Prolactinomas are the most common type of pituitary tumor, accounting for approximately 40% of all cases. They are generally benign and occur more frequently in women than in men. Prolactinomas can cause a number of different symptoms, including infertility, galactorrhea, visual field defects, and headaches.
The prevalence of prolactinomas is thought to be between 0.2% and 0.3%. However, the exact incidence is difficult to determine due to the lack of symptomatic presentation in many cases. The majority of prolactinomas are microadenomas, which are less than 10 mm in diameter. These tumors are generally slow-growing and rarely cause significant damage to the surrounding tissues (mass effect).
Macroprolactinomas, which are larger than 10 mm in diameter, are rare but can cause a more significant impact on health due to their size and location. Treatment for prolactinomas typically involves the use of dopamine agonists.
Pathophysiology of Prolactinoma
The hypothalamus is responsible for the regulation of prolactin secretion from the anterior pituitary gland. Dopamine receptors, specifically D2 receptors, are located on lactotrophs in the anterior pituitary gland and are activated by dopamine released from hypothalamic neurons. Activation of D2 receptors inhibits prolactin secretion. Prolactinomas are tumors that develop in the anterior pituitary gland and secrete high levels of prolactin.
This results in hyperprolactinemia, which can lead to a number of different clinical manifestations. In order to treat a prolactinoma, it is necessary to reduce prolactin secretion to normal levels. This can be done through the use of dopamine agonists, which stimulate dopamine release from hypothalamic neurons and activate D2 receptors, leading to decreased prolactin secretion.
Prolactinomas are the most common type of pituitary adenoma, and they are generally benign. However, they can cause a wide range of symptoms due to the excessive production of prolactin. The most common symptom is galactorrhea. Women with prolactinomas may also experience amenorrhea, infertility, and lowered libido. In men, prolactinomas can cause erectile dysfunction and decreased libido.
Additionally, prolactinomas can cause visual field defects and headaches due to the pressure they place on the optic nerve. If left untreated, prolactinomas can grow large enough to compress vital structures in the brain, resulting in serious complications.
Causes of hyperprolactinemia
|• Primary hypothyroidism
• Adrenal insufficiency.
|Medications (inhibit dopamine release, leading to reduced negative feedback secretion of prolactin)
|• Antipsychotics - phenothiazines, haloperidol
• Antihypertensives - calcium-channel blockers, methyldopa
• Psychotropic agents - tricyclic antidepressants
• Anti-ulcer agents – H2 receptor antagonists
• Opiates and opiate antagonists
|Neurogenic (via autonomic nervous system)
|• Chest wall injury
• Breast stimulation
• Breast feeding.
|Physiological causes (via oestrogen stimulation)
|Increased prolactin production
|• Ovarian: Polycystic ovarian syndrome
• Pituitary tumours - adenomas, hypothalamic stalk interruption, hypophysitis
|Reduced prolactin elimination
|• Renal failure
• Hepatic insufficiency
The most common symptom is galactorrhea. Women with prolactinomas may also experience amenorrhea, infertility, and lowered libido. In men, prolactinomas can cause erectile dysfunction and decreased libido. Additionally, prolactinomas can cause visual field defects and headaches due to the pressure they place on the optic nerve. If left untreated, prolactinomas can grow large enough to compress vital structures in the brain, resulting in serious complications. Patients may also present with apoplexy, a potentially lifethreatening endocrine emergency.
- Free T4 , TSH, ACTH, IGF-1, 8am cortisol, testosterone/estradiol, and prolactin
- Pituitary MRI findings
In most cases, prolactinomas can be treated with medication, surgery, or a combination of both. However, giant prolactinomas (tumors that are larger than 5 cm in diameter) often require surgical intervention. In addition, some prolactinomas may become resistant to the usual medical treatments, such as cabergoline. When this occurs, surgery may be the best option for treatment. The goal of surgery for prolactinoma is to remove the tumor and preserve normal pituitary function. In most cases, this can be achieved through a transphenoidal approach.
Indications for medical treatment of prolactinomas
- Neurological symptoms due to tumor expansion
- Bothersome galactorrhea
- Peri-pubertal (as they will be hypogonadal)
- Longstanding hyperprolactinemia complicated by reduced bone mineral density.
Dopamine is a neurotransmitter that is produced in the brain. D2 receptors are located in the pituitary gland, and when dopamine binds to these receptors, it helps to control the release of prolactin from the pituitary gland. Cabergoline is a drug that mimics the effects of dopamine. When cabergoline binds to D2 receptors, it results in a decrease in prolactin levels. This mechanism of action is thought to be responsible for its efficacy in treating prolactinoma, a condition characterized by elevated levels of prolactin in the blood. Cabergoline has been shown to be not only effective in reducing prolactin levels but also in shrinking tumors in some patients with prolactinoma.
Prolactinoma can be confirmed by response to dopamine-agonist. There should be normalization of prolactin levels and a reduction in adenoma size by 75%.
Cabergoline (started at 0.25 mg twice weekly and up-titrated to 3 mg per week) is better tolerated but more expensive than bromocriptine (commenced at 1.25 mg OD and up-titrated to 2.5 mg). MRI should be repeated at 2-3 months after commencing therapy. Ideally prolactin levels should have normalised for at least 2 years prior to tapering down dose.
What is dopaminergic agonist resistance?
It has been suggested that dopaminergic agonist resistance (DAR) in prolactinoma patients may be associated with changes in dopamine receptor (DR) signaling. Studies have shown that DAR is associated with a decrease in DR density and/or an increase in DR desensitization. The mechanisms underlying these changes are not fully understood, but they may involve alterations in DR gene expression, post-translational modification of the receptor, or changes in the levels of dopaminergic ligands. However, the precise nature of the relationship between DAR and changes in DR signaling remains to be elucidated. Further studies are required to confirm these findings and to determine the molecular mechanisms underlying dopaminergic agonist resistance in prolactinoma patients.
Temozolomide (TMZ) is an alkylating drug that is used to treat various types of cancer, including prolactinoma. The mechanism of action of TMZ is not fully understood, but it is thought to work by inhibiting the repair of DNA damage. This leads to the accumulation of DNA damage and eventually cell death. TMZ is thought to be particularly effective against prolactinoma because of its ability to cross the blood-brain barrier. Additionally, TMZ may be more effective against prolactinoma than other cancers due to the high levels of the protein methylguanine-DNA methyltransferase (MGMT) in this type of tumor. MGMT is thought to play a role in repairing DNA damage, and thus, tumors with high levels of MGMT may be more resistant to TMZ.
Regulation of prolactin secretion
- Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JA; Endocrine Society. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Feb;96(2):273-88.
- Mah PM, Webster J. Hyperprolactinemia: etiology, diagnosis, and management. Semin Reprod Med. 2002 Nov;20(4):365-74.