individuals, while in 83% of patients the microadenoma remains unchanged.[38]  Clinical follow-up is usually not required unless symptoms arise. Typically, it is recommended that nonsecreting pituitary microadenomas be followed with MRI of the hypophyseal region at 1, 3, and 5 years.[38]  If the tumor does not change in size, no further studies are normally indicated. If there is tumor growth or if, in extremely rare cases, abnormal visual fields ensue, then TSS is recommended.[38, 54]  Disease recurrence decreases if postoperative stereotactic radiosurgery is utilized.[38]

Radiation therapy

Microprolactinomas

Stereotactic radiosurgery is the preferred mode of radiotherapy for treating patients with microprolactinomas who refuse TSS or in whom the surgery has failed and who are resistant or intolerant to dopamine agonists.[61, 62]  Research showed that 54% of patients with microprolactinomas had normalized prolactin levels at 8 years following stereotactic radiosurgery, and fewer patients had hypopituitarism. Approximately 25% had new hormonal deficiency, and 3% of patients had visual complications.[23, 38] Conventional radiotherapy has a less prominent role in treating microprolactinomas due to lower success rates and higher complication rates.

Acromegaly

Stereotactic radiosurgery for acromegaly is recommended if there is disease resistance despite surgery and/or medical therapy.[60, 36]  It can be used as primary therapy if surgery is contraindicated or refused by the patient. In a study by Sheehan et al of 1303 patients, biochemical remission was achieved in 43.5% of patients, the mean follow-up period being 51.5 months. Hypopituitarism was seen in 14.9% of patients.[60, 36, 63] Stereotactic surgery is often used in conjunction with medical therapy because of delayed onset of maximal effect of radiotherapy.

Cushing disease

Stereotactic radiosurgery for Cushing disease is a second-line therapy that is carried out in patients who have failed TSS. Due to its delayed effect, it is frequently, in Cushing disease, used together with medical therapy.[43]  Stereotactic radiosurgery is more successful in patients with Cushing disease than in those with prolactinomas or acromegaly.[45]

TSH-secreting microadenomas

Stereotactic radiosurgery of TSH-secreting microadenomas is used as an adjunct to TSS. If there is incomplete tumor removal after TSS, without hyperthyroidism, then stereotactic radiosurgery is used. On the other hand, if there is incomplete tumor removal after TSS and hyperthyroidism persists, then radiosurgery and iSRLs are used together. These are extremely rare scenarios in patients with TSH-secreting microadenomas, more often happening in patients with TSH-secreting macroadenomas.[53]

Nonfunctioning pituitary microadenomas

Stereotactic radiosurgery may be employed after TSS for nonfunctioning pituitary microadenomas that have enlarged during follow-up. It was found that if no visible tumor was revealed on postoperative MRI, stereotactic radiotherapy decreased regrowth of nonfunctioning pituitary microadenomas.[54]

Management of microprolactinoma during pregnancy

Enlargement of microprolactinomas in pregnancy is very unusual, occurring in about 2.4% of pregnant patients with these lesions.[31]  Dopamine agonists used for the treatment of microprolactinomas should be stopped at the diagnosis of pregnancy. Follow-up of patient symptoms is needed every 3 months. If headache worsens or (in unusual cases) new visual symptoms develop, MRI of the brain as well as visual field testing must be performed. Dopamine agonists may be reinstituted if there is evidence of tumor enlargement, with the usual accepted practice during pregnancy being bromocriptine therapy. There is no need to monitor prolactin levels during pregnancy.

 

Medication

Medication Summary

For the most common microadenomas, that is, prolactinomas, administer a dopaminergic drug such as bromocriptine or cabergoline (see Hyperprolactinemia). Cabergoline is preferentially used because in patients with microprolactinomas it leads to normalization of prolactin levels in 83% of patients, compared with 53-70% of patients taking bromocriptine. Also, with cabergoline, restoration of ovulatory cycles and fertility is achieved in 72% of patients with microprolactinomas, compared with 52% of patients taking bromocriptine. Tumor shrinkage and resolution of galactorrhea occur in, respectively, 80% and 86% of patients with microprolactinomas taking cabergoline, while in patients taking bromocriptine, tumor shrinkage is achieved in 60% of patients.[20, 32]

The superior efficacy of cabergoline is related to the drug's higher affinity to D2 receptors on microprolactinomas. Also, cabergoline is preferentially used because of better patient compliance, being taken once or twice a week versus daily or up to three times a day for bromocriptine (this difference being due to cabergoline's longer half-life). In addition, cabergoline has fewer side effects than bromocriptine and so is better tolerated. Moreover, in 70-80% of patients with microprolactinomas who are resistant to bromocriptine, switching to cabergoline leads to normalization of prolactin levels.

For patients with microadenomas that are oversecreting TSH and who present with hyperthyroidism, the use of iSRLs is appropriate before TSS. They normalize FT4/FT3 in 96% of patients and decrease TSH by more than 50%; iSRLs also reduce tumor size in more than half of patients. Sometimes they are used long-term in patients refusing TSS, which is the primary treatment for the disease. Research found that approximately 4% of patients required methimazole or PTU in addition to iSRLs to control their hyperthyroidism before surgery.[53]

Dopamine agonists

Class Summary

Dopamine agonists directly stimulate dopamine receptors on the lactotrope. The dopaminergic neurons in the tuberoinfundibular process normally inhibit the secretion of prolactin from the anterior pituitary by secreting dopamine. In a study of 827 patients with hyperprolactinemia (81 of whom had macroadenomas), Corenblum found that treatment with bromocriptine normalized hyperprolactinemia in 85%, reversed symptoms in 93%, and reversed hypogonadism in 94%.[64] Similar results are reported with cabergoline, which has less intolerance and resistance.[18]

Bromocriptine (Parlodel)

Bromocriptine is a semisynthetic ergot alkaloid derivative, strong dopamine D2-receptor agonist, and partial dopamine D1-receptor agonist. It inhibits prolactin secretion, with no effect on other pituitary hormones. It may be administered with food to minimize the possibility of gastrointestinal irritation. Bromocriptine is given 1-2 times per day.

Cabergoline (Dostinex)

Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Prolactin secretion by the anterior pituitary is primarily under hypothalamic inhibitory control exerted through dopamine. Cabergoline is administered 1-2 times per week.

Somatostatin Analogs

Lanreotide (Somatuline Depot)

Lanreotide depot is long-acting somatostatin analog given to patients with acromegaly who have inadequate response to or cannot be treated with transsphenoidal surgery (TSS) or radiotherapy. The drug is given via deep subcutaneous injection every 4 weeks. It decreases oversecretion of growth hormone in acromegaly. There is, additionally, an autogel form, which is also administered subcutaneously. Lanreotide decreases growth hormone and IGF-1 levels.

Octreotide (Sandostatin LAR, Bynfezia Pen, Mycapssa)

Octreotide depot is a long-acting somatostatin analog for long-term treatment of patients with acromegaly who have an inadequate response to or cannot be treated with surgery and/or radiotherapy. The drug is given by deep subcutaneous injection every 4 weeks. It may sometimes be used in conjunction with radiotherapy, because of the delayed effect of radiation treatment. It reduces the oversecretion of growth hormone in acromegaly, decreasing growth hormone and IGF-1 levels.

Pasireotide (Signifor, Signifor LAR)

Pasireotide long-acting release (LAR) is a long-acting somatostatin analog for long-term treatment of patients with Cushing disease or acromegaly who have an inadequate response to or cannot be treated with surgery and/or radiotherapy. The drug must be given intramuscularly by a trained health-care specialist every 4 weeks. It may sometimes be used in conjunction with radiotherapy, because of the delayed effect of radiation treatment. The drug decreases growth hormone oversecretion and IGF-1 in acromegaly and the oversecretion of ACTH in Cushing disease.

There is a short-acting form of the drug used in the treatment of Cushing disease, that is administered twice daily subcutaneously.

Octreotide (Mycapssa, Bynfezia Pen, Sandostatin)

Mycapssa is an oral octreotide administered as a delayed-released capsule. It is a somatostatin analog for the treatment of acromegaly that is resistant to TSS or radiotherapy, for use in patients who refuse both treatments, or for administration when TSS for acromegaly is contraindicated. It is administered (with a glass of water) on an empty stomach at least 1 hour before or 2 hours after a meal. Its effect is comparable to that of iSRLs for the treatment of acromegaly. It decreases growth hormone and IGF-1 levels.

Metabolic & Endocrine, Other

Pegvisomant (Somavert)

Pegvisomant is a highly selective growth hormone receptor antagonist that is used to treat acromegaly. The drug blocks hepatic production of IGF-1 under the influence of growth hormone. It is given subcutaneously once daily, with titration based on IGF-1 level. The drug is used in patients who have recurrent disease after TSS for acromegaly or who refuse surgical/radiation treatment for acromegaly; it is also sometimes given with iSRLs to control the disease.

Selective Estrogen Receptor Modulators

Clomiphene (Clomid, Serophene)

This drug is used in patients with acromegaly accompanied by hypogonadism who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy, as an add-on therapy to somatostatin analogs and dopamine agonists. The dose used is 50 mg PO daily. Clomiphene decreases growth hormone–mediated IGF-1 production by the liver.

Raloxifene (Evista)

This drug is used in patients with acromegaly who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. The dose used is 60 mg twice daily PO. However, raloxifene is used only rarely for the treatment of acromegaly. It decreases IGF-1 production by the liver resulting from oversecretion of growth hormone.

Antifungals, Systemic

Ketoconazole (Nizoral)

Ketoconazole is used for the medical management of Cushing disease. It discourages the first step in cortisol synthesis by inhibiting 11-beta-hydroxylase. The daily dose is usually 600-800 mg PO.

Diagnostics, Endocrine

Metyrapone (Metopirone)

Metyrapone treats Cushing disease by inhibiting the production of adrenal steroids. It inhibits 11-beta-hydroxylase, the enzyme required for synthesis of cortisol from 11-deoxycortisol. It also inhibits aldosterone synthase, the enzyme required for synthesis of aldosterone from 11-deoxycorticosterone. The dose varies between 0.5-6 g per day. It is usually given to patients who are resistant to or refuse TSS and in those patients who are resistant to or refuse radiotherapy.  

Steroidogenesis Inhibitors

Osilodrostat

Osilodrostat treats Cushing disease by inhibiting the production of adrenal steroids. It inhibits 11-beta-hydroxylase, the enzyme required for the synthesis of cortisol from 11-deoxycortisol. It also inhibits aldosterone synthase, the enzyme required for the synthesis of aldosterone from 11-deoxycorticosterone. To a lesser degree, it inhibits a proximal step in steroidogenesis. It is usually given to patients who are resistant to or refuse TSS and to patients who are resistant to or refuse radiotherapy. The dose is 2-7 g tablets given twice daily.

Antithyroid Agents

Methimazole (Northyx, Tapazole)

Methimazole is used, albeit rarely, in patients with TSH-producing microadenomas and central hyperthyroidism, in those who refuse TSS and who remain hyperthyroid despite the use of iSRLs, and, together with iSRLs, in patients with central hyperthyroidism (in order to achieve euthyroidism before TSS).

Propylthiouracil (PropylThyracil, PTU)

Propylthiouracil is used, albeit rarely, in patients with TSH-producing microadenomas and central hyperthyroidism, in patients who refuse TSS and who remain hyperthyroid despite the use of iSRLs, or, together with iSRLs, in patients with central hyperthyroidism (in order to achieve euthyroidism before TSS).

 

Follow-up

Further Outpatient Care

The natural history for nonfunctioning microadenomas appears to be benign.[1, 2]  Follow-up MRI can be performed at 1, 3, and 5 years to assess for growth. For nonsecreting microadenomas, clinical follow-up is usually not needed unless clinical symptoms arise. If the tumor enlarges or the clinical picture dictates, full endocrine testing and potential therapy are justified.

Prognosis

The prognosis depends on the hormonal activity of the adenoma.[4] Most incidentalomas are inactive and do not cause morbidity, and a meta-analysis showed that microadenomas rarely enlarge (3.3 per 100 patient-years).[2]  Patient anxiety may result from the discovery of the microadenoma, and appropriate support may be needed.

Patient Education

The patient must be informed of the frequency of incidentalomas and the benign nature of those that do not enlarge or secrete excess hormones.

 

Questions & Answers

Overview

What are pituitary microadenomas?

How are pituitary microadenomas diagnosed and treated?

What is the pathophysiology of pituitary microadenomas?

What is the prevalence of pituitary microadenomas in the US?

What is the mortality and morbidity associated with pituitary microadenomas?

What are the racial predilections of pituitary microadenomas?

What are the sexual predilections of pituitary microadenomas?

Which age groups are at highest risk for pituitary microadenomas?

Presentation

What are the signs and symptoms of pituitary microadenomas?

Which physical findings are characteristic of pituitary microadenomas?

What causes pituitary microadenomas?

DDX

Which conditions should be included in the differential diagnoses of pituitary microadenomas?

What are the differential diagnoses for Pituitary Microadenomas?

Workup

What is the role of lab testing in the workup of pituitary microadenomas?

What is the role of imaging studies in the workup of pituitary microadenomas?

What is the role of visual-field testing in the diagnosis of pituitary microadenomas?

Which histologic findings are characteristic of pituitary microadenomas?

How are pituitary microadenomas staged?

Treatment

How are pituitary microadenomas treated?

What is the role of surgery in the treatment of pituitary microadenomas?

Which specialist consultations are beneficial to patients with pituitary microadenomas?

Which dietary modifications are used in the treatment of pituitary microadenomas?

Which activity modifications are used in the treatment of pituitary microadenomas?

Medications

What is the role of medications in the treatment of pituitary microadenomas?

Which medications in the drug class Dopamine agonists are used in the treatment of Pituitary Microadenomas?

Follow-up

What is included in the long-term monitoring of pituitary microadenomas?

Which medications are used in the treatment of pituitary microadenomas?

What are the possible complications of pituitary microadenomas?

What is the prognosis of pituitary microadenomas?

What is included in patient education about pituitary microadenomas?