What is hyperprolactinemia

Hyperprolactinemia is a condition in which a person has higher-than-normal levels of the prolactin hormone in the blood of women who are not pregnant and in men. Hyperprolactinemia is relatively common in women. About a third of women in their childbearing years with irregular periods but normal ovaries have hyperprolactinemia. When this happens, a woman might have trouble getting pregnant or her breasts may start producing milk outside of pregnancy (galactorrhea). Ninety percent of women with galactorrhea also have hyperprolactinemia. High prolactin levels interfere with the normal production of other hormones, such as estrogen and progesterone. This can change or stop ovulation (the release of an egg from the ovary). It can also lead to irregular or missed periods. Some women have high prolactin levels without any symptoms.

In men, hyperprolactinemia (high prolactin levels) can cause galactorrhea (breast milk production), impotence (inability to have an erection during sex), reduced desire for sex, and infertility. A man with untreated hyperprolactinemia may make less sperm or no sperm at all.

Prolactin is a hormone whose primary role is to stimulate breast milk production (lactation) after childbirth. It is normally elevated in women during pregnancy and just after childbirth, so high prolactin levels are normal in pregnancy. It is normally low in men and non-pregnant women.

Prolactin also affects the levels of sex hormones (estrogen and testosterone) in both women and men.

Prolactin is made by the front portion (anterior) of the pituitary gland, a pea-sized organ found at the base of your brain. The brain chemical dopamine and hormone estrogen control prolactin production and release from the pituitary gland. During pregnancy, the hormones prolactin, estrogen, and progesterone stimulate breast development and milk production. Following childbirth, prolactin helps initiate and maintain the breast milk supply. If a woman does not breastfeed, her prolactin level soon drops back to pre-pregnancy levels. If she does nurse, suckling by the infant plays an important role in the release of prolactin. There is a feedback mechanism between how often the baby nurses and the amount of prolactin released by the pituitary as well as the amount of milk produced.

The secretion rate of prolactin is about 200 to 536 mcg/day/meter square ¹ and the half-life is 25 to 50 minutes. Prolactin is metabolized by the liver (75%) and the kidney (25%). The basal level of prolactin in women averages 13 ng/ml and in men it averages is 5 ng/ml. The upper normal limit of serum prolactin level in most laboratories is 15 to 20 ng/ml. When the amount of serum prolactin exceeds the upper limit, doctors call it hyperprolactinemia.

A common cause of an abnormally elevated prolactin level is a prolactinoma, a tumor of the pituitary gland that causes excess production of prolactin. Prolactinoma is the most common type of pituitary tumor and is usually benign, accounting for up to 40% of all clinically recognized pituitary adenomas ². They develop more frequently in women but are also found in men. Symptoms can arise both from the unintended effects of excess prolactin, such as milk production in a woman who is not pregnant or nursing and, rarely, in a man (galactorrhea), as well as from the size and location of the tumor.

If the anterior pituitary gland and/or the tumor enlarge significantly, it can put pressure on the optic nerve, causing headaches and problems with vision. It can also interfere with the other hormones that the pituitary gland produces. In women, prolactinomas can cause infertility and irregularities in menstruation, while in men these tumors can cause a gradual loss in sexual function and libido. Left untreated, prolactinomas may eventually damage the surrounding tissues.

Hyperprolactinemia causes

One common cause of hyperprolactinemia is a growth or tumor on the pituitary gland called a prolactinoma. The tumor produces high levels of prolactin. These tumors can be large or small and are usually benign, meaning they are not cancerous. Large tumors can also cause headaches, vision problems, or both. Prolactinomas are more common in women than in men and rarely occur in children.

Certain prescription medicines can also increase prolactin levels. These include medicines for:

• High blood pressure (such as calcium-channel blockers and methyldopa)
• Depression (tricyclic and SSRI antidepressants)
• Heartburn and gastroesphageal reflux disease
• Nausea and vomiting
• Pain (opiates—drugs derived from opium)
• Birth Control Pills
• Serious mental health disorders (antipsychotics such as risperdal and haloperidol)
• Menopausal symptoms (estrogen)

Pharmacological Causes

• Estrogen therapy
• Thyrotropin-releasing hormone
• Antipsychotic/dopamine receptor blocking agents: risperidone, haloperidol, fluphenazine, among others
• Antiemetic/dopamine receptor blocking agents: metoclopramide, domperidone, prochlorperazine
• Tricyclic antidepressant, selective serotonin receptor inhibitor: amitriptyline, clomipramine, fluoxetine
• Anticonvulsant: Phenytoin
• Antihypertensive: Verapamil, methyldopa, labetalol
• H2 Antihistamines: Cimetidine, ranitidine
• Opioid analgesics: Methadone, morphine, apomorphine, heroin
• Cholinergic agent: Physostigmine

Other causes include:

• Hypothyroidism or underactive thyroid—meaning the thyroid gland does not produce enough thyroid hormone
• Chest-wall injuries or other conditions that affect the chest wall, such as shingles, surgical scars, or even a too-tight bra
• Other tumors and diseases affecting the pituitary gland, or radiation treatment for tumors on or near the pituitary
• Chronic liver and kidney diseases
• Stress or exercise (usually excessive or extreme)
• Certain foods
• Nipple stimulation
• Herbs, including fenugreek, fennel seeds, and red clover

Pituitary Disease

• Prolactinoma
• Acromegaly
• Cushing disease
• Macroadenoma (compressive)
• Plurihormonal adenoma
• Lymphocytic hypophysitis
• Parasellar mass
• Macroprolactinemia

Prolactinoma is a benign tumor of lactotrophs. It accounts for up to 40% of all pituitary adenomas. It can present with any level of prolactin elevation from mild elevation to 50,000 ng/ml. In contrast, prolactin elevation from other causes rarely exceeds 200 ng/ml ³.

Hypothalamic Disease – Stalk Damage

• Tumors like craniopharyngioma, suprasellar pituitary mass extension, meningioma, dysgerminoma, hypothalamic metastases
• Granulomas (sarcoidosis, tuberculosis)
• Infiltrative disease (histiocytosis disease)
• Rathke’s cyst
• Pituitary stalk transection (Sellar surgery, head trauma)
• Cranial Irradiation

Systemic Disorder

• Chronic renal failure
• Polycystic ovarian disease (PCOS)
• Liver cirrhosis
• Pseudocyesis
• Reflex causes: Chest wall trauma, surgery, herpes zoster
• Primary hypothyroidism

Genetic

• Inactivating prolactin receptor mutation ⁴

Ectopic Production

• Bronchogenic carcinoma and hypernephromas ²

Sometimes, no cause is found in about a third of all cases of hyperprolactinemia (idiopathic hyperprolactinemia).

Hyperprolactinemia symptoms

Patients with hyperprolactinemia may remain asymptomatic or can present with sign and symptoms of hypogonadism and galactorrhea (breast milk production not associated with pregnancy or breast-feeding).

Both men and women may have infertility, decreased sex drive, and bone loss.

In addition, women may have:

• Vaginal dryness, leading to pain during intercourse
• Problems with menstruation—having no periods or irregular periods (oligomenorrhea, amenorrhea, menorrhagia or infertility)
• Production of breast milk (galactorrhea) when not pregnant or nursing

Men may also have:

• Erectile dysfunction—trouble getting or keeping an erection
• Breast enlargement, called gynecomastia
• Decreased muscle mass and body hair
• Hypogonadotropic hypogonadism: Decreased libido, impotence, infertility, oligospermia or gynecomastia ⁵

Sign and symptoms caused by prolactinoma mass effect:

• Headache
• Visual field defect
• Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles.

Hyperprolactinemia complications

• Mass effect leading to visual deficits, cranial nerve palsies and pituitary apoplexy
• Infertility
• Osteoporosis
• Blindness
• Complications related to cerebrospinal fluid (CSF) leak and hypopituitarism
• Hypogonadism

Hyperprolactinemia diagnosis

A blood test is used to detect excess prolactin. Levels are sometimes higher if you have eaten recently or are under stress. The blood test may be done again after you’ve fasted and are relaxed. Your doctor may also perform a physical exam to find any obvious causes or any breast discharge. If prolactin levels are high, more tests are usually done to check blood levels of thyroid hormone. Normal thyroid hormone levels rule out hypothyroidism as a cause of hyperprolactinemia. Doctors will also ask about other conditions and medication use, and rule out pregnancy.

Laboratory Tests

Following tests are generally needed depending upon gender, age, and clinical presentation:

• Serum prolactin
• Thyroid function test
• Renal function test
• Insulin-like growth factor-1 (IGF-1)
• Adrenocorticotrophic hormone (ACTH)
• Luteinizing hormone (LH)
• Follicle-stimulating hormone (FSH)
• Testosterone/estradiol
• Pregnancy test

Imaging Test

If a prolactinoma is suspected, an MRI (magnetic resonance imaging) of the brain and pituitary is often the next step. Using a special machine that creates images of body tissues, an MRI can reveal a pituitary tumor and show its size.

Pitfalls in diagnosis

Hook Effect: It is because of an artifact in the immunoradiometric assay giving a falsely low concentration of prolactin. Hook effect should be kept in mind with large pituitary adenoma with mild or moderate elevation in prolactin. When there is very high serum prolactin concentration, both the capture and tracer antibodies used in immunoradiometric assays become saturated, preventing the binding of the two, to create a sandwich. Then the test result will read low. This effect can be overcome by repeating the test using a 1:100 dilution of serum. This artifact is uncommon.

Macroprolactin represents large circulating aggregates of prolactin and antibodies of size about 150 kD; whereas, native prolactin in serum is 23 kD ⁶. These complexes are detectable in test assay but are biologically inactive. They can be misdiagnosed as prolactin hypersecretion ⁷. Clinicians can avoid this misdiagnosis by precipitating macroprolactin by pretreating with polyethylene glycol before measuring prolactin.

Hyperprolactinemia treatment

Hyperprolactinemia treatment is based on the cause. Some people with high prolactin levels, but few or no signs and symptoms, do not need any treatment. Options for treating tumors include:

• Prescription medicines. Bromocriptine and cabergoline decrease prolactin production. Medicines work well for most people with prolactinomas.
• Surgery to remove a tumor. Surgery may be used if medicines have not been effective. Surgery is sometimes needed if the tumor is affecting vision.
• Radiation. Rarely, if medicines and surgery have not been effective, radiation is used to shrink the tumor.

Bromocriptine and cabergoline are also used to treat hyperprolactinemia with no known cause. Hypothyroidism is treated with synthetic thyroid hormone, which should bring prolactin levels back to normal. If high prolactin levels are caused by prescription medications, other types of medications can be explored. Hypothyroidism is treated with thyroid replacement medicine, which should also make prolactin levels return to normal.

Medicines used to treat hyperprolactinemia

The most commonly used dopamine agonists are cabergoline and bromocriptine. Quinagolide is not available in the United States but used in some other countries. Your doctor will start you on a low dose of one of these medications and slowly increase the dose until your prolactin levels go back to normal. Treatment continues until your symptoms lessen or you get pregnant (if that is your goal). Usually, your doctor will stop treatment once you are pregnant.

Cabergoline is preferred to other dopamine agonists due to higher efficacy in normalizing prolactin levels and tumor shrinkage ⁸. Cabergoline has a long duration of action than bromocriptine and is administered once or twice a week and has fewer side effects than bromocriptine. Generally, cabergoline drops prolactin levels to normal faster than bromocriptine does. Cabergoline can cause heart valve regurgitation when taken in high doses ⁹, but these doses are not used in women who are trying to get pregnant. Bromocriptine is preferred during pregnancy because of more favorable data than cabergoline ¹⁰. Bromocriptine is administered once daily. Common side effects are nausea, vomiting, nasal stiffness, digital vasospasm, depression, and postural hypotension. Another way to decrease the side effects is to give bromocriptine in a suppository directly in the vagina. This is an off-label use of the medicine.

Bromocriptine and cabergoline can been used when woman is pregnant. The most common side effects are lightheadedness, nausea, and headache. Slowly increasing the dose helps with side effects.

Dopamine agonist therapy can be tapered and discontinued after 2 years of continuous therapy if serum prolactin level is normal and no adenoma is visible in MRI.

No treatment

Not all women with hyperprolactinemia need treatment, although women with hyperprolactinemia who do not make estrogen as a result need a treatment that either causes her to make estrogen or provides estrogen to the patient. No treatment may be needed if a cause can’t be found or if the high prolactin level is due to a small tumor in the pituitary gland and the patient is still making estrogen. Women with hyperprolactinemia can still take birth control pills to keep from getting pregnant or make their periods regular.

Surgery

Most of the prolactinomas are treated with medical therapy only. If a tumor is big, surgery may be needed if medical therapy with the dopamine agonists doesn’t improve symptoms. An MRI will be done every so often to check on the size of the tumor. Endoscopic endonasal transsphenoidal surgery is preferred surgical method. Prophylactic surgery is considered in women with large prolactinoma which potentially threaten vision during pregnancy ¹¹. Adjuvant radiation therapy should be considered for residual tumor. Gamma knife stereotactic radiosurgery is often effective in treating prolactinomas resistant to or intolerant of dopamine agonists ¹².

Drug-induced hyperprolactinemia

Treatment is only necessary if patients develop hypogonadism, osteoporosis or troublesome galactorrhea ¹³. If hyperprolactinemia is suspected because of drugs, it should be discontinued temporarily, if possible, to see if prolactin level normalizes. If medication cannot be discontinued, especially antipsychotics, it should be changed to a different antipsychotics that does not increase prolactin, e.g., quetiapine. If that is not possible, addition of dopamine agonist should be considered. These changes should be made in consultation with a psychiatrist. Addition of estradiol in women and testosterone in men can be considered for hypogonadism and low bone mass. If prolactin level does not normalize after stopping meds or if discontinuation of meds is not possible, pituitary MRI should be done.

Hypothalamic Disease: Stalk Damage

Removal of the cause should be the first choice; if not, hyperprolactinemia should be treated with the dopamine agonist.

Idiopathic Hyperprolactinemia

Idiopathic hyperprolactinemia is treated with the dopamine agonist. However, these patients are relatively resistant to dopamine agonist. Dosage can be adjusted to keep the lowest possible dose with the normal level of prolactin. If the patient attains normal prolactin on the lowest dose of a dopamine agonist for 2 years, the drug can be discontinued as a trial.

Hyperprolactinemia prognosis

Most patients with micro prolactinomas have a good prognosis and normalize prolactin levels with treatment. These patients can be managed with medical therapy for a prolonged period. The success of the pituitary surgery also depends upon the size of the tumor, the serum prolactin level, and experience of the neurosurgeon. The success rate of pituitary surgery is related inversely to tumor size and prolactin levels ¹⁴. Although micro prolactinoma surgery has a high success rate, recurrence of hyperprolactinemia is relatively high ¹⁵, which is about 17% in patients initially considered cured. In the case of macroprolactinoma, around 50% of the patients are in remission after the surgery. In case of invasive tumors, complete resection may not be possible, and prolactin normalizes in only 32% of patients with a recurrence rate of about 19%.

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