Prolactinoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omar Elshafei, MD[2] Anmol Pitliya, M.B.B.S. M.D.[3], Faizan Sheraz, M.D. [4]

Synonyms and keywords: Prolactin secreting pituitary adenoma, lactotroph adenoma, prolactin cell adenoma, prolactin secreting adenoma, prolactin cell tumor, lactotroph pituitary neuroendocrine tumor, lactotroph PitNET, PRL-PitNET

Overview

Prolactinoma is a benign tumor of the lactotroph cells of the anterior pituitary that secretes prolactin. It is the most common hormone-secreting pituitary adenoma and a leading pathological cause of hyperprolactinemia. The 2022 World Health Organization classification names these tumors lactotroph pituitary neuroendocrine tumors (PitNETs), while the term "adenoma" remains widely used in clinical practice. By size, prolactinomas are classified as microprolactinomas (less than 10 mm), macroprolactinomas (10 mm or more) and giant prolactinomas (40 mm or more). Microprolactinomas predominate in women of reproductive age, whereas men usually present later with larger and more invasive tumors.

Excess prolactin suppresses hypothalamic kisspeptin and gonadotropin-releasing hormone secretion and causes hypogonadotropic hypogonadism. Women present with oligomenorrhea, amenorrhea, galactorrhea and infertility, and men present with reduced libido, erectile dysfunction and infertility. Long-standing hypogonadism leads to bone loss and fractures. Macroprolactinomas may also cause headache, visual field defects, cranial nerve palsies, hypopituitarism and, rarely, pituitary apoplexy or cerebrospinal fluid rhinorrhea.

The diagnosis requires a serum prolactin level above the upper limit of normal, exclusion of pregnancy, medications, primary hypothyroidism and chronic kidney disease, and magnetic resonance imaging of the pituitary. Macroprolactinemia, the high-dose hook effect and pituitary stalk compression by nonfunctioning sellar masses are the main diagnostic pitfalls.

Dopamine agonists, preferably cabergoline, are the standard first-line treatment and normalize prolactin, shrink the tumor and restore gonadal function in most patients. Transsphenoidal surgery is indicated for dopamine agonist resistance or intolerance and is increasingly offered as primary therapy for selected small, well-circumscribed tumors in experienced centers. Radiotherapy and temozolomide are reserved for refractory or aggressive tumors. Dopamine agonists can be withdrawn in selected patients after long-term control, but hyperprolactinemia recurs in many, so follow-up continues after withdrawal. Pregnancy, menopause, childhood, psychiatric illness, gender-affirming estrogen therapy and hereditary syndromes such as multiple endocrine neoplasia type 1 require individualized management.

Historical Perspective

• Surgery was the primary treatment for prolactinomas until dopamine agonists were introduced in the 1970s and changed therapeutic practice.
• Bromocriptine received its initial United States approval in 1978, and cabergoline in 1996.
• In 1989, a prospective study of 30 untreated women with hyperprolactinemia followed for an average of 5.2 years showed that disease progression was uncommon.
• In 1993, Knosp and colleagues introduced a magnetic resonance imaging classification of cavernous sinus invasion that is still used to predict surgical outcome.
• In 1994, a randomized trial in 459 women with hyperprolactinemic amenorrhea showed that cabergoline was more effective and better tolerated than bromocriptine.
• In 2003, a prospective study of 200 patients showed that cabergoline can be safely withdrawn in patients with normalized prolactin levels and no evidence of tumor.
• In 2006, the Pituitary Society published guidelines for the diagnosis and management of prolactinomas, followed in 2011 by the Endocrine Society clinical practice guideline on hyperprolactinemia.
• In 2007, two studies in patients with Parkinson's disease linked the ergot-derived dopamine agonists, including cabergoline, to cardiac valve regurgitation. High-dose cabergoline in Parkinson's disease was largely abandoned, and stringent regulatory recommendations for echocardiographic screening now apply to patients treated for hyperprolactinemia.
• In 2013, Trouillas and colleagues proposed a five-tier clinicopathological classification of pituitary tumors based on invasion and proliferation.
• In 2017, an international group proposed replacing "pituitary adenoma" with the term pituitary neuroendocrine tumor (PitNET).
• In 2018, the European Society of Endocrinology published its first guideline on aggressive pituitary tumors and carcinomas, which reported a positive treatment effect of temozolomide in 47% (95% CI: 36-58%) of treated patients.
• In 2020, a recurrent somatic hotspot mutation in SF3B1 was reported in prolactinomas, and a meta-analysis reappraised transsphenoidal surgery as a viable alternative first-line treatment.
• In 2021, the Pituitary Society's Pituitary Neoplasm Nomenclature (PANOMEN) workshop recommended that the term "adenoma" be retained.
• In 2022, the fifth edition of the World Health Organization classification adopted the PitNET terminology and advocated the term "metastatic PitNET" to replace "pituitary carcinoma". In the same year, an Italian (AME) and international (ICCE) position statement noted that refined endoscopic surgery allows definitive cure in some patients, with permanent discontinuation of medical therapy.
• In 2023, the Pituitary Society recommended surgery as a first-line option for selected prolactinomas, particularly according to Knosp grade.
• In 2025, the Congress of Neurological Surgeons published evidence-based guidelines on surgery and radiosurgery for functioning pituitary adenomas, the European Society of Endocrinology revised its guideline on aggressive pituitary tumors, and new international guidelines and an American Association of Clinical Endocrinology consensus statement on multiple endocrine neoplasia type 1 were released.

Classification

Prolactinomas may be classified by size, by cavernous sinus invasion, by histopathological type, by clinicopathological grade and by clinical behavior.

Classification by Size

Category	Definition	Characteristics
Microprolactinoma	Maximal diameter less than 10 mm	Prevalent in women; symptoms are mainly due to hyperprolactinemia and hypogonadism
Macroprolactinoma	Maximal diameter of 10 mm or more	Prevalent in men; mass effects such as headache, visual loss, optic chiasm compression, cranial nerve deficits and hypopituitarism occur predominantly in men
Giant prolactinoma	Diameter of 40 mm or more, significant extrasellar extension, very high prolactin (usually above 1000 μg/L) and no concomitant growth hormone or ACTH secretion	2-3% of prolactin-secreting tumors, with a male to female ratio of about 9:1; may present with cranial nerve palsies, hydrocephalus, temporal epilepsy or exophthalmos; other estimates range from 1% to 5% of prolactinomas

Classification by Cavernous Sinus Invasion (Knosp Grade)

• The Knosp classification grades parasellar extension on coronal MRI using three lines drawn on the intracavernous and supracavernous internal carotid artery: a medial tangent, the intercarotid line through the cross-sectional centers, and a lateral tangent.
• Grade 3 was later subdivided into grade 3A (extension into the superior compartment of the cavernous sinus) and grade 3B (extension into the inferior compartment), because their outcomes differ markedly.

Knosp grade	MRI definition	Surgically confirmed invasion	Gross total resection / endocrine remission
0	Normal condition; tumor does not cross the medial tangent	None in the original series	Not assessed
1	Extension beyond the medial tangent but not beyond the intercarotid line	1.5%	83% / 88%
2	Extension beyond the intercarotid line but not beyond the lateral tangent	9.9%	71% / 60%
3A	Extension beyond the lateral tangent into the superior cavernous sinus compartment	26.5%	85% / 67%
3B	Extension beyond the lateral tangent into the inferior cavernous sinus compartment	70.6%	64% / 0%
4	Total encasement of the intracavernous internal carotid artery	All tumors	0% / 0%

• The endoscopic validation series included 137 pituitary macroadenomas of all types, and endocrine remission applied to functioning adenomas. In prolactinomas, biochemical remission after transsphenoidal surgery was 75% (95% CI 67%-82%) for Knosp grades 0-2 compared with 22% (95% CI 16%-31%) for grades 3-4.

Histopathological Classification

• The 2022 WHO classification calls well-differentiated adenohypophyseal tumors pituitary neuroendocrine tumors (PitNETs) and subtypes them by cell lineage using immunohistochemistry for the pituitary transcription factors PIT1, TPIT, SF1, GATA3 and estrogen receptor alpha (ERα).
• Prolactinomas show positive immunostaining for prolactin, PIT1 and ERα.
• The PANOMEN workshop concluded that there is not yet a case for adopting the PitNET nomenclature, because most pituitary adenomas are benign and do not shorten life expectancy, and recommended that the term adenoma be retained.

PIT1-lineage tumor type	Key features
Lactotroph tumor (sparsely granulated and densely granulated subtypes)	Prolactin-secreting tumor with positive immunostaining for prolactin, PIT1 and ERα
Mammosomatotroph tumor	Co-secretes growth hormone and prolactin; recognized as a distinct PIT1-lineage type in the 2022 classification
Acidophil stem cell tumor	Recognized as a distinct PIT1-lineage type in the 2022 classification
Mature plurihormonal PIT1-lineage tumor and immature PIT1-lineage tumor	Replace the 2017 category of PIT1-positive plurihormonal tumor; the immature PIT1-lineage tumor was formerly known as silent subtype 3 tumor
Metastatic PitNET	Term advocated to replace "pituitary carcinoma" to avoid confusion with poorly differentiated neuroendocrine carcinoma; the 2025 European Society of Endocrinology guideline uses both terms

Clinicopathological Classification (Trouillas Grade)

Grade	Definition
1a	Noninvasive
1b	Noninvasive and proliferative
2a	Invasive
2b	Invasive and proliferative
3	Metastatic

• Invasion of the cavernous or sphenoid sinus is assessed on MRI, and proliferation is assessed with Ki-67, mitotic count and p53. Among 410 surgically treated patients followed for 8 years, invasive and proliferative (grade 2b) tumors had a 25-fold higher probability of tumor persistence and a 12-fold higher probability of progression than noninvasive grade 1a tumors.

Classification by Clinical Behavior

Category	Definition	Frequency
Dopamine agonist-responsive	Normal prolactin and tumor shrinkage on standard doses	Prolactin normalized in 94% of 122 macroprolactinomas treated primarily with cabergoline, 83% of them with doses of 1.5 mg/week or less
Dopamine agonist-resistant	Failure to achieve normal prolactin and a 30% or more reduction in maximal tumor diameter (in macroprolactinoma) on maximally tolerated doses	20-30% with bromocriptine and around 10% with cabergoline
Aggressive pituitary tumor	Multiple local recurrences or tumor progression despite combined surgical, medical or radiotherapeutic treatment	4.3% of patients in a multicenter series of cabergoline-resistant prolactinomas
Metastatic PitNET (pituitary carcinoma)	Pituitary tumor with metastases	3.3% of patients in the same series

Pathophysiology

Physiology of Prolactin Secretion

• Prolactin is a protein hormone of the anterior pituitary gland that is also synthesized in the central nervous system, the immune system, the uterus and the mammary gland.
• Prolactin circulates in multiple posttranslational forms, ranging from size variants to phosphorylated and glycosylated forms. Macroprolactin, a high molecular mass complex of prolactin with immunoglobulin G autoantibody, remains immunoreactive in prolactin assays but has little biological activity in vivo.
• Dopamine of hypothalamic origin provides inhibitory control over prolactin secretion; dopamine agonists act on the dopamine D2 receptor to lower prolactin levels and reduce prolactinoma size.
• Prolactin release is stimulated by suckling, stress, light, audition and olfaction. During pregnancy, increased placental estrogen secretion causes physiological enlargement of the anterior pituitary and progressive hyperprolactinemia.

Pathogenesis

• Pituitary adenomas are triggered by somatic or germline mutations that disrupt intrapituitary signaling and promote benign cell proliferation associated with chromosomal instability; cellular senescence acts as a buffer against malignant transformation, which is extremely rare.
• Prolactinomas are PIT1-lineage tumors that express ERα. In a transgender woman, initiation of gender-affirming estrogen therapy was followed by biochemical and radiological progression of a residual macroprolactinoma despite cabergoline dose escalation, and estrogen withdrawal was needed to stabilize the disease.
• Germline predisposition
  • MEN1 is a tumor-suppressor gene that encodes the scaffold protein menin; multiple endocrine neoplasia type 1 is inherited in an autosomal dominant pattern.
  • Germline AIP mutations cause a pituitary adenoma predisposition of variable penetrance and are associated with large tumors at a young age; they usually cause somatotropinomas, but prolactinomas also occur.
  • In a cohort of 506 patients with prolactinoma, 2.8% carried a pathogenic or likely pathogenic variant in MEN1 or AIP, all of whom had developed a macroprolactinoma before 30 years of age; none had a CDKN1B variant.
• Somatic SF3B1 mutation
  • After whole genome sequencing of 21 prolactinomas, validation by digital PCR in 227 prolactinomas identified the same hotspot somatic SF3B1 mutation in 19.8%. The mutation caused aberrant splicing of estrogen related receptor gamma (ESRRG), stronger binding of PIT1 and excessive prolactin secretion, and mutant tumors had higher prolactin levels and shorter progression-free survival.
  • In an independent European cohort of 282 lactotroph tumors, SF3B1 variants were found in 2.5% of all tumors but in 50% of metastatic tumors, and were associated with larger tumor size, a higher Ki-67 index and worse survival.
  • A digital PCR study of 127 patients found the SF3B1 R625H mutation in 17%, associated with younger age and larger tumor diameter but not with invasiveness, recurrence or dopamine agonist resistance.
  • No germline SF3B1 R625H mutation was found in 264 patients with macroprolactinoma. Because reported prevalence and prognostic associations differ across cohorts, SF3B1 testing remains investigational.
• Sex differences: men have higher prolactin levels and larger tumors than women, whether they harbor a microprolactinoma or a macroprolactinoma. Male sex and cavernous sinus invasion independently predict resistance to cabergoline.

Mechanisms of Clinical Manifestations

• Hypogonadism: hyperprolactinemia suppresses hypothalamic gonadotropin-releasing hormone (GnRH) secretion and impairs gonadal function. Kisspeptin neurons, which express prolactin receptors, play a major role in this effect; in hyperprolactinemic mice, kisspeptin expression, GnRH and gonadotropin secretion fell, and kisspeptin administration restored gonadotropin secretion and ovarian cyclicity.
• Galactorrhea: prolactin promotes lactation by acting on the mammary gland.
• Bone disease: skeletal fragility with a high risk of fractures is a common complication of hyperprolactinemia. Pituitary diseases generally affect bone quality more than bone quantity, so fractures may occur even with normal or low-normal bone mineral density. In prolactinoma, trabecular bone is predominantly affected.
• Mass effects: macroadenomas compress the optic chiasm, cranial nerves and normal pituitary tissue, causing visual field defects, headache and hypopituitarism.
• Body weight: weight gain is a common presenting feature. In one series of 42 patients with prolactinoma, recent weight gain was a presenting symptom in 13; during prolactin-lowering therapy, 17 patients lost weight (11 of whom had normalized prolactin), whereas 14 of the 18 patients who did not lose weight still had elevated prolactin.

Pathology

• On histopathology, lactotroph tumors stain for prolactin, PIT1 and ERα, and proliferation markers such as Ki-67 and mitotic count support prognostic grading.
• The 2025 European Society of Endocrinology guideline proposes standardized histopathological reporting of aggressive pituitary tumors and discusses the role of molecular analysis.
• Preoperative bromocriptine is associated with tumor fibrosis: dopamine agonist-pretreated macroadenomas had a higher collagen volume fraction than tumors treated first with surgery (23.6% vs 13.2%), and the collagen volume fraction correlated with the cumulative bromocriptine dose.

Causes

• Most prolactinomas are sporadic.
• Hereditary syndromes account for a minority of cases:

Hereditary cause	Gene	Pituitary phenotype
Multiple endocrine neoplasia type 1	MEN1 (menin)	Pituitary tumors in 35 to 60% of patients; prolactin-secreting tumors are the most common functional type (50% to 75%)
Familial isolated pituitary adenoma (FIPA)	AIP in 20% of FIPA families	FIPA accounts for approximately 2% of pituitary adenomas; AIP-related tumors are large and occur in children, adolescents and young adults
Other syndromes tested in pituitary tumor gene panels	CDKN1B (multiple endocrine neoplasia type 4) and MAX (multiple endocrine neoplasia type 5)	Rare; no CDKN1B variant was found in a cohort of 506 patients with prolactinoma

Differentiating Prolactinoma from other Diseases

• Prolactinoma must be differentiated from other causes of hyperprolactinemia and from other sellar and parasellar masses that raise prolactin by compressing the pituitary stalk.
• Pregnancy, drug-induced hyperprolactinemia, primary hypothyroidism and renal failure should be ruled out before macroprolactin screening and pituitary MRI.
• Clinical manifestations are similar irrespective of the cause, and prolactin values overlap between causes, although values above 500 ng/mL were seen only in patients with prolactinomas in a cohort of 1234 patients.
• On MRI, the main differential diagnoses of a microadenoma are a clinically nonfunctioning microadenoma, Rathke's cleft cyst and pars intermedia cyst; those of a macroadenoma include pituitary hyperplasia, meningioma, metastasis, craniopharyngioma, carcinoma, aneurysm, hypophysitis and chordoma.

Cause of hyperprolactinemia	Referral cohort, Brazil (n = 1234)	Population cohort, Scotland (n = 1301)
Prolactinoma	56.2%	Pituitary disorder: 25.6%
Drug-induced	14.5%	45.9%
Macroprolactinemia	9.3%	7.5%
Nonfunctioning pituitary adenoma	6.6%	Included under pituitary disorder
Primary hypothyroidism	6.3%	6.1%
Idiopathic	3.6%	15.0%
Acromegaly	3.2%	Included under pituitary disorder

Condition	Mechanism	Typical prolactin level	Distinguishing features and investigations
Prolactinoma	Autonomous prolactin secretion by a lactotroph tumor	Values above 250 ng/mL are highly suggestive; up to 25% of microprolactinomas or cystic macroprolactinomas have prolactin below 100 ng/mL	Hypogonadism and galactorrhea; mass effects in macroprolactinomas; adenoma on pituitary MRI
Pregnancy and lactation	Placental estrogen drives physiological pituitary enlargement and progressive hyperprolactinemia; suckling stimulates prolactin release	Rises progressively during pregnancy	Amenorrhea with a positive pregnancy test; pregnancy must be excluded first
Drug-induced hyperprolactinemia	Antipsychotics (most common), antidepressants, antihypertensive agents and drugs that increase bowel motility such as metoclopramide	Most patients have prolactin below 100 ng/mL, but values above 250 ng/mL can occur; antipsychotic effects on prolactin range from -77.05 ng/mL (clozapine) to 48.51 ng/mL (paliperidone) relative to placebo	Temporal relationship with the drug; if safe, stop the drug for 3 days or substitute an alternative drug, then remeasure prolactin; obtain MRI if the drug cannot be stopped and the onset did not coincide with its initiation; antipsychotics are not stopped or switched without consulting the prescribing physician
Primary hypothyroidism	Increased thyrotropin-releasing hormone stimulates lactotrophs; long-standing disease may cause pituitary hyperplasia that mimics an adenoma	Usually below 100 ng/mL	Elevated thyroid-stimulating hormone with low free thyroxine
Chronic kidney disease	Reduced prolactin clearance	Usually below 100 ng/mL, but values above 250 ng/mL can occur in chronic renal failure	Elevated creatinine and reduced glomerular filtration rate
Macroprolactinemia	Excess macroprolactin with normal concentrations of bioactive monomeric prolactin	Typically moderate: across 33 studies, the median study-level total prolactin was 61.4 ng/mL, and post-polyethylene glycol (PEG) monomeric prolactin was usually within or near the normal range (median study-level value 11.7 ng/mL)	Present in approximately 4% to 40% of hyperprolactinemic patients; up to 40% have hypogonadal symptoms, infertility or galactorrhea; confirmed by PEG precipitation or gel filtration chromatography
Stalk effect (disconnection hyperprolactinemia) from a nonfunctioning pituitary adenoma, craniopharyngioma, Rathke's cleft cyst, meningioma, hypophysitis or other parasellar mass	Compression of the pituitary stalk interrupts the inhibitory dopamine supply to lactotrophs	Below 2000 mU/L in 98.7% of histologically verified nonfunctioning macroadenomas	Large sellar mass with disproportionately modest prolactin elevation; serial dilution testing should be considered to exclude the hook effect, because pre-dilution values in hook-effect macroprolactinomas often fall in the range attributed to stalk effect
Acromegaly and mixed growth hormone and prolactin-secreting tumors	Co-secretion by mammosomatotroph or plurihormonal PIT1-lineage tumors, or stalk compression	Variable	Enlargement of the lips, tongue, nose, hands and feet; elevated insulin-like growth factor 1 (IGF-1)
Idiopathic hyperprolactinemia	No identifiable cause	Usually mild	Diagnosis of exclusion with normal pituitary MRI and negative macroprolactin screen; persisting normoprolactinemia after dopamine agonist withdrawal is more likely than in prolactinoma (32% vs 21% in microprolactinomas)
Venipuncture-related stress	Stress-induced prolactin release	Mild	Normal prolactin when repeated under stress-free conditions; in 105 patients with mild hyperprolactinemia, 59% had normal prolactin during cannulated testing

Epidemiology and Demographics

Prevalence and Incidence

• Clinically evident pituitary adenomas occur in approximately 1 in 1100 persons, and approximately 53% of pituitary adenomas are prolactinomas.
• A 2025 meta-analysis of 15 studies (16 000 cases) estimated the prevalence of prolactinoma at 41 (95% PI: 12-89) per 100,000 persons and the incidence at 2.3 (95% PI: 1.2-4.3) per 100,000 person-years.
• Population-based estimates vary with case ascertainment, study period and diagnostic criteria:

Setting	Design	Key estimates
Liège, Belgium	Cross-sectional case-finding study (n = 71,972)	Pituitary adenoma prevalence 94 ± 19.3 per 100,000 (one case in 1064 individuals); prolactinomas comprised 66% of cases
Banbury, United Kingdom	Community-based cross-sectional study	Pituitary adenoma prevalence 77.6 per 100,000; prolactinoma prevalence 44.4 per 100,000 (57% of adenomas)
Iceland	Nationwide study, 1955 to 2012	Prolactinoma prevalence 54.37 per 100,000 in 2012, the most prevalent subtype
Northern Finland	Regional cohort, 1992 to 2007	Standardized incidence of prolactinoma 2.2 per 100,000, the highest of all subtypes
Western Sweden	Registry-based study, 2001 to 2011	Standardized incidence of prolactinoma 1.6 per 100,000; prolactinomas comprised 32% of adenomas, and 37% of them were macroadenomas
North Denmark	Cohort study, 2017 to 2022	Incidence of prolactinoma 2.8 (95% CI: 2.2-3.5) per 100,000 person-years
The Netherlands	Dispensing database of dopamine agonist-treated hyperprolactinemia	Incidence 8.7 per 100,000 person-years in women and 1.4 in men; prevalence 93.9 vs 19.6 per 100,000

• Incidental pituitary adenomas are far more common than clinically relevant tumors, with an estimated prevalence of 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies). Pituitary adenomas occur in 10% of the population, but fewer than one-thousandth cause clinically significant disease.

Trends

• Between 2017 and 2022, the prevalence of prolactinoma in North Denmark increased by 41% (95% CI: 25%-60%). Pooled data showed a phenotypic shift over the last two decades toward more men (from 10%-20% to 20%-30%), more macroprolactinomas (from about 25% to about 30%) and more incidentalomas (from about 6% to about 10%).
• In Tayside, Scotland, the prevalence of hyperprolactinemia of any cause rose from 0.02% to 0.23% between 1993 and 2013, and drug-induced causes tripled.

Age

• The median age at diagnosis of prolactinoma was 32.0 years in a community-based study, and prolactinoma was the most frequent pituitary adenoma diagnosed up to 60 years of age.
• In women, incidence peaks at 25 to 34 years of age; the incidence of dopamine agonist-treated hyperprolactinemia reached 23.9 per 100,000 person-years in women aged 25-34 years, with no peak in men.
• Macroprolactinomas are rare before 20 years of age and occur mainly in girls and during adolescence.
• Prolactinomas diagnosed after menopause are uncommon; in a UK series, the median age at diagnosis was 63 years.

Sex

• Women predominate, with a strong incidence peak in women aged 25-34 years. Prolactinomas accounted for 76% of pituitary adenomas in women in a community-based study.
• In a cohort of 219 patients, microprolactinomas (56% vs 22%) and nontumoral hyperprolactinemia (10% vs 0%) were more frequent in women than in men, so most men had macroprolactinomas; men also had higher prolactin levels and larger tumors.
• Giant prolactinomas are much more frequent in young to middle-aged men, with a male to female ratio of about 9:1; 89% of patients in a Swedish nationwide cohort of giant prolactinomas were men.

Risk Factors

• Female sex during the reproductive years.
• Multiple endocrine neoplasia type 1.
• Germline MEN1 or AIP pathogenic variants, particularly with a macroprolactinoma diagnosed before 30 years of age or a family history of pituitary tumors.
• Familial isolated pituitary adenoma (FIPA).
• Estrogen exposure is not an established risk factor for tumor development: prior estrogen use and previous pregnancies did not increase the likelihood of tumor appearance or growth in untreated hyperprolactinemia. However, high-dose estrogen in gender-affirming hormone therapy may promote progression of an existing macroprolactinoma.

Screening

• Screening is targeted at individuals with a hereditary predisposition and at patients with incidentally discovered pituitary lesions.

Population	Recommended approach	Comments
Patients with MEN1 and MEN1 mutation carriers	Yearly prolactin and IGF-1 measurement, with pituitary MRI periodically, for example every 1 to 3 years; contrast-enhanced dynamic MRI is the most sensitive technique	MEN1 manifestations have been identified as early as 5 years of age, and genetic testing and tumor surveillance are generally started between 5 and 10 years of age; to reduce cost and burden, some suggest delaying routine pituitary screening of asymptomatic patients until 16 years of age or older
Patients diagnosed with a pituitary tumor, including prolactinoma	Checking serum calcium to screen for primary hyperparathyroidism is reasonable	There is no consensus on routine MEN1 screening of patients with pituitary tumors; if hyperparathyroidism is not present, the likelihood of MEN1 is very low
Young patients with macroprolactinoma	Germline testing for MEN1 and AIP; gene panels for pituitary tumors may also include CDKN1B and MAX	Pathogenic variants were found in 4% of sporadic and 15% of familial macroprolactinomas diagnosed before 30 years of age, and in sporadic cases younger than 18 years in 15% of males and 7% of females; none were found in patients older than 30 years
FIPA kindreds and relatives of AIP mutation carriers	AIP testing and clinical screening for pituitary disease	Prospectively diagnosed carriers had smaller tumors, needed fewer treatments and fewer operations, and received no radiotherapy, compared with clinically presenting carriers
Pituitary incidentaloma	Screening for hormone hypersecretion and hypopituitarism, with visual field examination if the lesion abuts the optic nerves or chiasm	Lesions not meeting surgical criteria are followed with MRI at 6 months (macroincidentaloma) or 1 year (microincidentaloma)

Natural History, Complications and Prognosis

Natural History

• Most microprolactinomas do not progress. In a prospective study of 30 untreated women with hyperprolactinemia followed for an average of 5.2 years, 2 of the 13 women with abnormal baseline imaging had tumor progression, no patient developed a macroadenoma or pituitary hypofunction, and serum prolactin was normal in 6 women at the last observation.
• Changes in serum prolactin did not accurately predict changes in tumor size in untreated patients.
• In giant prolactinomas, endocrine symptoms are often present but overlooked for a long period, and the diagnosis is made when neurological complications arise from extension into surrounding structures.
• Pregnancy may cause symptomatic tumor enlargement, particularly in macroprolactinomas. Pregnancy and menopause may also promote a spontaneous decline in prolactin and allow earlier withdrawal of cabergoline.

Complications

Complication	Details
Hypogonadism and infertility	Hyperprolactinemia is among the most common causes of hypogonadotropic hypogonadism in both sexes; 84% of patients with giant prolactinoma had hypogonadotropic hypogonadism
Bone loss and fractures	Lower lumbar spine Z-scores (mean difference -1.08; 95% CI: -1.57 to -0.59) and more fractures (OR 3.21; 95% CI: 1.64-6.26) than controls; fractures may occur despite normal bone mineral density
Visual loss and hypopituitarism	In pituitary macroadenomas, visual field defects occur in 18% to 78%, headache in 17% to 75% and hypopituitarism in 34% to 89% of patients; 71% of patients with giant prolactinoma had visual field defects
Pituitary apoplexy	A medical emergency caused by hemorrhage or infarction of the pituitary, in which rapid hydrocortisone replacement may be life saving; diagnosed at presentation or during follow-up in 18% of prolactinomas diagnosed after menopause
Cerebrospinal fluid rhinorrhea	Among 52 nonsurgical CSF leaks associated with pituitary adenomas, 81% occurred with prolactinomas; 73% developed after the start of medical therapy (dopamine agonists in 97%), at a mean of 3.3 months
Neurological complications of giant tumors	Cranial nerve palsies, hydrocephalus, temporal epilepsy and exophthalmos
Weight gain	More common in women than in men at presentation (70% vs 46%); male patients with prolactinoma weighed more than those with nonfunctioning macroadenomas (93 ± 3.4 kg vs 78 ± 2.7 kg)
Fatigue, cognitive and psychological complaints	Fatigue in 92.6% of women with active and 86.4% with controlled disease, and concentration problems in 79.0% and 64.5%; subtle deficits in verbal memory, selective attention and processing speed persist despite biochemical control
Treatment-related complications	Dopamine agonist adverse effects, including impulse control disorders; surgical complications such as permanent diabetes insipidus and CSF leak; and radiation-induced hypopituitarism (see Treatment)

Prognosis

• The prognosis is favorable in most patients. Cabergoline normalized prolactin in 81.9% of patients with prolactinoma in a multicenter cohort. Dopamine agonists definitively cure about one-third of patients, permitting treatment discontinuation.
• Hyperprolactinemia was associated with a higher overall cancer risk (HR 1.31; 95% CI: 1.02-1.68), mainly from upper gastrointestinal cancer (HR 3.69) and, in women, hematopoietic cancer (HR 3.51), but not with breast cancer (HR 1.09; 95% CI: 0.60-1.99), and prostate cancer risk was reduced (HR 0.40; 95% CI: 0.16-0.99). A population-based cohort and meta-analysis found no increase in breast cancer risk (SIR 0.99; 95% CI 0.60-1.52; pooled RR 1.04; 95% CI 0.75-1.43).
• Male sex, cavernous sinus invasion, a high proliferation index and dopamine agonist resistance are associated with a less favorable course. In 92 patients with cabergoline-resistant prolactinoma followed for a median of 88 months, prolactin normalized in 28% and the tumor disappeared in 19.9%, and mortality was 4.8%.
• In a series of 171 aggressive pituitary tumors and carcinomas of all types, median survival was 17.2 years for aggressive tumors and 11.3 years for carcinomas.
• Pituitary tumors in MEN1 were previously thought to be more aggressive and less responsive to treatment, but recent studies refute this notion.

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | ECG | X-ray| Ultrasound | CT | MRI | Other Imaging Findings | Other Diagnostic Studies

Diagnostic Approach

• Prolactin should be measured in all patients with oligo-amenorrhea, erectile dysfunction, galactorrhea or infertility, and in patients with pathological findings on MRI of the sellar region.
• The diagnostic workup of prolactinoma involves a single prolactin measurement and pituitary imaging, but laboratory artifacts such as the hook effect and macroprolactin can complicate or delay the diagnosis.
• A single serum prolactin level above the upper limit of normal confirms hyperprolactinemia, provided the sample was obtained without excessive venipuncture stress; dynamic testing of prolactin secretion is not recommended.
• A randomly elevated prolactin should be confirmed on a sample drawn after insertion of an intravenous catheter and saline infusion for 15-20 minutes, unless prolactin is clearly elevated (above 80-100 ng/mL). A stepwise approach is supported, in which prolactin is first repeated under stress-free conditions and full cannulated testing is reserved for persistent elevation; across 12 series (1700 patients), 53.7% of patients with mild hyperprolactinemia normalized prolactin during cannulated testing.
• Physiological causes (pregnancy and breastfeeding), drug-induced hyperprolactinemia, primary hypothyroidism and renal failure should be excluded before macroprolactin screening and pituitary MRI.
• In possible drug-induced hyperprolactinemia, MRI is performed only if hyperprolactinemia persists after withdrawal or replacement of the offending drug, or if the drug cannot be withdrawn.
• Macroprolactin screening is recommended in asymptomatic patients, in patients with an atypical clinical picture, conflicting results between assays or no decline in prolactin with dopamine agonists, and in patients without an obvious cause of hyperprolactinemia; it is also suggested in macroadenomas with prolactin in the 100-200 ng/mL gray area.
• In large adenomas (more than 3 cm) with normal or mildly elevated prolactin, prolactin should be measured after serial sample dilution to rule out the hook effect; the hook effect has also been documented in tumors as small as 22 mm.
• In a patient with a pituitary tumor, prolactin levels above 200-250 ng/mL are almost always due to a macroprolactinoma.
• Pituitary MRI confirms the adenoma, defines its size and invasion, and guides treatment.

Diagnostic Algorithm

The algorithm below summarizes the diagnostic approach to suspected prolactinoma.

Elevated serum prolactin: confirm with a stress-free or cannulated sample if only mildly elevated

Exclude pregnancy, medications, primary hypothyroidism and renal failure

Secondary cause identified: manage the cause and remeasure prolactin; change drugs only with the prescriber, and obtain MRI if the drug cannot be stopped

No secondary cause: screen for macroprolactin (PEG precipitation) if asymptomatic or atypical

Normal monomeric prolactin: macroprolactinemia

True hyperprolactinemia: pituitary MRI with gadolinium

No lesion: idiopathic hyperprolactinemia

Adenoma <10 mm: microprolactinoma

Adenoma ≥10 mm: compare prolactin level with tumor size

Markedly elevated prolactin (usually >250 ng/mL): macroprolactinoma

Normal or mildly elevated prolactin: repeat after serial (1:100) dilution

Marked rise: macroprolactinoma with hook effect. No rise: stalk effect from a nonfunctioning adenoma or other sellar mass is likely

• In macroadenomas with intermediate prolactin values (the 100-200 ng/mL gray area), macroprolactin screening is suggested. Prolactin was below 2000 mU/L in 98.7% of nonfunctioning macroadenomas, so higher values in a macroadenoma point to a prolactinoma.

History and Symptoms

Patient group	Typical presentation	Reported frequencies
Premenopausal women	Amenorrhea, loss of libido, galactorrhea and infertility; usually microprolactinomas	Oligo-amenorrhea or a short luteal phase in 85% to 90%; galactorrhea in 52% and weight gain in 70% of women, compared with 19% and 46% of men; gonadal or sexual dysfunction was similarly frequent in men and women (85% vs 83%)
Men	Loss of libido, erectile dysfunction and infertility; mass effects such as visual loss, cranial nerve deficits and headache occur predominantly in men	Men with prolactinoma may also have anemia, metabolic syndrome and, if the disease is long-standing, osteoporosis
Children and adolescents	Pubertal disorders, visual problems and growth retardation	Revealing symptom in macroprolactinomas: pubertal disorder 49%, visual problems 24% and growth retardation 24%; menstrual disturbance in 86.7% of girls, and headache (42.6%), reduced height velocity (25.9%) and delayed puberty (18.2%) in boys
Postmenopausal women	Headache and/or visual deterioration from a macroprolactinoma	Headache and/or visual deterioration in 47%; macroprolactinomas in 94%, with supra- or parasellar extension in 88% of them; pituitary apoplexy at presentation or during follow-up in 18%
Giant prolactinoma	Visual impairment and headache in men; amenorrhea in women	Visual impairment in 73% and headache in 50% of men, and amenorrhea in 58% of women

• Symptoms of mass effect include visual field loss, headache and symptoms of hypopituitarism.
• Pituitary apoplexy presents with sudden headache, vomiting, visual impairment and decreased consciousness, with or without palsies of the second, third, fourth and sixth cranial nerves.
• Clear nasal discharge suggests cerebrospinal fluid rhinorrhea, which was the presenting symptom in 27% of nonsurgical CSF leaks associated with pituitary adenomas and followed medical therapy in 73%.
• The history should include current medications (especially antipsychotics, antidepressants, antihypertensive agents and prokinetic drugs), menstrual and reproductive history, possible pregnancy, and symptoms of hypothyroidism or renal disease.
• A family history of pituitary, parathyroid or pancreatic endocrine tumors suggests a hereditary syndrome such as MEN1 or FIPA.

Physical Examination

• Visual fields: confrontation testing, with formal visual field examination when the lesion abuts or compresses the optic nerves or chiasm.
• Cranial nerves: palsies of the third, fourth and sixth cranial nerves suggest cavernous sinus invasion or pituitary apoplexy.
• Breasts: expressible galactorrhea, which is more common in women than in men.
• Signs of hypogonadism and hypopituitarism, including signs of long-standing estrogen or testosterone deficiency.
• Body weight: weight gain is frequent at presentation.
• Signs of other endocrine disorders: features of acromegaly in mixed growth hormone and prolactin-secreting tumors and signs of hypothyroidism.
• Growth and pubertal assessment in children and adolescents.
• Exophthalmos in giant invasive tumors.

Laboratory Findings

Serum prolactin

• Prolactin values can help determine the cause of hyperprolactinemia, but exceptions are common:

Laboratory finding	Interpretation
Mild elevation, usually below 100 ng/mL	Typical of drug-induced hyperprolactinemia, macroprolactinemia, nonfunctioning pituitary adenomas and systemic diseases, but found in up to 25% of microprolactinomas or cystic macroprolactinomas; venipuncture-related stress should be excluded by repeat sampling
Above 250 ng/mL	Highly suggestive of prolactinoma and virtually excludes nonfunctioning adenomas and other sellar masses; may also occur with macroprolactinemia, drug-induced hyperprolactinemia or chronic renal failure
Above 500 ng/mL	Seen exclusively in patients with prolactinoma in a multicenter cohort of 1234 patients
Usually above 1000 μg/L	Typical of giant prolactinomas, in which prolactin usually ranges from 1000 to 100,000 μg/L
Normal or mildly elevated (250 ng/mL or less) with a large adenoma	Suspect the hook effect and repeat the measurement after a 1:100 serum dilution
Below 2000 mU/L with an apparently nonfunctioning macroadenoma	Consistent with stalk compression; prolactin was below 2000 mU/L in 98.7% of histologically verified nonfunctioning macroadenomas

• Prolactin is higher in men than in women for tumors of similar size category: 2848 ± 2954 vs 1132 ± 2351 μg/L in macroprolactinomas and 187.8 ± 51.8 vs 135.4 ± 60.5 μg/L in microprolactinomas.
• Prolactin units differ between laboratories; in one population study, 1000 mU/L corresponded to 47.2 ng/mL.

Hook effect

• The immunoassay hook effect causes spuriously low prolactin measurements in patients with macroprolactinomas and may lead to misdiagnosis and inappropriate management.
• In an individual-patient review of 23 confirmed cases, the smallest tumor showing a hook effect measured 22 mm, and 39.1% of tumors were below the 40 mm giant adenoma threshold. Median prolactin rose from 100.0 ng/mL before dilution to 6,460.0 ng/mL after dilution (a median 64.7-fold increase), and pre-dilution values ranged from 26 to 200 ng/mL in 82.6% of cases, often misattributed to stalk effect. Unrecognized hook effect led to unnecessary surgery in 55.6% of cases with documented outcomes.
• Because macroprolactinomas with a hook effect resemble those without it clinically, dilution studies are advised for all pituitary macroadenomas with normal or mildly elevated prolactin, regardless of whether the tumor reaches the giant threshold.

Macroprolactin

• Macroprolactin is screened for by polyethylene glycol (PEG) precipitation, and the post-PEG monomeric prolactin is compared with assay-specific reference intervals.
• In confirmed macroprolactinemia, total prolactin elevation is typically moderate: across 33 studies, the median study-level total prolactin was 61.4 ng/mL (IQR 42.0-80.0) and the median study-level post-PEG monomeric prolactin was 11.7 ng/mL (IQR 8.3-13.2); extreme elevations were attributable to coexisting prolactinomas.
• The post-PEG monomeric prolactin value, rather than percent recovery alone, best distinguishes isolated macroprolactinemia from coexisting true hyperprolactinemia.

Tests to exclude other causes and assess pituitary function

• Pregnancy test, thyroid-stimulating hormone, free thyroxine and renal function are measured to exclude pregnancy, primary hypothyroidism and renal failure.
• IGF-1 should be measured in all prolactin-secreting tumors at diagnosis to screen for growth hormone co-secretion.
• Screening for hypopituitarism is recommended at diagnosis in all patients with macroprolactinoma, and in microprolactinoma only if there is clinical suspicion. Testing includes free thyroxine, TSH, morning cortisol, IGF-1, testosterone in men and menstrual history in premenopausal women.
• A clear baseline prolactin value should be defined in macroprolactinomas, rather than a vague value such as "higher than 1000 ng/mL", to make follow-up on medical treatment easier.

Electrocardiogram

There are no ECG findings associated with prolactinoma.

X-ray

Skull radiography may show enlargement or erosion of the sella turcica in macroprolactinomas, but it is insensitive and has no role in the current diagnosis of prolactinoma.

Echocardiography or Ultrasound

• There are no echocardiography or ultrasound findings associated with prolactinoma.
• Transthoracic echocardiography is performed before starting cabergoline and repeated during treatment to monitor for cardiac valvulopathy (see Medical Therapy).

CT scan

• Contrast-enhanced dynamic MRI is the most sensitive imaging technique for pituitary tumors.
• Computed tomography is performed only in patients with absolute contraindications to MRI; it can demonstrate prolactinomas, but its accuracy for microadenomas is definitely lower. CT is usually performed after MRI, before transsphenoidal surgery, to assess the anatomy of the sinuses.

MRI

• Pituitary MRI with gadolinium is the imaging study of choice for prolactinoma, and contrast-enhanced dynamic sequences are the most sensitive technique for small tumors. Pituitary MRI should be performed at 1.5 T or more and interpreted by neuroradiologists to avoid false-positive diagnoses.
• Pituitary adenomas are usually mildly hypointense or isointense on T1-weighted images and have variable intensity on T2-weighted images; in one study, 80% of prolactinomas were hyperintense on T2-weighted sequences compared with gray matter. Most macroadenomas enhance strongly but heterogeneously after gadolinium.
• Small cysts and hemorrhagic foci are common. Pituitary hemorrhage is more frequent in macroprolactinomas (20%) than in microprolactinomas (3%), regardless of dopamine agonist therapy, and is usually asymptomatic.
• MRI defines tumor size and the extent of parasellar extension; invasion of the cavernous sinus is graded with the Knosp classification. The distance between the tumor and the optic chiasm on MRI is part of the criteria for dopamine agonist withdrawal.
• On T2-weighted sequences, pituitary hemorrhage usually appears hypointense in both acute and chronic stages, whereas cystic components are hyperintense.
• The Knosp grade on preoperative MRI predicts intraoperative tumor invasion, total resection and postoperative hormonal remission.
• Large cystic components do not preclude response to dopamine agonists.
• Follow-up MRI is recommended within 3-6 months after starting a dopamine agonist in macroprolactinomas and within 1 year in microprolactinomas, earlier in non-responders or if new symptoms develop; the use of gadolinium during follow-up should be limited, especially in macroprolactinomas.
• During pregnancy, MRI is performed without gadolinium in women with severe headaches or visual field changes.
• In giant prolactinomas, the reduction in tumor size after the first year of dopamine agonist treatment predicts the long-term combined response.

Other Imaging Findings

• Gallium-DOTATATE PET/CT has not been shown to be sensitive for the detection of pituitary tumors in patients with MEN1.
• For aggressive pituitary tumors and metastatic PitNETs, the 2025 European Society of Endocrinology guideline proposes standardized reporting of imaging investigations.

Other Diagnostic Studies

• Formal visual field testing for tumors that abut or compress the optic nerves or chiasm.
• Pituitary function testing in patients with macroadenomas.
• Bone health assessment in patients with long-standing hypogonadism, recognizing that fractures may occur despite normal or low-normal bone mineral density on dual-energy x-ray absorptiometry.
• Genetic testing for MEN1 and AIP in patients with a macroprolactinoma before 30 years of age or a familial context. A genetic basis should be suspected with a family history, onset before 20 years of age, aggressive behavior despite appropriate treatment, or other endocrine diseases.
• Histopathology after surgery, including immunohistochemistry for pituitary transcription factors and proliferation markers.
• Patient-reported outcomes and cognitive assessment, because fatigue, cognitive impairment and psychological complaints persist despite biochemical control.

Treatment

Medical Therapy | Surgery |Primary prevention |Secondary prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Initial Management

Goals of treatment

• Normalize prolactin, reduce tumor size and restore gonadal function.
• Relieve mass effects, preserve pituitary function and vision, and prevent bone loss.
• Improve quality of life, which is worse in patients with prolactinoma than in healthy controls and correlates with prolactin levels.

Who should be treated

• Dopamine agonist therapy is recommended for patients with symptomatic prolactin-secreting adenomas.
• Microprolactinoma: the aim of treatment is reversal of the clinical picture, mainly hypogonadism. Asymptomatic patients do not need dopamine agonists, and simple observation is appropriate when hypogonadism or galactorrhea are not an issue; oral estrogen-progestin contraceptives are an option in women with amenorrhea who are not seeking pregnancy.
• Macroprolactinoma: first-line cabergoline is recommended regardless of tumor size or the severity of neurological and ophthalmological damage, under tight clinical and laboratory control.
• Asymptomatic medication-induced hyperprolactinemia should not be treated.

Urgent situations

• Visual compromise: dopamine agonists are first-line even in giant prolactinomas and rapidly alleviate neurological symptoms in most patients. Resection by an expert pituitary surgeon is recommended if severe neuro-ophthalmological damage does not improve quickly (within 2 weeks) on dopamine agonists.
• Pituitary apoplexy: a medical emergency in which rapid hydrocortisone replacement may be life saving; patients should be referred to a multidisciplinary team including a neurosurgeon and an endocrinologist, and surgery is indicated for worsening neurological symptoms.
• CSF rhinorrhea: urgent evaluation by an ear, nose and throat surgeon or a neurosurgeon is recommended, and surgical repair, preferably by a transsphenoidal approach, is the recommended initial treatment.

Choice of first-line therapy

• Dopamine agonists, particularly cabergoline, are typically used as primary therapy.
• Transsphenoidal surgery is increasingly used as primary therapy for small prolactinomas because of a high chance of remission. In 2023, the Pituitary Society recommended surgery as a first-line option for selected prolactinomas, particularly according to Knosp grade, and a subsequent meta-analysis found that resection of Knosp grade 0-2 prolactinomas appears to be an effective first-line option.
• The AME/ICCE position statement recommends that transsphenoidal resection be presented as a viable option to any patient with a radically resectable adenoma (microprolactinoma or enclosed macroprolactinoma), ideally after joint evaluation by the endocrinologist and the neurosurgeon, and suggests surgery whenever treatment is required and the patient is unwilling to take chronic medical treatment.
• In contrast, the 2025 Congress of Neurological Surgeons guideline found Class III evidence favoring medical management over surgery for prolactinomas at primary diagnosis.
• The available evidence is observational, and further studies comparing surgical and medical strategies across Knosp grades are needed. The first-line choice should therefore be individualized and made with the patient, considering tumor size and invasiveness, surgical expertise, the patient's wish for a chance of cure and the expected duration of medical therapy.
• The therapeutic strategy should be discussed by a multidisciplinary tumor board, especially in macroprolactinomas, and patients should be referred to an expert pituitary surgeon whenever surgery is considered.

Treatment algorithm The algorithm below summarizes the initial management of prolactinoma.

Prolactinoma confirmed

Treatment indicated? (macroprolactinoma, hypogonadism, infertility, bothersome galactorrhea, bone loss or mass effect)

No: asymptomatic microprolactinoma; observe with periodic prolactin measurement

Yes

Cabergoline first line: 0.25 mg twice weekly, titrated at intervals of at least 4 weeks

Alternative first line for a radically resectable microprolactinoma or enclosed macroprolactinoma: transsphenoidal surgery by an expert pituitary surgeon

Normal prolactin and tumor shrinkage

Resistance or intolerance

Remission: monitor prolactin for recurrence

Persistent hyperprolactinemia: dopamine agonist, reoperation or radiotherapy

After at least 2 years of normal prolactin and no visible tumor: taper to the lowest dose, then withdraw with monitoring

Resistance: switch bromocriptine to cabergoline and escalate the dose. Intolerance or persistent resistance: surgery. Aggressive tumors: radiotherapy and temozolomide

Medical Therapy

Mechanism of action

• Dopamine agonists stimulate the dopamine D2 receptor, which lowers prolactin levels and reduces prolactinoma size.

Choice of agent

• Cabergoline is preferred over other dopamine agonists because it has higher efficacy in normalizing prolactin and a higher frequency of tumor shrinkage.
• Cabergoline is used at the lowest effective dose that controls prolactin hypersecretion and tumor volume; bromocriptine is suggested for patients intolerant of cabergoline who are not candidates for surgery, or when cabergoline is unavailable.
• In the largest randomized trial, cabergoline was more effective and better tolerated than bromocriptine in 459 women with hyperprolactinemic amenorrhea:

Outcome	Cabergoline (0.5 to 1.0 mg twice weekly)	Bromocriptine (2.5 to 5.0 mg twice daily)
Stable normoprolactinemia	83%	59%
Ovulatory cycles or pregnancy	72%	52%
Persistent amenorrhea	7%	16%
Any adverse effect	68%	78%
Discontinuation because of intolerance	3%	12%

• A meta-analysis of four randomized trials favored cabergoline for normalization of prolactin (RR 0.67; 95% CI 0.57-0.80) and for menstruation with ovulatory cycles (RR 0.74; 95% CI 0.67-0.83), and adverse effects were more frequent with bromocriptine (RR 1.43; 95% CI 1.03-1.98).
• Compared with no treatment, dopamine agonists reduced prolactin (weighted mean difference -45; 95% CI -77 to -11) and the likelihood of persistent hyperprolactinemia (RR 0.90; 95% CI 0.81 to 0.99).
• In a multicenter cohort, cabergoline normalized prolactin more often than bromocriptine (81.9% vs 67.1%), and drug resistance occurred in 10% vs 18.4%.

Dosing

Drug	Starting dose	Titration	Usual or maximum dose	Key cautions
Cabergoline	0.25 mg orally twice weekly	Increase by 0.25 mg twice weekly at intervals of no less than 4 weeks until prolactin normalizes	Label maximum 1 mg twice weekly; higher doses are used in resistant prolactinomas, and patients resistant to previous treatment needed a mean 5.2 ± 0.6 mg/week to normalize prolactin	Contraindicated in uncontrolled hypertension, hypersensitivity to ergot derivatives, a history of cardiac valvular disorders, and a history of pericardial fibrosis or of pleural, pulmonary or retroperitoneal fibrotic disorders; labeled for adults
Bromocriptine	1.25 mg (one-half tablet) to 2.5 mg once daily	Prolactin-secreting adenomas: increase as tolerated until an optimal response is achieved; hyperprolactinemia-associated dysfunction: increase by up to 2.5 mg once daily every 2 to 7 days as tolerated	2.5 mg to 10 mg once daily for adenomas and 2.5 mg to 15 mg once daily for hyperprolactinemia-associated dysfunction	Approved for prolactin-secreting adenomas in adults and in children 11 years of age and older; generally withdrawn when pregnancy is diagnosed

Expected response

• Cabergoline at doses of up to 2.0 mg per week for at least 6 months normalizes prolactin, shrinks the adenoma by at least 30% and restores gonadal function in most patients.
• In 122 macroprolactinomas treated primarily with cabergoline, prolactin normalized in 94%, and 83% of the responders were controlled with 1.5 mg/week or less; most tumors (82%) shrank significantly.
• In 219 newly diagnosed patients, cabergoline normalized prolactin more often in microprolactinomas than in macroprolactinomas (86% vs 64%), with similar rates in men and women; menses resumed in 82% of women, libido improved in 57% of men, and visual field defects resolved in 61% of women and 71% of men.
• In untreated patients and in patients intolerant of previous treatment, individualized cabergoline titration normalized prolactin in 83% at 3 months and 95% at 6 months.

Dopamine agonist resistance

• Resistance is defined as failure to achieve normal prolactin and a 30% or more reduction in maximal tumor diameter on maximally tolerated doses; its prevalence is 20-30% for bromocriptine and around 10% for cabergoline, and the main predictors are male sex and tumor invasiveness.
• About 20% of macroprolactinoma patients, mainly men or those with invasive tumors, require cabergoline doses above 1.5 mg/week; beyond 3.5 mg/week there was no clear advantage in further dose increases compared with continuing the same dose.
• Other factors associated with resistance include very young age, cystic, hemorrhagic or necrotic tumor components before treatment, and genetic predisposition such as MEN1 or AIP mutations.
• Management options for resistant prolactinomas:

Strategy	Evidence
Switch from bromocriptine to cabergoline	Normalizes prolactin in 80% of bromocriptine-resistant patients
Escalate cabergoline to the maximally tolerated dose	Individualized high-dose cabergoline normalized prolactin in all but one of 150 patients; only 35% of previously resistant patients normalized at 3 mg/week; complete resistance occurred in only 7 of 122 (6%) macroprolactinomas despite maximal doses for more than 12 months
Transsphenoidal debulking	Debulking improved prolactin control and reduced the required cabergoline dose in 14 patients with cabergoline-resistant prolactinoma
Radiotherapy	Considered for aggressive prolactinomas; normal prolactin eventually occurs in only one-third of patients after many years
Temozolomide	Therapeutic option for malignant or aggressive prolactinomas

• In 92 patients with uncontrolled hyperprolactinemia on cabergoline of 2.0 mg/week or more, the median maximal dose was 3.5 mg/week (range 2.0-10.5), 60.9% underwent surgery and 14.1% received postoperative radiotherapy.
• Reports conflict on whether MEN1-related prolactinomas respond less well: a MEN1 mutation independently predicted dopamine agonist resistance in a cohort of children and adolescents, whereas a systematic review (10 studies, 505 patients) found similar rates of failure to normalize prolactin in patients with and without MEN1 (low or very low certainty).

Adverse effects

Adverse effect	Evidence and management
Common adverse effects	Nausea, vomiting, postural hypotension, drowsiness, somnolence, nasal stuffiness, headache, Raynaud's phenomenon and constipation; with cabergoline they usually subside over time but persist in 3-4% of patients, requiring dose reduction or withdrawal and referral to neurosurgery. Adverse effects occurred in 68% of women on cabergoline vs 78% on bromocriptine, and gastrointestinal symptoms were less frequent, less severe and shorter-lived with cabergoline; side effects occurred in 26% (95% CI 13-41) of patients during dopamine agonist treatment
Impulse control disorders	Any impulse control disorder in 17% and hypersexuality in 6.5% of 308 patients, more common in men and with a history of gambling, smoking or alcohol use; pooled odds ratio 2.39 (95% CI 1.78-3.21) compared with unexposed patients or controls; usually reversible after dopamine agonist discontinuation; patients and caregivers should be alerted to this risk when cabergoline is started, and psychiatric symptoms should be asked about regularly
Depression, mania and psychosis	Reported in case reports temporally associated with dopamine agonist therapy, regardless of prior psychiatric history, and improved after discontinuation and psychiatric treatment; dopamine agonists should be used with caution in patients with a history of neuropsychiatric disease
Cardiac valvulopathy	At the high doses used in Parkinson's disease, current cabergoline use increased cardiac-valve regurgitation (incidence-rate ratio 4.9; 95% CI 1.5 to 15.6), and clinically important regurgitation occurred in 28.6% of cabergoline users vs 5.6% of controls. At doses used for hyperprolactinemia, moderate valvular abnormalities occurred in 3.2% of 747 patients without association with cumulative dose; tricuspid regurgitation was more frequent (OR 3.74; 95% CI 1.79-7.8) but never clinically diagnosed
CSF rhinorrhea	May follow rapid shrinkage of invasive tumors after dopamine agonists are started
Tumor fibrosis	Preoperative bromocriptine is associated with fibrotic, tenacious tumors that are more difficult to resect

Echocardiographic monitoring during cabergoline therapy

Aspect	British Society of Echocardiography, British Heart Valve Society and Society for Endocrinology (2019)	United States cabergoline prescribing information
Baseline	Standard transthoracic echocardiogram before starting dopamine agonist therapy	Cardiovascular evaluation including an echocardiogram before starting cabergoline
Total weekly dose of 2 mg or less	Repeat at 5 years after starting cabergoline; if unchanged, repeat at 5-yearly intervals	Echocardiogram at intervals of 6 to 12 months or as clinically indicated
Total weekly dose above 2 mg	Annual echocardiography	Echocardiogram at intervals of 6 to 12 months or as clinically indicated
Abnormal findings	Mild or moderate tricuspid regurgitation without leaflet thickening, restriction or retraction should not be attributed to the drug; discontinuation is decided only after review of serial imaging by an experienced echocardiographer	Do not give cabergoline if valvular disease is detected

• The AME/ICCE position statement suggests periodic cardiac auscultation, with echocardiography in patients who have a murmur or take more than 2 mg of cabergoline per week, without overlooking causes of valve disease unrelated to the drug.

Gonadal, fertility and bone management

• Early testosterone replacement is recommended in men with persistent hypogonadism within 3-6 months after starting a dopamine agonist, provided that prolactin is progressively decreasing.
• Gonadal replacement in hypogonadal women with macroprolactinoma is decided case by case and continued at least until the age of physiological menopause; estrogen-progestin contraception is a safe option in dopamine agonist-responsive women with microprolactinoma or well-responsive macroprolactinoma who require contraception.
• Fertility can be restored with gonadotropins when required.
• Bone health should be evaluated to decide whether additional bone-active treatment is needed.

Other medical options

• In drug-induced hyperprolactinemia that is symptomatic, options include switching to an alternative medication that does not cause hyperprolactinemia, estrogen or testosterone replacement, or cautious addition of a dopamine agonist.
• Estrogen and progestin replacement is an alternative in women with a macroprolactinoma and psychosis.
• Investigational approaches for uncontrolled prolactinomas include alternative hormonal treatments, cytotoxic drugs, peptide receptor radionuclide therapy, mTOR/Akt inhibitors, tyrosine kinase inhibitors and immunotherapy, but experience is scant. Kisspeptin restored gonadotropin secretion and ovarian cyclicity in hyperprolactinemic mice and may become an alternative for women who are resistant or intolerant to dopamine agonists.

Procedural / Surgical Therapy

Transsphenoidal surgery

• Surgery is performed by microscopic or endoscopic transsphenoidal techniques. There are insufficient data to support endoscopic over microscopic surgery for remission or complications, although the endoscopic technique may achieve shorter operative times and better resection and remission in noninvasive macroadenomas.
• Indications:
  • Dopamine agonist intolerance, which was the most frequent indication in a prospective series of 100 consecutive operations.
  • Dopamine agonist resistance not overcome by dose escalation.
  • Patient preference for a chance of cure instead of long-term medical therapy, particularly with microprolactinomas or well-circumscribed intrasellar macroprolactinomas.
  • Women with macroprolactinomas who wish to become pregnant.
  • Pituitary apoplexy with worsening neurological symptoms, and CSF leakage.
  • Cystic prolactinomas that do not respond to dopamine agonists.
  • Patients with psychosis in whom dopamine agonists are problematic.
• Surgery should be discussed in young patients, to avoid the unpredictable sequelae of long-term dopamine agonist treatment, and in men, because of a higher likelihood of resistance and aggressive behavior.
• Surgical expertise is the major determinant of outcomes, and surgery should be performed by experienced surgeons at high-volume centers. The best surgical results are obtained by neurosurgeons who perform at least 50 pituitary operations per year.
• Endocrine remission after surgery is inversely related to adenoma size and is about 10% for giant or invasive tumors.

Study	Population	Main outcomes
Zamanipoor Najafabadi 2020	Meta-analysis of 25 surgical studies (n = 1836) and 55 medical studies (n = 3564)	Long-term remission 67% (95% CI, 60-74) after surgery vs 34% (95% CI, 26-46) after dopamine agonist withdrawal; in microprolactinomas, 83% (95% CI, 76-90) vs 36% (95% CI, 21-52); surgical mortality 0%, permanent diabetes insipidus 2% (95% CI, 0-5) and CSF leakage 3% (95% CI, 2-5)
Ordoñez-Cure 2026	Meta-analysis of 12 studies (n = 1010)	Biochemical remission 75% (95% CI 67%-82%) for Knosp grades 0-2 vs 22% (95% CI 16%-31%) for grades 3-4; no deaths reported
Tampourlou 2016	Review of contemporary series in microprolactinomas	Normal prolactin after transsphenoidal surgery in 71-100%, with very low complication rates; cabergoline achieves biochemical control in 85% to 93%
Kreutzer 2008	Consecutive surgical series of 212 patients	Long-term remission 84.8% in microprolactinomas, 72.5% in intrasellar tumors and 80% in cystic prolactinomas; relapse in microprolactinomas 7.1%
van Trigt 2025	Prospective expert-center series of 100 consecutive operations	Remission in 91% after elective total resection and in 89% after reoperation; long-term complications in 4%; improved quality-of-life scores
Andereggen 2017	Women treated first with surgery (n = 71) or dopamine agonists (n = 36); median follow-up 90 months	Long-term dopamine agonist dependence in 32% after primary surgery vs 64% after primary medical therapy

Effect of preoperative dopamine agonist treatment

• In 290 surgically treated prolactinomas, dopamine agonist pretreatment was associated with tenacious tumor consistency (27.8% vs 9.8%), more surgical morbidity in macroadenomas (19.4% vs 8.9%) and a lower initial remission rate in microadenomas (86.7% vs 100%).
• Whether dopamine agonist treatment impairs later surgical results remains controversial and unsettled.

Perioperative care

• After transsphenoidal surgery in patients without diabetes insipidus, limited fluid restriction (1000-1500 mL/day for about 7 days) lowers the risk of delayed hyponatremia and readmission.
• After pituitary surgery, new endocrine deficiencies occur in 5% to 15% of patients, and arginine vasopressin deficiency (central diabetes insipidus) occurs in up to 30%, mostly transiently.

Cost-effectiveness

• Transsphenoidal surgery may be cost-effective in young patients with microprolactinoma and a life expectancy greater than 10 years when performed by experienced surgeons at high-volume centers, and cost-utility analysis favors surgery over dopamine agonist treatment.

Radiotherapy

• Radiotherapy is reserved mostly for aggressive or high-risk prolactinomas and for tumors resistant or intolerant to medical therapy, usually after surgical failure, because of its adverse effects, notably hypopituitarism.
• In aggressive and high-risk prolactinomas, tumor control ranged from 68% to 100%; in resistant prolactinomas, secretion control ranged from 28% to 89%-100%; and the 5-year rate of hypopituitarism was around 12%-25%.
• In 289 patients treated with stereotactic radiosurgery, endocrine remission rates were 28%, 41% and 54% at 3, 5 and 8 years; endocrine control was achieved in 63%, new hormone deficiency developed in 25%, new visual complications in 3% and tumor progression in 5%. A pretreatment prolactin level of 270 ng/ml or less predicted remission.
• Stereotactic radiosurgery and fractionated radiotherapy provide excellent radiographic control with variable hormonal remission, and hormonal reduction may continue for up to 10 years after treatment.
• Evidence on continuing dopamine agonists during radiosurgery addresses different outcomes: the 2025 Congress of Neurological Surgeons guideline states that suppressive medical treatment may be continued before radiosurgery because it may not affect radiographic control, whereas in a Gamma Knife series, taking a dopamine agonist at the time of radiosurgery tended to decrease the probability of endocrine remission.
• The AME/ICCE position statement recommends irradiation for macroprolactinomas that cannot be controlled by dopamine agonists and surgery, discussion of radiotherapy within a multidisciplinary pituitary team, radiosurgery rather than fractionated radiotherapy when available and technically feasible (unless the tumor is too close to the optic pathways or diffusely infiltrates surrounding structures), and prolonged yearly follow-up after radiotherapy.

Long-Term Management

Monitoring

Parameter	Approach
Serum prolactin	Cabergoline is titrated to achieve normal prolactin, and after cabergoline is discontinued, prolactin is monitored periodically to determine whether treatment should be reinstituted; in good responders with macroprolactinoma (normal prolactin and tumor shrinkage), yearly prolactin assessment is sufficient in most cases
Pituitary MRI	Within 3-6 months after starting a dopamine agonist in macroprolactinomas and within 1 year in microprolactinomas, earlier in non-responders or with new symptoms; in good responders with macroprolactinoma, MRI every other year or longer, or not at all if prolactin remains normal; in giant prolactinomas, the reduction in prolactin or tumor size after the first year identifies patients who need closer monitoring or additional treatment
Visual fields	Formal visual field testing in patients with tumors compressing the optic chiasm
Echocardiography	According to the cabergoline dose and the monitoring scheme adopted (see Medical Therapy)
Impulse control and mood	Screen at follow-up visits, particularly in men and in patients with a history of gambling, smoking or alcohol use
Pituitary and gonadal function, bone health	Test for hypopituitarism after pituitary surgery and during follow-up after radiotherapy, because the 5-year rate of hypopituitarism is around 12%-25%; evaluate bone health to decide whether bone-active treatment is needed
Patient-reported outcomes	Fatigue, cognitive and psychological complaints are common despite disease control and should be addressed

Dopamine agonist withdrawal

• With careful clinical and biochemical follow-up, therapy may be tapered and perhaps discontinued in patients treated for at least 2 years who no longer have elevated prolactin and have no visible tumor remnant on MRI.
• In the prospective study that established withdrawal criteria, cabergoline was withdrawn when prolactin was normal, MRI showed no tumor (or a tumor reduction of 50% or more, with the tumor more than 5 mm from the optic chiasm and no invasion of the cavernous sinuses or other critical areas), and follow-up after withdrawal could continue for at least 24 months.
• Reducing cabergoline to the lowest dose before withdrawal was associated with success, whereas treatment for longer than 2 years showed no trend of effect in one meta-analysis.
• In macroprolactinomas, the AME/ICCE position statement suggests withdrawal only after complete disappearance of the tumor (or at least a 50% decrease in tumor size) with persistently low-normal prolactin after progressive dose reduction, followed by careful quarterly monitoring of prolactin and gonadal status, and recommends against withdrawal when tumor tissue and pathological prolactin levels persist. After a withdrawal attempt, prolactin is measured at 3 months and thereafter according to this first result.

Study	Design	Outcome after withdrawal	Factors associated with success
Colao 2003	Prospective study, 200 patients	Recurrence 24% (nontumoral), 31% (microprolactinoma) and 36% (macroprolactinoma) 2 to 5 years after withdrawal	No visible tumor at withdrawal: estimated 5-year recurrence 33% without vs 78% with a visible remnant in macroprolactinomas, and 26% vs 42% in microprolactinomas
Dekkers 2010	Meta-analysis, 19 studies, 743 patients	Persisting normoprolactinemia 21% (95% CI, 14-30%): idiopathic 32%, microprolactinoma 21%, macroprolactinoma 16%	Longer treatment duration; best results with cabergoline for at least 2 years
Hu 2015	Meta-analysis of cabergoline withdrawal	Recurrence 65% (95% CI 55-74%)	Lowest cabergoline dose and significant tumor shrinkage before withdrawal
Xia 2018	Meta-analysis	Persisting normoprolactinemia 36.6% (95% CI, 29.4-44.2%); 41.2% with cabergoline alone and 48.7% with cabergoline for more than 24 months	Idiopathic hyperprolactinemia (73.2%), low maintenance dose (51.5%) and tumor reduction over 50% (49.4%)
Zamanipoor Najafabadi 2020	Meta-analysis, 55 medical studies	Long-term remission 34% (95% CI, 26-46); 36% (95% CI, 21-52) in microprolactinomas	Not assessed
Constantinescu 2025	Retrospective study, 56 postmenopausal women who stopped dopamine agonists	73% remained in remission; recurrence in 27%, mostly within the first year	Prolactin measured 3 to 6 months after discontinuation was the only independent predictor of recurrence

• At recurrence, prolactin levels were lower than at diagnosis and no renewed tumor growth occurred, but gonadal dysfunction redeveloped in 22% of women and 39% of men with recurrent hyperprolactinemia. Because follow-up was too short to rule out delayed tumor growth, close monitoring is advised, particularly in macroprolactinomas.

Aggressive and metastatic prolactinomas

• Aggressive pituitary tumors are associated with increased morbidity and mortality even without metastases and should be managed by a multidisciplinary expert team, following the treatment algorithm of the 2025 European Society of Endocrinology guideline.
• The 2018 guideline established temozolomide monotherapy as first-line chemotherapy after failure of standard therapies, with response evaluated after 3 cycles and treatment continued for at least 6 months in responders. The 2025 revision adds data on temozolomide, immune checkpoint inhibitors and bevacizumab.
• The AME/ICCE position statement recommends tight follow-up of all macroprolactinomas, particularly in men; a quick multimodal approach (repeated surgery, radiotherapy and dopamine agonists) by an expert pituitary team for resistance, escape from dopamine agonist control or uncontrolled tumor growth; temozolomide for dopamine agonist-resistant macroprolactinomas after unsuccessful surgery and/or radiotherapy or with metastases; and withdrawal of temozolomide after the third cycle if the disease progresses.
• Outcome data come mainly from series of aggressive pituitary tumors and carcinomas of all subtypes. In a European survey of 166 patients, in which corticotroph tumors were the most frequent subtype (45%), temozolomide was first-line chemotherapy in 157 patients and produced a complete response in 6%, partial response in 31%, stable disease in 33% and progression in 30%; response was more frequent with concomitant radiotherapy, with low MGMT expression and in clinically functioning tumors.
• In a later survey of 171 patients, in which ACTH-secreting tumors constituted 30%, temozolomide in 156 patients produced a complete response in 9.6%, partial response in 30.1%, stable disease in 28.1% and progression in 32.2%. Partial regression occurred with bevacizumab in 1 of 10, with immune checkpoint inhibitors in 1 of 6 and with peptide receptor radionuclide therapy in 3 of 11 patients.
• In uncontrolled prolactinomas, temozolomide may be used alone or combined with radiotherapy, and other approaches remain experimental.

Assessment of treatment outcomes

• A systematic review identified 27 different definitions of remission, 3 of disease control and 20 of recurrence, and proposed separate biochemical and clinical definitions of remission and recurrence with a 3-tier outcome set.
• Quality of life approaches the population baseline with prolonged biochemical control and improves with both dopamine agonists and surgery, although improvement is more rapid after surgery.

Special Populations

Pregnancy and Lactation

Before conception

• Counseling about fertility and the optimal preconception treatment should start at diagnosis, and pregnant women with pituitary adenomas should usually be managed by a multidisciplinary team in a specialized center.
• Treatment before conception, either a dopamine agonist or surgery, should lower prolactin enough to allow conception and, in macroprolactinomas, shrink the tumor within the sellar limits to minimize the risk of enlargement during pregnancy.
• Women with macroprolactinomas who desire pregnancy may be considered for surgery before conception. In a prospective series of 310 prolactinomas treated with individualized-dose cabergoline, prophylactic medical debulking restored the optic-pituitary distance to more than 5.0 mm before conception in tumors at risk of gestational enlargement; overall, 294 patients (95%) had 365 uneventful pregnancies, with no symptomatic tumor enlargement during pregnancy.
• Pregnancy should be planned, and a dopamine agonist (preferably cabergoline, for better tolerability) is used while seeking pregnancy and discontinued when pregnancy is confirmed.
• Bromocriptine has about sevenfold more reported pregnancy experience than cabergoline, but cabergoline is increasingly preferred because of its greater efficacy and better tolerability, and both drugs may be used safely during gestation.

During pregnancy

• Dopamine agonist therapy should be stopped as soon as pregnancy is discovered; in selected women with invasive macroadenomas or tumors abutting the optic chiasm who have not had surgery or radiotherapy, continuing the dopamine agonist may be prudent.
• Continuing cabergoline during gestation was associated with a lower live birth rate (RR 0.81; 95% CI 0.67-0.98) than stopping it at the diagnosis of pregnancy, without more malformations, preterm births or low birth weight. In a Brazilian cohort, miscarriage was more frequent when cabergoline was maintained after pregnancy was confirmed (38% vs 7.5%).
• Cabergoline exposure at conception did not increase the risk of miscarriage or malformations: spontaneous abortion occurred in 9.1% of 143 pregnancies with no neonatal malformations in one cohort, and malformations occurred in 3.4% of infants compared with 6.3% in matched controls in another.
• Serum prolactin is not measured during pregnancy, and routine MRI is not performed in women with microadenomas or intrasellar macroadenomas without clinical evidence of tumor growth. Pituitary MRI is not recommended during an uneventful pregnancy or in the early postpartum period.
• Only clinical follow-up is needed in microprolactinomas or small intrasellar remnants of macroprolactinomas, whereas women with macroprolactinomas need clinical, pituitary function and neuro-ophthalmological evaluation in each trimester. Visual fields should be assessed periodically during gestation in women with macroadenomas.
• Women who develop severe headaches, visual field changes or other mass-effect symptoms need neuro-ophthalmological evaluation, MRI without gadolinium and assessment of pituitary function.

Risk of symptomatic tumor growth during pregnancy	Frequency
Microprolactinoma	2.4%
Macroprolactinoma without prior surgery or irradiation	21%
Macroprolactinoma with prior surgery or irradiation	4.7%
All prolactinomas, pooled across 2544 pregnancies	4% (95% CI, 2-8)

Maternal or fetal outcome (52 studies, 2544 pregnancies in 1928 women)	Pooled frequency (95% CI)
Miscarriage	10% (8-12)
Prematurity	3% (2-5)
Visual impairment	4% (2-7)
Headache	6% (4-9)
Gestational diabetes	4% (3-7)
Congenital malformations	2% (1-4)
Perinatal mortality	2% (1-2)
Low birth weight	6% (3-9)

• Tumor size is a significant modifier of the risk of visual impairment.
• If significant tumor growth occurs, most patients respond to reinstitution of the dopamine agonist; delivery may be considered if the pregnancy is sufficiently advanced, and transsphenoidal debulking is rarely necessary. In symptomatic macroprolactinomas, the dopamine agonist (preferably cabergoline) is reinstituted to obtain rapid remission of symptoms and is maintained after delivery.
• Vaginal delivery is suggested in microprolactinomas unless otherwise indicated by the obstetrician, with case-by-case evaluation in macroprolactinomas.
• Pituitary apoplexy during pregnancy may be managed with close observation, dopamine agonist therapy, glucocorticoid replacement when indicated or transsphenoidal surgery, depending on the severity of clinical and neuro-ophthalmological findings.
• The 2025 European Society of Endocrinology guideline includes a section on aggressive pituitary tumors in pregnancy.

Lactation and postpartum course

• Breastfeeding can generally be permitted, so dopamine agonist therapy is withheld during lactation unless treatment is clinically necessary. Breastfeeding is allowed if the pregnancy was uneventful, postponing any restart of the dopamine agonist.
• Nonhormonal contraception after delivery or after breastfeeding ends allows prolactin to be evaluated at 3-6 months in all women, followed by MRI in macroprolactinomas; the dopamine agonist is reinstituted in women with relapsing symptomatic hyperprolactinemia.
• Dopamine agonists should not be used to suppress physiological postpartum lactation, and cabergoline is not recommended in women who are breastfeeding or plan to breastfeed.
• Breastfeeding did not increase the recurrence of hyperprolactinemia.
• After pregnancy, 68% of women needed no additional therapy for up to 60 months in one cohort. In another, 41% were in remission at a median of 22 months after delivery or the end of lactation, with a nonsignificantly higher rate in microprolactinomas than in macroprolactinomas (46% vs 26%); remission was associated with smaller initial adenoma size and normalization of MRI after pregnancy.

Postmenopausal Women

• Menopause has a beneficial effect on the evolution of prolactinomas. Among 99 women who reached menopause while on dopamine agonists, median prolactin in those continuing stable doses fell from 18.0 µg/L before menopause to 9.8 µg/L 3 to 6 months after menopause (n = 71) and to 7.9 µg/L after 24 months (n = 45), and tumor coronal surface decreased from 16.5 to 8.2 mm² at 24 months (n = 34).
• Dopamine agonists were successfully discontinued in 56 of these women, and 41 (73%) remained in remission; estrogen-progestin replacement therapy did not influence the outcome.
• Microadenomas diagnosed before menopause can be followed without treatment after menopause, with at least annual follow-up.
• The AME/ICCE position statement recommends dopamine agonist withdrawal after menopause in women with microprolactinoma, and continuation at the lowest dose that controls tumor growth in women with macroprolactinoma.
• Prolactinomas diagnosed after menopause are usually macroadenomas with frequent supra- or parasellar extension and a relatively high rate of pituitary apoplexy, but they respond well to dopamine agonists: normal prolactin was achieved in 94% of macroprolactinomas and visual disturbances improved or resolved in 86%.

Men

• Prolactinomas in men are usually large and invasive and present with hypogonadism and mass effects, including visual damage.
• Cabergoline is the preferred first-line treatment in men and normalizes prolactin in about 80%, with tumor shrinkage, improved visual fields and recovery of hypogonadism in most patients.
• Prolactin normalization with cabergoline was similar in the two sexes (70% and 69%), although men had higher prolactin levels and larger tumors at diagnosis.
• Any impulse control disorder and hypersexuality on dopamine agonists were more common in men, whereas compulsive eating was more common in women.
• Prolactinomas in men are usually larger and more invasive, frequently have cystic components and are less sensitive to dopamine agonists; tight follow-up is recommended, and early testosterone replacement is recommended for persistent hypogonadism (see Medical Therapy).

Children and Adolescents

• Dopamine agonists are the first-line treatment in children and adolescents. In 77 patients younger than 20 years with macroprolactinoma, prolactin normalized in 74%, and resistance was associated with young age, higher prolactin, larger tumor volume and a MEN1 mutation.
• In 170 patients aged 20 years or younger, dopamine agonist resistance occurred in 22.5% and was independently associated with maximal tumor diameter; long-term surgical remission was 32.9% overall, 59.4% in noninvasive tumors and 5.0% in invasive tumors.
• In a pediatric series of 27 patients, dopamine agonist treatment was safe and effective, threat to vision was the indication for surgery in three of seven operated patients, and long-term functional capacity was not impaired; the authors advise surgery only for threatened vision without a fast response to dopamine agonists.
• The AME/ICCE position statement suggests dopamine agonist treatment in children to preserve normal pituitary function, reserving neurosurgery for resistance or intolerance.
• AIP or MEN1 mutations were found in 14% of young patients with macroprolactinoma, so genetic testing should be considered.
• Bromocriptine is approved for prolactin-secreting adenomas in children 11 years of age and older, whereas cabergoline is labeled for adults.

Giant Prolactinomas

• Dopamine agonists are the treatment of choice irrespective of tumor size and the presence of visual impairment.
• In a Swedish nationwide cohort of 84 patients, prolactin normalized in 55%, significant tumor reduction occurred in 69% and a combined response in 43%; 27% received one or more additional therapies.
• In a systematic review of 196 adult cases, dopamine agonists led to normoprolactinemia, tumor shrinkage and visual improvement in 51%, 88% and 85% of cases, respectively; all patients who underwent surgery had tumor remnants and persistent hyperprolactinemia.
• Because these tumors are rarely completely resectable and neurosurgery carries significant morbidity and mortality, surgery is restricted to acute complications such as apoplexy or CSF leakage, or to insufficient tumor response or progression. Endocrine remission after surgery is about 10% for giant or invasive tumors.
• Prolactin may be underestimated by the high-dose hook effect, and serial dilution testing should be considered when prolactin is disproportionately low relative to tumor size.

Cystic Prolactinomas

• Contrary to long-held assumptions, dopamine agonists can reduce cystic prolactinomas: persistent cyst reduction occurred in 20 of 22 treated patients, with a median volume reduction of 83.5%.
• Medical therapy is usually attempted first, but poor shrinkage of cystic prolactinomas on dopamine agonists is not unusual, and surgery may be preferred, particularly when a visual defect persists. Long-term remission after surgery was 80% for cystic prolactinomas in a surgical series.

Patients with Psychiatric Disease or Taking Antipsychotics

• In patients with macroprolactinoma and psychosis, observation, estrogen and progestin replacement and surgery can be considered in addition to dopamine agonists.
• Antipsychotics may blunt the effect of dopamine agonists, so higher doses may be needed; antipsychotics with less D2 receptor blockade, such as aripiprazole, can be tried if appropriate.
• In patients already taking antipsychotics who need a dopamine agonist, treatment is started at a low dose and escalated slowly, with careful monitoring of psychiatric status.
• Antipsychotics differ markedly in their effect on prolactin, from -77.05 ng/mL (clozapine) to 48.51 ng/mL (paliperidone) relative to placebo.
• Prolactin should be measured before neuroleptic treatment is started, and the endocrinologist and psychiatrist should collaborate closely; patients with prolactinoma who take antipsychotics can be managed with dopamine agonists after individual evaluation of efficacy and safety.

Patients with Breast Cancer

• The treatment of prolactinoma does not change in the presence of breast cancer.
• Population-based studies have not shown an increased risk of breast cancer in patients with hyperprolactinemia.

Transgender Women

• Twenty-four prolactinomas in transgender women have been reported, most diagnosed after initiation of gender-affirming hormone therapy and lacking baseline prolactin data.
• Gender-affirming estrogen therapy might induce rapid progression and dopamine agonist resistance in a residual macroprolactinoma; individualized multidisciplinary management is needed, and current guidelines provide no specific recommendations.

Multiple Endocrine Neoplasia Type 1 and Other Hereditary Syndromes

• Medical therapy is first-line for prolactinomas in MEN1, as in sporadic cases; cabergoline is the preferred agent, and surgery is reserved for intolerance or resistance.
• In a large Dutch cohort, all patients with MEN1-related prolactinomas responded well to dopamine agonists.
• Prospectively diagnosed AIP mutation carriers have smaller tumors and require fewer treatments than clinically presenting carriers.

Case Studies

Case #1