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

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Pituitary adenoma (microadenoma, macroadenoma), hyperprolactinemia syndrome

Pituitary adenomas are noncancerous tumors found in the pituitary gland, which is located at the base of the brain and is responsible for hormone production. Pituitary adenoma and hyperprolactinemia syndrome — is a symptom, that develops in women and men due to prolonged increased secretion of the anterior pituitary hormone prolactin and characterized by pathological galactorrhea (milk expiry), menstrual irregularities (amenorrhea) in women, and impotence, oligospermia, gynecomastia, and (rarely) galactorrhea in men.

Cross section of pituitary (front view): Brain, Pituitary gland, Microadenoma (<10mm), Macroadenoma (≥10mm).

Depending on the tumor's size and function, different symptoms may occur. Functioning pituitary adenomas produce excess hormones, causing health problems:

Health problems
Prolactin - Menstrual irregularity, milky breast discharge, and infertility in people with female reproductive organs
- Low libido and testosterone and erectile dysfunction in people with male reproductive organs
Growth hormone
- 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 (sweating, rapid or irregular heartbeat, irritability, and unintentional weight loss)

Nonfunctioning pituitary adenomas do not produce hormones but can cause headaches or vision loss or disrupt normal pituitary function.


Pituitary microadenomas

Description of pituitary microadenomas

Microadenoma of the pituitary gland is a tumor with a diameter less than 10 mm. Pituitary adenoma can secrete hormones, but most adenomas are not clinically active. Pathology of the pituitary gland may be accidentally detected during examination for other neurological diseases. This perceived anomaly of the pituitary gland is also called "incidentalomas". Such microadenomas identified by magnetic resonance imaging, cause clinical problems.

In patients with hyperprolactinemia, magnetic resonance imaging may identify unchanged areas microadenomas of the pituitary gland.

Microadenoma of the pituitary gland can be identified in patients diagnosed with hyperprolactinemia syndrome, acromegaly or during diagnosing of a patient with Cushing's syndrome. Not secreting hormones microadenoma in 90% of cases is a non-functioning pituitary adenoma (NFPAs), although there may be other types of cysts, vascular, neoplastic, hyperplastic or inflammatory processes that clinically will not manifest.


Pathophysiology of pituitary microadenomas

Most tumors of the pituitary gland are unstable. Some of them to be part of a genetic syndrome such as multiple endocrine neoplasia type 1 (MEN1), McQune-Albright syndrome or Carney complex. Clinical analysis of cells (cytology) shows that in their origin they are all monoclonal mutations of the same cell.

From the hormones producing tumors, prolactinomas are the most common. Other tumors secreting hormones:

  • corticotrophin, which causes Cushing's disease
  • growth hormone (somatotropin) which causes acromegaly
  • a gonadotropin, clinically the manifestations of which depend on his level and less – from patient gender
  • thyroid-stimulating hormone (TSH), which can cause hyperthyroidism (rare)

Most clinically non-functioning pituitary adenomas (NFPAs) in origin are gonadotropin and secrete alpha and beta fragments of the gonadotropin peptide.

Emphasizes the role of genetic mutations in the case when the observed patients of four Irish families who had a pituitary tumor had the same mutation as the patient of the 18th century with a tumor of the pituitary gland, suffering from gigantism.


Epidemiology of pituitary microadenomas

Frequency of pituitary microadenomas

In 10-14% of the autopsies revealed pituitary adenomas, almost all of them were microadenoma. A meta-analysis of the autopsies revealed a 22% macroadenomas, on tomography — 14%. Pituitary microadenomas occur at any age regardless of gender.

Previously, when not identifying microadenoma in life, often observed an increase in the prolactin levels in the blood laboratory study. Now with the help of magnetic resonance imaging can identify pituitary microadenomas, which have not been suspected previously in the patient's study.

High frequency of pituitary microadenomas and low macroadenomas in autopsies indicates that microadenomas rarely progress and reach the stage of macroadenoma, and macroadenoma manifests themselves clinically during life.

In the 3048 cases of autopsies conducted in the U.S. studies have shown in 316 cases (10%) the presence of one or more pituitary adenomas, their size was less than 3 mm. Immunological test for prolactin was positive in 40% of cases. International studies have also recorded similar results.


Pituitary macroadenomas

Description of pituitary macroadenomas

In the Sella turcica can be formed various types of tumors. The most frequent of them – the pituitary adenoma. It formed from epithelial pituitary cells and account for 10-15% of the total number of brain tumors. Tumors larger than 10 mm are considered as macroadenoma, if the diameter of the tumor less than 10 mm, as microadenomas. Most pituitary adenomas are microadenomas.

Prospective and randomized studies have revealed how the drug Lanreotide affects the healing process of patients with newly diagnosed acromegaly compared to transsphenoidal neurosurgical operation. The study included 49 patients who before surgery for 4 months were administered of preoperative Lanreotide treatment and 49 patients who underwent surgery without preoperative medical therapy. Identified a 49% cure rate (24 patients) in the first group (preoperative medical therapy with Lanreotide, then surgery) and 18.4 cure rate (9 patients) in the second group (surgery without preoperative medical therapy). On observation was concluded: in patients with growth hormone–secreting pituitary adenomas (somatotropin), preoperative Lanreotide treatment increases cure rates of transsphenoidal surgery.

In another study comparing single-and be-portal approaches (through one or both nostrils) during transsphenoidal surgery of pituitary macroadenoma. It was revealed that the single- portal (through one nostril) allows perform the surgery faster, with minimal impact on healthy tissue, and such access is adequate for the resection (removal) of other types of pituitary adenomas.

Remove of adenomas with a dumbbell configuration during transsphenoidal surgery is technically difficult, and in such cases, extended endoscopic endonasal approach more indicated.


Pathophysiology of pituitary macroadenomas

Pituitary macroadenoma is a benign epithelial neoplasm composed of adenohypophysial cells. Primary malignant tumors of the pituitary gland are quite rare. The development of pituitary adenomas consists of several stages and includes the irreversible stage of initiation, after which the growth of the tumor itself.

The development of the pituitary tumor is a monoclonal process with multiple contributing factors. Causal factors include genetic inheritance, mutation, and hormonal effects. It is assumed that the monoclonal nature of most pituitary tumors is derived from the mutated cells of the pituitary gland. Although the pathophysiology (molecular mechanism), which precedes the development of pituitary adenomas remains unclear.

In this case, as in the case of pituitary microadenomas, assumes the leading role of a genetic mutation.

Some pituitary tumors can be a part of any clinical syndrome. In multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant genetic disorder, pituitary adenomas (most often a prolactinomas) is observed in combination with the parathyroid glands tumor and pancreatic islet cells (of Langerhans) tumor.

McQune-Albright syndrome, skin lesions, multiple bone fibrous dysplasia found together with hyperfunctioning endocrinopathies. This syndrome is the result of activation of the alpha subunit of the Gs protein and activates tissues that respond to hormonal effects by adenylate cyclase. In McQune-Albright syndrome is the most common of the pituitary tumor is somatotropinoma, which accompanies acromegaly. A significant portion of the somatotropin in sporadic cases of acromegaly hides the same mutation.

Carney complex is an autosomal dominant disorder, which characterized by primary pigmented nodular lesions of the adrenal glands, spots on the skin (pigmented nevus), Sertoli cell tumors of the testes, acromegaly, melanocytic schwannomas, and cardiac myxomas.


Epidemiology of pituitary macroadenomas

Frequency of pituitary macroadenomas

Pituitary tumors found at autopsy in 25% of cases. Detection of pituitary neoplasms is from 1 to 7 during the year per 100,000 population (based on neurosurgical interventions).


Morbidity and mortality in pituitary macroadenomas

Morbidity in pituitary macroadenomas ranges from the revealed non-functioning pituitary adenomas (NFPAs) to clinically to disabling macroadenomas. Morbidity is the result of mass effect (bitemporal hemianopsia), hormonal imbalance (deficiency of pituitary hormones as a result of compression of normal pituitary cells, or excess of hormones produced by the tumor), and patient comorbidities. The increase in morbidity is also associated with the treatment of these tumors.

No racial predilection exists for pituitary macroadenomas.

Normal pituitary size changes dramatically with age and pregnancy status in women on the pituitary MRI. A - older woman, B - normal young woman, C - post-partum.

The results of the autopsies show no differences in the incidence of pituitary macroadenomas between men and women. The only exception is corticotropinomas , which is more common in women than in men (4:1). Among children pituitary macroadenoma detected more often in girls than in boys. This difference in incidence is not clear, but may be associated with the clinical picture in such patients. Amenorrhea (or irregular menstrual cycle), which is a relatively common symptom in women along with macroadenomas, reinforces the suspicion about the presence of pituitary disease. Pituitary macroadenoma occurs at any age, but its incidence increases with age and reaches a peak between the 3rd and 6th decades of life.


Nonfunctioning pituitary adenomas (NFPAs)

Nonfunctioning pituitary adenomas are benign (not malignant) growths of the pituitary gland tissue, located at the base of the brain. According to the results of the brain autopsies and imaging studies (MRI or CT scan), it was revealed that in every 6 cases can meet such type of pituitary adenoma.

While most tumors of the pituitary gland produce hormones, and nonfunctioning pituitary adenomas not capable of this — that's why they are called "non-functioning". According to statistics, up to 30% of pituitary adenomas are nonfunctioning.

Pituitary adenoma and hyperprolactinemia syndrome diagnosis

Magnetic resonance imaging (MRI) of the pituitary gland is performed with suspicion of adenoma (microadenoma, macroadenoma or prolactinoma of the pituitary gland).

The level of the hormone prolactin (lactotropin) in the serum:

3.2-20 ng/mL or 3.2-20 mcg/L
3-15 ng/mL or 3-15 mcg/L
Nonpregnant women
4-23 ng/mL or 4-23 mcg/L
Pregnant women
34-386 ng/mL or 34-386 mcg/L

There are many reasons for an abnormal increase in prolactin levels (hyperprolactinemia). If you did not reveal specific organic causes for the pituitary MRI or CT scans of the sella turcica (adenoma or microadenoma prolactinoma or pituitary gland can not be detected), we need to think about other possible causes for this disorder:

  • medical manipulations
  • exercise
  • sleep
  • hypoglycemia
  • psychological stress
  • pregnancy
  • breast-feeding (the act of sucking)
  • irritation of the nipple of the breast
  • sexual intercourse (in women)
  • reception protein foods
Localization of pituitary adenoma on the brain MRI.

The cause of hyperprolactinemia can also be:

  • insufficiency of thyroid function (hypothyroidism), which quite easily detected by measuring TSH levels in the blood and can easily be cured on the background of substitution therapy with thyroid hormone (L-thyroxine)
  • ovarian disease (polycystic ovary syndrome, adhesions)
  • liver pathology
  • chronic renal failure (hyperprolactinaemia occurs in 65% of patients on hemodialysis)


Pituitary adenoma and hyperprolactinemia syndrome treatment

The following therapeutic measures depending on the stage and the manifestations of the disease:

The proposed therapy is to appoint mild homeopathic regulators, respectively, due to hyperprolactinemia, conducting visceral osteopathic diagnosis and therapy. And if there is a connection with the experiences or stressful events are held on psychological adjustment.


Treatment of nonfunctioning pituitary adenomas (NFPAs)

Nonfunctioning pituitary adenomas are a common benign tumor that may be present for many years before causing any of the symptoms. These nonfunctioning pituitary adenomas may remain unnoticed for many years before they become large enough to mechanically impact on adjacent structures ("mass effect"). Such cases (effects on neighboring brain structures) is a clear indication for surgery. In other cases, a nonfunctioning pituitary adenoma treatment will be different.

Choosing of treatment method for a patient with a nonfunctioning pituitary adenoma the neurosurgeon must be guided by the following data:

  • Visualization of a nonfunctioning pituitary adenoma. Leading value has magnetic resonance imaging (MRI) and computed tomography (CT).
  • Endocrine (hormonal) status. Many patients with a nonfunctioning pituitary adenoma have abnormal levels of pituitary hormones, growth hormone, and sex hormones.
  • Eyes and vision (ophthalmological status). In some patients with nonfunctioning pituitary adenoma can develop symptoms of visual impairment, which subsequently can be eliminated or significantly reduced after surgery (operation).
  • Treatment for a nonfunctioning pituitary adenoma at the initial stage. Studies have shown the efficacy of surgical treatment for patients with symptomatic nonfunctioning pituitary adenoma, including improvement in visual and hormonal status. If surgery cannot be performed, then the option can be radiation therapy and other treatments.
  • Surgical treatment of nonfunctioning pituitary adenoma. Patients can be operated by the transsphenoidal (through the ethmoid sinus), by classical craniotomy with endoscopic access, or a combination of these two surgical techniques.
  • Methods for the treatment of patients with a nonfunctioning pituitary adenoma that recur or grow again, typically, require the use of some types of radiation therapy.
  • Subsequent monitoring of the patient. Patients require prolonged monitoring after surgery for a nonfunctioning pituitary adenoma, including the identification of possible recurrence of the tumor, hormonal status, and vision.