Merck Manual

Please confirm that you are a health care professional

honeypot link

Multiple Endocrine Neoplasia, Type 1 (MEN 1)

(Multiple Endocrine Adenomatosis, Type I; Wermer Syndrome)


Patricia A. Daly

, MD, University of Virginia;

Lewis Landsberg

, MD, Northwestern University Feinberg School of Medicine

Last full review/revision Apr 2021| Content last modified Apr 2021
Click here for Patient Education

Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as pancreatic neuroendocrine tumors), and/or pituitary gland tumors. Duodenal gastrinomas, carcinoid tumors of the foregut, benign adrenal adenomas, and lipomas also occur. Clinical features most commonly include hyperparathyroidism and asymptomatic hypercalcemia. Genetic screening is used to detect carriers. Diagnosis is by hormonal and imaging tests. Tumors are surgically removed when possible.

MEN 1 is caused by an inactivating mutation of the gene that encodes the nuclear protein menin; > 500 mutations of this gene have been identified. The exact function of menin is unknown, but it appears to have tumor suppressing effects. Some mutations are thought to be associated with a higher rate of pancreatic neuroendocrine tumor development, a higher rate of distant metastases, and more aggressive disease (1, 2).

About 40% of MEN 1 cases involve tumors of all 3 affected glands:

  • Parathyroids

  • Pancreas

  • Pituitary

Almost any combination of the tumors and symptom complexes outlined below is possible. A patient with a MEN 1 gene mutation and one of the MEN 1 tumors is at risk of developing any of the other tumors later on. Age at onset ranges from 4 to 81 years, but peak incidence occurs in the 20s to 40s. Men and women are equally affected.

General references

  • 1. Perrier ND: From initial description by Wermer to present-day MEN1: What have we learned? World J Surg 42(4):1031–1035, 2018.

  • 2. Marx SJ: Recent topics around multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 103(4):1296–1301, 2018.

Symptoms and Signs of MEN 1

The clinical features depend on the glandular elements affected (see table Conditions Associated With Multiple Endocrine Neoplasia Syndromes).


Hyperparathyroidism is present in 95% of patients. Asymptomatic hypercalcemia is the most common manifestation, but about 25% of patients have evidence of nephrolithiasis or nephrocalcinosis. In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia, which is often asymmetric, is typical.


Pancreatic islet cell tumors (also known as pancreatic neuroendocrine tumors) occur in 30 to 90% of patients. Tumors are usually multicentric and sometimes synthesize several hormones. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs; such tumors may arise from the small bowel rather than the pancreas. About 30% of tumors are malignant and have local or distant metastases. Malignant islet cell tumors due to MEN 1 syndrome often have a more benign course than do sporadically occurring malignant islet cell tumors.

The most common functional enteropancreatic tumor in MEN 1 is the gastrinoma, which can arise from the pancreas or the duodenum. Up to 80% of patients with MEN 1 have either multiple peptic ulcers due to gastrin-stimulated increased gastric acid secretion or asymptomatic elevated gastrin levels.

Insulinomas are the second most common functional pancreatic tumor and can cause fasting hypoglycemia. The tumors are often small and multiple. Age of onset is often < 40.

Nonfunctioning enteropancreatic tumors occur in about one third of MEN 1 patients. Most islet cell tumors, including nonfunctioning tumors, secrete pancreatic polypeptide. Although the clinical significance is unknown, pancreatic polypeptide may be helpful for screening. The size of the nonfunctioning tumor correlates with risk of metastasis and death.

Less commonly, other functional enteropancreatic tumors can occur in MEN 1. A severe secretory diarrhea can develop and cause fluid and electrolyte depletion with non–beta-cell tumors. This complex, referred to as the watery diarrhea, hypokalemia, and achlorhydria syndrome (WDHA, or pancreatic cholera), has been ascribed to vasoactive intestinal polypeptide, although other intestinal hormones or secretagogues (including prostaglandins) may contribute. Hypersecretion of glucagon, somatostatin, chromogranin, or calcitonin, ectopic secretion of ACTH or corticotropin-releasing hormone (causing Cushing syndrome), and hypersecretion of growth hormone–releasing hormone (causing acromegaly) sometimes occur in non–beta-cell tumors.


Pituitary tumors occur in 15 to 42% of MEN 1 patients. From 25 to 90% are prolactinomas. About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Excess prolactin may cause galactorrhea in affected women, and excess growth hormone causes acromegaly clinically indistinguishable from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, causing Cushing disease. Most of the remainder are nonfunctional.

Local tumor expansion may cause visual disturbance, headache, and hypopituitarism.

Pituitary tumors in patients with MEN 1 may be larger and behave more aggressively and may occur at an earlier age than sporadic pituitary tumors; however, a recent long-term cohort study found MEN 1–associated pituitary tumors were more indolent, similar to sporadic pituitary tumors (1).

Other manifestations

Carcinoid tumors, particularly those derived from the embryologic foregut (thymus, lungs, stomach), occur in 5 to 15% of MEN 1 patients. Thymic carcinoids are more common in affected males. Carcinoid syndrome may occur.

Adrenal adenomas occur in 10 to 20% of patients and may be bilateral.

Adenomatous hyperplasia of the thyroid occurs occasionally in MEN 1 patients. Hormone secretion is rarely altered as a result, and the significance of this abnormality is uncertain.

Multiple subcutaneous and visceral lipomas, angiofibromas, meningiomas, ependymomas, and collagenomas may also occur.

The relative risk of breast cancer in MEN 1 patients was 2.3 to 2.8-fold higher than in non-MEN 1 control subjects in Holland, the US, Tasmania, and France, and the age at diagnosis was somewhat younger than that in controls (2).

Symptoms references

Diagnosis of MEN 1

  • Genetic testing

  • Clinical evaluation for other tumors of the triad

  • Serum calcium, parathyroid hormone (PTH), gastrin, and prolactin levels

  • Tumor localization with MRI, CT, ultrasonography, or 18F-FDG PET/CT

MEN 1 syndrome should be considered in patients with tumors of the parathyroids, pancreas, or pituitary, particularly those with a family history of endocrinopathy. Screening should also be considered in individuals diagnosed with hyperparathyroidism prior to age 30 (1). At risk individuals should undergo genetic testing with direct DNA sequencing of the MEN 1 gene and clinical screening for other tumors of MEN 1, including the following:

Additional laboratory or radiologic tests should be done if these screening tests suggest an endocrine abnormality related to MEN 1.

A gastrin-secreting non–beta-cell tumor of the pancreas or duodenum is diagnosed by elevated basal plasma gastrin levels, an exaggerated gastrin response to infused calcium, and a paradoxical rise in gastrin level after infusion of secretin. An insulin-secreting beta-cell tumor of the pancreas is diagnosed by detecting fasting hypoglycemia with an elevated plasma insulin level. An elevated basal level of pancreatic polypeptide or gastrin or an exaggerated response of these hormones to a standard meal may be the earliest sign of pancreatic involvement.

Ultrasonography or computed tomography (CT) can help localize tumors. Because these tumors are often small and difficult to localize, other imaging tests (eg, helical [spiral] CT, angiography, MRI, endoscopic ultrasonography, intraoperative ultrasonography) may be necessary. Thoracic imaging with fluorine-18 [18F]–labeled deoxyglucose (18F-FDG) positron emission tomography (PET)/CT may be useful in distinguishing bronchopulmonary neuroendocrine tumors from benign pulmonary nodules and in identifying thymic carcinoid (2). For pancreatic and duodenal neuroendocrine tumors, 68gallium-dotatate positron emission tomography/CT was threefold more sensitive than octreotide scanning or CT scanning in a study of multiple imaging modalities in 26 cases of MEN 1; when available this test should replace octreotide scanning for periodic imaging (3).

Acromegaly is diagnosed by elevated growth hormone levels that are not suppressed by glucose administration and by elevated levels of serum insulin-like growth factor 1 (somatomedin C).


When an index case is identified, 1st-degree relatives should be given the option of genetic screening. Although early presymptomatic screening of family members of patients with MEN 1 has not been shown to reduce morbidity or mortality, a recent large cohort study reported a clinically relevant lag time between diagnosis of the index case and diagnosis in the rest of the family (4).

Preimplantation genetic diagnosis on embryos conceived via assisted reproductive techniques is also available.

Some clinicians monitor gene carriers by doing pancreatic and pituitary imaging every 3 to 5 years, although such screening has not been shown to improve outcomes.

Screening for breast cancer is recommended beginning at age 40 in women with MEN 1 (5).

Diagnosis references

Treatment of MEN 1

  • Surgical excision when possible

  • Drug management of hormone excess

Treatment of hyperparathyroidism is primarily surgical, with subtotal parathyroidectomy; however, the hyperparathyroidism frequently recurs. Octreotide and cinacalcet may help control recurrent or persistent postoperative hypercalcemia.

Prolactinoma is usually managed with dopamine agonists; other pituitary tumors are treated surgically.

Islet cell tumors are more difficult to manage because the lesions are often small and difficult to find, multiple lesions are common, and surgery often is not curative. Small (< 2 cm) nonfunctioning pancreatic islet cell tumors may be managed by active surveillance; risk of hepatic metastases is significantly higher for tumors > 3 cm (1).

The treatment of gastrin-secreting non–beta-cell tumors is complex. When possible, the tumor is located and removed, although it is unclear whether surgery decreases the likelihood of late metastatic disease. If localization is impossible, a proton pump inhibitor frequently provides long-term control of symptomatic peptic ulcer disease.

If a single tumor cannot be found in patients with insulinomas, distal subtotal pancreatectomy with enucleation of any palpable tumors in the head of the pancreas is recommended. Diazoxide or a somatostatin analogue (octreotide, lanreotide) may help treat hypoglycemia. Streptozocin and other cytotoxic drugs may relieve symptoms by reducing tumor burden.

Somatostatin analogs also can block hormone secretion from other nongastrin-secreting pancreatic tumors and are well tolerated. Palliative treatments for metastatic pancreatic tumors include hepatic debulking surgery and hepatic artery chemoembolization. Streptozocin, doxorubicin, and other cytotoxic drugs may relieve symptoms by reducing tumor burden.

Because MEN 1 tumors do not occur simultaneously, patients tend to have a high fear of disease occurrence for additional tumors in themselves or for disease beginning in their relatives. Studies indicate this leads to lower quality of life (as measured by emotional and physical well-being), suggesting that medical care should also address and treat the psychological burden of this condition (2).

Treatment references

  • 1. Nell S, Verkooijen HM, Pieterman CRC, et al: Management of MEN1 related nonfunctioning pancreatic NETs: A shifting paradigm. Results from the Dutch MEN1 Study Group. Ann Surg 267(6):1155-1160, 2018.

  • 2. Leeuwaarde R Pieterman CRC, Bleiker EMA, et al: High fear of disease occurrence is associated with low quality of life in patients with multiple endocrine neoplasia type 1: Results from the Dutch MEN1 Study Group. J Clin Endocrinol Metab 103(6): 2354–2361, 2018.

Key Points

  • Consider multiple endocrine neoplasia, type 1 (MEN 1) in patients with tumors of the parathyroids, pancreas, and/or pituitary.

  • The main clinical manifestations are those of hormone excess, particularly hypercalcemia due to hyperparathyroidism.

  • Patients should have genetic testing of the MEN 1 gene and clinical evaluation for other tumors of the syndrome.

  • Tumors are excised when possible, but lesions are often multiple and/or difficult to find.

  • Sometimes hormone excess can be managed by drugs.

Click here for Patient Education
NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
Professionals also read

Test your knowledge

Primary Aldosteronism
Primary aldosteronism is caused by autonomous production of aldosterone by the adrenal cortex due to hyperplasia, adenoma, or carcinoma. Which of the following is an uncommon symptom of this disorder? 
Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID
Download the Manuals App iOS ANDROID

Also of Interest