Prolactinoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Faizan Sheraz, M.D. [3]

A prolactinoma is a benign tumor (adenoma) of the pituitary gland that produces prolactin. It is the most common type of pituitary tumor. Symptoms of prolactinoma are caused either by hyperprolactinemia or by pressure of the tumor on surrounding tissues. In women, these adenomas are often small (<10 mm). In either sex, however, they can become large enough to enlarge the sella turcica. These adenomas represent the most common hormone-producing pituitary tumors and account for 45% of all pituitary tumors. MRI is the most sensitive diagnostic test for detecting pituitary tumors (including prolactinoma). Medical therapy for prolactinoma includes dopamine agonists. Surgery is indicated in patients if medical therapy cannot be tolerated. Transsphenoidal resection of the tumor is rarely done among patients with prolactinoma as most of the patients respond to medical management.

In 1970, prolactin was discovered in humans by sensitive bioassay. In 1978, V C Medvei, the President of the Section of History of Medicine (1986-87) of the Royal Society of Medicine in London, wrote in his paper that Queen Mary I of England was believed to have prolactinoma.

Prolactinoma can be classified based either on size or local invasion. Based on size, a prolactinoma can be classified as a microprolactinoma (<10 mm diameter) or macroprolactinoma (>10 mm diameter).

Prolactinoma is the most common type of pituitary adenoma. Prolactinoma may occur in approximately 30% of multiple endocrine neoplasia type 1 patients. It may also occur with Carney complex or McCune-Albright syndrome. There are a few reports of familial cases of prolactinoma unrelated to MEN 1 syndrome. Prolactinoma is also associated with various familial syndromes. On gross pathology, prolactinoma is divided on the basis of size into microprolactinoma and macroprolactinoma. On histological analysis, prolactinoma may be divided into sparsely granulated and densely granulated prolactinomas.

There are no established causes for prolactinoma. Most cases of prolactinoma are sporadic. Prolactinoma may occur in approximately 30% of multiple endocrine neoplasia type 1 patients. It may also occur with Carney complex or McCune-Albright syndrome.

Prolactinoma must be differentiated from other causes of hyperprolactinemia that may also present as galactorrhea, amenorrhea, (in females) and infertility (in both males and females). Causes of hyperprolactinemia can be categorized as physiological, pathological, and medication-induced.

45% of pituitary adenomas are prolactinomas, making it the most common type of all pituitary adenomas. Worldwide, the prevalence of sporadic prolactinoma is 6 to 10 per 100,000 persons. The prevalence of prolactinoma in people less than 20 years old is 10 per 100,000 individuals worldwide. Prolactinoma most commonly affects women in reproductive age group (20 to 50 years). Prolactinoma is more common in females than males in people between 20 and 50 years old. Frequency becomes similar after age 50.

There are no established risk factors for prolactinoma. Some conditions increase the risk of prolactinoma, such as multiple endocrine neoplasia type 1 (MEN 1), Carney complex, McCune-Albright syndrome, familial isolated pituitary adenoma, and MEN 1 like syndrome.

There is insufficient evidence to recommend routine screening for prolactinoma.

If left untreated, 95% of cases of prolactinoma will not show any signs of growth during the first 4 to 6 years. Complications of prolactinoma include pituitary apoplexy and vision loss. Prognosis is generally excellent for cases of microprolactinoma.

Common symptoms of prolactinoma include headache, vision changes, decreased libido, infertility, and osteoporosis. In women, common symptoms of prolactinoma include breast tenderness, galactorrhea, and amenorrhea or oligomenorrhea.

Patients with prolactinoma generally appear healthy. The most common physical examination finding of prolactinoma is visual field defects (bitemporal hemianopsia).

Laboratory findings consistent with the diagnosis of prolactinoma include markedly elevated prolactin levels.

There are no ECG findings associated with prolactinoma.

There are no X-ray findings associated with prolactinoma.

There are no ultrasound findings associated with prolactinoma.

CT scan of head is usually normal in patient of prolactinoma. Sometimes, enlargement of sella turcica may be found in case of macroprolactinoma.

MRI may be diagnostic of prolactinoma. Magnetic resonance imaging (MRI) is the most sensitive test for detection of pituitary tumors and determination of their size.

Medical therapy for prolactinoma includes dopamine agonists (either cabergoline or bromocriptine). The goal of treatment is to return prolactin secretion to normal, reduce tumor size, correct any visual abnormalities, and restore normal pituitary function.

Surgery is not the first-line treatment option for patients with prolactinoma. Surgery is usually reserved for patients whose medical therapy fails to reduce the size of the tumor.

There is no established method for primary prevention of prolactinoma.

There is no established method for secondary prevention of prolactinoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Faizan Sheraz, M.D. [3]

In 1970, prolactin was discovered in humans by a sensitive bioassay (Nb2 cell bioassay). In 1978, V C Medvei, the President of the Section of History of Medicine (1986-87) of the Royal Society of Medicine in London, wrote in his paper that Queen Mary I of England was believed to have prolactinoma.

• In 1928, prolactin was first extracted from cows as a lactogenic substance.^[1]

• In 1970, prolactin was also discovered in humans by a sensitive bioassay (Nb2 cell bioassay).^[1]

• In 1978, V C Medvei, the President of the Section of History of Medicine (1986-87) of the Royal Society of Medicine in London, wrote in his paper that Queen Mary I of England was believed to have prolactinoma.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Faizan Sheraz, M.D. [2], Anmol Pitliya, M.B.B.S. M.D.[3]

Prolactinoma can be classified based upon either size or local invasion. Based on size, a prolactinoma can be classified as a microprolactinoma (<10 mm diameter) or macroprolactinoma (>10 mm diameter).

Prolactinoma may be classified based on either size or local invasion.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Faizan Sheraz, M.D. [3]

Prolactinoma is the most common type of pituitary adenoma. Prolactinoma may occur in approximately 30% of multiple endocrine neoplasia type 1 patients. It may also occur with Carney complex or McCune-Albright syndrome. Prolactinoma is also associated with various familial syndromes for example MEN1 syndrome. There have been familial cases of prolactinoma unrelated to MEN 1 syndrome as well. On gross pathology, prolactinoma is divided on the basis of size into microprolactinoma and macroprolactinoma. On histological analysis, prolactinoma may be divided into sparsely granulated and densely granulated.

• Prolactinoma arises from lactotrophs, which are secretory cells of anterior pituitary lobe and are normally involved in secretion of prolactin hormone.
• The increase in amount of lactotrophs produces excess amount of prolactin causing hyperprolactinemia.
• Hyperprolactinemia causes symptoms such as amenorrhoea/oligomenorrhoea and galactorrhea in females and impotence in males. Hyperprolactinemia also causes infertility, decreased libido and osteoporosis in both sexes.
• As prolactinoma increase in size, it causes mass effect. The most common mass effect include headache and defect in peripheral vision (bitemporal hemianopsia).

Prolactinoma may be associated with:^[1]

• Multiple endocrine neoplasia type 1 (MEN 1)

• Carney complex
• McCune-Albright Syndrome

• Prolactinoma are monoclonal in nature. This suggests that the somatic cell mutation responsible for the development of prolactionoma, occurs before clonal expansion of lactotrophs.^[2]

• One gene involved in the pathogenesis of prolactinoma is the pituitary tumor transforming gene-1 (PTTG-1).^[3][4]
  • The PTTG-1 gene is related to various endocrine and non-endocrine tumors such as:
    • Endocrine related tumors: pituitary, thyroid, breast, ovarian, and uterine tumors.
    • Non-endocrine related tumors: central nervous system, pulmonary, and gastrointestinal tumors.
  • Prolactinomas with a higher expression of the PTTG-1 gene tend to be more invasive.

• Many prolactinomas are related to multiple endocrine neoplasia type 1.^[5]
  • The MEN1 gene is located on 11q13.
  • The MEN1 gene is a tumor suppressor gene that follows the concept of ‘two-hit hypothesis,’ which implies that both alleles that code for a particular gene must be affected before an effect manifests.
  • The consequence of this mode of tumor development is that if one allele for the gene is damaged, the second can still produce the correct form of normal protein.
  • Affected individuals carry one altered copy of the MEN1 gene and the other copy is lost due to somatic mutation.

• A pituitary adenoma may be part of a familial syndrome:^[6]

The gross pathology of prolactinoma is as follows:^[8]

• Microprolactinomas (<10mm size) are usually found in the lateral wing of the pituitary gland. They are most often surrounded by well defined pseudocapsules composed of reticulin.
• Macroprolactinomas (>10mm size) differ substantially in size and behavior. Some cause sellar expansion while others invade the base of the skull.
• About 50% of all prolactinoma grossly invade surrounding structures.

• Prolactinoma are divded into two types based on microscopy:^[8]
• Sparsely granulated variant
  • This is common type of variant.
  • This contains chromophobic cells.
• Densely granulated variant
  • This is a rare varaint.
  • This contains acidophilic cells.

Note: There is no clinical, biological and prognostic difference between the two variants.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Faizan Sheraz, M.D. [3]

There are no established causes of prolactinoma. Most cases of prolactinoma are sporadic. Prolactinoma may occur in approximately 30% of multiple endocrine neoplasia type 1 patients. It may also occur with Carney complex or McCune-Albright syndrome.

• Sporadic
• Hereditary causes:
  • Multiple endocrine neoplasia type 1 (MEN 1)

• Hereditary causes:
  • A minority of prolactinoma are associated with:^[1][2]
    1. Carney complex
    2. McCune-Albright Syndrome
    3. Isolated familial pituitary adenoma
    4. MEN1-like syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Prolactinoma must be differentiated from other causes of hyperprolactinemia that may present as galactorrhea, amenorrhea, (in females) and infertility (in both males and females). Causes of hyperprolactinemia can be categorized as physiological, pathological, and medication-induced.

Prolactinoma must be differentiated from other causes of hyperprolactinemia that may present as galactorrhea, amenorrhea, (in females) and infertility (in both males and females) including:

• Physiological:
  • Normal pregnancy^[1]
• Pathological:
  • Pituitary tumors (other than prolactinoma):^[2]
    • Somatotroph adenoma: Acromegaly
    • Corticotroph adenoma: Cushing’s syndrome
  • Suprasellar tumors (tumors present in the region of the pituitary stalk)
  • Hypothyroidism^[3]
  • Chronic renal failure^[4]
  • Liver disease^[5]
    • Cirrhosis (with or without encephalopathy)
    • Viral hepatitis (with encephalopathy)
  • Seizure disorder^[6][7]
• Medication-induced:
  • Antipsychotic medications:^[8]
    • Haloperidol
    • Risperidone
  • Antiemetic medications:
    • Metoclopramide^[9]
    • Domperidone^[10]
  • Antihypertensive medications:
    • Methyldopa^[11]
    • Verapamil^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Faizan Sheraz, M.D. [3]

About 45% of pituitary adenomas are prolactinomas, making it the most common type of all pituitary adenomas. Worldwide, the prevalence of sporadic prolactinoma is 6 to 10 per 100,000 persons. The prevalence of prolactinoma in people less than 20 years old is 10 per 100,000 individuals worldwide. Prolactinoma most commonly affects women in reproductive age group (20 to 50 years). Prolactinoma is more common in females than males in people between 20 and 50 years old. Distribution among males and females becomes similar after age 50.

• 45% of pituitary adenomas are prolactinomas, making it the most common type of all pituitary adenomas.^[1]
• Worldwide, the prevalence of sporadic prolactinoma ranges from a low of 6 persons per 100,000 persons to a high of 10 persons per 100,000 persons.
• Worldwide, the prevalence of prolactinoma in people less than 20 years old is 10 individuals per 100,000 individuals.
• Clinically significant pituitary tumors affect the health of approximately 14 people per 100,000 people in United States.
• Some growth hormone-producing tumors also co-secrete prolactin.
• Microprolactinoma are much more common than macroprolactinoma.

• Worldwide, the incidence of sporadic prolactinoma is 1 person per 100,000 persons per year.^[1]

• Age specific distribution of prolactinoma is as follows:^[1][2]
  • Prolactinoma commonly affects individuals between 20 and 50 years old.
  • Prolactinoma occur less commonly in people less than 20 years old, with a prevalence of 10 per 100,000 individuals. These tumors account for less than 2% of intracranial tumors in this age group.

• Women usually have microprolactinoma whereas men usually have macroadenoma.^[1]
• Gender-based frequency of prolactinoma depends on the age of the individual:
  • Age group: 20 to 50 years
    • Women are more commonly affected by prolactinoma than men. The female to male ratio is approximately 10:1.^[1]
    • Women aged 20 to 30 years have the highest prevalance of prolactinoma, with a female to male ratio of approximately 14:1.
  • Age group: >50 years^[2]
    • Men and women are affected equally after age 50 years.
    • The prevalence of prolactinoma increases with age in men after age 50 and peaks during ages 60 to 70 years. At this time, the female to male ratio is 1:3.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Conditions increasing the risk of prolactinoma inlude multiple endocrine neoplasia type 1 (MEN 1), Carney complex, McCune-Albright Syndrome, familial isolated pituitary adenoma, and MEN-1 like syndrome.

• Most commonly, prolactinomas are sporadic.

• Prolactinoma may occur as part of:^[1][2]
  • Multiple endocrine neoplasia type 1 (MEN 1)
  • Carney complex
  • McCune-Albright Syndrome
  • Familial isolated pituitary adenoma
  • MEN-1 like syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

There is insufficient evidence to recommend routine screening for prolactinoma.

There is insufficient evidence to recommend routine screening for prolactinoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2], Faizan Sheraz, M.D. [3]

If left untreated, 95% of cases of prolactinoma will not show any signs of growth during the first 4 to 6 years. Complications of prolactinoma include pituitary apoplexy and vision loss. Prognosis is generally excellent for cases of microprolactinoma.

If left untreated, 95% of cases of prolactinoma will not show any signs of growth during the first 4 to 6 years. Sometimes, it may lead to premature osteoporosis in both sexes due to hyperprolactinomia.^[1]

Complications of prolactinoma include:

• Pituitary apoplexy^[1]
  • Pituitary apoplexy usually presents with sudden onset of excruciating headache, diplopia, and visual impairment.
  • Headache is most common symptom and is usually associated with nausea and vomiting.

• Tumor regrowth (after resection)
• Blindness
• In pregnancy, excessive estrogen may cause increased tumor growth

• Prognosis is excellent for cases of microprolactinoma.
• Depending on the size of the tumor and the extent of tumor resection, the rate of recurrence may range from 20% to 50%.
• The majority of recurrent prolactinomas develop within the first 5 years.^[2]

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