Prolactinoma

A 28-year-old woman presents to her GP complaining of irregular periods and milky discharge from her breasts for the past six months. She also reports decreased libido and has been unable to conceive. On examination, she is found to have a normal visual field.

Pathophysiology

Prolactinomas are benign tumours of lactotrophs within the pituitary gland which secrete excessive amounts of prolactin. Elevated prolactin levels inhibit the secretion of gonadotropin-releasing hormone (GnRH), leading to decreased levels of luteinising hormone (LH) and follicle-stimulating hormone (FSH). Consequently, hypogonadism develops, resulting in menstrual irregularities, infertility, decreased libido, and other related symptoms.

Lactotrophs are under the inhibitory control of dopamine, making dopamine antagonists a favourable treatment option.

Other pituitary tumours can cause elevated prolactin by compressing the pituitary stalk and disrupting the normal inhibitory effect of dopamine on prolactin release. This is known as the "stalk effect". 

Other causes of hyperprolactinemia include:

• Physiological: Pregnancy, breastfeeding, stress, and even sexual intercourse can transiently increase prolactin levels.
• Medications: Certain medications, such as dopamine receptor antagonists (e.g. metoclopramide, domperidone) and some antidepressants, can increase prolactin levels.
• Hypothyroidism: Elevated TRH levels in hypothyroidism can stimulate prolactin secretion.
• Chronic renal failure: Impaired prolactin excretion can lead to hyperprolactinemia.

Aetiology

The most common cause of pathologically elevated prolactin is a prolactinoma. Prolactinomas can rarely occur in the context of multiple endocrine neoplasia type 1 (MEN1).

Prolactinomas are classified by size:

• Microadenomas: <10mm
• Macroadenomas: >10mm

Epidemiology & Risk Factors

Prolactinomas are the most common functioning pituitary adenomas, accounting for around 40% of all pituitary tumors. Microadenomas, tumors smaller than 10mm, are more common than macroadenomas.  Microadenomas are more common in women, while macroadenomas are more prevalent in men. Asymptomatic microprolactinomas are common, found in up to 25% of the population based on autopsy studies.

Clinical Features

The clinical presentation of prolactinomas depends on the size of the tumor and the degree of prolactin elevation.

Microadenomas often present with symptoms related to hyperprolactinemia:

• Women: Menstrual irregularities (amenorrhea, oligomenorrhea), infertility, galactorrhea, decreased libido, vaginal dryness.
• Men: Erectile dysfunction, decreased libido, infertility, gynecomastia (rare).

Macroadenomas can cause mass effect symptoms due to their size and location within the skull, in addition to the features of hyperprolactinemia:

• Headache
• Visual field defects, particularly bitemporal hemianopsia
• Cranial nerve palsies, particularly affecting cranial nerves III, IV, and VI, due to cavernous sinus invasion

Investigations

Laboratory Tests:

• Serum prolactin level: A prolactin level above 200 ng/mL is typically diagnostic of a prolactinoma, although lower levels can be significant depending on the clinical context. Extremely elevated levels (e.g. > 5000 mU/l) are more suggestive of a macroprolactinoma. Moderate elevations (e.g. 1000-3000 mU/l) are more suggestive of a microprolactinoma. It is important to rule out other causes of hyperprolactinemia (see above).
• Pregnancy test: Essential to exclude pregnancy as a cause of elevated prolactin.
• Other pituitary hormone levels: Measuring levels of TSH, free T4, LH, FSH, and IGF-1 can help assess for other pituitary hormone deficiencies that may occur due to tumor compression.

Imaging:

• MRI of the pituitary gland: The gold standard for visualizing prolactinomas and assessing their size and location. MRI can detect tumors as small as a few millimeters.

Management

The goals of prolactinoma management are to:

• Normalise prolactin levels
• Restore gonadal function
• Reduce tumor size
• Prevent tumor recurrence and complications

Medical Therapy:

• Dopamine agonists are the first-line treatment for prolactinomas. These inhibit prolactin secretion and often shrinking the tumour.
  • Bromocriptine and cabergoline are commonly used dopamine agonists. Cabergoline is generally preferred due to its longer half-life, once-weekly dosing, and better tolerability.
  • Dopamine agonists are typically effective in normalising prolactin levels and restoring gonadal function in the majority of patients. They can reduce tumor size in about 90% of cases.
  • Side effects of dopamine agonists can include nausea, vomiting, headache, dizziness, and orthostatic hypotension.  Cabergoline has been associated with cardiac and retroperitoneal fibrosis in rare cases. Patients should be advised to stop these medications immediately if they become pregnant.

Surgery:

• Transsphenoidal surgery is considered for patients who:
  • Do not respond to or cannot tolerate dopamine agonists
  • Have rapidly growing tumors
  • Experience persistent mass effect symptoms
  • Have tumors that are resistant to dopamine agonist therapy
• Surgery can be curative in some cases but carries risks, including hypopituitarism, CSF leak, and infection.

Radiation Therapy:

• Radiation therapy may be used as an adjunct to surgery or for patients who are not surgical candidates or have tumors that cannot be controlled with medication.

Complications and Prognosis

Complications:

• Infertility and hypogonadism: These are common consequences of untreated hyperprolactinemia and can have a significant impact on quality of life.
• Osteoporosis: Prolactinomas can contribute to osteoporosis due to estrogen deficiency in women and testosterone deficiency in men.
• Visual field defects: Large macroadenomas can compress the optic chiasm, leading to visual impairment, including bitemporal hemianopsia.
• Hypopituitarism: Compression of the pituitary gland by a macroadenoma can result in deficiencies of other pituitary hormones.
• Pituitary apoplexy: This rare but life-threatening complication involves hemorrhage or infarction of the pituitary gland, often in the setting of a pre-existing adenoma. It can cause sudden onset of headache, visual disturbances, altered mental status, and hormonal deficiencies.

Prognosis:

• The prognosis for prolactinomas is generally good with appropriate treatment.  Dopamine agonists are highly effective in controlling prolactin levels and shrinking tumors in most cases.
• Tumour recurrence is possible, especially after surgical resection.
• Regular follow-up with an endocrinologist is essential to monitor hormone levels, tumor size, and potential complications.