Pituitary Microadenomas 

Updated: Mar 23, 2018
Author: Bernard Corenblum, MD, FRCPC; 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 MRI increasing, the discovery of such incidental microadenomas will become more of a clinical problem.

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 of hyperprolactinemia, acromegaly, or Cushing syndrome. A nonsecreting microadenoma is a nonfunctioning pituitary adenoma in more than 90% of cases, although a variety of other cystic, vascular, neoplastic, hyperplastic, or inflammatory processes may present in a similar manner.

Workup and management

In the absence of symptoms or signs suggesting excess of specific hormones, the most cost-effective strategy is simply measurement of the prolactin level.[1]

If clinical suspicion of Cushing syndrome, acromegaly, or other hormone excess exists, order appropriate tests. Because excess growth hormone secretion may not produce the clinical phenotype in all cases, especially if early in the course, a serum insulinlike growth factor-1 (IGF-1) level is recommended in all cases.

Magnetic resonance imaging (MRI) studies have shown sensitivity and specificity of about 90% for secretory tumors. Enhancement with gadolinium diethylenetriaminepentaacetic acid (DTPA) improves the detection rate. Sensitivity for detection of corticotropin-secreting adenomas is much less (60-75%); diagnosis may require specialized tests such as petrosal sinus sampling.

For prolactinomas, therapy with a dopaminergic drug is the treatment of choice (see Hyperprolactinemia). The most common are bromocriptine and cabergoline. Cabergoline is the primary dopamine agonist used, or it is used if there is bromocriptine intolerance or resistance. Nonsecreting microadenomas only need observation.

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.

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.

Of the secretory tumors, the most common are prolactinomas.[2] 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.[3]

The role of genetic mutations was highlighted in a report suggesting that patients with pituitary tumors from 4 Irish families share a common mutation with a patient from the 18th century who had pituitary tumor–mediated gigantism.[4]

Epidemiology

Frequency

United States

Autopsy studies find pituitary adenomas, almost all microadenomas, in 10-14%. Meta-analysis of autopsy studies showed microadenomas in 22% and 14% on imaging studies.[5, 6] They occur in persons of all ages, with no sex predisposition.

Although clinically silent during life, the most frequent did immunostain for the presence of prolactin. The use of MRI now may identify these previously unsuspected presumed pituitary microadenomas.

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.

International

A study of 3048 autopsies found one or more adenomas in 316 pituitary glands (10%), the majority being less than 3 mm. Immunostaining for prolactin was positive in 40%.[7] There does not appear to be any difference in incidence from worldwide studies.

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[8] or patient anxiety.

Secretory microadenomas are almost all medically or surgically treated.

Nonsecretory 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%, decreased size in 10%, and no change in 80% of microadenomas.[9] 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.[10]

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.[11]

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.[12]

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, but 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.

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

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).[13] 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.

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

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).

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. 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.

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.[14]

 

DDx

Diagnostic Considerations

Other problems to be considered

The radiological pituitary lesion may reflect nonadenomatous causes, which include cysts (eg, Rathke cleft cyst, which is usually in the midline), vascular changes, or other local pathological neoplastic or inflammatory processes.

As with all pituitary adenomas, it may be part of a multiple endocrine neoplasia type 1 (MEN1) syndrome. Family history is usually present. Other hypersecretory states, such as hyperparathyroidism, may need to be assessed.

Differential Diagnoses

 

Workup

Laboratory Studies

Current management strategies are controversial.[15] In the absence of symptoms or signs suggesting excess of specific hormones, the most cost-effective strategy is simply measurement of the prolactin level.[1]

If clinical suspicion of Cushing syndrome, acromegaly, or other hormone excess exists, order appropriate tests. Because excess growth hormone secretion may not produce the clinical phenotype in all cases, especially if early in the course, a serum insulinlike growth factor-1 (IGF-1) level is recommended in all cases. Screening tests for Cushing syndrome, such as overnight dexamethasone suppression test, 24-hour urinary free cortisol, or midnight salivary cortisol are usually not routinely performed unless there is clinical suspicion for this disorder.

Autonomous secretion by a tumor usually shows an inappropriate relationship between the level of the hormone secreted by the peripheral gland (thyroid, adrenal, gonadal) and the stimulating pituitary hormone (thyroid-stimulating hormone [TSH], corticotropin, gonadotropins). For example, a patient may be hyperthyroid without TSH suppression (must be differentiated from thyroid hormone resistance) or a patient with Cushing disease may have an elevated or normal (nonsuppressed) corticotropin level.

Imaging Studies

MRI studies (as seen in the image below) have shown sensitivity and specificity of about 90% for secretory tumors. Enhancement with gadolinium diethylenetriaminepentaacetic acid (DTPA) improves the detection rate. Sensitivity for detection of corticotropin-secreting adenomas is much less (60-75%); diagnosis may require specialized tests such as petrosal sinus sampling.

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.

Computed tomography (CT) scans are not very specific or sensitive for microadenomas.

Unless the microadenoma is secretory, the actual pathology remains presumptive.[16, 17]

Other Tests

Other tests are dictated by the clinical picture of hormonal excess or, very rarely, hormonal deficiency. For larger functional microadenomas, especially those located in an area where upward pressure on the optic chiasm may exist, assessment of visual fields may be useful in monitoring therapy. Computer-assisted perimetry may be more sensitive than Goldman perimetry. In contrast to pituitary macroadenomas, microadenomas rarely cause any visual-field defects.

Histologic Findings

If the tumor is removed surgically, immunohistochemical staining for secretory granules is advisable. This would be the only definitive tissue diagnosis for the cause of a nonsecreting tumor.

Staging

Staging is determined primarily by the size of the microadenoma. By definition, all are less than 10 mm.

 

Treatment

Medical Care

For prolactinomas, therapy with a dopaminergic drug is the treatment of choice (see Hyperprolactinemia). The most common are bromocriptine and cabergoline. Cabergoline is the primary dopamine agonist used, or it is used if there is bromocriptine intolerance or resistance.

Acromegaly may be medically controlled with long-acting somatostatin analogues, dopamine agonists such as cabergoline, or growth hormone receptor antagonists. For microadenomas, medical therapy is an alternative to surgical resection.

Cushing syndrome is best treated with surgical resection of the microadenoma, if possible. Medical alternatives, especially after surgical failure, include a new long-acting somatostatin agonist pasireotide, a glucocorticoid receptor antagonist mifepristone, or adrenal steroidogenesis inhibitors such as ketoconazole.

Nonsecreting microadenomas only need observation. Clinical observation may be routine or may only occur if new symptoms develop. Whether serial MRI scanning is needed is controversial, as few microadenomas enlarge and only rarely cause clinical symptoms. Some guidelines and expert opinion recommend no routine follow-up MRI scanning unless clinical symptoms occur, others suggest a repeat MRI after 1 year, and some recommend serial MRI scanning over many years. The best cost-effective approach is yet to be identified.[18, 1]

Surgical Care

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. Some centers have used gamma-knife radiation for recurrent tumors.

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.[19]

A study by Fraioli et al found that in patients with prolactin-secreting microadenomas who, following dopamine agonist treatment, underwent transsphenoidal surgery, better postoperative results were achieved in patients 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%.[20]

A retrospective study by Shirvani et al indicated that in patients with Cushing disease undergoing transsphenoidal surgery, remission is influenced by tumor size and consistency and by cavernous sinus extension. Among the 96 patients in the study (mean follow-up 44 mo), early remission occurred in 94.8%, with 68.8% of the study’s patients having microadenomas. Lower remission rates were found in cases of macroadenomas, cavernous sinus invasion, and harder tumor consistency.[21]

Nonsecreting pituitary microadenomas do not need to be surgically resected.[22]

Consultations

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

Diet

No specific diet is necessary.

Activity

No restriction of activity is necessary.

 

Medication

Medication Summary

If the tumor is secreting excess hormone (eg, prolactin, growth hormone, corticotropin, gonadotropins (rarely), thyroid-stimulating hormone [TSH] [rarely), initiate appropriate medical therapy as described in the articles on Acromegaly and Cushing disease. For the most common microadenoma, ie, prolactinomas, administer a dopaminergic drug such as bromocriptine or cabergoline (see Hyperprolactinemia).

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%.[23] Similar results are reported with cabergoline, which has less intolerance and resistance.[24]

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 possibility of gastrointestinal irritation.

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.

 

Follow-up

Further Outpatient Care

The natural history for nonfunctioning microadenomas appears to be benign.[9, 18] Follow-up MRI scans can be performed at 12 months to assess progression, but generally they are not needed for most microadenomas, For nonsecreting adenomas, follow-up is usually not needed unless clinical symptoms arise. If the tumor enlarges, full endocrine testing and therapy are justified.

Inpatient & Outpatient Medications

If the tumor is secreting excess hormone, initiate appropriate medical therapy as described in the articles Hyperprolactinemia, Acromegaly, and Cushing disease.

Complications

Complications are caused by the rare enlargement of the tumor to a macroadenoma or by excessive hormone secretion.

Inactive microadenomas rarely cause complications unless they are pressing on the pituitary stalk.

Prognosis

Prognosis depends on the hormonal activity of the adenoma.[8] Most incidentalomas are inactive and do not cause morbidity, except morbidity related to excessive investigation. Patient anxiety may result from the discovery of the microadenoma, and appropriate support may be needed. A meta-analysis showed that microadenomas rarely enlarge (3.3 per 100 patient-years [95% confidence interval, 2.1-4.5]).[3]

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 hormone.

For excellent patient education resources, visit eMedicineHealth's Women's Health Center and Men's Health Center. Also, see eMedicineHealth's patient education articles Amenorrhea and Impotence/Erectile Dysfunction.

 

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 global prevalence of pituitary microadenomas?

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 vision 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?