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It is the most common type of functioning [[pituitary tumor]].<ref>{{cite journal | doi = 10.1016/j.ecl.2014.11.003|vauthors=Glezer A, Bronstein MD | year = 2015 | title = Prolactinomas | journal = Endocrinol Metab Clin North Am. | volume = 44|issue=1 | pages = 71–78 | pmid = 25732643 }}</ref> Symptoms of prolactinoma are due to abnormally high levels of prolactin in the blood ([[hyperprolactinemia]]), or due to pressure of the tumor on surrounding brain tissue and/or the [[optic nerve]]s. Based on its size, a prolactinoma may be classified as a '''microprolactinoma''' (<10mm diameter) or a '''macroprolactinoma''' (>10mm diameter). == Signs and symptoms == {{See also|Hyperprolactinaemia}} The most common symptoms at the time of diagnosis often differ between males and females. Women tend to experience more symptoms related directly to [[prolactin]] levels, such as amenorrhea and galactorrhea. By contrast, men frequently exhibit fertility issues and hormonal disruptions, such as a loss of [[libido]], but are also more likely to show signs of the tumor compressing their brain tissue, such as headaches, vision changes, and other symptoms outlined below.<ref name=":0">{{Cite book |last1=Melmed |first1=Shlomo |title=Harrison's Principles of Internal Medicine |last2=Jameson |first2=J. Larry |publisher=McGraw Hill |year=2022 |isbn=978-1264268504 |edition=21st |location=New York |chapter=Chapter 380: Pituitary Tumor Syndromes}}</ref> The symptoms due to a prolactinoma are broadly divided into those that are caused by increased prolactin levels or mass effect. Those that are caused by increased prolactin levels are:<ref name=":0" /><ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001377/ |title=Prolactinoma - PubMed Health |publisher=Ncbi.nlm.nih.gov |access-date=2012-05-28}}</ref> * [[Amenorrhea]] (disappearance of ovulation periods) * [[Galactorrhea]] (Milk production; infrequent in men) * Loss of axillary and pubic hair * [[Hypogonadism]] (Reduced function of the gonads.) * [[Gynecomastia]] (an increase in male breast size)<ref>{{cite web |url=https://www.lecturio.com/concepts/gynecomastia/| title=Gynecomastia |website=The Lecturio Medical Concept Library | date=September 2020 |access-date= 24 July 2021}}</ref> * [[Erectile dysfunction]] (in males) Those that are caused by mass effect are:<ref name=":0" /> * Headaches<ref name=sp2020>{{cite journal | vauthors = Yatavelli RK, Bhusal K| title = Prolactinoma | journal = StatPearls| date = 2020 | pmid = 29083585 }}</ref> * Vision Changes-visual field deficits, blurred vision, decreased visual acuity<ref name=sp2020/> * Cranial nerve palsies-especially with invasive tumors or with pituitary apoplexy<ref name=sp2020/> * [[Seizures]], [[Hydrocephalus]], Unilateral [[exophthalmos]] are rare presentations<ref name=sp2020/> * [[Hypopituitarism]] * [[Pituitary apoplexy]] is a medical emergency because of spontaneous hemorrhage into the pituitary tumor and presents with severe headaches, vision changes, and acute panhypopituitarism.<ref name="sp2020" /> === Infertility === A prolactinoma can cause [[infertility]], temporary or permanent, in both male and female patients.<ref name=":0" /><ref name=":1" /> It is one of the most common causes of infertility in women, with some sources estimating as much as 20% of female infertility being caused by [[Hyperprolactinaemia|hyperprolactinemia]]. It represents a smaller proportion of male infertility. However, among people who have prolactinomas, males are more likely to experience infertility, as their tumors are often more aggressive and more frequently cause hypogonadism.<ref name=":1">{{Cite journal |last1=Auriemma |first1=Renata S. |last2=Pirchio |first2=Rosa |last3=Pivonello |first3=Claudia |last4=Garifalos |first4=Francesco |last5=Colao |first5=Annamaria |last6=Pivonello |first6=Rosario |date=2023-08-18 |title=Approach to the Patient With Prolactinoma |journal=The Journal of Clinical Endocrinology and Metabolism |volume=108 |issue=9 |pages=2400–2423 |doi=10.1210/clinem/dgad174 |issn=1945-7197 |pmc=10438891 |pmid=36974474}}</ref> == Causes == Prolactinoma is most frequently a [[Sporadic disease|sporadic]] tumor, occurring in people without any concrete risk factors or family members with similar conditions.<ref name=":0" /><ref name=":1" /> In a minority of cases, genetics predispose the patient to having one or more pituitary gland tumors during their lifetime. Most cases of prolactinoma have no known causes or risk factors.<ref name=":1" /> === Pathogenesis === Though most pituitary tumors are sporadic, some genetic syndromes include increased risk for pituitary adenomas including [[Multiple endocrine neoplasia type 1]] (caused by a mutation in the [[MEN1|MEN1 gene]]), [[multiple endocrine neoplasia type 4]] ([[MEN4]] gene), [[Carney complex]], and [[Familial isolated pituitary adenoma]] (FIPA).<ref name=":0" /> Despite their frequent association with genetic [[syndrome]]s that cause multiple cancers in affected body tissues, the large majority of prolactinomas are [[Monoclonality|monoclonal]] in origin (originating from a single cell developing a random [[mutation]]), even in cases where the tumor begins producing multiple distinct [[hormone]]s aside from prolactin.<ref>{{Cite journal |last1=Ma |first1=Wenbin |last2=Ikeda |first2=Hidetoshi |last3=Yoshimoto |first3=Takashi |date=2002-07-15 |title=Clinicopathologic study of 123 cases of prolactin-secreting pituitary adenomas with special reference to multihormone production and clonality of the adenomas |url=https://pubmed.ncbi.nlm.nih.gov/12124824 |journal=Cancer |volume=95 |issue=2 |pages=258–266 |doi=10.1002/cncr.10676 |issn=0008-543X |pmid=12124824}}</ref><ref name=":0" /> A ''micro''-prolactinoma usually does not grow to become a ''macro''-prolactinoma, and also does not often become [[Metastasis|metastatic]]. As such, it is considered a [[benign tumor]], even if it causes symptoms due to excess prolactin. However, it is still recommended that patients with known microprolactinomas should receive an MRI and visual field assessment every 6 to 12 months, to detect unexpected progression and expansion of the tumor before it becomes an emergency.<ref name=":0" /> ==== Splicing factor 3B1 ==== Among cases of sporadic prolactinoma, in patients with no family history of pituitary tumors, the [[SF3B1|splicing factor 3B1 gene]] (SF3B1) has been found as a common causative mutation. This mutation, most commonly a [[missense mutation]] replacing a single [[amino acid]], has also been identified in some familial cases of prolactinoma. However, it is more commonly a [[somatic mutation]], occurring later in life in someone who was not born with the mutated gene. This gene is responsible for [[RNA splicing|splicing]] a wide variety of RNA products inside the cell, and a mutation of it can thus cause the creation of numerous abnormal proteins as [[Messenger RNA|RNA templates]] are produced in unpredictable ways.<ref name=":2">{{Cite journal |last1=Fukuhara |first1=Noriaki |last2=Nishiyama |first2=Mitsuru |last3=Iwasaki |first3=Yasumasa |date=2022-07-24 |title=Update in Pathogenesis, Diagnosis, and Therapy of Prolactinoma |journal=Cancers |volume=14 |issue=15 |pages=3604 |doi=10.3390/cancers14153604 |doi-access=free |issn=2072-6694 |pmc=9331865 |pmid=35892862}}</ref> Sporadic cases of prolactinoma which are ''not'' related to a mutation of SF3B1 remain poorly understood. However, many studies show a link between [[estrogen]] and prolactinoma. This is theorized to be related to why prolactinomas are more common in women than men.<ref name=":2" /> ==== Vision problems and headaches ==== While headaches are a symptom common to any tumor within the [[cranium]], vision problems are especially frequent in pituitary adenomas because the pituitary gland rests over the [[optic chiasm]]. As the tumor grows, it begins to compress one or both [[optic nerve]]s, depending on the size and direction of growth. This is an example of [[Mass effect (medicine)|mass effect]]. As such, smaller tumors which may produce excess prolactin or other hormones may not cause any vision problems, while still having major symptomatic effects on the body.<ref name=":0" /><ref name=":1" /> ===== Other causes of elevated prolactin ===== The majority of moderately raised prolactin levels (up to 5000 mIU/L) are not due to microprolactinomas but other causes. The effects of some prescription drugs are the most common. Other causes are other pituitary tumours and normal pregnancy and breastfeeding.<ref>{{cite journal | vauthors = Mancini T, Casanueva FF, Giustina A | title = Hyperprolactinemia and prolactinomas | journal = Endocrinology and Metabolism Clinics of North America | volume = 37 | issue = 1 | pages = 67–99, viii | date = March 2008 | pmid = 18226731 | doi = 10.1016/j.ecl.2007.10.013 }}</ref> {{Further|Hyperprolactinaemia}} == Diagnosis == Prolactinoma is often one of the first diagnoses considered by a physician when a patient presents with symptoms of [[Hyperprolactinaemia|hyperprolactinemia]].<ref name=":2" /> Specifically, the presence of several of these symptoms in the same person are indicative of elevated prolactin:<ref name=":3">{{Cite journal |last1=Wildemberg |first1=Luiz Eduardo |last2=Fialho |first2=Christhiane |last3=Gadelha |first3=Monica R. |date=2021-12-01 |title=Prolactinomas |journal=La Presse Médicale |series=Pituitary disorders |volume=50 |issue=4 |pages=104080 |doi=10.1016/j.lpm.2021.104080 |issn=0755-4982|doi-access=free |pmid=34687915 }}</ref> * Galactorrhea * Amenorrhea (in women) * Erectile dysfunction (in men) * Infertility * Diminished libido * Weight gain If these symptoms occur with the simultaneous presence of mass effects, particularly vision problems or severe [[Neurology|neurological]] symptoms such as seizures or coma, aggressive prolactinoma is highly likely.<ref name=":1" /><ref name=":2" /> A patient with these symptoms should immediately undergo [[Magnetic resonance imaging|MRI]] to assess the size and extent of the tumor. MRI is also useful in patients with smaller tumors, as it can be used to monitor the tumor for signs of growth, allowing a [[Neurosurgery|surgical intervention]] to be performed before it becomes a medical emergency.<ref name=":0" /> === Imaging === All patients with hyperprolactinemia should receive MRI imaging to determine the size and characteristics of the tumor.<ref name=":0" /><ref name=":2" /><ref name=":3" /> Prolactinomas have somewhat variable appearance on MRI, most commonly appearing hypointense on T1 weighted MRI, and heterogenous or hyperintense on T2 weighted MRI. If MRI is not available, other imaging techniques may be used if they can examine the region around the sella turcica in sufficient detail.<ref name=":3" /> Identification of pituitary tumor on MRI, with accompanying symptoms, is considered a definitive diagnosis of prolactinoma.<ref name=":2" /> Unlike macroprolactinomas which compress the optic nerves, microprolactinomas are usually not large enough to be seen on MRI. However, the addition of [[gadolinium]] [[Contrast agent|contrast enhancement]] can make them much easier to detect. Thus, evaluation of a suspected prolactinoma usually uses this form of contrast enhancement.<ref name=":2" /> Notably, this contrast can also visualize a pituitary gland with no disease at all, so precise measurement of the gland's size and shape is essential.<ref name=":0" /> === Biochemical testing === Elevated prolactin levels in the patient's serum are indicative of hyperprolactinemia, but are not specific to prolactinoma, meaning that other diseases causing similar symptoms could produce the same test results. Similarly, tests that use [[dopamine agonist]]s to suppress prolactin production are not able to rule out other diagnoses.<ref name=":0" /> As a result, biochemical testing is used only in a supplementary role, and MRI is the only definitive diagnostic tool available.<ref name=":2" /><ref name=":3" /> Dopamine agonist testing can, however, be used to determine the effectiveness of DAs like [[bromocriptine]] as a potential non-surgical treatment option.<ref name=":2" /> == Treatments == The goal of treatment is to return prolactin secretion to normal, reduce tumor size, correct any visual abnormalities, and restore normal pituitary function. The impact of stress should be ruled out before the diagnosis of prolactinoma is given. Exercise can significantly reduce stress and, thereby, prolactin levels. In the case of very large tumors, only partial reduction of the prolactin levels may be possible.<ref name="Prolactinoma">{{cite web |url=https://www.niddk.nih.gov/health-information/endocrine-diseases/prolactinoma| title=Prolactinoma|website=National Institute Of Diabetes And Digestive And Kidney Diseases |access-date= 24 July 2021}}</ref> === Medications === [[Dopamine]] is the chemical that normally inhibits prolactin secretion, so clinicians may treat prolactinoma with drugs that act like [[dopamine]] such as [[bromocriptine]] and [[cabergoline]].<ref name="pmid12808385">{{cite journal | vauthors = Bankowski BJ, Zacur HA | title = Dopamine agonist therapy for hyperprolactinemia | journal = Clin Obstet Gynecol | volume = 46 | issue = 2 | pages = 349–62 | date = June 2003 | pmid = 12808385 | doi = 10.1097/00003081-200306000-00013 | s2cid = 29368668 | url = }}</ref> This type of drug is called a [[dopamine agonist]].<ref name="pmid12808385" /> These drugs shrink the tumor and return prolactin levels to normal in approximately 80% of patients. Both bromocriptine and cabergoline have been approved by the [[Food and Drug Administration]] for the treatment of [[hyperprolactinemia]]. Bromocriptine is associated with side-effects such as [[nausea]] and [[dizziness]] and [[hypotension]] in patients with already low blood pressure readings. To avoid these side-effects, it is important for bromocriptine treatment to start slowly.<ref name="Prolactinoma"/> Bromocriptine treatment should not be interrupted without consulting a qualified [[endocrinologist]]. Prolactin levels often rise again in most people when the drug is discontinued. In some, however, prolactin levels remain normal, so the doctor may suggest reducing or discontinuing treatment every two years on a trial basis. Recent studies have shown increased success in remission of prolactin levels after discontinuation, in patients having been treated for at least 2 years prior to cessation of bromocriptine treatment.<ref>{{cite journal |author=Bronstein MD |title=Potential for long-term remission of microprolactinoma after withdrawal of dopamine-agonist therapy |journal=Nat Clin Pract Endocrinol Metab |volume=2 |issue=3 |pages=130–1 |date=March 2006 |pmid=16932269 |doi=10.1038/ncpendmet0135 |s2cid=10873443 }}</ref> Cabergoline is also associated with side effects such as [[nausea]] and [[dizziness]], but these may be less common and less severe than with bromocriptine. However, people with low blood pressure should use caution when starting cabergoline treatment, as the long half-life of the drug (4–7 days) may inadvertently affect their ability to keep their blood pressure within normal limits, creating intense discomfort, dizziness, and even fainting upon standing and walking until the single first dose clears from their system. As with bromocriptine therapy, side effects may be avoided or minimized if treatment is started slowly. If a patient's prolactin level remains normal for 6 months, a doctor may consider stopping treatment. Cabergoline should not be interrupted without consulting a qualified endocrinologist.{{citation needed|date=August 2020}} Other dopamine agonists that have been used less commonly to suppress prolactin include [[dihydroergocryptine]], [[ergoloid]], [[lisuride]], [[metergoline]], [[pergolide]], [[quinagolide]], and [[terguride]].<ref name="pmid12808385" /> === Surgery === Surgery should be considered if medical therapy cannot be tolerated or if it fails to reduce prolactin levels, restore normal reproduction and pituitary function, and reduce tumor size. If medical therapy is only partially successful, this therapy should continue, possibly combined with surgery or [[radiation]] treatment.<ref name="Prolactinoma"/> The results of surgery depend a great deal on tumor size and prolactin level. The higher the prolactin level the lower the chance of normalizing [[blood plasma|serum]] prolactin. In the best medical centers, surgery corrects prolactin levels in 80% of patients with a serum prolactin less than 250&nbsp;ng/ml. Even in patients with large tumors that cannot be completely removed, drug therapy may be able to return serum prolactin to the normal range after surgery. Depending on the size of the tumor and how much of it is removed, studies show that 20 to 50% will recur, usually within five years.{{citation needed|date=August 2020}} == Prognosis == People with microprolactinoma generally have an excellent prognosis. In 95% of cases, the tumor will not show any signs of growth after a 4 to 6-year period.{{citation needed|date=August 2020}} Macroprolactinomas often require more aggressive treatment otherwise they may continue to grow. There is no way to reliably predict the rate of growth, as it is different for every individual. Regular monitoring by a specialist to detect any major changes in the tumor is recommended.{{citation needed|date=August 2020}} === Osteoporosis risk === [[Hyperprolactinemia]] can cause reduced [[estrogen]] production in women and reduced [[testosterone]] production in men. Although estrogen/testosterone production may be restored after treatment for hyperprolactinemia, even a year or two without estrogen/testosterone can compromise bone strength, and patients should protect themselves from osteoporosis by increasing exercise and [[calcium]] intake through diet or supplementation, and by avoiding smoking. Patients may want to have bone density measurements to assess the effect of estrogen/testosterone deficiency on bone density. They may also want to discuss testosterone/estrogen replacement therapy with their physician.{{citation needed|date=August 2020}} === Pregnancy and oral birth control === If a woman has one or more small prolactinoma, there is no reason that she cannot conceive and have a normal pregnancy after successful medical therapy. The pituitary enlarges and prolactin production increases during normal pregnancy in women without pituitary disorders. Women with prolactin-secreting tumors may experience further pituitary enlargement and must be closely monitored during pregnancy. However, damage to the pituitary or eye nerves occurs in less than one percent of pregnant women with prolactinoma. In women with large tumors, the risk of damage to the pituitary or eye nerves is greater, and some doctors consider it as high as 25%. If a woman has completed a successful pregnancy, the chances of her completing further successful pregnancies are extremely high.{{citation needed|date=August 2020}} A woman with a prolactinoma should discuss her plans to conceive with her physician, so she can be carefully evaluated prior to becoming pregnant. This evaluation will include a magnetic resonance imaging (MRI) scan to assess the size of the tumor and an eye examination with measurement of visual fields. As soon as a patient is pregnant, her doctor will usually advise that she stop taking bromocriptine or cabergoline, the common treatments for prolactinoma. Most endocrinologists see patients every two months throughout the pregnancy. The patient should consult her endocrinologist promptly if she develops symptoms — in particular, headaches, visual changes, nausea, vomiting, excessive thirst or urination, or extreme lethargy. Bromocriptine or cabergoline treatment may be renewed and additional treatment may be required if the patient develops symptoms from growth of the tumor during pregnancy.{{citation needed|date=August 2020}} At one time, oral contraceptives were thought to contribute to the development of prolactinomas. However, this is no longer thought to be true. Patients with prolactinoma treated with bromocriptine or cabergoline may also take oral contraceptives. Likewise, post-menopausal estrogen replacement is safe in patients with prolactinoma treated with medical therapy or surgery.{{citation needed|date=August 2020}} == Epidemiology == [[Autopsy]] studies indicate that 6-25% of the U. S. population have small pituitary tumors.<ref name="pmid20809113">{{cite journal | vauthors = McDowell BD, Wallace RB, Carnahan RM, Chrischilles EA, Lynch CF, Schlechte JA | title = Demographic differences in incidence for pituitary adenoma | journal = Pituitary | volume = 14 | issue = 1 | pages = 23–30 | date = March 2011 | pmid = 20809113 | doi = 10.1007/s11102-010-0253-4 | pmc=3652258}}</ref> Forty percent of these pituitary tumors produce prolactin, but most are not considered clinically significant. Clinically significant pituitary tumors affect the health of approximately 14 out of 100,000 people. In non-selective surgical series, this tumor accounts for approximately 25-30% of all pituitary adenomas.<ref>{{Cite journal|last1=Gandhi|first1=Chirag D.|last2=Post|first2=Kalmon D.|date=2003-01-01|title=PrL-Secreting Pituitary Adenomas|publisher=BC Decker |url=https://www.ncbi.nlm.nih.gov/books/NBK14001/|language=en}}</ref> Some growth hormone (GH)–producing tumors also co-secrete prolactin. More than 90% of prolactinoma is microprolactinomas, which are much more common than macroprolactinomas.<ref>{{Cite web |title=Macroprolactinoma: a diagnostic and therapeutic update| url=https://academic.oup.com/qjmed/article/106/6/495/1538299 |access-date=2022-11-04 |website=academic.oup.com |pages=495–504 |date=2013-01-16}}</ref> ==See also== * [[Hypothalamic–pituitary–prolactin axis]] * [[Hyperprolactinaemia]] == References == {{reflist}} * Adapted from '''Prolactinoma'''. U. S. National Institutes of Health Publication No. 02-3924 June 2002. 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