Multiple Endocrine Neoplasia (MEN)

What is multiple endocrine neoplasia?

Multiple endocrine neoplasia (MEN) is a rare genetic condition characterized by multiple tumors and/or cancer that affect specific endocrine system glands and tissues.

There are two main types of the condition:

• Multiple endocrine neoplasia (MEN) type 1: This is a genetic condition in which multiple tumors affect different aspects of your endocrine system.
• Multiple endocrine neoplasia type 2 (MEN2): This is a genetic polyglandular (multiple glands) cancer syndrome. People with MEN2 will develop medullary thyroid cancer (carcinoma) and have an increased risk of developing other tumors that affect other glands in the endocrine system.

Other names for multiple endocrine neoplasia type 1 include:

• MEN-1.
• MEN-1 syndrome.
• Multiple endocrine adenomatosis.
• Wermer's syndrome.

Other names for multiple endocrine neoplasia type 2 include:

• MEN-2.
• MEN2 syndrome.
• Sipple syndrome.

What is the endocrine system?

Your endocrine system is a network of several glands and organs that create and secrete (release) hormones.

Hormones are chemicals that coordinate different functions in your body by carrying messages through your blood to your organs, skin, muscles and other tissues. These signals tell your body what to do and when to do it.

The following organs and glands make up your endocrine system and produce and release hormones:

• Hypothalamus: This gland is located on the undersurface of your brain and controls aspects of your endocrine system.
• Pituitary gland: This little gland, which is attached to your hypothalamus, makes hormones that control several other glands, such as your thyroid gland, adrenal glands, ovaries and testicles.
• Thyroid: Your thyroid is a butterfly-shaped gland in the front of your neck. It’s partially responsible for your metabolism (how your body uses energy from the food you eat).
• Parathyroid glands: These four tiny glands, which are usually located next to your thyroid gland, control the level of calcium and phosphorus in your body.
• Adrenal glands: You have two adrenal glands, one on top of each kidney. They control your metabolism, blood pressure, sexual development and response to stress.
• Pineal gland: This gland manages your sleep cycle by releasing melatonin.
• Pancreas: Your pancreas produces insulin, which is crucial to metabolism and controlling blood sugar levels. It’s also part of your digestive system.
• Ovaries: The ovaries release sex hormones called estrogen, progesterone and testosterone.
• Testes: The testes (testicles) make sperm and release the hormone testosterone.

What parts of the endocrine system are affected by multiple endocrine neoplasia type 1?

People with MEN type 1 develop tumors in multiple glands of their endocrine system. The most common affected areas include:

• Parathyroid glands (most common).
• Gastroenteropancreatic tract (a tumor can form in your pancreas or in other parts of the gastrointestinal tract, including your stomach and duodenum).
• Pituitary gland.

Most tumors associated with MEN type 1 are benign (noncancerous), but some tumors can be cancerous (malignant) and can spread to other areas of your body (metastasize).

Endocrine glands that are affected by tumors usually release excessive amounts of hormones into your bloodstream, which can result in a variety of symptoms and health issues.

Since MEN type 1 was discovered, healthcare providers have identified more than 20 different endocrine and non-endocrine tumors in individuals with MEN type 1. Other less common types of tumors that can form due to MEN type 1 include:

• Neuroendocrine tumors of your thymus (a lymphoid organ in your chest) and bronchi (the air passages in your lungs).
• Adrenocortical tumors (form in the outer layer of your adrenal glands).
• Lipomas (fatty tumors located just below your skin).
• Visceral leiomyomas (smooth muscle tumors).
• Truncal and facial collagenomas (excess collagen in the trunk of your body and face).
• Facial angiofibromas (a group of lesions that form on your face).
• Breast cancer.
• Meningioma (a primary central nervous system tumor, meaning it begins in your brain or spinal cord).
• Ependymomas (a type of tumor that can form in your brain or spinal cord).

What parts of the endocrine system are affected by multiple endocrine neoplasia type 2?

All people with MEN type 2 will develop medullary thyroid cancer (carcinoma), known as MTC. Medullary thyroid cancer represents approximately 1% to 2% of thyroid cancers in the United States. MTC is different from other types of thyroid cancers because it originates from a certain type of cell called C cells of the thyroid gland. These cells do not make thyroid hormone, like other cells in your thyroid do. C cells make a hormone called calcitonin, which lowers blood calcium levels.

MTC can spread (metastasize) to lymph nodes and other organs. The primary treatment for MTC is surgery in which a surgeon removes your thyroid (thyroidectomy).

People with MEN type 2 also develop one or both of the following two conditions:

• Pheochromocytoma: This is a rare tumor that forms in the middle of one or both of your adrenal glands (adrenal medulla). The tumor is made of a certain type of cell called chromaffin cells, which produce and release certain hormones. Most pheochromocytomas are benign (not cancer). Approximately 10% to 15% of pheochromocytomas may be malignant (cancer) and metastasize.
• Hyperparathyroidism (overactive parathyroid gland): Hyperparathyroidism happens when your parathyroid gland(s) release too much parathyroid hormone (PTH), which causes calcium levels in your blood to rise. This is usually caused by a benign parathyroid tumor (adenoma) or when two or more of your parathyroid glands become enlarged, a condition called hyperplasia.

Who does multiple endocrine neoplasia (MEN) affect?

Multiple endocrine neoplasia (MEN) affects males and females equally.

The onset of MEN type 1 can vary widely. It has been diagnosed in children as young as 8 and in adults as old as 80.

How common is multiple endocrine neoplasia (MEN)?

Multiple endocrine neoplasia (MEN) is a rare condition. MEN type 1 affects approximately 1 in 30,000 individuals, and MEN type 2 affects approximately 1 in 35,000 people.

Some researchers think that many cases of each type go undiagnosed or misdiagnosed, so the rate of the conditions could be higher.

What are the symptoms of multiple endocrine neoplasia type 1?

The symptoms of MEN type 1 vary depending on which glands are affected by the overgrowth of tissue (hyperplasia) or a tumor. Although most MEN type 1 tumors are benign (noncancerous), tissue overgrowth or tumors can cause the affected glands to produce and release more hormones than your body needs. Higher-than-normal hormone levels are the main reason people who have MEN type 1 experience certain symptoms.

Since people with MEN type 1 can develop several different tumors, symptoms can vary widely from person to person — even within members of the same family and identical twins. In addition, people with MEN type 1 can develop tumors and symptoms at different ages, and symptoms can range from none (asymptomatic) or mild to severe and life-threatening.

It’s important to note that not everyone with MEN type 1 will have the same symptoms. Below are symptoms related to the following types of tumors and conditions associated with MEN type 1:

• Hyperparathyroidism.
• Gastrinomas.
• Insulinomas.
• Prolactinomas.

This is not a complete list of symptoms, since a person with MEN type 1 can develop any number of several different types of tumors, which each have different side effects and symptoms.

Symptoms related to parathyroid gland hyperplasia and tumors

The parathyroid glands are the most commonly affected endocrine glands in MEN type 1. Over 90% of people with MEN type 1 develop hyperparathyroidism (overactive parathyroid) by age 50.

Symptoms of mild hyperparathyroidism include:

• Joint pain.
• Muscle weakness.
• Fatigue.
• Depression.
• Trouble concentrating.
• Loss of appetite.

Symptoms of severe hyperparathyroidism include:

• Nausea and vomiting.
• Confusion and forgetfulness.
• Increased thirst and frequent urination.
• Constipation.
• Bone pain.

Symptoms related to pancreas and duodenum tumors (gastrinomas)

Approximately 40% of adults with MEN type 1 develop multiple gastrinomas, which are benign tumors that release a hormone called gastrin. People with MEN type 1 usually have gastrinomas located in the first portion of their duodenum (the first part of the small intestine that connects to the stomach), and sometimes in their pancreas.

Gastrinomas cause higher-than-normal levels of gastrin, which causes your stomach to release too much acid. Symptoms of gastrinomas include:

• Abdominal pain.
• Diarrhea.
• Acid reflux (esophageal reflux).
• Peptic ulcers.

The second most common tumor that affects the gastroenteropancreatic tract in people with MEN type 1 is insulinoma, a benign tumor that secretes insulin. It occurs in approximately 10% of cases. Insulinoma can cause low blood sugar (hypoglycemia), which can cause the following symptoms:

• Confusion.
• Shakiness.
• Sweating.
• Hunger.
• Anxiety.
• Heart palpitations.
• Temporary vision changes.

Symptoms related to pituitary gland tumors

Approximately 25% of people with MEN type 1 develop benign tumors in their pituitary gland. Your pituitary gland is often called the “master gland” because it creates and releases several important hormones, such as growth hormone, prolactin and thyroid-stimulating hormone.

Prolactinomas, benign tumors that secrete prolactin, are the most common pituitary gland tumors associated with MEN type 1. They are the third most common tumors associated with MEN type 1 after parathyroid tumors and gastrinomas.

Among women and people who are assigned female at birth (AFAB), symptoms of prolactinomas include:

• Changes in menstruation unrelated to menopause, such as irregular periods (menstruation) or no periods (amenorrhea).
• Infertility.
• Milky discharge from the nipples when not pregnant or breastfeeding (chestfeeding) called galactorrhea.
• Loss of interest in sex.

Among men and people assigned male at birth (AMAB), common symptoms of a prolactinoma include:

• Loss of interest in sex associated with low levels of testosterone.
• Erectile dysfunction (ED).
• Infertility.

If the prolactinoma is large, it may also cause the following symptoms:

• Headaches.
• Nausea and/or vomiting.
• Vision changes, such as double vision or decreased peripheral vision.

What are the symptoms of multiple endocrine neoplasia type 2?

The symptoms of MEN type 2 vary depending on which glands are affected and can vary widely from person to person — even within members of the same family. Symptoms are usually caused by medullary thyroid cancer (MTC) and higher-than-normal hormone levels caused by certain tumors.

It’s important to note that not everyone with MEN type 2 will have the same symptoms. Below are symptoms related to the following types of tumors and conditions associated with MEN type 2:

• Medullary thyroid cancer (MTC).
• Pheochromocytomas.
• Hyperparathyroidism.

This is not a complete list of symptoms, since a person with MEN type 2 can develop other tumors.

Symptoms related to medullary thyroid cancer (MTC)

All people with MEN type 2 develop medullary thyroid cancer. Symptoms of medullary thyroid cancer include:

• A lump in the front of your neck.
• Pain in the front of your neck.
• Changes to your voice, such as hoarseness.
• Coughing.
• Trouble swallowing.
• Shortness of breath.

Symptoms related to pheochromocytomas

Approximately 50% of people with MEN type 2 will develop a pheochromocytoma, a usually benign tumor in your adrenal gland(s).

Symptoms of pheochromocytoma happen when the tumor releases too much adrenaline or noradrenaline into your blood. However, some pheochromocytoma tumors don’t make these hormones and don’t cause symptoms (are asymptomatic). Common symptoms of pheochromocytoma, which often occur as spells include:

• High blood pressure (hypertension).
• Headache.
• Excessive sweating for no known reason.
• A pounding, fast or irregular heartbeat.
• Feeling shaky.

Symptoms related to hyperparathyroidism

Symptoms of hyperparathyroidism include:

• Joint pain.
• Muscle weakness.
• Fatigue.
• Depression.
• Trouble concentrating.
• Loss of appetite.
• Nausea and vomiting.
• Increased thirst and frequent urination.
• Constipation.
• Bone pain.

What causes multiple endocrine neoplasia (MEN)?

Both types of multiple endocrine neoplasia are caused by gene mutations (changes), and both types can either be inherited (passed from biological parent to child) or occur randomly at the embryo level (when you were developing in the uterus). If a biological parent has MEN, their child has a 50% chance of having the condition.

MEN type 1 is caused by mutations of the MEN1 gene. The MEN1 gene is a tumor suppressor gene, meaning it helps prevent tumors from forming by controlling cell division and instructing cells when to die (a normal process). When tumor suppressor genes, such as MEN1 malfunction, certain cells may continue to grow and reproduce, causing tumors to form.

MEN type 2 is caused by mutations of the RET gene, which is a gene that plays a role in the development of cancer. When working as it should, the RET gene helps control cell division and regulation of cell death. Mutations of the RET gene lead to uncontrolled growth of cells, causing tumors to form in certain organs and glands.

How is multiple endocrine neoplasia type 1 diagnosed?

A person is diagnosed with MEN type 1 if they have at least two of the three endocrine tumors associated with the condition (parathyroid tumor, pituitary tumor and/or a tumor in the gastroenteropancreatic tract) or if they have one of the associated tumors and a family history of MEN type 1.

What tests are used to diagnose MEN type 1?

Before a healthcare provider can diagnose MEN type 1, they need to diagnose one or more different types of tumors in the individual. A variety of blood tests can detect elevated levels of certain hormones, which can be a sign of certain tumors. For example, higher-than-normal levels of parathyroid hormone (PTH) in addition to hypercalcemia (excess calcium in your blood) can indicate the presence of a parathyroid tumor.

Healthcare providers then use imaging tests, such as CT (computed tomography) scans or MRI (magnetic resonance imaging) scans, to help find and diagnose tumors.

Providers can also confirm a MEN type 1 diagnosis through genetic testing of the MEN1 gene.

How is multiple endocrine neoplasia type 2 diagnosed?

A person is diagnosed with MEN type 2 if they have medullary thyroid cancer (MTC) and pheochromocytoma and/or parathyroid enlargement (hyperplasia) or tumor (adenoma).

What tests are used to diagnose MEN type 2?

Before a healthcare provider can diagnose MEN type 2, they need to diagnose medullary thyroid cancer (MTC) and other types of tumors in the individual.

A variety of blood tests can detect elevated levels of certain hormones, which can be a sign of MTC and other tumors. For example:

• Higher-than-normal levels of calcitonin can indicate MTC.
• Higher-than-normal levels of parathyroid hormone (PTH) can indicate a parathyroid tumor (adenoma) or hyperplasia.
• Higher-than-normal levels of catecholamines (a group of hormones produced by your adrenal glands) may indicate pheochromocytoma.

Healthcare providers then use imaging tests, such as CT (computed tomography) scans or MRI (magnetic resonance imaging) scans, to help find and diagnose tumors associated with MEN type 2.

Providers can also confirm a MEN type 2 diagnosis through genetic testing of the RET gene.

How is multiple endocrine neoplasia (MEN) treated?

The treatment of multiple endocrine neoplasia (MEN) depends entirely on what endocrine glands and organs are affected and usually requires a team of healthcare providers, including:

• Endocrinologists.
• Surgeons.
• Oncologists (cancer specialists).
• Pediatricians, if applicable.

Treatment may include:

• Medications to treat symptoms and to counteract the effects of excess hormones.
• Surgery to remove tumors or entire affected glands, such as the thyroid.
• Replacement hormones if an endocrine gland is surgically removed.
• Cancer treatment, such as chemotherapy and radiation therapy, cancer has metastasized (spread to other areas of your body).

Each case of MEN is unique and each requires specific treatment. Don’t be afraid to ask your healthcare provider about treatment options that’ll work best for you.

Is there a cure for multiple endocrine neoplasia (MEN)?

There is currently no cure for multiple endocrine neoplasia, but it is manageable. Healthcare providers treat the changes in each gland as they happen with surgery or with medications.

Can I prevent multiple endocrine neoplasia (MEN)?

Unfortunately, you cannot prevent developing multiple endocrine neoplasia since it’s a genetic mutation. The gene mutations that cause MEN are either inherited from a biological parent or happen randomly for no known reason at the embryo level (when you were developing in the uterus).

If one of your first-degree relatives (biological parents and siblings) has been diagnosed with MEN, talk to your healthcare provider about genetic testing that can screen for MEN. If you do have MEN, genetic testing could help detect the tumors in their early phases.

What is the prognosis (outlook) for multiple endocrine neoplasia (MEN)?

The prognosis (outlook) for MEN depends on several factors, including:

• How early MEN is diagnosed.
• Which endocrine glands are affected.
• If the tumors are benign or cancerous.
• The type of treatment used.
• If a cancerous tumor has spread to other parts of your body (metastasized).

If you have been diagnosed with MEN, your healthcare provider will be able to give you a better idea of what you can expect for your treatment and prognosis.

When should I see my healthcare provider?

If you have been diagnosed with multiple endocrine neoplasia, you will need to see your healthcare provider regularly to monitor your condition and to see if treatment is working.

If one of your first-degree relatives (biological parents or siblings) has been diagnosed with MEN, talk to your healthcare provider about genetic testing that can screen for MEN.

What questions should I ask my doctor?

If you have been diagnosed with multiple endocrine neoplasia (MEN), it may be helpful to ask your healthcare provider the following questions:

• What type of MEN do I have?
• How will MEN affect my body?
• What symptoms should I look out for?
• What are my treatment options?
• What are the benefits and risks of different types of treatment?
• How long will it take for treatment to work?
• Should my family members be tested for MEN?

A note from Cleveland Clinic

Multiple endocrine neoplasia (MEN) is a rare condition. Since MEN can have so many different symptoms and no two cases look the same, it can be difficult to know if you have it. If you’re ever experiencing new concerning symptoms or changes to your body, it’s a good idea to contact your healthcare provider. While some MEN cases can happen randomly, it also runs in families. If one of your first-degree relatives has been diagnosed with MEN, it’s important to go through genetic testing to see if you could also have the condition. If you have any questions about your risk of developing MEN, talk to your healthcare provider. They’re there to help you.