Pituitary microadenoma, macroadenoma and nonfunctioning adenomas (NFPAs), hyperprolactinemia syndrome

Pituitary adenoma (microadenoma, macroadenoma), hyperprolactinemia syndrome

Pituitary adenomas are benign tumors that develop in the pituitary gland, a gland at the base of the brain responsible for hormone production.

Hyperprolactinemia syndrome, often associated with pituitary adenomas, results from prolonged, excessive prolactin secretion by the anterior pituitary. In women, it manifests as galactorrhea (milk discharge) and menstrual irregularities (amenorrhea). In men, it presents as impotence, oligospermia, gynecomastia, and, less commonly, galactorrhea.

Symptoms of pituitary adenomas vary with tumor size and function. Hormone-secreting adenomas can cause health problems due to excess hormone production:

Hormones	Health Problems
Prolactin	- Menstrual irregularities, galactorrhea (milky breast discharge), and infertility in individuals with female reproductive systems. - Decreased libido, reduced testosterone, and erectile dysfunction in individuals with male reproductive systems.
Growth Hormone (Somatotropin)	- Enlarged facial features, hands, and feet - Osteoarthritis - Sleep apnea - High blood pressure - Diabetes
Corticotropin	- Obesity and osteoporosis - Anxiety and depression - Diabetes - High blood pressure - Sleep problems
Thyrotropin	- Hyperthyroidism (characterized by sweating, tachycardia or arrhythmias, irritability, and unintentional weight loss).

Nonfunctioning pituitary adenomas do not secrete hormones, but can cause headaches, vision loss, or pituitary dysfunction.

 

Pituitary microadenomas

Description of pituitary microadenomas

A pituitary microadenoma is a tumor with a diameter less than 10 mm. While some pituitary adenomas secrete hormones, many are clinically inactive. These incidental pituitary findings, often termed 'incidentalomas,' may be discovered during imaging for unrelated neurological conditions. However, even these microadenomas, when identified by MRI, can cause clinical problems.

Magnetic resonance imaging in patients with hyperprolactinemia may reveal subtle microadenomas of the pituitary gland.

Pituitary microadenomas can be identified in patients with hyperprolactinemia, acromegaly, or Cushing's syndrome. Non-hormone-secreting microadenomas are non-functioning pituitary adenomas (NFPAs) in approximately 90% of cases. However, other lesions, such as cysts, vascular malformations, neoplasms, hyperplastic processes, or inflammatory conditions, can mimic NFPAs and may remain clinically silent.

 

Pathophysiology of pituitary microadenomas

Most pituitary tumors are clonal in origin. Some are associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1), McCune-Albright syndrome, or Carney complex. Cytological analysis reveals that these tumors arise from monoclonal mutations of a single cell.

Prolactinomas are the most common hormone-secreting pituitary tumors. Other hormone-secreting tumors include:

• corticotropinomas, which cause Cushing's disease
• growth hormone-secreting tumors (somatotropinomas), which cause acromegaly
• gonadotropinomas, whose clinical manifestations vary depending on hormone levels and, to a lesser extent, patient gender
• thyrotropinomas (TSH-secreting), which can cause hyperthyroidism (rare)

Most clinically non-functioning pituitary adenomas (NFPAs) are gonadotropin-derived and may secrete alpha and beta subunits of the gonadotropin peptide.

The role of genetic mutations is highlighted by the observation that patients from four Irish families with pituitary tumors shared the same mutation as an 18th-century patient with gigantism caused by a pituitary tumor.

 

Epidemiology of pituitary microadenomas

Frequency of pituitary microadenomas

Pituitary microadenomas are found in 10-14% of autopsies. A meta-analysis of autopsy studies showed a 22% incidence of macroadenomas, while tomographic studies reveal a 14% incidence. Pituitary microadenomas occur across all age groups and genders.

Prior to the widespread use of magnetic resonance imaging, elevated prolactin levels in blood tests were often the primary indicator of unsuspected pituitary microadenomas. Now, MRI allows for direct identification of these tumors.

The high incidence of microadenomas and the relatively low incidence of macroadenomas in autopsy studies suggest that microadenomas infrequently progress to macroadenomas, and that macroadenomas typically present clinically during the patient's lifetime.

A U.S. autopsy study of 3048 cases found pituitary adenomas in 316 cases (10%), with most tumors measuring less than 3 mm. Immunological prolactin testing was positive in 40% of these cases. Similar findings have been reported in international studies.

 

Pituitary macroadenomas

Description of pituitary macroadenomas

Various tumors can develop within the sella turcica, with pituitary adenomas being the most common. These tumors, arising from pituitary epithelial cells, account for 10-15% of all brain tumors. Tumors larger than 10 mm are classified as macroadenomas, while those smaller than 10 mm are microadenomas. The majority of pituitary adenomas are microadenomas.

Prospective, randomized studies have investigated the impact of Lanreotide on outcomes in patients with newly diagnosed acromegaly undergoing transsphenoidal surgery. A study involving 98 patients, 49 receiving preoperative Lanreotide for 4 months and 49 undergoing surgery alone, demonstrated a 49% cure rate in the Lanreotide-treated group and an 18.4% cure rate in the surgery-only group. These findings suggest that preoperative Lanreotide treatment improves cure rates in patients with growth hormone-secreting pituitary adenomas (somatotropinomas) undergoing transsphenoidal surgery.

A comparative study of single-portal versus bi-portal approaches in transsphenoidal surgery for pituitary macroadenomas revealed that the single-portal approach allows for faster surgery, minimizes damage to healthy tissue, and provides adequate access for resection of various pituitary adenomas.

Resection of dumbbell-shaped pituitary adenomas during transsphenoidal surgery is technically challenging, and an extended endoscopic endonasal approach is often preferred in these cases.

Pathophysiology of pituitary macroadenomas

Pituitary macroadenomas are benign epithelial neoplasms composed of adenohypophyseal cells. Primary malignant tumors of the pituitary gland are rare. The development of pituitary adenomas involves several stages, including an irreversible initiation stage followed by tumor growth.

The development of pituitary tumors is a monoclonal process influenced by multiple factors, including genetic inheritance, mutations, and hormonal effects. The monoclonal nature of these tumors is believed to originate from mutated pituitary cells. However, the precise molecular mechanisms underlying pituitary adenoma development remain unclear.

Similar to pituitary microadenomas, genetic mutations are thought to play a significant role in macroadenoma development.

Some pituitary tumors can occur as part of clinical syndromes. In multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant genetic disorder, pituitary adenomas (most commonly prolactinomas) are observed in conjunction with parathyroid and pancreatic islet cell tumors.

McCune-Albright syndrome, characterized by skin lesions, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies, results from the activation of the Gs protein alpha subunit, leading to adenylate cyclase activation in hormone-responsive tissues. In McCune-Albright syndrome, somatotropinomas, which cause acromegaly, are the most common pituitary tumor. A significant portion of sporadic acromegaly cases exhibit the same mutation.

Carney complex is an autosomal dominant disorder characterized by primary pigmented nodular adrenocortical disease, lentigines, Sertoli cell tumors, acromegaly, melanocytic schwannomas, and cardiac myxomas.

 

Epidemiology of pituitary macroadenomas

Frequency of pituitary macroadenomas

Pituitary tumors are found in approximately 25% of autopsies. The annual incidence of pituitary neoplasms requiring neurosurgical intervention ranges from 1 to 7 per 100,000 population.

Morbidity and mortality in pituitary macroadenomas

Morbidity associated with pituitary macroadenomas varies, ranging from asymptomatic non-functioning pituitary adenomas (NFPAs) to clinically significant, disabling macroadenomas. Morbidity results from mass effect (e.g., bitemporal hemianopsia), hormonal imbalances (e.g., pituitary hormone deficiency due to normal cell compression or hormone excess from the tumor), and patient comorbidities. Treatment of these tumors can also contribute to increased morbidity.

Pituitary macroadenomas do not exhibit racial predilection.

Mortality related to pituitary macroadenomas is generally low, and when present, it is often due to complications from treatment or underlying comorbidities.

Autopsy studies indicate no significant difference in the incidence of pituitary macroadenomas between men and women, with the exception of corticotropinomas, which are more prevalent in women (4:1). In pediatric cases, macroadenomas are more frequently observed in girls than in boys. The reason for this disparity is unclear but may be related to clinical presentation. Amenorrhea or menstrual irregularities, common symptoms in women with macroadenomas, heighten suspicion for pituitary disease. Pituitary macroadenomas can occur at any age, but their incidence increases with age, peaking between the third and sixth decades of life.

 

Nonfunctioning pituitary adenomas (NFPAs)

Non-functioning pituitary adenomas (NFPAs) are benign growths of pituitary gland tissue located at the base of the brain. Autopsy and imaging studies (MRI or CT scan) suggest that NFPAs may be found in approximately 1 in 6 individuals.

Unlike most pituitary tumors, NFPAs do not secrete hormones, hence the term 'non-functioning.' Statistics indicate that up to 30% of pituitary adenomas are non-functioning.