Pituitary Microadenomas Treatment & Management

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.

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]

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

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

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

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.

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]

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]

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.