Your pituitary gland is a pea-sized gland at the base of your brain. The pituitary is the "master control gland" - it makes hormones that affect growth and the functions of other glands in the body.

With pituitary disorders, you often have too much or too little of one of your hormones. Injuries can cause pituitary disorders, but the most common cause is a pituitary tumor.

The hypothalamus–pituitary complex can be thought of as the “command center” of the endocrine system. This complex secretes several hormones that directly produce responses in target tissues, as well as hormones that regulate the synthesis and secretion of hormones of other glands. In addition, the hypothalamus–pituitary complex coordinates the messages of the endocrine and nervous systems. In many cases, a stimulus received by the nervous system must pass through the hypothalamus–pituitary complex to be translated into hormones that can initiate a response.

The hypothalamus is a structure of the diencephalon of the brain located anterior and inferior to the thalamus. It has both neural and endocrine functions, producing and secreting many hormones. In addition, the hypothalamus is anatomically and functionally related to the pituitary gland (or hypophysis), a bean-sized organ suspended from it by a stem called the infundibulum (or pituitary stalk). The pituitary gland is cradled within the sellaturcica of the sphenoid bone of the skull. It consists of two lobes that arise from distinct parts of embryonic tissue: the posterior pituitary (neurohypophysis) is neural tissue, whereas the anterior pituitary (also known as the adenohypophysis) is glandular tissue that develops from the primitive digestive tract. The hormones secreted by the posterior and anterior pituitary, and the intermediate zone between the lobes are summarized in image.

Overview

The hypothalamus–pituitary complex is located in the diencephalon of the brain. The hypothalamus and the pituitary gland are connected by a structure called the infundibulum, which contains vasculature and nerve axons. The pituitary gland is divided into two distinct structures with different embryonic origins. The posterior lobe houses the axon terminals of hypothalamic neurons. It stores and releases into the bloodstream two hypothalamic hormones: oxytocin and antidiuretic hormone (ADH). The anterior lobe is connected to the hypothalamus by vasculature in the infundibulum and produces and secretes six hormones. Their secretion is regulated, however, by releasing and inhibiting hormones from the hypothalamus. The six anterior pituitary hormones are: growth hormone (GH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL).

Your pituitary gland is a pea-sized gland at the base of your brain. The pituitary is the "master control gland" - it makes hormones that affect growth and the functions of other glands in the body.

Pituitary tumors are common, but often they don't cause health problems. Most people with pituitary tumors never even know they have them. The most common type of pituitary tumor produces hormones and disrupts the balance of hormones in your body. This can cause endocrine diseases such as Cushing's syndrome and hyperthyroidism.

Symptoms of pituitary tumors include:

• Headaches
• Vision problems
• Nausea and vomiting
• Problems caused by the production of too many hormones

Pituitary tumors are usually curable. Treatment is often surgery to remove the tumor. Other options include medicines, radiation therapy, and chemotherapy.

A pituitary tumor is a growth of abnormal cells in the tissues of the pituitary gland.

Pituitary tumors form in the pituitary gland, a pea-sized organ in the center of the brain, just above the back of the nose. The pituitary gland is sometimes called the "master endocrine gland" because it makes hormones that affect the way many parts of the body work. It also controls hormones made by many other glands in the body.

Pituitary tumors are divided into three groups:

• Benign pituitary adenomas: Tumors that are not cancer. These tumors grow very slowly and do not spread from the pituitary gland to other parts of the body.
• Invasive pituitary adenomas: Benign tumors that may spread to bones of the skull or the sinus cavity below the pituitary gland.
• Pituitary carcinomas: Tumors that are malignant (cancer). These pituitary tumors spread into other areas of the central nervous system (brain and spinal cord) or outside of the central nervous system. Very few pituitary tumors are malignant.

Pituitary tumors may be either nonfunctioning or functioning.

• Nonfunctioning pituitary tumors do not make extra amounts of hormones.
• Functioning pituitary tumors make more than the normal amount of one or more hormones. Most pituitary tumors are functioning tumors. The extra hormones made by pituitary tumors may cause certain signs or symptoms of disease.

The pituitary gland hormones control many other glands in the body.

Hormones made by the pituitary gland include:

• Prolactin: A hormone that causes a woman’s breasts to make milk during and after pregnancy.
• Adrenocorticotropic hormone (ACTH): A hormone that causes the adrenal glands to make a hormone called cortisol. Cortisol helps control the use of sugar, protein, and fats in the body and helps the body deal with stress.
• Growth hormone: A hormone that helps control body growth and the use of sugar and fat in the body. Growth hormone is also called somatotropin.
• Thyroid-stimulating hormone: A hormone that causes the thyroid gland to make other hormones that control growth, body temperature, and heart rate. Thyroid-stimulating hormone is also called thyrotropin.
• Luteinizing hormone (LH) and follicle-stimulating hormone (FSH): Hormones that control the menstrual cycle in women and the making of sperm in men.

Having certain genetic conditions increases the risk of developing a pituitary tumor.

Anything that increases a person's chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop pituitary tumors, and they will develop in some people who don't have any known risk factors. Talk with your doctor if you think you may be at risk. Hereditary syndromes that increase a person's risk for pituitary tumors include the following:

• Multiple endocrine neoplasia type 1 (MEN1) syndrome.
• Carney complex.
• Isolated familial acromegaly.

Signs of a pituitary tumor include problems with vision and certain physical changes.

Signs and symptoms can be caused by the growth of the tumor and/or by hormones the tumor makes or by other conditions. Some tumors may not cause signs or symptoms. Check with your doctor if you have any of these problems.

Signs and symptoms of a nonfunctioning pituitary tumor

Sometimes, a pituitary tumor may press on or damage parts of the pituitary gland, causing it to stop making one or more hormones. Too little of a certain hormone will affect the work of the gland or organ that the hormone controls. The following signs and symptoms may occur:

• Headache.
• Some loss of vision.
• Loss of body hair.
• In women, less frequent or no menstrual periods or no milk from the breasts.
• In men, loss of facial hair, growth of breast tissue, and impotence.
• In women and men, lower sex drive.
• In children, slowed growth and sexual development.

Most of the tumors that make LH and FSH do not make enough extra hormone to cause signs and symptoms. These tumors are considered to be nonfunctioning tumors.

Signs and symptoms of a functioning pituitary tumor

When a functioning pituitary tumor makes extra hormones, the signs and symptoms will depend on the type of hormone being made.

Too much prolactin may cause:

• Headache.
• Some loss of vision.
• Less frequent or no menstrual periods or menstrual periods with a very light flow.
• Trouble becoming pregnant or an inability to become pregnant.
• Impotence in men.
• Lower sex drive.
• Flow of breast milk in a woman who is not pregnant or breast-feeding.

Too much ACTH may cause:

• Headache.
• Some loss of vision.
• Weight gain in the face, neck, and trunk of the body, and thin arms and legs.
• A lump of fat on the back of the neck.
• Thin skin that may have purple or pink stretch marks on the chest or abdomen.
• Easy bruising.
• Growth of fine hair on the face, upper back, or arms.
• Bones that break easily.
• Anxiety, irritability, and depression.

Too much growth hormone may cause:

• Headache.
• Some loss of vision.
• In adults, acromegaly (growth of the bones in the face, hands, and feet). In children, the whole body may grow much taller and larger than normal.
• Tingling or numbness in the hands and fingers.
• Snoring or pauses in breathing during sleep.
• Joint pain.
• Sweating more than usual.
• Dysmorphophobia (extreme dislike of or concern about one or more parts of the body).

Too much thyroid-stimulating hormone may cause:

• Irregular heartbeat.
• Shakiness.
• Weight loss.
• Trouble sleeping.
• Frequent bowel movements.
• Sweating.

Other general signs and symptoms of pituitary tumors:

• Nausea and vomiting.
• Confusion.
• Dizziness.
• Seizures.
• Runny or "drippy" nose (cerebrospinal fluid that surrounds the brain and spinal cord leaks into the nose).

Imaging studies and tests that examine the blood and urine are used to diagnose a pituitary tumor.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

• Eye exam: An exam to check vision and the general health of the eyes.
• Visual field exam: An exam to check a person’s field of vision (the total area in which objects can be seen). This test measures both central vision (how much a person can see when looking straight ahead) and peripheral vision (how much a person can see in all other directions while staring straight ahead). The eyes are tested one at a time. The eye not being tested is covered.
• Neurological exam: A series of questions and tests to check the brain, spinal cord, and nerve function. The exam checks a person’s mental status, coordination, and ability to walk normally, and how well the muscles, senses, and reflexes work. This may also be called a neuro exam or a neurologic exam.
• MRI (magnetic resonance imaging) with gadolinium: A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the brain and spinal cord. A substance called gadolinium is injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
• Blood chemistry study: A procedure in which a blood sample is checked to measure the amounts of certain substances, such as glucose (sugar), released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
• Blood tests: Tests to measure the levels of testosterone or estrogen in the blood. A higher or lower than normal amount of these hormones may be a sign of pituitary tumor.
• Twenty-four-hour urine test: A test in which urine is collected for 24 hours to measure the amounts of certain substances. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. A higher than normal amount of the hormone cortisol may be a sign of a pituitary tumor and Cushing syndrome.
• High-dose dexamethasone suppression test: A test in which one or more high doses of dexamethasone are given. The level of cortisol is checked from a sample of blood or from urine that is collected for three days. This test is done to check if the adrenal gland is making too much cortisol or if the pituitary gland is telling the adrenal glands to make too much cortisol.
• Low-dose dexamethasone suppression test: A test in which one or more small doses of dexamethasone are given. The level of cortisol is checked from a sample of blood or from urine that is collected for three days. This test is done to check if the adrenal gland is making too much cortisol.
• Venous sampling for pituitary tumors: A procedure in which a sample of blood is taken from veins coming from the pituitary gland. The sample is checked to measure the amount of ACTH released into the blood by the gland. Venous sampling may be done if blood tests show there is a tumor making ACTH, but the pituitary gland looks normal in the imaging tests.
• Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer.

  The following tests may be done on the sample of tissue that is removed:

  • Immunohistochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
  • Immunocytochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s cells. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to the antigen in the sample of the patient’s cells, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
  • Light and electron microscopy: A laboratory test in which cells in a sample of tissue are viewed under regular and high-powered microscopes to look for certain changes in the cells.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis depends on the type of tumor and whether the tumor has spread into other areas of the central nervous system (brain and spinal cord) or outside of the central nervous system to other parts of the body.

Treatment options depend on the following:

• The type and size of the tumor.
• Whether the tumor is making hormones.
• Whether the tumor is causing problems with vision or other signs or symptoms.
• Whether the tumor has spread into the brain around the pituitary gland or to other parts of the body.
• Whether the tumor has just been diagnosed or has recurred (come back).

What are pituitary tumors?

A pituitary tumor is an abnormal growth of cells within the pituitary gland.

The pituitary gland is a small, bean-sized gland located at the base of the brain below the hypothalamus. The pituitary gland controls a system of hormones in the body that regulate growth, metabolism, the stress response, and functions of the sex organs via the thyroid gland, adrenal gland, ovaries, and testes.

Most pituitary tumors are benign, which means they are non-cancerous, grow slowly, and do not spread to other parts of the body. However, the tumors can make the pituitary gland produce either too many or too few hormones, which can cause a variety of problems in the body. Symptoms largely depend upon the hormone affected and may include:

• Headaches
• Vision problems
• Nausea
• Vomiting

Pituitary hormones that impact the sex hormones, such as estrogen and testosterone, can make a woman produce breast milk even though she is not pregnant or nursing, or cause a man to lose his sex drive or lower his sperm count.

Pituitary tumors often go undiagnosed because their symptoms resemble those of so many other more common diseases.

Generally, treatment depends on the tumor's type and size, whether it has invaded or pressed on surrounding structures, such as the brain and visual pathways, and the individual's age and overall health. Three types of treatment are used:

1. Surgical removal of the tumor
2. Radiation therapy, in which high-dose x-rays are used to kill the tumor cells
3. Drug therapy to shrink or destroy the tumor

Medications also are sometimes used to block the tumor from overproducing hormones. Early diagnosis and treatment are key to a good prognosis.

Acromegaly is a disorder that occurs when your body makes too much growth hormone (GH). Produced mainly in the pituitary gland, GH controls the physical growth of the body. In adults, too much of this hormone causes bones, cartilage, body organs, and other tissues to increase in size. Common changes in appearance include enlarged or swollen nose, ears, hands, and feet.

Empty sella syndrome (ESS) is a disorder that involves the sella turcica, a bony structure at the base of the brain that surrounds and protects the pituitary gland. ESS is often discovered during imaging tests for pituitary disorders.

An individual with ESS may have no symptoms or may have symptoms resulting from partial or complete loss of pituitary function including:

• Headaches,
• Low sex drive
• Impotence (erectile dysfunction)

There are two types of ESS: Primary and Secondary.

1. Primary ESS happens when a small anatomical defect above the pituitary gland allows spinal fluid to partially or completely fill the sella turcica. This causes the gland to flatten out along the interior walls of the sella turcica cavity. Individuals with primary ESS may have high levels of the hormone prolactin, which can interfere with the normal function of the testicles and ovaries. Primary ESS is most common in adults and women, and is often associated with obesity and high blood pressure. In some cases, the pituitary gland may be smaller than usual
    
2. Secondary ESS is the result of the pituitary gland regressing within the cavity after an injury, surgery, or radiation therapy. Individuals with secondary ESS can sometimes have symptoms that reflect the loss of pituitary functions, such as
   • Ceasing of menstrual periods
   • Infertility
   • Fatigue
   • Intolerance to stress and infection

In children, ESS may be associated with early onset of puberty, growth hormone deficiency, pituitary tumors, or pituitary gland dysfunction. Magnetic resonance imaging (MRI) is useful in evaluating ESS.

Unless the syndrome results in other medical problems, treatment is symptomatic and supportive as ESS is not a life-threatening condition.

Introduction

Galactorrhea is milk production from the breast unrelated to pregnancy or lactation. Milk production one year after cessation of breastfeeding is non-lactational and is considered galactorrhea. Various hormones including prolactin, estrogens, thyrotropin-releasing hormone (TRH) can affect the production of milk.

Etiology

The various causes of galactorrhea broadly divide into hypothalamic-pituitary causes and non-hypothalamic-pituitary causes.

Hypothalamic-pituitary causes:

1. Prolactinomas: Prolactinomas are prolactin-secreting tumors and are the commonest hormone-secreting tumors of the pituitary glands. Prolactinomas which are less than 1 cm in size are known as macroprolactinomas, whereas those greater than 1 cm in size are known as macroprolactinomas. Prolactin levels correlate well with the size of the tumor with microprolactinomas having prolactin levels of >200 ng/ml and macroprolactinomas having higher prolactin levels of >1000 ng/ml.

2. Non-prolactin-secreting pituitary tumor and infiltrative disorders of the pituitary stalk/hypothalamus: These tumors can cause hyperprolactinemia by disrupting the flow of dopamine from the hypothalamus to the anterior pituitary by compressing the pituitary stalk. This disruption results in decreased inhibition of prolactin and results in mild hyperprolactinemia, usually less than 200 ng/ml.

Non-hypothalamic-pituitary causes:

1. Hypothyroidism: Elevated levels of TRH in hypothyroidism can stimulate the lactotrophs resulting in hyperprolactinemia and galactorrhea.

2. Medications: Several medications can cause hyperprolactinemia and galactorrhea. In most instances, the level of prolactin is less than 200 ng/ml; however, atypical antipsychotics like risperidone carry associations with prolactin levels of >200 ng/ml, which can be confused for a microprolactinoma. Atypical antipsychotics act on the D2 receptors in the hypothalamic tuberoinfundibular areas to cause hyperprolactinemia. Risperidone is a combined dopamine serotonin antagonist which can significantly raise the prolactin levels. Clozapine, olanzapine, and aripiprazole have both agonist and antagonist properties on the D2 receptor and only transiently raise the prolactin levels. Metoclopramide and domperidone, which are used in the treatment of vomiting, are D2 receptor blockers and cause hyperprolactinemia. Tricyclic antidepressants (especially clomipramine) and monoamine-oxidase inhibitors have been associated with mild hyperprolactinemia. The mechanisms by which these medications cause hyperprolactinemia is unknown. Opioids by acting through the µ receptors decrease the release of hypothalamic dopamine and can elevate prolactin levels. Verapamil has also been associated with hyperprolactinemia by decreasing the production of hypothalamic dopamine.

3. Renal failure: Hyperprolactinemia in renal failure is due to the failure of the kidneys to clear prolactin. Prolactin levels of >1000 mcg/liter have been reported with renal failure. Post-kidney transplant the hyperprolactinemia resolves rapidly within a few days.

4. Chest wall lesions: Various chest wall lesions including burns, surgeries, herpes zoster have associations with hyperprolactinemia. The hypothesis is that the pain signals transmit to the hypothalamus via the spinal cord which results in decreased dopamine release and causes hyperprolactinemia.

5. Idiopathic hyperprolactinemia: Occasionally hyperprolactinemia with no known cause has been reported. These could be secondary to small undiagnosed microprolactinomas. The hyperprolactinemia self resolves in 1/3rd patients and remains stable in half of the patients.

Epidemiology

Hyperprolactinemia is more common in women. The prevalence of hyperprolactinemia ranges from 0.4% in an unselected normal adult population to as high as 9 to 17% in women with reproductive disorders. Its prevalence was found to be as high as 17% among women with polycystic ovary syndrome.

Pathophysiology

Prolactin is responsible for the synthesis and secretion of milk. Prolactin is secreted by the lactotroph cells in the anterior pituitary. Dopamine secreted from the hypothalamus inhibits the secretion of prolactin. TRH and vasoactive intestinal polypeptide can stimulate prolactin secretion. Also, nipple stimulation, renal failure, chest wall lesions, and medications can cause hyperprolactinemia.

Estrogens cause hyperprolactinemia by inhibiting hypothalamic dopamine as well as stimulating lactotrophs directly. In pregnancy, the high levels of estrogen cause lactotroph hyperplasia and can even result in the growth of a preexisting prolactinoma. Excess secretion of estrogen from ovaries in ovarian hyperstimulation syndrome has also been associated with hyperprolactinemia.

History and Physical

Careful assessment of hyperprolactinemic related symptoms menstrual irregularities, decreased libido, galactorrhea, erectile dysfunction, infertility, and gynecomastia should be performed. Detailed medication history is important when considering medication induced hyperprolactinemia. If a pituitary lesion is suspected then evaluation for headaches, and visual deficits are in order.

For assessing galactorrhea on physical exam, the patient needs to be sitting and leaning forward. The areola needs to be squeezed in the direction of the nipple. The galactorrhea is usually bilateral and can be white or green. Bloody discharge could be due to breast tumors and will need further workup in that direction. A Sudan IV stain for fat droplets can confirm whether the discharge is milk or not.

Evaluation

Prolactin levels need to be taken at least once in the evaluation of hyperprolactinemia. Prolactin levels are measured using a sandwich ELISA assay where a prolactin molecule needs to bind to a capture as well as a detection antibody to be measured. Rarely the “hook effect” may be seen in large prolactinomas with an extremely high prolactin level. Due to the extremely high prolactin levels, the number of prolactin molecules binding to both the capture and detection antibody is actually low. Dilution of the sample to a 1:100 concentration and remeasuring shows a paradoxical increase in the prolactin level. The “hook effect” needs to be considered in large pituitary adenomas which present with galactorrhea, hypogonadism but only mildly elevated levels of prolactin.

Hormonal assessment of other pituitary hormones should be taken as indicated by the clinical history and exam. Magnetic resonance imaging (MRI) of the pituitary gland may reveal lesions of the pituitary gland responsible for hyperprolactinemia. Visual field assessment needs to be performed when the tumor is in contact with the optic chiasma on MRI.

Treatment / Management

After ruling out breast pathologies, therapy direction is towards the cause of hyperprolactinemia. Hyperprolactinemia is treated if there is a pituitary lesion or hypogonadism with problematic galactorrhea; if not troublesome, it can be monitored without therapy.

The mainstay of hyperprolactinemia is treatment with bromocriptine or cabergoline. These are dopamine agonists which act on the D2 receptors present on the lactotrophs and inhibit prolactin production. The doses for bromocriptine and cabergoline are 2.5-15 mg once daily and cabergoline 0.25-1 mg twice weekly, respectively. They are effective at normalizing prolactin levels as well as shrinking the size of the tumor. Side effects include nausea, vomiting, orthostatic hypotension, drowsiness, and headaches. Cardiac valvulopathy has been reported with high doses of cabergoline, and it is recommended to get an annual echocardiogram in patients on more than 3.5 mg/week.

In cases of medication-induced hyperprolactinemia, the offending medication should be stopped or changed to a different class. Use of dopamine agonists in these instances has associations with a slight risk of exacerbating the psychiatric disorder.

Normoprolactinemic galactorrhea occurs when the galactorrhea accompanies normal prolactin levels. If symptomatic with troublesome galactorrhea or menstrual cycle irregularities it can be treated with dopamine agonists to obtain symptomatic relief. The treatment is tapered off once the galactorrhea has resolved.[2][1]

Differential Diagnosis

• Acromegaly

• Breast stimulation

• Bronchogenic carcinoma

• Burns

• Breast surgery

• Craniopharyngioma

• Cushing's disease

• Chest wall irritation

• Hypothyroidism

• Idiopathic

• Lymphoma

• Molar pregnancy

• Meds and herbs

• Pituitary adenomas

• Renal failure

• Sarcoid

• TB

Enhancing Healthcare Team Outcomes

Galactorrhea is nonlactational production of milk. Prolactin, estrogens, and TRH all play a role in the production of milk from the breast. The condition is often managed by an interprofessional team that consists of a radiologist, endocrinologist, neurosurgeon, neurologist, and an internist. The galactorrhea associated with hyperprolactinemia is often associated with symptoms of hypogonadism (decreased libido, erectile dysfunction, and menstrual irregularities) and thus a thorough medical history and physical exam are needed. Serosanguinous discharge from the breast should prompt further evaluation for breast pathologies. Inquiring of the patient about their current medications is vital. In most cases, treatment with dopamine agonists (cabergoline or bromocriptine) normalizes prolactin levels and results in shrinkage of the tumor. (Level V)

ABSTRACT

Hyperprolactinemia is the most common hypothalamic-pituitary dysfunction, being an important cause of irregular menses and infertility amongst young women. Clinical and laboratorial investigation is crucial to determine the etiology of hyperprolactinemia and to indicate the proper treatment. Prolactinoma is the most common cause of pathological hyperprolactinemia. Macroprolactinemia is a laboratorial pitfall and must be ruled out in asymptomatic hyperprolactinemic individuals. Usually, treatment is not necessary. “Hook effect” is another laboratorial pitfall that underestimates prolactin levels and may confound diagnosis between macroprolactinomas and pseudoprolactinomas. Clinical treatment with dopamine agonists is effective in 80 to 90% of hyperprolactinemic patients leading to normal serum prolactin levels and a decrease in tumor size. Normoprolactinemia after dopamine agonist withdrawal is possible in around 20% of cases. Surgical treatment may be indicated in resistant/intolerant patients and symptomatic apoplectic tumors. Radiotherapy is rarely indicated and must be reserved to control tumor growth in aggressive cases. Temozolomide is an alternative of treatment for resistant/aggressive prolactinomas not responding to high doses of dopamine agonists, multiple surgeries, and radiotherapy. Bromocriptine is still the dopamine agonist of choice for inducing pregnancy. For complete coverage of this area and all of Endocrinology, visit www.endotext.org.

INTRODUCTION

Prolactin secreting pituitary tumors are the most common type of hormone secreting pituitary tumors. They are also the only pituitary tumors which can be effectively managed primarily by medical means. Therefore, their identification and diagnosis are imperative to avoid unnecessary pituitary surgery.

PROLACTIN SECRETION

Prolactin is secreted by the lactotrophs in the anterior pituitary gland. Prolactin secretion is regulated by the hypothalamus. Unlike the other anterior pituitary hormones, however, the hypothalamic influence is predominantly by tonic inhibition.

The hypothalamus secretes prolactin-release-inhibiting factors (PIF) and prolactin-releasing factors (PRF). PIF is predominantly mediated by dopamine, with GABA having a minor role. Prolactin controls its own secretion through a short loop negative feedback, stimulating TIDA cells. Nevertheless, the nature of the physiological PRF is unclear. Thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide (VIP), serotonin, histamine, oxytocin and estrogens can act as a PRF. Other neurotransmitters and neuropeptides can also modulate prolactin secretion (for example endothelin, TGFbeta1, angiotensin, somatostatin, substance P, neurotensin, calcitonin, EGF, natriuretic atrial peptide, bombesin, cholecystokinin, acetylcholine, and vasopressin).

CAUSES OF HYPERPROLACTINEMIA

The causes of hyperprolactinemia may be considered, in a simplified fashion, as resulting from four basic abnormalities. In some patients, however, it is not possible to elucidate the cause of hyperprolactinemia, discussed below. Also, stress from venipuncture can cause a slight increase in serum prolactin levels in asymptomatic individuals and normal serum prolactin measured after resting for 30 minutes can rule out this condition. Nevertheless, routinely resting before venipuncture is usually not recommended. In addition, prolactin should not be measured after a seizure, which can increase prolactin levels.

Hypothalamic Dopamine Deficiency

Diseases of the hypothalamus, such as tumors, arterio-venous malformations, and inflammatory processes such as sarcoidosis, result in either diminished synthesis or release of dopamine. Furthermore, certain drugs (e.g. alpha-methyldopa and reserpine) are capable of depleting the central dopamine stores.

Defective Transport Mechanisms

Section of the pituitary stalk results in impaired transport of dopamine from the hypothalamus to the lactotrophs. Pituitary or stalk tumors with abnormal blood supply, or pressure effects, may interfere with the circulatory pathway from the hypothalamus down the pituitary stalk to the normal lactotrophs. In addition, a tumor may produce effective dopamine deficiency due to a functional stalk section.

Lactotroph Insensitivity to Dopamine

Dopamine receptors have been found on human pituitary lactotroph adenoma cells. Receptor sensitivity to dopamine could be diminished, which would explain the lack of response to increased endogenous dopamine stimulation. However, an obvious response of the receptors to pharmacologic dopamine agonists (DA) makes this possibility less likely. Certain drugs act as dopamine-receptor-blocking agents, including phenothiazines (e.g. chlorpromazine), butyrophenones (haloperidol), and benzamides (metoclopramide, sulpiride, and domperidone). These drugs block the effects of endogenous dopamine and thus release lactotrophs from their hypothalamic inhibition. This sequence of events results in hyperprolactinemia. Table 1 summarizes the most common drugs causing hyperprolactinemia.

Table 1.

Effect of Drugs on Prolactin Levels

Stimulation of Lactotrophs

Hypothyroidism may be associated with hyperprolactinemia. If hypothyroidism results in increased TRH production, then TRH (which can act as a prolactin releasing factor) could lead to hyperprolactinemia. Estrogens act directly at the pituitary level, causing stimulation of lactotrophs, and thus enhance prolactin secretion. Furthermore, estrogens increase the mitotic activity of lactotrophs, increasing cell numbers. Pregnancy and lactation are physiological causes of hyperprolactinemia. Injury to the chest wall can also lead to hyperprolactinemia. This results from abnormal stimulation of the reflex associated with the rise in prolactin that is seen normally in lactating women during suckling.

CLINICAL MANIFESTATIONS OF HYPERPROLACTINEMIA

The symptoms associated with hyperprolactinemia may be due to several factors: the direct effects of excess prolactin, such as the induction of galactorrhea or hypogonadism 9), the effects of the structural lesion causing the disorder (i.e. the pituitary tumor), leading to, for example, headaches, visual field defects, or external ophthalmoplegia ; or associated dysfunction of secretion of other anterior pituitary hormones.

The incidence of galactorrhea in hyperprolactinemic patients is between 30% and 80%, depending on the skill of the examiner and the degree of estrogen deficiency. Approximately 50% of women with galactorrhea, however, have normal prolactin. As mentioned below, it is particularly those patients with very high prolactin levels, i.e. greater than 100ng/mL (2000mU/L), who often have no galactorrhea. Thus, galactorrhea is an inconsistent marker of hyperprolactinemia.

Women with hyperprolactinemia usually present with menstrual abnormalities – amenorrhea or oligomenorrhea – or regular cycles with infertility. Occasionally, patients may present with menorrhagia. Menstrual disorders are often not seen with mild hyperprolactinemia but it is unusual for there to be no menstrual problems if the prolactin is greater than 180 ng/l (3,600 mU/L).

In contrast, men often present late in the course of the disease with symptoms of expansion of their pituitary tumor (i.e. headaches, visual defects, and external ophthalmoplegia) or symptoms from secondary adrenal or thyroid failure. These men, however, have usually been impotent for many years before their presentation. Because the disease is occult for many years, men present late in the course of their disease. In contrast to women in whom microprolactinomas are most commonly seen, macroprolactinomas are usually found in men and the serum prolactin levels are usually much higher than those in women.

Occasionally, the syndrome may occur in prepubertal or peripubertal children, where it may present with delayed or arrested puberty or with headache and/or visual field defects or with growth arrest. Children and adolescents often present with aggressive prolactinomas, perhaps reflecting a different mechanism(s) of tumorigenesis rather than disease duration; it should not be forgotten that the rate of cell proliferation at this stage of the life cycle is greater.

DIFFERENTIAL DIAGNOSIS

It is important to exclude other causes of hyperprolactinemia: hypothyroidism, use of drugs that either deplete central dopamine or block dopamine receptors, renal and hepatic failure. Ruling out these important causes, and any hypothalamic lesion, three common diagnostic possibilities remain: the presence of a microadenoma, macroadenoma, or no visible tumor at all. If patients do not harbor an identifiable tumor, they are described as having idiopathic hyperprolactinemia. It is likely, however, that patients with this condition may harbor small microprolactinomas, which were undetected with less sensitive imaging tools used in the past, and even with magnetic resonance imaging (MRI).

A microadenoma has a maximum diameter of up to 10mm (the maximal diameter of the normal pituitary gland) and a macroadenoma has a diameter greater than 10mm. A microadenoma is often visualized using MRI. Usually, the serum prolactin level is below 200 ng/mL (4000 mU/L) in patients with microadenomas. A macroadenoma that secretes prolactin is usually associated with a serum prolactin level of more than 200 ng/mL (4000 mU/L). If the patient has a macroadenoma and a serum prolactin level of less than 200 ng/mL (4000 mU/L), consideration should be given to the possibility that a nonfunctioning pituitary adenoma (pseudo-prolactinoma) is present, the hyperprolactinemia resulting from deprivation of dopaminergic inhibition of lactotrophs. However, a laboratory artifact may lead to a wrong differential diagnosis between macroprolactinomas and pseudoprolactinomas. When serum prolactin is evaluated by two-site immunometric assays, large amounts of prolactin saturate both the capture and the signaling antibodies, impairing their binding, causing serum prolactin levels to be underestimated (the so-called “high-dose hook effect”). Therefore, patients bearing macroprolactinomas with extremely high serum prolactin levels (generally >1,000 ng/ml [>180,000 mU/L]) may present with falsely low levels, e.g. 30-120 ng/ml (600-2,400 mU/L) range, causing the patient to be misdiagnosed as harboring a nonfunctioning pituitary adenoma. In order to avoid unnecessary surgery (treatment of choice for nonfunctioning tumors), prolactin assays with serum dilution are recommended in patients with macroadenomas who may harbor a prolactinoma.

Another laboratory pitfall concerns the presence of high serum prolactin levels in subjects with few or no symptoms related to prolactin excess. Human prolactin circulates as monomeric prolactin and as larger forms, which are indistinguishable by routine assays. Monomeric prolactin is the most common form, but serum prolactin can be elevated due to the presence of aggregates with low biological activity, such as big-big prolactin, leading to so-called macroprolactinemia. The presence of molecular aggregates with low biological activity, macroprolactin, should be suspected when high serum prolactin levels are detected in patients without or with few signs and symptoms related to hyperprolactinemia. Precipitation with polyethylene glycol (PEG) is an excellent screening method. Chromatography confirms the presence of macroprolactin but is an expensive and time-consuming method; it is performed only when PEG precipitation results are inconclusive. Macroprolactinemia is a common finding, some reporting it as frequently as 8 to 42% of all cases; other centers find that it is extremely rare. Big-big prolactin biological activity is still controversial in the literature. Studies in vitro with rat Nb2 cells bioassays show either the presence or the absence of biological activity. A recent study using a human prolactin receptor-mediated assay compared with rat Nb2 cells assay showed that the activity displayed by macroprolactin toward the rat receptor may be inappropriate because it is not observed in the human prolactin receptor-mediated assay, consistent with the apparent absence of bioactivity in vivo. Most patients with macroprolactinemia do not manifest clinical features related to hyperprolactinemia, and do not need any treatment. Therefore, in order to avoid unnecessary medical or even surgical procedures, macroprolactin screening is important to consider when clinical features and serum prolactin assay results are not consonant with one another. Moreover, standardization of monomeric prolactin levels after PEG precipitation is crucial to evaluate conditions that could be associated with macroprolactinemia, as prolactinomas. Therefore, monomeric prolactin levels point to real hyperprolactinemia, even in the presence of macroprolactinemia.

Enlargement of the pituitary fossa on a skull X-ray may represent the expansion of the fossa by the macroadenoma, but care should be exercised to exclude the possibility of cisternal herniation (a partially empty fossa) as a cause for the enlargement. CT and MRI scans are useful and will also demonstrate any hypothalamic-pituitary pathologies, including solid and cystic lesions.

CHANGES IN THE BREAST DUE TO PROLACTIN

A woman with amenorrhea due to hyperprolactinemia does not develop the breast atrophy seen in postmenopausal women or women with amenorrhea who are gonadotropin-deficient or have primary ovarian failure. On examination, the breast and areola are well developed and the Montgomery tubercles are hyperplastic. If the breast is correctly examined, first by expressing it from the periphery towards the areola to empty milk ducts, followed by squeezing and lifting the areola (rather than the nipple itself) to empty the milk sinuses, galactorrhea can usually be found.

In patients with extremely high prolactin levels and hypogonadism, galactorrhea may not be found, as minimum estrogen levels are necessary for this physical sign to be observed. In male patients with hyperprolactinemia, there is usually no gynecomastia, but milk may be expressed from an entirely normal-sized male breast. The incidence of galactorrhea in men with hyperprolactinemia is low, less than 30% (i.e. it is much less common than in women). Nevertheless, the presence of galactorrhea in man with a pituitary mass is an important clinical clue to the presence of hyperprolactinemia and possible prolactinomas.

HYPERPROLACTINEMIC HYPOGONADISM

The pathogenesis of the hypogonadal state in hyperprolactinemia is poorly understood. Results from an animal model study suggest that hyperprolactinemia inhibits gonadotropin-releasing hormone (GnRH) pulsatility by reducing kisspeptin input, considered the major controlling point of reproduction.

In men, testosterone levels are usually low but can occasionally be normal, while in women, a hypoestrogenic state may occur, with loss of ovulation. The clinical features in hyperprolactinemic women, however, differ from those in the postmenopausal state since breast atrophy is absent and gonadotropin levels are not elevated.

Suppression of Gonadal Function in Hyperprolactinemia

In addition to GnRH inhibition, via kisspeptin, suppression of gonadotropin secretion through inhibition of positive estrogen feedback on luteinizing hormone (LH) secretion in women, an increase in adrenal androgen secretion, and blockade of the effects of gonadotropins at the gonadal level contribute to suppression of gonadal function in hyperprolactinemia. Reduction in the normal LH pulsatility, essential for normal gonadal function, also occurs. Prolactin may interfere with LH and FSH action at the gonad, blocking progesterone synthesis, and may stimulate adrenal androgen secretion.

IMAGING OF THE PITUITARY

The anatomy of the pituitary is optimally assessed by contrast-enhanced MRI. MRI allows imaging of the optic chiasm, the cavernous sinuses, the pituitary (both the normal gland and tumors), and its stalk. In addition, aneurysms of the carotid are immediately obvious. Thus, MRI allows accurate measurement of the size of the pituitary and of any tumor and its relationship to the optic chiasm and cavernous sinuses. Cisternal herniation is also readily seen. If MRI is not available, CT scanning is also helpful but the resolution is not as good and it is less satisfactory for delineating the relationship of the diaphragma sellae with the optic chiasm. There is little place for routine skull X-ray other than for delineating bony structures. For additional details see Endotext chapter on Radiology of the Pituitary.

TREATMENT OF HYPERPROLACTINEMIA

Therapeutic strategy must consider several aspects, such as the patient’s clinical presentation, the differences between microadenomas and macroadenomas concerning their natural history, the desire for pregnancy, and the patient’s treatment preference, if applicable. Medical treatment with dopamine agonist (DA) drugs is currently the gold standard approach both for microprolactinomas and macroprolactinomas. Pituitary surgery, usually by the transsphenoidal approach is generally reserved for prolactinomas resistant to DA drugs. For microadenomas, the results in the hands of most experienced surgeons are similar, with about 80% having serum prolactin normalization. However, ~25% develop recurrence of hyperprolactinemia by five years after surgery even with the most experienced transsphenoidal surgeons. Surgical therapy of large prolactin-secreting pituitary tumors is unsatisfactory since it is capable of normalizing serum prolactin levels or gonadal function in fewer than 20% of patients, particularly those with high prolactin levels, Thus, surgical results in macroprolactinomas are much poorer. Radiotherapy for prolactinomas generally brings poor results, especially regarding normoprolactinemia restoration, and is currently reserved only for macroadenomas refractory both to medical and surgical treatment.

Dopamine Agonist Drug Therapy

The first DA ergot compound to be used in clinical practice was bromocriptine, a peptide ergot. It was introduced in the early 1970s in Europe and thus there is more than 40 years of experience of the use of such compounds in the treatment of hyperprolactinemia. Bromocriptine has the advantage of having a long duration of action compared to dopamine itself or oral compounds such a levo-dopa.

Bromocriptine has a similar mode of action to dopamine in stimulating dopamine receptors on the prolactin-secreting pituitary cells – D2 receptors. Stimulation of these receptors leads to inhibition of both prolactin secretion and synthesis. Figure 1 illustrates a successful case of prolactinoma treatment with bromocriptine. Subsequently a variety of other compounds have been developed which are useful additions. These include quinagolide and cabergoline.

Figure 1.

A 34-year-old patient with amenorrhea and hyperprolactinemia (PRL 1630 ng/ml) had a sella CT imaging depicting a pituitary mass on the left (A). Bromocriptine was introduced and after 30 days on 7.5 mg a day, PRL dropped to 32 ng/mL with menses restoration. A repeat CT demonstrated a decrease in tumor size (B).

Cabergoline has an extremely long biological half-life and thus, generally only needs to be administered either once or twice per week, with a weekly dose of 0.5 to 2.0 mg. Doses higher than 2 mg per week may be used in refractory cases. In addition to its long biological half-life, cabergoline is generally better tolerated than bromocriptine, increasing patient adherence. Therefore, cabergoline is currently considered the first- choice drug for the treatment of prolactinomas, except for patients wishing pregnancy in the short-term (see below). In a study comparing bromocriptine (2.5 to 5.0 mg twice daily) to cabergoline (0.5 to 1.0 mg twice weekly) in 459 hyperprolactinemic women with amenorrhea, stable normoprolactinemia was achieved in 83% of patients on cabergoline and in 59% of patients on bromocriptine. Ovulatory cycles or pregnancy occurred in 72% of cases on cabergoline and in 52% of cases on bromocriptine. Drug withdrawal due to adverse effects was reported in 3% of cases on cabergoline and in 12% of cases on bromocriptine. Regarding tumor size, a decrease in at least 50% was obtained in 64% of patients on bromocriptine and in 93% of patients on cabergoline (as demonstrated in. This important beneficial effect of DA treatment can rapidly relieve mass effects symptoms such as visual impairment, without the need of surgical decompression.

Figure 2.

A 32-year-old female patient with hyperprolactinemia (PRL 80 ng/mL), irregular menses and galactorrhea had a sella MR showing a pituitary lesion of 0.8 cm on maximal diameter (A). After cabergoline treatment (0.5 mg/week), PRL levels normalized, with menses restoration and remission of galactorrhea. Tumor size decreased with a maximal diameter of 0.6 cm after two years of treatment (B). After seven years on cabergoline the tumor was no longer visible (C).

SIDE EFFECTS

Side effects of DA therapy usually occur at the start of treatment and frequently disappear with continued therapy. If treatment is started with full doses or increased too quickly, dizziness, nausea, and postural hypotension may occur. To avoid such effects, DA must always be taken during a meal. Administration should be started at night, with a snack, when the patient retires to bed. Doses can be gradually increased afterwards.

Cabergoline and pergolide were associated with a higher risk of cardiac valvulopathy in patients with Parkinson´s disease. These DA also have an agonist effect on serotonin receptor 5HT2B, present in fibroblast of cardiac valves and chordae tendineae. Fibroblast proliferation occurs after activation of this receptor, leading to valve insufficiency, especially of the tricuspid and pulmonary valves. This proposed mechanism was already described in carcinoid syndrome. Nevertheless, mean cabergoline dose for Parkinson patients is 3 mg a day, much higher than the usual dose for hyperprolactinemia. From 2008 to 2014, 17 observational studies addressed the issue of valvulopathy risk in hyperprolactinemic patients on cabergoline: only one of them pointed to a moderate tricuspid regurgitation associated with cabergoline. Nevertheless, as this issue is not completely elucidated, echocardiographic evaluations is recommended before and during DA treatment at the physician’s discretion.

Regarding pergolide, it was withdrawal from the market. Quinagolide, the only non-ergot derived DA, is only available in Europe.

Recently, impulse control disorders have been associated with DA treatment, including patients harboring prolactinomas. An active approach to screen for psychiatry disorders before and during DA treatment is recommended.

CAN DOPAMINE AGONIST DRUGS BE WITHDRAWN WITHOUT RECURRENCE?

One of the drawbacks of medical treatment of prolactinomas is the need for long-term therapy in the majority of the cases. As a matter of fact, treatment with bromocriptine and other DA drugs generally is considered as “symptomatic”, since DA discontinuation often leads to recurrence of hyperprolactinemia and to tumor regrowth in most patients at least after short-term use.

Nevertheless, remission and normoprolactinemia after DA withdrawal can occur, especially after long-term treatment. Concerning long-term therapy with bromocriptine, a recent retrospective study showed that 25.8% of 62 patients with microprolactinomas and 15.9% of 69 patients with macroprolactinomas treated with bromocriptine for a median time of 47 months had persistent normoprolactinemia after a median time of 44 months after drug withdrawal. Another study encompassed a large cohort of hyperprolactinemic patients on cabergoline. The drug was discontinued in patients who attained normoprolactinemia, with at least 50% of tumor reduction or disappearance on image, with at least 2 years of follow-up after cabergoline withdrawal. Serum prolactin remained normal in 76%, 70% and 64% of patients with “idiopathic” hyperprolactinemia, microprolactinomas, and macroprolactinomas, respectively. This great discrepancy between results with bromocriptine and cabergoline was not confirmed by a recent metanalysis, including 743 patients from nineteen studies: the pooled proportion of patients with remission was 21%. Stratifying those results, remission was obtained in 32% for idiopathic hyperprolactinemia, 21% for micro, and 16% for macroprolactinomas. A trend of cabergoline superiority over bromocriptine was observed albeit with no statistical significance. A second attempt to DA withdrawal was also described, with lower rates of success.

Although the exact mechanism of prolactinoma remission is not completely understood, it could also be linked to the natural history of the disease. Periodic withdrawal of DA is recommended, especially in cases with normal serum prolactin levels and tumor reduction. Prolactinoma remission is also described after pregnancy. It is suggested that estrogen-induced necrosis could lead to a decrease in tumor size and prolactin levels after delivery.

Prolactinomas Resistant to Dopamine Agonists

About 15% of patients with prolactinomas are resistant to DA therapy. The main mechanism is reduction of expression of D2 receptors in the tumor. If a patient has been responsive and then becomes unresponsive, a pituitary carcinoma should be ruled out. Similarly, patients with rising prolactin levels but without a change in the pituitary tumor size may have metastatic disease. The approach to the resistant prolactinoma includes pituitary surgery, radiotherapy and drugs such as temozolomide. Pituitary surgery, usually by transsphenoidal approach, aims for complete tumor removal or at least a vast debulking, which may lead to serum prolactin normalization with DA reintroduction in partially resistant cases. Surgery is more effective in microadenomas and non-invasive macroadenomas. In a metanalysis, surgical remission rate was 74.7% in microadenomas and 34% in macroadenomas. Nevertheless, the recurrence rates were 18% and 23% in micro and macroadenomas, respectively, leading to an even lower long-term remission rates. Radiotherapy is indicated in aggressive cases not controlled by surgery or drugs. The alkylating agent temozolomide has proven efficacy in aggressive pituitary adenomas and carcinomas, mainly the prolactin secreting ones. Complete and partial response was obtained in 56% of 32 cases reviewed in literature. Figure 3 illustrates the sella MR of a young man with an invasive/aggressive macroprolactinoma, resistant do dopamine agonist, multiple surgeries and radiotherapy.

Figure 3.

26-year-old man complaining of visual disturbance had a sella MRI (A): A sella mass 5cm in the maximal diameter with supra, infra and left parasella invasion was noted. Serum PRL levels were above 1000 ng/mL. After one year on cabergoline, 0.5 mg/day, there was no tumor reduction and PRL levels were around 800 ng/mL. He was then submitted to transsphenoidal surgery and radiotherapy. Sella MRI (B) two months after the surgery showed a pituitary mass 3.1 cm in the maximal diameter. Despite chiasmal decompression, visual dysfunction was not reversed and, during his follow-up, anterior pituitary function was lost. Prolactin levels on cabergoline, 1.5 mg/week, were 250 ng/ml. After two more years, sella MRI depicted a lesion 2.9 cm. in the maximal diameter (C). There was a progressive rise of PRL levels despite increased cabergoline doses (0.5 mg/d) and another sella MRI (D), after two years, depicted a lesion of 3.1 cm in the maximal diameter.

Fertility in Women

The efficacy of hyperprolactinemia/prolactinoma treatment allow fertility and pregnancy in many women. There are, however, several important considerations that must be recognized by both the physician and patient. It includes tumor growth risk and possible teratogenic sequelae of fetal exposure to bromocriptine and other drugs.

There is little doubt that patients with pituitary tumors run a small, but significant, risk of expansion of the tumor during pregnancy. It is very difficult, however, to assess the absolute risk. With microadenomas, which did not undergo previous surgery or radiotherapy, the incidence seems to be between 1.6% and 5.5%. In patients with macroadenomas not operated on or irradiated, the incidence is higher, between 15.5% and 41%. However, the risk of complications may be lower in women previously operated or irradiated. This risk is unrelated to bromocriptine therapy prior to pregnancy but may occur when fertility is induced with other drugs, including exogenous gonadotropins and clomiphene, and even when no drug therapy has been employed in patients with pre-existing pituitary adenomas.

In practice, the problem of pregnancy is not great, since the vast majority of women who present with hyperprolactinemia only have microadenomas. To avoid major problems, it is extremely important that patients undergo careful endocrine, neuroradiologic, and neuro-ophthalmologic evaluation prior to treatment. If there is no suprasellar extension, and if the patient harbors only a microadenoma, then the risk of clinically significant swelling of the pituitary is extremely small; it is therefore suggested that the patient be evaluated clinically in every trimester throughout pregnancy, with no routine serum prolactin assessment. If the patient has a macroadenoma and suprasellar extension, transsphenoidal decompression can be considered, mainly for resistant cases. However, in those patients with a good response to DA in terms of prolactin normalization and tumor shrinkage within sella boundaries, at least one year before pregnancy, the drug can be withdrawn and reintroduced if tumor re-growth is observed. If such an approach fails, pituitary surgery or premature delivery, if feasible, would be indicated. Additionally, in cases of tumor apoplexy, high-dose dexamethasone may improve clinical symptoms and also may reduce the chances of fetal respiratory distress if premature delivery is needed.

In recent years, pregnancies have been described in patients using other DAs such as quinagolide and cabergoline. Although there is no evidence of an increased frequency of abortions or malformations in cabergoline-induced pregnancies, the drug’s long action, which persists up to three weeks after its withdrawal, associated with fewer (albeit increasing) data when compared to bromocriptine (around 800 versus over 6,000 pregnancies), limit the confidence that it can be used for patients who wish to conceive or during pregnancy. In the United States, bromocriptine is the only FDA approved drug for inducing pregnancy in hyperprolactinemic women. The cabergoline label does not recommend use during pregnancy. Nevertheless, experience with cabergoline inducing pregnancy is accumulating. The incidence of spontaneous abortion, premature delivery, multiple births, and malformations is not different from women who used bromocriptine or from the general population. Quinagolide use was related to abortions and malformations.

Fertility in Men

Hyperprolactinemic men exhibit reduced quality of seminal fluid, including total sperm count, the sperm kinetic index, and sperm nuclear DNA integrity. Cabergoline significantly increased these indexes, mainly after 12 months of treatment.

Interestingly, clomiphene citrate administration can increase testosterone levels in men, even when serum prolactin levels were elevated. Fertility restoration is an additional advantage of this approach, while testosterone replacement would not help in that respect.

Treatment Summary

Dopamine-agonist therapy for hyperprolactinemia leads to a reversal of the hyperprolactinemic hypogonadal state without risk of the development of pituitary insufficiency, thus allowing pregnancy in former infertile patients. Dopamine-agonist therapy is effective not only in patients with microadenomas but also in the majority of patients with large prolactin-secreting tumors in reducing tumor size. Moreover, emerging evidence points to the possibility of drug withdrawal after long-term treatment. Surgery, radiotherapy and anti-blastic drugs, such as temozolomide, should be reserved for resistant/aggressive cases.

What is septo-optic dysplasia?

Septo-optic dysplasia (SOD), previously known as de Morsier syndrome, is a rare disorder of development that involves the septum pellucidum—the thin membrane located between the two cerebral hemispheres (halves of the brain)—as well as the eyes and the pituitary gland. 

SOD causes optic nerve abnormalities and affects the optic disc located at the back of the eye, where the optic nerve meets the retina. The pituitary gland produces hormones that regulate other bodily functions. In people living with SOD, the septum pellucidum may be missing. 

Symptoms include:

• Loss of eyesight in one or both eyes
• Pupils that get bigger in the light
• An uncontrollably fast side-to-side movement of the eyes
• Eyes that turn towards or away from the nose

• Poor muscle tone
• Problems with hormones (chemicals in the body)
• Development delays from eyesight or neurologic problems

Symptoms are different for each person. Treatment focuses on the symptoms. Some people may need physical, vision, and occupational therapy.

How can I or my loved one improve care for people with septo-optic dysplasia?

Consider participating in a clinical trial so clinicians and scientists can learn more about SOD and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease. 

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

Sheehan syndrome affects the function of the pituitary gland. The pituitary gland makes hormones and regulates other glands and many body processes, including reproduction. The cause of Sheehan syndrome is severe blood loss during or after childbirth (postpartum hemorrhage). This leads to lack of blood flow to the front part of the pituitary gland, causing it to gradually stop functioning. The symptoms of Sheehan syndrome occur as a result of the low hormone levels. These may include an inability to produce breast milk, irregular or absent periods, hot flashes, and a decreased sex drive. Other symptoms may include fatigue, headaches, low blood pressure, and hair loss. Symptoms usually do not appear from months to years after the hemorrhage. In some cases, the symptoms occur immediately and may be more severe and sometimes life threatening. Sheehan syndrome is diagnosed based on the symptoms, clinical history and exam, laboratory testing, and imaging studies. Treatment includes hormone replacement therapy, and steroids to help manage early symptoms.

Diabetes insipidus is a rare disorder that causes the body to make too much urine. While most people make 1 to 3 quarts of urine a day, people with diabetes insipidus can make up to 20 quarts of urine a day. People with this disorder need to urinate frequently, called polyuria. They may also feel thirsty all the time and drink lots of liquids, a condition called polydipsia.

Are diabetes insipidus and diabetes mellitus the same?

Diabetes insipidus is not the same as diabetes mellitus. Although both conditions can increase thirst, intake of liquids, and urination, they are not related.

• In diabetes mellitus, the level of glucose in your blood, also called blood sugar, is too high. Your kidneys try to remove the extra glucose by passing it in your urine.
• In diabetes insipidus, your blood glucose levels are normal, but your kidneys can’t properly concentrate urine.

Cushing’s syndrome is a disorder that occurs when your body makes too much of the hormone cortisol over a long period of time. Cortisol is sometimes called the “stress hormone” because it helps your body respond to stress. Cortisol also helps

• maintain blood pressure
• regulate blood glucose, also called blood sugar
• reduce inflammation
• turn the food you eat into energy

The adrenal glands, two small glands on top of your kidneys, make cortisol.