Pituitary Adenomas: From Anatomy to Diagnosis

Richard Kundelis / Faculty of Medicine, Lithuanian University of Health Sciences, Medical Academy

Introduction

The pituitary gland, also known as the hypophysis, consists of three parts: the anterior pituitary, or adenohypophysis; the intermediate lobe; and the posterior pituitary, or neurohypophysis. In the adenohypophysis, stimulated by releasing factors from the hypothalamus, prolactin (PRL), growth hormone (somatotropin), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH) are produced and secreted. The intermediate lobe of the pituitary gland is responsible for the production of melanotropin, while the neurohypophysis stores vasopressin and oxytocin synthesized in the supraoptic and paraventricular nuclei of the hypothalamus.

The pituitary gland is located in the sella turcica, a structure formed by the sphenoid bone. As a tumor grows, this bony structure causes it to expand upward toward the optic chiasm. The resulting mass effect may manifest as the most common symptoms of optic nerve compression, as well as other neurological symptoms. Furthermore, destruction of the pituitary gland or compression of the remaining healthy glandular tissue often leads to the development of partial or complete hypopituitarism (1).

Pituitary adenomas are usually benign lesions and are classified as functioning, secreting one or more hormones, or non-functioning tumors. Functionally active variants are further classified according to the hormone secreted into prolactinomas, somatotropinomas, ACTH-producing adenomas, and the less common TSH-secreting or gonadotropin-secreting adenomas. Non-functioning adenomas that do not cause clinical symptoms are called incidentalomas.

Classification according to size is equally important because it helps determine the treatment strategy. Adenomas smaller than 10 mm are considered microadenomas, while those larger than 10 mm are considered macroadenomas (1, 2). The latter occur approximately 15% less frequently.

Epidemiology

With expanding possibilities for clinical diagnosis and imaging, the previously prevailing view that pituitary adenomas belong to a group of rare pathologies is changing. According to cancer registry data, pituitary adenomas are among the most common intracranial tumors. According to data from the Central Brain Tumor Registry of the United States from 2005–2009, the most common brain tumors were meningiomas (35.5%), gliomas (15.8%), and pituitary adenomas (14.1%) (2). Pituitary adenomas also ranked third in Japanese statistics, accounting for 18.2% (2).

Despite these relatively high frequency rates, some researchers believe that data provided by cancer registries do not reflect the actual situation. Findings from autopsies and various imaging studies suggest that the frequency of pituitary tumors may be considerably higher. A systematic analysis conducted in 2004 showed that, on average, this pathology could be detected in 14.4% of autopsies and 25.5% of imaging studies. The same analysis also estimated the overall prevalence of this type of tumor in the general population at approximately 16.7% (3). Therefore, it is evident that the detection of adenomas during autopsies and radiological examinations does not reflect the true prevalence of clinically significant adenomas.

Data are available on the distribution of adenomas among different age groups, sexes, and races (2). In childhood, ACTH-secreting adenomas are the most common; however, pituitary gland lesions are very rare in childhood and adolescence, accounting for only 1–10% of all diagnosed tumors. Prolactinomas are most common between the second and fourth decades of life, while non-functioning variants are more common later in life.

These neoplasms are diagnosed more frequently in women under 50 years of age, with the highest incidence among women aged 20–39 years. After the sixth decade of life, this pathology is more common in men. A higher incidence rate has been observed among African Americans, although no clear correlation has been established.

Up to 95% of pituitary adenomas are sporadic, and tumorigenesis is associated with the activation of proto-oncogenes and reduced expression of tumor suppressor genes. The remaining 5% are closely associated with familial syndromes, the most common of which are MEN1 and MEN4 (multiple endocrine neoplasia) syndromes, Carney complex, and familial isolated pituitary adenomas (FIPA) (2).

MEN1 syndrome is characterized by clinical hyperparathyroidism, pancreatic islet tumors, and adenohypophyseal tumors. MEN4 syndrome develops due to a mutation in the cyclin-dependent kinase inhibitor (CDNK1B). It is characterized by tumors of the parathyroid glands and pituitary gland and, occasionally, tumors of the adrenal glands, kidneys, and reproductive organs (6).

Carney complex manifests with pigmented skin and mucosal lesions, cardiac and cutaneous myxomas, and multiple endocrine system tumors (7). FIPA is defined as pituitary adenomas objectively detected in two or more family members without other characteristic features of syndromes. This disorder may be caused by mutations in the AIP or GPR101 genes (8).

Clinical Presentation

Symptoms of pituitary adenomas most commonly arise due to increased or decreased hormone production and the pressure effects caused by the growing tumor. Depending on the histological type of the adenoma, increased hormone production may manifest as hyperprolactinemia, acromegaly, Cushing's disease, or other symptoms (Table 1).

Direct pressure from the tumor on healthy pituitary tissue or the vascular network may disrupt the normal secretion of biologically active substances and lead to partial or complete hypopituitarism—a condition characterized by a clinically significant deficiency of gonadotropic hormones of varying degrees (1, 9).

The most common neurological symptoms are headache and visual disturbances. Headache, which occurs due to stretching of the dura mater, does not necessarily correlate with tumor size. However, it has been observed that patients diagnosed with a non-functioning or gonadotropin-producing adenoma complain of headaches more frequently (1).

Pressure from the tumor on the optic chiasm may lead to visual field deficits, usually presenting as bitemporal hemianopia. As compression increases or invasion of the optic nerve occurs, visual acuity may deteriorate. If the tumor spreads laterally and invades the cavernous sinus, the nerves controlling eye movements—the oculomotor, trochlear, and abducens nerves—as well as cranial nerves innervating a significant part of the face, including branches of the trigeminal nerve, may be affected (10).

Diagnosis of Pituitary Adenomas

In patients presenting with symptoms related to hormone hypersecretion, specific tests may be performed to evaluate the hypersecretion syndrome (Table 2). In up to 30% of cases, pituitary adenomas are also associated with signs of insufficient secretion of other hormones.

For this reason, it is recommended to measure serum prolactin, insulin-like growth factor 1 (IGF-1), LH, FSH, and free thyroxine concentrations. Cortisol hypersecretion may be assessed by measuring cortisol concentration in a 24-hour urine sample, nighttime salivary cortisol, or performing a 1 mg overnight dexamethasone suppression test (1).

The imaging method of choice when a mass in the sellar region is suspected is MRI with and without contrast. CT is not recommended because of its limited ability to assess the optic chiasm, but it may be performed when MRI is contraindicated. Patients reporting visual disturbances should undergo a thorough ophthalmological examination to rule out other, simpler causes of these changes.

Prolactinoma

As mentioned, prolactinoma is both the most common pituitary adenoma and the most common cause of pathological hyperprolactinemia. However, when hyperprolactinemia is diagnosed, conclusions should not be drawn prematurely. It may be caused by physiological factors such as pregnancy, breastfeeding, and recent sexual intercourse; medications, particularly antipsychotics; systemic conditions such as kidney or liver failure; and endocrine disorders such as hypothyroidism and Cushing's disease.

Other pituitary or sellar region tumors may also cause hyperprolactinemia when compression of the pituitary stalk reduces the inhibitory effect of dopamine on lactotroph cells of the adenohypophysis. Other causes of hyperprolactinemia include macroprolactinemia, PRL receptor mutations, and idiopathic hyperprolactinemia, which is diagnosed after all other possible causes have been excluded.

In premenopausal women, the most common symptoms are oligomenorrhea or amenorrhea (90% of women), galactorrhea (80%), and infertility. In older postmenopausal women, these symptoms are less common, so they more frequently seek medical attention because of symptoms caused by the mass effect.

In men, the most common findings are macroprolactinomas, which present with typical neurological symptoms and nonspecific signs such as decreased libido and erectile dysfunction, while gynecomastia and galactorrhea are relatively rare.

When clinical symptoms of hyperprolactinemia are present, serum prolactin concentration should be evaluated. The increase in prolactin concentration often correlates with tumor size: in cases of microprolactinoma, the concentration is 50–300 ng/ml, while in cases of macroprolactinoma, it may reach up to 5,000 ng/ml.

In cases of very large prolactinomas, a hook effect may occur, in which concentrations of the analyzed substance greatly exceed the upper limits of the normal range, often resulting in falsely negative results. In such cases, it is recommended to repeat the test using a 1:100 dilution.

In a normally functioning body, dopamine released by the hypothalamus controls prolactin secretion through negative feedback. For this reason, first-line treatment for prolactinoma consists of dopamine agonists, which successfully reduce blood prolactin concentrations and tumor size in approximately two-thirds of cases. Approximately half of patients regain fertility.

Currently, the ergot derivatives bromocriptine and cabergoline are most commonly used, although non-ergot derivatives such as quinagolide are also available. Cabergoline, a specific D2 receptor agonist, is more effective and causes fewer adverse effects; therefore, it may be prescribed in cases of aggressive macroprolactinoma and to patients who are intolerant of bromocriptine or have not responded to treatment with it.

According to the literature, 80% of patients respond to the standard dose of cabergoline. However, in 3–12% of cases, the disease is resistant to medical treatment, and a similar proportion of patients cannot take medication because of adverse effects. In such cases, the only option is surgical treatment of the adenoma—transsphenoidal adenomectomy.

Other indications for surgical treatment include macroadenomas causing symptoms of optic chiasm compression, symptomatic pituitary apoplexy, and cerebrospinal fluid leakage due to tumor invasion into the sella turcica. Clinical studies show that remission after surgical treatment is achieved in approximately three-quarters of cases of microprolactinoma and only one-third of cases of macroprolactinoma.

Radiation therapy is the last resort for patients who, for certain reasons, cannot undergo medical or surgical treatment. Unfortunately, prolactinomas are considered among the most radiation-resistant pituitary neoplasms, with normalization of prolactin concentrations observed in approximately 31.4% of patients.

Somatotropinoma

The clinical presentation of somatotropinoma directly depends on age. If it develops before closure of the epiphyseal growth plates, gigantism develops over time. If the condition develops later, after closure of the growth plates, acromegaly occurs.

Acromegaly progresses slowly and affects all body systems, but patients often do not seek medical attention for a long time because of the gradual progression of the disease. On average, the diagnosis is established approximately 8 years after the onset of the first symptoms. Since more than 80% of diagnosed growth hormone-producing tumors are macroadenomas, visual disturbances are the most common reason for patients to consult a specialist.

During diagnostic evaluation, other typical signs of the disease are also identified: coarse facial features, enlarged hands and feet (55–100%), increased sweating (52–91%), menstrual cycle disturbances (32–87%), headaches (37–87%), and arthritis (30–45%). Other frequently diagnosed conditions include carpal tunnel syndrome, diabetes or impaired glucose tolerance, erectile dysfunction, sleep apnea, and hypertension.

Epidemiological studies have shown that approximately 60% of deaths in patients with acromegaly are due to cardiovascular diseases, 25% to respiratory diseases, and the remainder to malignant neoplastic processes. The diagnosis of acromegaly is confirmed by an elevated serum IGF-1 concentration. In cases of uncertain changes in the concentration of this substance, a dynamic glucose tolerance test may be performed: if growth hormone suppression is less than

ACTH-Producing Adenoma

An ACTH-secreting pituitary adenoma causes Cushing's disease, the most common cause of endogenous Cushing's syndrome. In approximately 50% of patients, a microadenoma smaller than 5 mm in diameter is detected, making it difficult to identify on imaging studies. For this reason, compression-related manifestations are not typical of this pathology, and the disease more commonly presents with increased cortisol and androgen secretion (20).

Cortisol hypersecretion results in weight gain and redistribution of adipose tissue in half of patients: fat accumulates in the face, neck, waist, and abdominal regions, manifesting as moon facies and a buffalo hump. Possible manifestations include skin changes such as stretch marks, arterial hypertension, impaired glucose tolerance or diabetes mellitus, and decreased bone mineral density or osteoporosis. Increased androgen concentrations in women cause amenorrhea, hirsutism, and decreased libido.

According to several studies, the standardized mortality ratio among patients with Cushing's disease ranges from 1.7 to 4.8 and is considerably higher in patients with persistently elevated cortisol production. Patients most commonly die from cardiovascular or cerebrovascular complications and less frequently from metabolic disorders or infections resulting from cortisol-induced immunosuppression (20, 21).

Specific tests are performed to confirm the diagnosis: an overnight salivary cortisol test, a 1 mg overnight dexamethasone suppression test, or measurement of cortisol concentration in a 24-hour urine sample. The overnight salivary cortisol test has the highest sensitivity and specificity (92–100%), followed closely by the 1 mg overnight dexamethasone suppression test, which has a sensitivity of 95% and specificity of 80%. Measurement of cortisol concentration in a 24-hour urine sample is associated with relatively frequent false-positive results, so its use in clinical practice remains debatable (14).

Serum ACTH concentration will be decreased if the cause of increased cortisol production is adrenal pathology, while a normal or increased concentration indicates pituitary pathology or ectopic ACTH secretion. A high-dose dexamethasone suppression test or corticotropin-releasing hormone test may be performed to differentiate pituitary pathology from an ectopic ACTH-producing focus, but caution is required because approximately 10% of these tests may yield false-positive results (13).

Because microadenomas are detected in Cushing's disease, half of MRI examinations may be uninformative. Therefore, when biochemical markers are elevated but imaging findings are inconclusive, inferior petrosal sinus sampling is recommended. If the central ACTH concentration is three times higher than that in the periphery, Cushing's disease is diagnosed (14).

Tumor resection, as in somatotropinoma, is the first-line treatment and results in biochemical remission in more than 80% of patients (13). Nine out of 10 tumors can be operated on transsphenoidally, with two-thirds of patients achieving complete remission. Endoscopic methods are becoming increasingly popular, but no significant differences in postoperative outcomes between these surgical approaches have been observed to date.

If the adenoma cannot be identified on imaging studies or during surgery, partial or complete pituitary resection is performed. However, remission is achieved in only 70% of patients, and the risk of hypopituitarism and other postoperative complications increases significantly (20).

After remission is achieved, hypocortisolism often occurs and lasts an average of 6–18 months. Therefore, patients should receive hormone replacement therapy and be educated about the possible development of adrenal insufficiency (13).

When surgery is unsuccessful or cannot be performed, a combination of medical and radiation therapy is administered. Medications are used to achieve eucortisolemia until the effects of radiation therapy become apparent, which may take up to 5 years. Steroidogenesis inhibitors commonly used in practice include ketoconazole, metyrapone, mitotane, and etomidate. Ketoconazole effectively reduces cortisol concentrations in 49% of patients, while metyrapone achieves approximately half that reduction. Etomidate effectively lowers high cortisol concentrations, but because it is administered intravenously, it is rarely used for outpatient treatment. Mitotane is currently not recommended because of its teratogenic effects and frequent gastrointestinal disturbances.

Another possible option for medical treatment is pasireotide, which acts directly on corticotroph somatostatin receptors in the pituitary gland (13). In treatment-resistant cases, bilateral adrenalectomy is performed. Although this treatment is effective, it is also associated with a high rate of postoperative complications: acute adrenal insufficiency develops in up to one-fifth of patients (13, 14). Nelson's syndrome may develop in 8–28% of cases, characterized by rapid and uncontrolled adenoma growth due to disrupted feedback regulation.

TSHoma

TSH-secreting pituitary adenomas manifest with classic clinical and laboratory signs of hyperthyroidism, including increased heart rate, excessive sweating and thirst, and elevated levels of free thyroxine and TSH. Up to 80% of thyrotropinomas are invasively growing macroadenomas at the time of diagnosis, and one-quarter also secrete prolactin or growth hormone (13, 23).

For these reasons, in addition to symptoms typical of hyperthyroidism, approximately 35% of patients report visual disturbances, 33% menstrual cycle irregularities, and 28% galactorrhea (24). In some cases, blood TSH concentrations may remain normal, so patients are treated for thyroid pathology, and the true cause of hyperthyroidism may only become apparent several years later.

To refine the diagnosis, a thyrotropin-releasing hormone test is performed, and the serum concentration of the α-subunit, the ratio of the α-subunit to thyrotropin-releasing hormone, and the ratio of the α-subunit to thyrotropin are determined by laboratory methods (13).

The first-line treatment is surgery, with euthyroidism achieved pharmacologically before the procedure. Remission is achieved in only approximately 40% of cases (23). The first-line medications used to achieve euthyroidism before surgical treatment or to continue treatment when surgery is ineffective are somatostatin analogs. According to clinical trial data, octreotide normalized free thyroxine levels in 73% of patients, with a reduction in adenoma size observed in 21%. In cases of ineffective surgical or medical treatment, radiation therapy may be administered (13).

Gonadotropinoma

Although a significant proportion of non-functioning adenomas exhibit clinically insignificant FSH and LH production, functioning gonadotropin-producing adenomas are considered very rare, accounting for only 0.2% of all pituitary tumors (13).

The clinical manifestations of these adenomas may include polycystic ovary syndrome, infertility, menstrual cycle irregularities, and ovarian hyperstimulation syndrome in women, as well as testicular hypertrophy and sexual dysfunction in men. However, it is important not to draw conclusions prematurely, as all of these symptoms are characteristic of many other disorders. Therefore, gonadotropin-producing adenomas are usually diagnosed only when headaches, visual disturbances, and hypopituitarism caused by the mass effect develop (25).

The standard treatment is surgical resection, as medical treatment with dopamine agonists and somatostatin analogs is ineffective (13, 25).

Non-Functioning Adenomas

This is the second most common pituitary lesion and is characterized by a broad spectrum of clinical manifestations, ranging from asymptomatic incidentalomas detected on MRI or CT to pronounced adenomas causing parasellar or pituitary dysfunction (14).

Pituitary microincidentalomas may grow, but only 5% exceed the 10 mm threshold. In contrast, macroadenomas, when reassessed after 4 and 8 years, increased by 20–24% and 34–40%, respectively (26). The most common patient complaints are headaches, visual disturbances, ophthalmoplegia, and hypopituitarism. When these symptoms occur, surgical treatment of the adenoma is indicated.

Conclusion

Pituitary gland tumors are among the most common intracranial lesions and are characterized by a broad and often nonspecific spectrum of clinical symptoms. The most commonly diagnosed forms are prolactinoma and non-functioning pituitary adenoma, while ACTH-producing tumors are less common.

Depending on adenoma size and hormone production, these lesions usually manifest with increased or decreased pituitary hormone concentrations or focal neurological symptoms. The treatment strategy is selected according to the type and size of the tumor and the symptoms it causes, but transsphenoidal adenomectomy is usually performed or medical treatment is prescribed.

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