Hyperprolactinemia: Signs, Symptoms, Causes, Diagnosis, Treatment, Complications and Prognosis

It is a condition of elevated serum prolactin.

Prolactin is a 198 amino acid protein (23 kD) produced in the lactotroph cells of the anterior pituitary gland; it is an anterior pituitary hormone that has its main physiological action in the initiation and maintenance of lactation.

Its primary function is to improve breast development during pregnancy and induce lactation. However, prolactin binds to specific receptors on the gonads, lymphoid cells, and the liver.

In human reproduction, pathological hyperprolactinemia often presents as an ovulatory disorder and is often associated with secondary amenorrhea or oligomenorrhea.

The secretion is pulsatile; it increases with sleep, stress, pregnancy, and chest wall stimulation or trauma and therefore must be removed after fasting. Average fasting values ​​are generally less than 30ng / ml depending on the individual laboratory.

Normal levels are less than 500mIU / L [20ng / ml or μg / L] for women, and less than 450mIU / L for men. It can also be caused by diseases that affect the hypothalamus and the pituitary gland.

The main action of prolactin is to stimulate the proliferation of epithelial cells in the breasts and induce milk production.


Estrogen stimulates the proliferation of lactotroph cells in the pituitary, increasing the number of these cells in premenopausal women, especially during pregnancy.

However, breastfeeding is inhibited by high levels of estrogen and progesterone during pregnancy. The rapid decline in estrogen and progesterone in the postpartum period allows breastfeeding.

During lactation and lactation, ovulation can be suppressed due to the suppression of gonadotropins by prolactin.

Dopamine has the dominant influence on prolactin secretion. Prolactin secretion is under tonic inhibitory control by dopamine, which acts through D2-type receptors located on lactotrophs.

Prolactin production can be stimulated by hypothalamic peptides, thyrotropin-releasing hormone (TRH), and vasoactive intestinal peptide (VIP).

Therefore, primary hypothyroidism (a high state of thyrotropin-releasing hormone) can cause hyperprolactinemia.

The vasoactive intestinal peptide increases prolactin in response to sucking, probably due to its action on receptors that increase cyclic adenosine phosphate (cAMP).

The most commonly encountered physical findings in patients with hyperprolactinemia are galactorrhea and, occasionally, visual field defects. Diagnosis is usually made through laboratory studies.

Signs and symptoms of hyperprolactinemia

Sex can become difficult or painful due to vaginal dryness. They may not recognize a gradual loss of sexual function or libido. Only after treatment does some men realize that they have a problem with sexual function.

Galactorrhea, a typical symptom of hyperprolactinemia, occurs in less than half of the cases. Of the causes of hyperprolactinemia, pituitary tumors may account for nearly 50% of patients and should be investigated, especially in the absence of a history of drug-induced hyperprolactinemia.

Due to hypoestrogenism and hypoandrogenism, hyperprolactinemia can lead to osteoporosis.

Women have a history of oligomenorrhea, amenorrhea, or infertility, usually resulting from gonadotropin-releasing hormone (GnRH) prolactin suppression. Galactorrhea is due to the direct physiological effect of prolactin on the epithelial cells of the breast.

Men generally present with complaints of sexual dysfunction, visual problems, or headaches and are later diagnosed with hyperprolactinemia in the evaluation process.

Prolactin suppresses gonadotropin-releasing hormone, causing a decrease in luteinizing hormone and follicle-stimulating hormone, ultimately leading to decreased serum testosterone levels and hypogonadism.

Prolactinoma in men can also cause neurological symptoms, particularly visual field defects.

In both sexes, the presence of a pituitary tumor can cause visual field defects or headaches. Most patients with prolactinoma (the most common type of pituitary adenoma) are women.


Hyperprolactinemia inhibits gonadotropin-releasing hormone secretion from the hypothalamus (by increasing dopamine release from the arcuate nucleus).

This, in turn, inhibits the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland and results in decreased gonadal sex hormone production (called hypogonadism).

In many people, elevated prolactin levels remain unexplained and may represent a form of dysregulation of the hypothalamic-pituitary-adrenal axis.

The diagnosis of hyperprolactinemia should be included in the differential for female patients presenting with oligomenorrhea, amenorrhea, galactorrhea, or infertility or for male patients presenting with sexual dysfunction.

The condition is discovered in the course of evaluating the patient’s problem. Once located, hyperprolactinemia has a broad differential that includes many normal physiological conditions.

Pregnancy should permanently be excluded unless the patient is postmenopausal or has had a hysterectomy. Additionally, hyperprolactinemia is a normal finding in the postpartum period.

Other common conditions to exclude include a non-fasting specimen, excessive exercise, a history of surgery or trauma to the chest wall, kidney failure, and cirrhosis. Posttictal patients also develop hyperprolactinemia within 1-2 hours after a seizure.

These conditions generally produce a prolactin level of less than 50ng / ml. Hypothyroidism, an easily-treated disease, can also have a similar prolactin level.

A detailed drug history should be obtained because many common medications cause hyperprolactinemia, usually with less than 100 ng/ml prolactin levels. Medicines that can cause the condition include the following:

Dopamine receptor antagonists (such as phenothiazines, butyrophenones, thioxanthenes, risperidone, metoclopramide, sulpiride, and pimozide), dopamine-depleting agents (such as methyldopa and reserpine).

Others (isoniazid, danazol, tricyclic antidepressants, monoamine antihypertensives, verapamil, estrogens, antiandrogens, cyproheptadine, opiates, H2 blockers [cimetidine], cocaine). An MRI should be done if no apparent cause is identified or if a tumor is suspected.

Although no test can help determine the etiology of hyperprolactinemia, a prolactinoma is likely if the prolactin level is more significant than 250ng / ml and less likely if the story is less than 100ng / ml.

Prolactin-secreting adenomas are divided into two groups:

  1. Microadenomas (more common in premenopausal women) are smaller than 10mm.
  2. Macroadenomas (common in postmenopausal men and women) are 10mm or larger.

If the prolactin level is more significant than 100ng / ml or less than 250ng / ml, the evaluating physician must decide whether a radiographic study is indicated.

With the availability of MRI scans, plaques are performed at lower prolactin levels to rule out a non-prolactin-producing tumor.

When the underlying cause (physiological, medical, pharmacological) cannot be determined, and an MRI does not identify an adenoma, idiopathic hyperprolactinemia is diagnosed.

Exams and Tests to diagnose hyperprolactinemia

Clinicians who are comfortable with the initial evaluation of a patient (with no evidence of mass tumor effect) can quickly initiate treatment and follow up.

However, given the time constraints of modern outpatient medicine, consultation with an endocrinologist is often necessary.

The problem is the diagnosis and treatment of hyperprolactinemia is the appearance of the “large prolactin molecule” that is biologically inactive (called macroprolactinomas) but detected by the same radioimmunoassay as biologically active prolactin.

This may explain many very high prolactin levels that are sometimes found in women who usually ovulate and do not require any treatment.

The dopamine agonist is the mainstay of treatment. However, the presence of a pituitary macroadenoma may require surgical or radiological management.

Laboratory studies

Generally, hyperprolactinemia is discovered when evaluating a patient’s presenting condition, i.e., amenorrhea, galactorrhea, and erectile dysfunction. Occasionally, several measures of fasting prolactin should be obtained.

Current thyroid-stimulating hormone assays are very sensitive for detecting hypothyroid conditions. Measuring blood urea nitrogen and creatinine is essential in detecting kidney failure.

The history of alcohol abuse and the abdominal examination can give clues to the possible etiology of cirrhosis. Pregnancy tests are required unless the patient is postmenopausal or has had a hysterectomy.

Patients with macroadenoma should be evaluated for possible hypopituitarism. Male patients must have controlled testosterone levels.

Many patients with acromegaly have growth hormone co-secreted prolactin. Anyone thought to have acromegaly should be evaluated with an insulin level similar to growth factor 1 (IGF-1) and a glucose tolerance test for non-suppressible growth hormone levels if necessary.

Imaging studies

Although modern high-speed helical computed tomography scanners produce highly detailed images, MRI is the imaging study of choice. MRI can detect adenomas that are as small as 3-5 mm.

Other tests

Any identified cause will determine these, for example, visual field tests, mainly if a pituitary macroadenoma is found or if optic nerve involvement is seen in imaging studies.


Natural treatment is aimed at the resolution of hyperprolactinaemic symptoms or reduction in tumor size. Patients taking medications that cause hyperprolactinemia should withdraw them if possible. Patients with hypothyroidism should receive thyroid hormone replacement therapy.

When there are symptoms, medical treatment is the treatment of choice. Patients with hyperprolactinemia and without symptoms (idiopathic or macroprolactinomas) can be managed without treatment.

Consider treatment for women with amenorrhea. In addition, a duo-energy absorptiometry (DEXA) examination should be considered to assess bone density.

Persistent hypogonadism associated with hyperprolactinemia can lead to osteoporosis. The treatment significantly improves the quality of life of the patient.

If the goal is to treat hypogonadism only, patients with idiopathic hyperprolactinemia or microadenoma can be treated with estrogen replacement, and prolactin levels can be controlled.

Radiation treatment is another option. However, the risk of hypopituitarism makes this a poor choice. It may be necessary for fast-growing tumors, but its benefits in routine treatment have not been shown to outweigh the risks.


The goal of drug therapy is to reduce morbidity and prevent complications. The dopamine agonist bromocriptine mesylate is the initial drug of choice. The decreases in prolactin levels in 70-100% of patients.

Agents other than bromocriptine (e.g., cabergoline, quinagolide) have been used. Cabergoline and pergolide are available; cabergoline, in particular, is probably more effective and causes fewer adverse effects than bromocriptine.

However, it is much more expensive. Cabergoline is often used in patients who cannot tolerate bromocriptine’s adverse effects or those who do not respond to bromocriptine.

Pergolide has not been approved by the US Food and Drug Administration (FDA) for use in patients with this condition.

Response to therapy should be monitored by checking fasting serum prolactin levels and monitoring tumor size with MRI.

Most women (approximately 90%) regain cyclical menstruation and achieve resolution of galactorrhea. Testosterone levels in men increase but can remain below average.

Therapy should be continued for approximately 12-24 months (depending on the degree of symptoms or tumor size) and then withdrawn if prolactin levels have returned to normal.

After withdrawal, approximately one-sixth of patients maintain normal prolactin levels. Bromocriptine is also used to shrink macroadenomas.

Normalization of visual fields is seen in up to 90% of patients. A failure to improve within 1-3 months indicates surgery. Tumors generally shrink to 50% of their original size in approximately 90% of patients treated for macroadenomas for one year.

In patients with non-prolactinoma tumors (masses that compress the pituitary stalk), medical treatment reduces serum prolactin levels but does not reduce tumor size. Cabergoline is somewhat more effective than bromocriptine in terms of shrinking the tumor.

Surgical care

General indications for pituitary surgery include the patient’s drug intolerance, tumors resistant to medical therapy, patients with persistent visual field defects despite medical treatment, and patients with large cystic or hemorrhagic tumors.

Additional outpatient care

Once the diagnosis has been established, and therapy has been started, fasting prolactin levels should be monitored monthly.

Later, prolactin levels can be checked every 3-6 months. Formal visual field tests and MRI should follow tumor shrinkage.

Possible complications

The possible complications of hyperprolactinemia are mainly related to the size of the tumor and the physiological effects of the disease. These include blindness, bleeding, osteoporosis, and infertility.

An essential consequence of estrogen deficiency is osteoporosis in women with hyperprolactinemic amenorrhea, which deserves specific therapeutic consideration.

Prognosis of hyperprolactinemia

When followed for more than seven years, 90-95% of the microadenomas remained stable or gradually decreased prolactin secretion.

One-third of patients with idiopathic hyperprolactinemia may experience resolution without treatment. This number increases to two-thirds of the patient’s baseline prolactin levels are more minor than 40ng / ml.

Surgery is often not curative for macroprolactinomas, with a recurrence rate of up to 40% within five years.

Recurrence rates for hyperprolactinemia are as high as 80%, and patients subsequently require long-term medical therapy.

Patient education

A decrease in prolactin levels can restore ovulation. Advice on contraceptive methods should be given when prolactin levels are normal.