Prolactin-secreting tumors of the pituitary gland are called prolactinomas. It is the most common secretory tumors of the pituitary gland accounting for up to 40% of total pituitary adenomas. Prolactinomas cause a wide variety of symptoms either due to mass effect of the tumor or due to hypersecretion of prolactin. Based on the size of the tumors, prolactinomas can be classified as micro prolactinoma (smaller than 10 mm), macroprolactinoma (larger than 10 mm) or giant prolactinoma (larger than 4 cm). Hyperprolactinemia is not always due to prolactinoma and other causes like pregnancy, drugs, hypothyroidism, and pituitary stalk effect due to other pituitary tumors should be considered in the differential. 
The exact cause of prolactinoma is poorly understood. Prolactinomas arise from monoclonal expansion of pituitary lactotrophs which have undergone somatic mutation. Pituitary tumor transforming gene (PTTG) overexpression and mutation of a receptor of fibroblast growth factor 4 (FGF4) have been found in pituitary adenoma mainly prolactinoma. Most prolactinomas are sporadic in origin but can also occur as part of familial syndromes. Familial isolated prolactinoma and other pituitary adenomas have been described. It can be a part of multiple endocrine neoplasia type 1 (MEN1), up to 15% to 60% of MEN1 can have a pituitary adenoma, and the majority of them are prolactinomas.
Prolactinomas account for up to 40% of all clinically recognized pituitary adenomas. Mean prevalence of prolactinoma is estimated to be approximately 10 per 100,000 in men and 30 per 100,000 in women, with a peak prevalence in women aged 25 to 34 years. Macroprolactinoma is diagnosed more commonly in a female with a female to male ratio of 1:20; whereas, macroprolactinoma is equally common in both genders.
Prolactinomas arise from monoclonal expansion of pituitary lactotrophs and are mostly benign, often sharply demarcated without evidence of invasion. A few prolactinomas could behave aggressively with the invasion of surrounding local structures, and they generally have higher mitotic activity and are more cellular and pleomorphic. Distance extracranial involvement is required to be called as a malignant prolactinoma. Lateral parts of anterior pituitary are most common sites involved with prolactinoma.
Rarely mixed tumors which secrete growth hormone and prolactin, adrenocorticotropic hormone (ACTH) and prolactin or thyroid stimulating hormone (TSH) and prolactin can also be seen which is recognized with immunohistochemistry.
Microadenomas (smaller than 1 cm) usually are confined to sella turcica and do not cause any compressive symptoms, but macroadenomas (greater than 1 cm) can expand to an adjacent structure like optic chiasm, cavernous sinuses and causes various compressive symptoms like visual field defects, cranial nerve palsy, and headaches. Symptoms of microadenoma are mainly due to elevated levels of prolactin.
Prolactin levels are usually directly proportionate to the size of tumor ranging from below 200 ng/ml with less than 1 cm, 200 ng/ml to 1000 ng/ml with 1 cm to 2 cm and more than 1000 ng/ml with tumor sized more than 2 cm in diameter. If prolactin level does not match with tumor size, then it can be either due to not well-differentiated prolactinoma or presence of a large cystic component in the tumor.
Hypothalamus has a predominant inhibitory influence on prolactin secretion via dopamine and any factor which disrupts this mechanism causes hyperprolactinemia. It is important to consider the various causes of hyperprolactinemia as increased prolactin secretion is noted in many physiological and pathological states other than prolactinomas.
Prolactinomas clinically present because of the mass effect of the tumor or because of hyperprolactinemia. Microprolactinomas (less than 1 cm) can present with symptoms of hyperprolactinemia or are detected incidentally on neuroimaging done for other reasons. Macroprolactinomas on the other hand present with mass effects on the surrounding structures.
Signs and symptoms due to mass effect
Signs and symptoms due to Hyperprolactinemia
Children and Adolescents
Other features like osteopenia, anxiety, depression, fatigue, emotional instability can be seen in both sexes. About 10% of prolactinomas can be co-secreting growth hormone so gigantism/acromegaly can be seen in those patients.
An extensive history and physical examination are needed to exclude other causes of hyperprolactinemia and to document any visual field deficits, galactorrhea, growth changes, hypopituitarism, menstrual irregularities, impotence, infertility. Formal visual field testing by an ophthalmologist should be done especially for macroadenomas.  The following differential diagnosis should be considered during evaluation:
The test begins with serum prolactin level. If prolactin level is high, comprehensive metabolic panel, TSH and a pregnancy test (for women of childbearing age) should be obtained. Assessment of other pituitary hormones including cortisol, ACTH, IGF-1, LH, FSH and testosterone/estradiol should be done based on age and gender to exclude any hypopituitarism or other co-secreting tumors.
Patients can have very high prolactin levels; however, when measured they can be reported as falsely low due to a phenomenon called “Hook effect.” When there is a suspicion, serial dilution of the serum sample and re-measuring the prolactin levels will be helpful.
Another condition where measured prolactin can be high although true prolactin level is low is when patients have higher molecular weight prolactin called macroprolactin. Macroprolactin levels should be obtained in asymptomatic hyperprolactinemia. The laboratory can pretreat the serum with polyethylene glycol to precipitate the macroprolactin before the immunoassay for prolactin.
CT scan may demonstrate the mass, but MRI with gadolinium is the preferred imaging modality for evaluation of hyperprolactinemia as it best describes the anatomy of the hypothalamic-pituitary area. All patients with tumors adjacent to or compressing to optic chiasm should be referred for formal visual field testing.
Macroprolactinoma or symptomatic microadenoma should be treated with dopamine agonist therapy. Goals of treatment would be tumor shrinkage, restoration of visual fields if any defect, reversal of galactorrhea and restoration of fertility or abnormal sexual function. Cabergoline is preferred due to a higher frequency in normalizing prolactin level and tumor shrinkage. Amenorrhea caused by macroprolactinoma can be treated with oral contraceptive if fertility is not desired without dopamine agonists.
Most prolactinomas are managed with medical therapy only with surgery and radiotherapy reserved for refractory cases.
Unlike other pituitary tumors, the preferred treatment for prolactinomas is medical therapy. Oral contraceptive alone can be given if only symptoms are amenorrhea and or osteoporosis. Specific treatment for prolactinomas is one of the dopamine agonists.
Cabergoline and bromocriptine are two commonly used dopamine agonists. Pergolide is withdrawn from the market due to concerns about valvular heart disease, and quinagolide is not available in the United States. Dopamine agonists suppress the synthesis and release of prolactin and lactotroph cellular proliferation causing shrinkage of the tumor. They can cause nausea and dizziness.
Bromocriptine is preferred during pregnancy if needed due to more available data than cabergoline. It is also cheaper but has more side effects than cabergoline like nausea, vomiting, nasal stuffiness, postural hypotension. It is started as 1.25 mg at bedtime or after dinner daily for one week then increased to 1.25 mg 2 times a day (after breakfast and dinner). The dose should be increased every 4 weeks if prolactin level is not normalized up to a maximum dose of 5 mg two times a day. If bromocriptine is unsuccessful, cabergoline should be started.
Treatment with dopamine agonist should be tapered and stopped if prolactin level is normal and the tumor is not visible in MRI after at least two years of treatment.
Estrogen replacement is an option in a woman with inadequate response to treatment and not desiring fertility. For a man with inadequate treatment response, testosterone therapy (if no fertility desired) or human chorionic gonadotropin (if fertility desired) should be started.
Transsphenoidal surgery is preferred surgical option if surgery is indicated for following reasons:
Usually, in pregnancy, there is hyperplasia of pituitary lactotrophs and prolactin levels increase. Prolactinomas increase in size during pregnancy and in patients with known macroadenomas one can consider surgery before pregnancy or those on medical therapy should be monitored carefully with periodic visual field testing. Bromocriptine has the largest safety database in pregnancy and is preferred drug during pregnancy.
Pituitary apoplexy is an endocrine emergency when there is spontaneous hemorrhage into the pituitary adenoma/prolactinoma and patients present with sudden onset headaches, vision changes. Any patient with known prolactinoma/pituitary adenoma presenting with above symptoms would need an urgent MRI and neurosurgical/endocrine evaluation.
Once a prolactinoma has been diagnosed, patient education is key to prevent the high morbidity. All patients must be closely followed and patients must be educated about the symptoms of a prolactinoma and when to seek help. If the decision is made to taper or withdraw medical therapy, the patient must undergo imaging studies periodically to monitor for recurrence of growth. The pharmacist should educate the patient on drugs used to treat prolactinomas and their adverse effects. Finally, the oncology nurse should educate the patient on the possibility of radiation therapy for large lesions and the possibility of hypopituitarism. (Level V)
The majority of patients with microprolactinomas have an excellent prognosis. These patients can be managed medically for extended periods. Macroprolactinomas, on the other hand, can grow over time and require more aggressive treatment. The growth rate of macroprolactinomas is unpredictable, and the patient must be closely followed up. The decision to taper medical therapy requires sound judgment because the tumor can grow in size, without treatment. (Level V)
|||Pekic S,Soldatovic I,Miljic D,Stojanovic M,Doknic M,Petakov M,Popovic V, Familial Cancer Clustering in Patients with Prolactinoma. Hormones [PubMed PMID: 30196424]|
|||Cooper O,Greenman Y, Dopamine Agonists for Pituitary Adenomas. Frontiers in endocrinology. 2018 [PubMed PMID: 30186234]|
|||Araújo C,Marques O,Almeida R,Santos MJ, Macroprolactinomas: longitudinal assessment of biochemical and imaging therapeutic responses. Endocrine. 2018 Aug 7 [PubMed PMID: 30088141]|
|||Atluri S,Sarathi V,Goel A,Boppana R,Shivaprasad C, Etiological Profile of Galactorrhoea. Indian journal of endocrinology and metabolism. 2018 Jul-Aug [PubMed PMID: 30148095]|
|||Breil T,Lorz C,Choukair D,Mittnacht J,Inta I,Klose D,Jesser J,Schulze E,Bettendorf M, Clinical Features and Response to Treatment of Prolactinomas in Children and Adolescents: A Retrospective Single-Centre Analysis and Review of the Literature. Hormone research in paediatrics. 2018 [PubMed PMID: 29455199]|
|||Hoffmann A,Adelmann S,Lohle K,Claviez A,Müller HL, Pediatric prolactinoma: initial presentation, treatment, and long-term prognosis. European journal of pediatrics. 2018 Jan [PubMed PMID: 29168011]|
|||Saleem M,Martin H,Coates P, Prolactin Biology and Laboratory Measurement: An Update on Physiology and Current Analytical Issues. The Clinical biochemist. Reviews. 2018 Feb [PubMed PMID: 30072818]|
|||Maldaner N,Serra C,Tschopp O,Schmid C,Bozinov O,Regli L, [Modern Management of Pituitary Adenomas - Current State of Diagnosis, Treatment and Follow-Up]. Praxis. 2018 Jul [PubMed PMID: 30043702]|
|||Bettencourt-Silva R,Pereira J,Belo S,Magalhães D,Queirós J,Carvalho D, Prolactin-Producing Pituitary Carcinoma, Hypopituitarism, and Graves' Disease-Report of a Challenging Case and Literature Review. Frontiers in endocrinology. 2018 [PubMed PMID: 29928263]|
|||Krajewski KL,Rotermund R,Flitsch J, Pituitary adenomas in children and young adults. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2018 Sep [PubMed PMID: 29850940]|
|||Vilar L,Abucham J,Albuquerque JL,Araujo LA,Azevedo MF,Boguszewski CL,Casulari LA,Cunha Neto MBC,Czepielewski MA,Duarte FHG,Faria MDS,Gadelha MR,Garmes HM,Glezer A,Gurgel MH,Jallad RS,Martins M,Miranda PAC,Montenegro RM,Musolino NRC,Naves LA,Ribeiro-Oliveira Júnior A,Silva CMS,Viecceli C,Bronstein MD, Controversial issues in the management of hyperprolactinemia and prolactinomas - An overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism. Archives of endocrinology and metabolism. 2018 Mar-Apr [PubMed PMID: 29768629]|
|||Nakhleh A,Shehadeh N,Hochberg I,Zloczower M,Zolotov S,Taher R,Daoud Naccache D, Management of cystic prolactinomas: a review. Pituitary. 2018 Aug [PubMed PMID: 29654440]|
|||Beshyah SA,Sherif IH,Chentli F,Hamrahian A,Khalil AB,Raef H,El-Fikki M,Jambart S, Management of prolactinomas: a survey of physicians from the Middle East and North Africa. Pituitary. 2017 Apr [PubMed PMID: 27783196]|
|||Maiter D, Current Challenges in the Management of Prolactinomas. European endocrinology. 2015 Apr [PubMed PMID: 29632566]|
|||Salazar-López-Ortiz CG,Hernández-Bueno JA,González-Bárcena D,López-Gamboa M,Ortiz-Plata A,Porias-Cuéllar HL,Rembao-Bojórquez JD,Sandoval-Huerta GA,Tapia-Serrano R,Vázquez-Castillo GG,Vital-Reyes VS, [Clinical practice guideline for the diagnosis and treatment of hyperprolactinemia]. Ginecologia y obstetricia de Mexico. 2014 Feb [PubMed PMID: 24779268]|
|||Langlois F,McCartney S,Fleseriu M, Recent Progress in the Medical Therapy of Pituitary Tumors. Endocrinology and metabolism (Seoul, Korea). 2017 Jun [PubMed PMID: 28685507]|
|||Cuny T,Barlier A,Feelders R,Weryha G,Hofland LJ,Ferone D,Gatto F, Medical therapies in pituitary adenomas: Current rationale for the use and future perspectives. Annales d'endocrinologie. 2015 Feb [PubMed PMID: 25556152]|
|||Rutkowski MJ,Aghi MK, Medical versus surgical treatment of prolactinomas: an analysis of treatment outcomes. Expert review of endocrinology [PubMed PMID: 30063440]|