Prolactinoma (ORPHA:2965)
A rare, usually benign, neoplasm of the anterior pituitary gland that results in hyperprolactinemia. The most common clinical manifestations are amenorrhea and infertility in women; and impotence, decreased libido and infertility in men.
Epidemiology
In Europe, the prevalence of prolactinoma is reported at between 1/1,600-2,200 (Belgium, UK and Switzerland). A notable female preponderance is observed, particularly among premenopausal women. Prolactinoma accounts for 66% of clinically relevant pituitary adenomas.
Clinical description
Disease onset is usually in the second to fourth decades of life with galactorrhea, amenorrhea and infertility presenting in women and impotence, decreased libido and infertility in men. In male patients prolactinoma may exhibit more aggressive clinical course. Prolactinoma can also cause mass effects (visual field defects, headaches) or psychiatric manifestations (anxiety, depression).
Etiology
Prolactinoma is a prolactin-secreting pituitary adenoma. The mechanism that leads to this benign growth of prolactin secreting cells is still unknown in most cases, however; very rarely, inactivating mutations of the AIP gene (11q13.3) in young patients can rarely lead to sporadic, isolated prolactinoma. Almost all AIP mutation-related prolactinomas are macroadenomas with male predominance and a young age at diagnosis. Hyperprolactinemia inhibits secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus, which results in decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and finally in decreased estrogen (females) and testosterone (males) levels. Prolactin itself stimulates lactation from breast tissue.
Diagnostic methods
Diagnosis includes laboratory hormonal testing showing hyperprolactinemia and decreased sex hormone levels (estrogen in females, testosterone in males). Pituitary adenomas may be visualized by pituitary magnetic resonance imaging (MRI). Tumors are classified according to their size: microadenomas (less than or equal to 10 mm), macroadenomas (greater than 10 mm), or giant adenomas (greater than 40 mm). Pre-menopausal females with prolactinomas usually have microadenomas, while male patients more frequently have macroadenomas.
Differential diagnosis
Prolactinoma can rarely occur as part of multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenoma (FIPA). Causes of hyperprolactinemia without pituitary adenoma include: pregnancy, lactation, exercise, stress and polycystic ovary syndrome. Pituitary lesions that do not produce prolactin can also cause hyperprolactinemia by pituitary stalk impingement (stalk effect).
Genetic counseling
Prolactinomas usually occur sporadically and with the exception of prolactinoma due to MEN1 or FIPA, the occurrence of prolactinomas as part of inherited syndromes is exceptionally rare. In patients with a pathogenic variant of AIP, the inheritance is autosomal dominant and thus offspring of an affected individual have a 50% risk of inheriting the mutation; however, penetrance is variable.
Management and treatment
Initial therapy is a dopamine agonist (cabergoline or bromocriptine) for normalizing hyperprolactinemia and decreasing tumor size. Dopamine agonist treatment should start at low doses and be titrated upwards gradually according to hormonal response and tolerability. For dopamine analog-resistant patients, changing to another dopamine agonist, increasing the dose of the drug, or neurosurgery may be proposed. Patients receiving high doses of dopamine agonists should be screened and monitored with echocardiography to identify cardiac valve dysfunction. Other medical therapies (e.g. temozolamide) may be needed for aggressive, invasive prolactinomas or rare carcinomas that are refractory to other therapies. Radiotherapy can also be considered in cases where both dopamine agonists and surgery have failed.
Prognosis
Prolactinomas are usually readily controlled with dopamine agonists that improve symptoms/signs and shrink and/or control the pituitary tumor mass. Patients with MEN1 and those harboring mutations in AIP can have a poorer response to therapy.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Pr Albert BECKERS  - Dr Adrian DALY