Clinical and endocrine features of pituitary microadenomas

Prolactin-releasing pituitary microadenomas

Prolactin-releasing pituitary microadenomas (microprolactinomas) are mainly found in young women of reproductive age, while macroprolactinomas are more common in men [20—22]. Clinical picture is manifested by hyperprolactinemia syndrome. Women have menstrual irregularities [23]. Unlike macroprolactinoma with high incidence of amenorrhea, microprolactinoma is often associated with oligomenorrhea.

Microprolactinomas are rarely detected in men. Probably, this is due to unclear clinical picture. Clinical symptoms are impaired libido, erectile dysfunction, impaired sperm quality and infertility.

Blood prolactin level usually correlates with tumor dimension. Macroprolactinomas are usually followed by prolactin level of 10,000 mU/L (500 ng/L) and even 1 million mU/L (50,000 ng/L) in case of giant tumor. On the contrary, microprolactinomas are usually associated with prolactin level of 3,000—5,000 mU/L (150—250 ng/L). In a large-scale multiple-center study conducted in Brazil, mean prolactin level for microprolactinoma was 165.6 ng/L (͌3477 mU/L), for macroprolactinoma — 1244.9 ng/L (͌26000 mU/L) [24].

Dopamine agonist therapy is preferred for prolactinoma and ensures normalization of prolactin level and decrease of tumor dimension in most patients. Cabergoline is the most effective drug with prolonged action. This medicine is highly effective in the treatment of prolactin-releasing pituitary micro- and macroadenomas.

According to current international and national guidelines, decrease or cancellation of dose is recommended no earlier than after 2 years of continuous treatment. Essential requirements are long-term normalization of prolactin level and significant reduction of tumor or its absence according to MRI data. Complete recovery is highly likely in patients with microprolactinoma undergoing dopamine agonist therapy for at least two years [10].

Some patients with microprolactinoma and asymptomatic course of disease do not require medication due to low probability of tumor growth. This approach is advisable in premenopausal patients with ensured preservation of menstrual cycle and in peri- and postmenopausal women when elevated prolactin levels do not contribute to the development of hypogonadism [10, 25].

Surgical treatment of microprolactioma is indicated in patients with resistance to dopamine agonists or intolerance to these drugs. Moreover, this approach may also be an alternative to medication. Transsphenoid surgery is an effective treatment for microprolactinoma and small endosellar tumors. Clinical outcomes and economic costs of simultaneous resection of these tumors are comparable to those with medication over a 10-year period. Various trials included a total of 627 patients. According to these data, effectiveness of surgical treatment of microprolactinoma determined by early postoperative normalization of prolactin reaches 83.2% with a recurrence rate of 10.3%. In general, these values ensure successful long-term outcomes in 75% of cases if surgery is performed by experienced “pituitary” surgeons [26—29].

In our opinion, R. Salvatori correctly noted that surgical treatment should be discussed in a patient (especially young age) with microprolactinoma considering the modern achievements of endoscopic technologies. Indeed, an effectiveness of surgical and drug treatment is approximately equal while timing of achievement of the desired result differs fundamentally (years for drug therapy and immediate result for surgical treatment) [26, 30].

Differential diagnosis of PMA followed by hyperprolactinemia includes endocrine-inactive PMA and benign hyperprolactinemia, in particular, primary hypothyroidism, macroprolactinemia syndrome (prevalence of complexes of prolactine molecules with immunoglobulin G characterized by high molecular weight and low activity), drug-induced hyperprolactinemia. The drugs affecting dopamine system include anticonvulsants, antidepressants (amitriptyline, etc.), H2-histamine receptor blockers (cimetidine, etc.), dopamine synthesis inhibitors (methyldopa, etc.), calcium channel blockers (verapamil), dopamine blockers (metoclopramide etc.), acetylcholine antagonists, various antipsychotics, opiates and cocaine drugs, as well as combined oral contraceptives with high level of estrogen.

Growth hormone-releasing PMA

Acromegaly is a severe neuroendocrine disease caused by growth hormone-releasing pituitary adenoma. Acromegaly is associated with chronic hypersecretion of growth hormone and insulin-like growth factor 1 (IGF-1). Acromegaly is a rare disease. The prevalence of acromegaly is 2.8—13.7 cases per 100,000, incidence is 0.2–1.1 cases per 100,000 [4, 31, 32].

Diagnostic criteria for acromegaly have dramatically changed over the years and the number of patients with this disease has increased significantly. This is due to a better awareness of physicians about this disease and improved laboratory diagnosis and MRI scanners. So, L.M. Davidoff reported 100 surgical cases of acromegaly in 1926. X-ray data of enlarged sella turcica were observed in 93% of patients, large pituitary tumors followed by compression of chiasm and optic nerves and visual disturbances – in 62% [33]. These indicators have significantly changed in subsequent years. Incidence of visual impairment has decreased to 27% for the period from 1951 to 1975 as a result of better awareness of this disease. Availability of growth hormone level analysis and CT has resulted decrease of the incidence of visual impairment to 15.4% in 1976—1996. Analysis of IGF-1 was used for diagnosis of acromegaly at the end of the 70s of the last century, MRI – since the 90s. These measures ensured early diagnosis in patients with mild manifestations and small tumors, so that prevalence of large adenomas associated with visual impairment has decreased to 5.2% in 1982—2006 [34].

Nevertheless, PMAs are much less common in patients with acromegaly in contrast to prevalence of PMA among microprolactinomas. According to the trial conducted in the Liège city (Belgium), pituitary macroadenomas were identified in 71.6% out of 3173 patients with acromegaly. PMA were significantly more common in older patients, while macroadenomas with invasion into cavernous sinuses predominated in young people [35].

According to the literature, patients with growth hormone-releasing PMA have less pronounced clinical manifestations of acromegaly than patients with macroadenoma. A special group of patients with "micromegaly" and mild symptoms (or their absence) has been recently identified. Moderate hypersecretion of IGF-1 and normal level of growth hormone are typical for these patients. Patients with micromegaly were significantly older (mean age 52±2 years) while mean age of patients with high levels of growth hormone was 44±1.4 years. Moreover, PMAs were significantly more common compared with patients with high levels of growth hormone. P. Petrossians et al. revealed PMAs in 48% of cases among 48 patients with micromegaly. However, PMAs were diagnosed only in 12% among 108 patients with high levels of growth hormone. In patients with PMAs, normal level of growth hormone was detected in 64% of cases, high level of growth hormone — only in 36% of cases [34].

Thus, growth hormone-releasing PMAs are more often detected in older people, accompanied by milder clinical manifestations compared to macroadenomas, normal levels of growth hormone and moderate elevation of IGF-1.

The goals of treatment of growth hormone-releasing PMAs are elimination of tumor, normalization of the levels of growth hormone and IGF-1, regression of symptoms, management of complications of acromegaly and reducing the risk of mortality from comorbidities (cardiovascular and respiratory dysfunction, diabetes mellitus, etc.).

Pituitary adenomectomy is preferred for the management of acromegaly. In specialized “pituitary” centers, complete resection of PMA is performed in 80–95% of patients with acromegaly [36].

Medication is used in case of contraindications for surgery, partial resection of pituitary tumor. Preferable drugs are prolonged analogues of somatostatin, which are more effective for PMA compared with macroadenomas. Adjuvant therapy after partial resection of tumor also includes dopamine agonists. These drugs may be prescribed for moderate manifestations of acromegaly and/or more than 2 norms of IGF-1. These signs usually characterize growth hormone-releasing PMAs [37].

Radiotherapy for acromegaly is used only if surgical approach and medication are ineffective.

ACTH-releasing pituitary microadenoma

In 85% of cases, ACTH-releasing tumors are represented by microadenomas with a diameter of 1—2 mm localized in the central part of adenohypophysis [19].

Pituitary hypersecretion of ACTH results chronic hypersecretion of cortisol in adrenal cortex and manifestation of Cushing's disease. The last one is followed by dysplastic obesity, hypertension, impaired fertility, carbohydrate metabolism, osteoporosis, cognitive impairment and other disorders [38, 39].

According to the guidelines, at least two tests are necessary for diagnosis of hypercorticism: saliva cortisol at 23:00 and serum cortisol in the morning after previous oral intake of dexamethasone 1 mg at 23:00 (suppression test). Additional examinations are indicated if data of these tests are controversial (cortisol urine test, serum cortisol in the evening). Analysis of ACTH in the morning is necessary if two tests confirm hypercorticism. Contrast-enhanced MRI of the brain (1.5—3.0 T MRI scanner) is required in case of cortisol level ≥10 pg/ml [40]. Imaging of microcorticotropinoma was an extremely difficult task until 1980 when MRI became the main method for diagnosis of these tumors. MRI was able to detect tumors up to 5 mm in diameter [41, 42].

Undoubtedly, endoscopic endonasal transsphenoid adenomectomy is the main and most effective method of treatment of PMA in patients with Cushing's disease. This procedure ensures high remission rate (65—90%) after preoperative MRI [43, 44].

However, Cushing's disease may be caused by very small PMA which cannot be detected even on the most sensitive MRI scanners. These are the so-called MRI negative PMAs. These tumors are characterized by significantly lower remission rates [45]. High-resolution MRI with a slice width of 1 mm may be valuable to detect PMA prior to surgery. This method makes it possible to diagnose PMA even if visualization is absent during conventional MRI [45, 46]. Another option is contrast-enhanced MRI [46].

These cases comprise an extremely difficult problem for pituitary surgeons considering the absence of a clear surgical target. Diagnostic bilateral blood sampling from inferior petrous sinuses is usually used to determine ACTH gradient including stimulation with corticoliberin in patients with suspected Cushing's disease and no MRI data on pituitary adenoma [39]. However, this method is not absolutely reliable for pituitary adenomas [45]. Some ACTH-releasing PMAs may be outside the sella turcica including mucosa of sphenoid sinus, cavernous sinus or neurohypophysis. Surgeons should analyze advisability of total or partial resection of pituitary gland if adenoma is not found after a thorough intraoperative examination of adenohypophysis. Remission occurs in 60—75% of patients after total or partial hypophysectomy. However, almost all of these patients develop postoperative panhypopituitarism.

R.F. Dallapiazza offers hemihypophysectomy (on the side of high ACTH gradient determined by selective blood sampling from inferior petrous sinuses) or subtotal hypophysectomy. Thus, 30% of the gland is resected from the either side and 20% from the lower side. Only 20—30% attached to pituitary stalk is preserved. In these cases, incidence of postoperative pituitary insufficiency is only 15—20%. The criterion of hypercorticism remission after resection of pituitary micro- and macroadenomas is a decrease of cortisol level in the morning <50 nmol/L in early postoperative period.

Recurrence rate after resection of microcorticotropinoma is 5—10% after 5 years and 10—20% after 10 years [45, 46]. Redo neurosurgical treatment is also preferred for recurrent Cushing's disease. Medication and radiotherapy for microcorticotropinoma are mainly used in case of contraindications to surgery or absence of remission of hypercorticism after neurosurgical treatment.

TSH-secreting microadenoma

The criterion of TSH-secreting pituitary adenoma (thyrotropinoma) is visualization of tumor at normal or elevated levels of TSH, elevated concentrations of thyroxine and triiodothyronine. TSH hypersecretion is followed by advanced stimulation of thyroid function and clinical picture of “central” hyperthyroidism.

TSH-PMA is a rare pituitary tumor. These neoplasms account for 0.5% –2% of all pituitary tumors, overall prevalence is 1—2 cases per 1 million [47]. According to the recent data of the Swedish registry of pituitary tumors, there is an increase of the incidence of TSH-PMA for the period from 1990 to 2009. In 2010, this value was 2.8 per 1 million [12].

Previously, TSH-PMA were considered casuistic tumors and usually diagnosed at the stage of large invasive pituitary macroadenomas. However, supersensitive endocrine laboratory methods and high-resolution neuroimaging, as well as higher awareness of endocrinologists and general practitioners ensured earlier identifying TSH-PMA of small dimensions. Thus, PMA are recorded more often in the last decade.

TSH-PMA are manifested by hyperthyroidism (from asymptomatic and mild symptoms to severe thyrotoxicosis) [48, 49]. Severity of PMA-associated hyperthyroidism is often much less than expected by the level of thyroid hormones. Cardiac toxicosis with atrial fibrillation and/or heart failure are very rare [50].

By the moment of tumor diagnosis, these patients may have a long history of incorrectly diagnosed Graves’ disease (diffuse toxic goiter). Symptoms of this disease are also associated with hyperthyroidism, but they develop due to the effect of antibodies on TSH-receptors rather TSH per se [51]. Rare diagnosis of these tumors and insufficient awareness of physicians on clinical features and diagnosis of central hyperthyroidism may be followed by overdiagnosis of diffuse toxic goiter or other thyroid diseases accompanied by hyperthyroidism. Moreover, unjustified thyroid surgery (for example, thyroidectomy and/or therapy with radioactive iodine in 30% of patients) is also possible [50, 52]. In this case, treatment is followed by decrease of the level of circulating thyroid hormones and tumor growth activation. The mechanism is similar to the development of Nelson's syndrome after bilateral adrenalectomy in patients with Cushing's disease.

Some patients can appeal for a medical care due to symptoms of acromegaly or menstrual irregularities in women. This is caused by concomitant production of prolactin (10% of cases) or growth hormone (16% of cases) by TSH-releasing tumors [50].

Adenomectomy is preferred for TSH-PMA. The goal of surgical treatment of TSH-releasing micro- and macroadenomas is their total resection and normalization of thyroid hormones [53].

Remission rate in patients with TSH-releasing PMA is 80—100% compared with 44—81% in patients with macroadenomas [54]. Undetectable serum TSH may be a good indicator of total resection. Importantly, undetectable level of TSH is accepted as concentration below functional sensitivity of diagnostic method (<0.01 mU/l).

Therapy with somatostatin analogues reduces TSH level, normalizes levels of thyroxine and triiodothyronine and restores euthyroidism in 90% of cases although adenomectomy is preferable approach. Analogues of somatostatin are effective in achieving euthyroidism in patients with TSH-PMA and mixed TSH- and growth hormone-releasing tumors and may be an alternative to surgical treatment [47].

Early diagnosis of these tumors and differential diagnosis with other diseases accompanied by hyperthyroidism are extremely important. Currently, diagnosis of TSH-PMA at the stage of microadenoma accompanied by hyperthyroidism without compression symptoms (visual and neurological disorders) is being gradually improved.

Endocrine-inactive pituitary microadenoma

Endocrine-inactive pituitary microadenoma are not associated with clinical manifestations and usually detected as incidentalomae. Perhaps, endocrine-inactive pituitary microadenoma is expectable approximately in every fifth human. Management of these patients is of great interest [1].

Currently, availability of MRI scanners and various examinations has significantly increased the number of people who are referred by various specialists without regard to endocrine disorders (headache, dizziness, etc.) or go on their own for “check-up” diagnosis (a set of preventive medical examinations for analysis of person’s health) including diagnostic MRI.

Interpretation of MRI data may be ambiguous. Not all suspicious neoplasms within sella turcica are pituitary adenomas. Microadenoma may be suspected in case of intrasellar small neoplasm with a diameter of less than 10 mm. The tumor is localized in anterior lobe of pituitary gland and displaces pituitary stalk posteriorly. If endocrine disorders are absent, differential diagnosis should include Rathke’s cleft cyst, small intrasellar craniopharyngioma, etc. [15, 55].

It is also necessary to differentiate pituitary adenoma and pituitary hyperplasia. The last one may be observed in physiological conditions (pregnancy, adolescence), inflammation of pituitary gland and intracranial hypotension syndrome (confirmed by orthostatic headache and MRI data) [56]. In recent series, pituitary adenomas accounted 71% of initially diagnosed pituitary incidentalomas [57].

According to national and international guidelines, it is necessary to exclude endocrine activity of the tumor in a patient with microincidentaloma (namely, hyperprolactinemia, acromegaly, hypercorticism) [5, 58]. Therefore, analysis of serum prolactin and IGF-1, saliva cortisol at 23:00 and suppression test are required. Some authors propose an additional analysis of TSH and T4 to exclude rare central hyperthyroidism. Surveillance may be advisable if endocrine activity of tumor is absent.

Can endocrine-inactive pituitary microadenoma lead to hypopituitarism? There is no clear answer this question in the latest clinical guidelines of the European Society of Endocrinology. Examination for hypopituitarism is recommended for microincidentalomas over 6—9 mm. Routine screening for hypopituitarism is not required for smaller PMA since its probability is very low. Follow-up endocrine testing is also not recommended for endocrine-inactive pituitary microadenoma because clinical picture of these tumors remains the same. None patient with endocrine-inactive pituitary microadenoma had pituitary disorders. However, these trials are extremely few [5].

A follow-up MRI of pituitary gland is recommended in 1 year after detection of endocrine-inactive pituitary microadenoma. If dimensions of microincidentaloma do not change, “wait and see” approach is advisable (MRI after 1—2 years for 3 years with subsequent increase of interval between studies) (Fig. 2).

Neuroophthalmological examination (visual fields and visual acuity) is necessary in patients with PMA if the tumor is being enlarged and localized near to optic nerve chiasm. This survey is not indicated in patients without symptoms, tumor enlargement and compression of optic nerve chiasm.

Medication for pituitary incidentaloma has not been systematically studied. Some parallels with the effects of drug therapy on hormone-inactive macroadenomas are possible. According to the literature, effectiveness of therapy with dopamine agonists for endocrine-inactive macroadenomas significantly varies. Administration of cabergoline or bromocriptine in patients with residual postoperative tumor tissue is followed by reducing tumor dimensions 8—45% of cases, degree of reduction varied from 10 to 62% (3—14 mm). Administration of somatostatin analogues ensured decrease of tumor dimensions in 5—25% of cases, stabilization — in 83% of cases of endocrine-inactive adenomas. Nevertheless, current data are insufficient for routine therapy of microincidentaloma [5].

Considering high prevalence of endocrine-inactive pituitary microadenoma and need for follow-up examination of these patients, it should be remembered that the cost of this survey is an important issue. American researchers B.R. Randall et al. analyzed the cost of examination in a specialized pituitary center including 2-fold contrast-enhanced MRI, serum hormones, initial and repeated consultations of neurosurgeon, endocrinologist and radiologist. The cost ranged from 6061 to 6215$ per a patient with microincidentaloma. Therefore, high costs in healthcare system are expected [59].