eMedicine Specialties > Endocrinology > Pituitary Gland

Pituitary Macroadenomas

Author: James R Mulinda, MD, FACP, FACE, Consulting Staff, Department of Endocrinology, Endocrinology Associates, Inc
Contributor Information and Disclosures

Updated: Aug 3, 2009

Introduction

Background

The sellar region is a site of various types of tumors. Pituitary adenomas are the most common. They arise from epithelial pituitary cells and account for 10-15% of all intracranial tumors. Tumors exceeding 10 mm are defined as macroadenomas, and those smaller than 10 mm are termed microadenomas. Most pituitary adenomas are microadenomas.

Pathophysiology

Pituitary macroadenomas are benign epithelial neoplasms composed of adenohypophysial cells. Primary malignant tumors of the pituitary are extremely rare. Evidence suggests that pituitary adenoma development occurs in several steps, including an irreversible initiation phase followed by tumor promotion.

Pituitary tumor development is a monoclonal process with several contributing factors. Causal contributors include heredity and hormonal influence and genetic mutations. The monoclonal nature of most pituitary tumors suggests that they arise from a mutated pituitary cell. However, the exact pathophysiologic/molecular mechanisms leading to the development of pituitary adenomas remain unknown.

Some pituitary tumors may occur as part of a clinical syndrome. In multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant genetic disorder, pituitary adenomas (most often prolactinomas) occur in association with tumors of the parathyroid and pancreatic islet cells.

In McCune-Albright syndrome, skin lesions and polyostotic fibrous dysplasia occur with hyperfunctioning endocrinopathies. This syndrome results from an activating mutation (somatic mutation) of the alpha subunit of the Gs protein and involves tissues whose response to hormonal signals is mediated by adenylate cyclase. The most common pituitary tumor in McCune-Albright syndrome is somatotropinoma, resulting in acromegaly. Interestingly, a significant proportion of somatotropinomas in sporadic cases of acromegaly harbor the same mutations.

Carney complex is an autosomal dominant disorder characterized by primary pigmented nodular adrenal disease, cutaneous pigmented lesions (lentigines, blue nevi), Sertoli cell tumors of the testes, acromegaly, melanocytic schwannomas, and cardiac myxomas.

Frequency

United States

Pituitary tumors are found on autopsy in as many as 25% of unselected cases. The annual incidence of pituitary neoplasms varies from 1-7 cases per 100,000 population based on neurosurgical series.

Mortality/Morbidity

Morbidity in pituitary macroadenomas varies from incidentally discovered nonfunctioning tumors to disabling macroadenomas. Morbidity results from mass effects (eg, bitemporal hemianopsia), hormonal imbalance (pituitary hormone deficiency due to compression of the normal pituicytes or hormonal excess from the tumor), and patient comorbidities. Significant morbidity is also associated with treatment of these tumors.

Race

No racial predilection exists for pituitary macroadenomas.

Sex

Autopsy series show an equal distribution of pituitary tumors between men and women. Corticotropinomas are an exception, occurring mainly in women, with a female-to-male ratio of 4:1. In general, women of childbearing age are diagnosed more frequently with pituitary adenomas than men. The reason for this higher rate of diagnosis is unclear but might be related to the clinical presentation of such patients. Amenorrhea (or menstrual irregularities), which is a relatively common symptom in women with macroadenomas, raises the suspicion of a pituitary lesion.

Age

Tumors affect individuals of all ages, but incidence increases with age, peaking between the third and sixth decades of life.

Clinical

History

Patients with pituitary macroadenomas may be asymptomatic or may present with complaints due to hormonal imbalance or mass effects.

• Tumors in asymptomatic patients may be discovered when imaging the head for unrelated medical conditions. The frequency of diagnosis of pituitary tumors has increased with widespread use of computed tomography (CT) and magnetic resonance imaging (MRI) scans.
• Pituitary hormone effects depend on the hormones involved. Panhypopituitarism may present with a deficiency of all the pituitary hormones, but often some are spared. The larger the tumor, the more likely it is to involve most hormones. Anterior pituitary cells are not equally sensitive to mass effects. The most sensitive are the somatotrophs and the gonadotrophs, whereas corticotrophs and thyrotrophs tend to be more resistant. Distinct clinical syndromes, specifically the following, are the result of the hormonal activity of the tumor:
  • Hyperprolactinemia presents with hypogonadism, infertility, amenorrhea, and galactorrhea. Hyperprolactinemia can be due to increased hormone production by a prolactinoma, or it can be the result of stalk compression by the macroadenoma regardless of hormone activity. In this regard, it is a very common sequela of a pituitary macroadenoma.
  • Corticotropin excess presents with Cushing disease. Corticotropinomas are rarely macroadenomas. Corticotropin suppression due to compression of the normal corticotrophs presents with glucocorticoid insufficiency. The clinical picture of secondary glucocorticoid deficiency is much milder than primary adrenal insufficiency, where combined mineralocorticoid and glucocorticoid deficiency occur.
  • Thyrotropin excess presents with secondary hyperthyroidism. Thyrotropinomas are very rare tumors. They present most frequently as macroadenomas. Whether thyrotropinomas are naturally aggressive or whether the aggressive and invasive behavior is the result of delayed diagnosis is unclear. Biologically inadequate thyrotropin presents with secondary hypothyroidism.
  • Excess growth hormone presents with acromegaly as the result of a somatotropinoma (often a macroadenoma), while inadequate growth hormone presents with failure to thrive in children but often no complaints in adults.
  • Gonadotropinomas most often are asymptomatic and usually secrete inactive follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-like glycoproteins and/or alpha subunit. They often are macroadenomas and usually result in hypopituitarism. Rarely, they can lead to testicular enlargement in men and ovarian hyperstimulation in women. Deficiency of gonadotropins presents with hypogonadism and infertility.
• Mass effects of the macroadenoma may present with visual deficits, headache, elevated intracranial pressure, or intracranial hemorrhage.
• Pituitary apoplexy results from infarction of a pituitary tumor or sudden hemorrhage within. This presents as a medical emergency with a headache, sudden collapse, shock, and death if not treated emergently. This tends to occur in macroadenomas. Administration of stimulatory agents, such as thyroid-stimulating hormone TSH, gonadotropin-releasing hormone (GnRH), and insulin-hypoglycemia, have been postulated to lead to increased metabolic needs by the macroadenoma (which has deficient blood supply), leading to necrosis. In this context, apoplexy may be the presenting symptom of a gonadotropinoma in an elderly men receiving GnRH agonist therapy for prostate cancer.
• Nelson syndrome results from treatment of Cushing disease with bilateral adrenalectomy. The lack of negative glucocorticoid feedback is postulated to lead to excessive tumor growth. Such tumors are much more aggressive and locally invasive compared to the usual corticotroph adenomas.

Physical

• Most patients do not have physical findings associated with macroadenomas. Physical findings may be attributable to the mass effects or hormonal disruption.
  • When the tumor extends onto the optic chiasm, visual field deficits may be demonstrable. Sudden increase in tumor size, such as can occur with hemorrhage, may lead to elevated intracranial pressure.
  • Hormonally active tumors might present with symptoms due to target organ stimulation, such as hyperthyroidism, Cushing syndrome, or hyperprolactinemia.

Causes

The cause of pituitary macroadenomas is unknown. The most favored theory attributes monoclonal neoplastic transformation of pituitary cells as the cause of tumor initiation and growth. The monoclonal nature of most pituitary tumors and their retention of a response to negative feedback by hormones produced by target organs support this hypothesis.

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