eMedicine Specialties > Endocrinology > Pituitary Gland

Hyperprolactinemia

Donald Shenenberger, MD, FAAFP, Staff Dermatologist, Department of Dermatology, Naval Medical Center Portsmouth

Updated: Aug 12, 2009

Introduction

Background

Hyperprolactinemia 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. Its primary function is to enhance breast development during pregnancy and to induce lactation. However, prolactin also binds to specific receptors in the gonads, lymphoid cells, and liver.¹ Secretion is pulsatile; it increases with sleep, stress, pregnancy, and chest wall stimulation or trauma, and therefore must be drawn after fasting. Normal fasting values are generally less than 30 ng/mL, depending on the individual laboratory.

Pathophysiology

The primary action of prolactin is to stimulate breast epithelial cell proliferation and induce milk production. Estrogen stimulates the proliferation of pituitary lactotroph cells, resulting in an increased quantity of these cells in premenopausal women, especially during pregnancy. However, lactation is inhibited by the high levels of estrogen and progesterone during pregnancy. The rapid decline of estrogen and progesterone in the postpartum period allows lactation to occur. During lactation and breastfeeding, ovulation may be suppressed due to the suppression of gonadotropins by prolactin.

Dopamine has the dominant influence over prolactin secretion. Secretion of prolactin is under tonic inhibitory control by dopamine, which acts via D2-type receptors located on lactotrophs. Prolactin production can be stimulated by the hypothalamic peptides, thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP). Thus, primary hypothyroidism (a high TRH state) can cause hyperprolactinemia. VIP increases prolactin in response to suckling, probably because of its action on receptors that increase adenosine 3',5'-cyclic phosphate (cAMP).

Frequency

United States

This condition occurs in less than 1% of the general population and in 10-40% of patients presenting with secondary amenorrhea. Approximately 75% of patients presenting with galactorrhea and amenorrhea have hyperprolactinemia. Of these patients, approximately 30% have prolactin-secreting tumors.

Mortality/Morbidity

• Mortality is unlikely; however, in cases where the condition is due to a large prolactin-secreting tumor, local mass effect can lead to significant morbidity.
• The condition causes systemic complaints that often resolve when the prolactin level returns to normal or once the tumor shrinks.

Sex

• Clinical presentation in women is more obvious and occurs earlier than in men. They typically present with oligomenorrhea, amenorrhea, galactorrhea, or infertility. Galactorrhea is less common in postmenopausal women due to lack of estrogen. If a pituitary tumor is present, it is a microadenoma (<10 mm) approximately 90% of the time.
• Prolactinoma is less common in men than in women, typically presenting as an incidental finding on a brain CT scan or MRI, or with symptoms of tumor mass effect. This is most evident as a complaint of visual disturbances or headache. By the time of diagnosis in men, approximately 60% have macroprolactinomas.

Clinical

History

• Women typically present with a history of oligomenorrhea, amenorrhea, or infertility, which generally results from prolactin suppression of gonadotropin-releasing hormone (GnRH). Galactorrhea is due to the direct physiologic effect of prolactin on breast epithelial cells.
• Men typically present with complaints of sexual dysfunction, visual problems, or headache and are subsequently diagnosed with hyperprolactinemia in the evaluation process. Prolactin suppresses GnRH, causing a decrease in luteinizing hormone and follicle-stimulating hormone, ultimately leading to decreased serum testosterone levels and hypogonadism. Prolactinoma in men also may cause neurological symptoms, particularly visual-field defects.
• In both sexes, the presence of a pituitary tumor may cause visual-field defects or headache. Most patients with a prolactinoma (the most common type of pituitary adenoma) are women.

Physical

Physical findings most commonly encountered in patients with hyperprolactinemia are galactorrhea and, occasionally, visual-field defects. Typically, the diagnosis is made via the aid of laboratory studies.

Causes

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 discovered, hyperprolactinemia has a broad differential that includes many normal physiologic conditions.

• Pregnancy should always be excluded unless the patient is postmenopausal or has had a hysterectomy. In addition, hyperprolactinemia is a normal finding in the postpartum period.
• Other common conditions to exclude include a nonfasting sample, excessive exercise, a history of chest wall surgery or trauma, renal failure, and cirrhosis. Postictal patients also develop hyperprolactinemia within 1-2 hours after a seizure. These conditions usually produce a prolactin level of less than 50 ng/mL.
• Hypothyroidism, an easily treated disorder, also may produce a similar prolactin level.
• Detailed drug history should be obtained because many common medications cause hyperprolactinemia, usually with prolactin levels of less than 100 ng/mL. Drugs that may cause the condition include the following:
  • Dopamine-receptor antagonists (eg, phenothiazines, butyrophenones, thioxanthenes, risperidone, metoclopramide, sulpiride, pimozide)
  • Dopamine-depleting agents (eg, methyldopa, reserpine)
  • Others (eg, isoniazid, danazol, tricyclic antidepressants, monoamine antihypertensives, verapamil, estrogens, antiandrogens, cyproheptadine, opiates, H2-blockers [cimetidine], cocaine)
• If no obvious cause is identified or if a tumor is suspected, MRI should be performed.
  • Although no single test can help determine the etiology of hyperprolactinemia, a prolactinoma is likely if the prolactin level is greater than 250 ng/mL and less likely if the level is less than 100 ng/mL.²
  • Prolactin-secreting adenomas are divided into 2 groups: (1) microadenomas (more common in premenopausal women), which are smaller than 10 mm and (2) macroadenomas (more common in men and postmenopausal women), which are 10 mm or larger.
  • If the prolactin level is greater than 100 ng/mL or less than 250 ng/mL, the evaluating physician must decide whether a radiographic study is indicated. In many cases, with the availability of MRI scanners, imaging is performed earlier and at lower prolactin levels to rule out a non–prolactin-producing tumor.
  • When the underlying cause (physiologic, medical, pharmacologic) cannot be determined and an MRI does not identify an adenoma, idiopathic hyperprolactinemia is diagnosed.
  • Another potential cause of hyperprolactinemia is macroprolactinemia. Macroprolactinemia is the apparent increase in serum prolactin without symptoms. In this condition, serum prolactin molecules can polymerize and subsequently bind to immunoglobulin G (IgG). This form of prolactin is unable to bind to prolactin receptors and exhibits no systemic response. In the asymptomatic patient with hyperprolactinemia, this condition should be considered. The discovery of macroprolactinemia could save the patient the inconvenience and cost of an in-depth evaluation for a microadenoma. If this condition is suspected, specific serum immunoassays must be performed to detect this form of prolactin. Consult laboratory personnel for any special collecting requirements. Women with macroprolactinemia are able to conceive. This condition generally requires no treatment.

Differential Diagnoses

Other Problems to Be Considered

Alcoholic cirrhosis
Pregnancy
Postparturition
Nipple stimulation
Nonfasting specimen
Drug effect
Postictal state
Chest wall trauma
Chest wall tumors

Workup

Laboratory Studies

• Generally, hyperprolactinemia is discovered in the course of evaluating a patient's presenting complaint, for instance amenorrhea, galactorrhea, or erectile dysfunction. Occasionally, several fasting measurements of prolactin must be obtained.
• Current thyroid-stimulating hormone assays are very sensitive for detecting hypothyroid conditions.
• Measuring blood urea nitrogen and creatinine is important for detecting renal failure.
• History of alcohol abuse and abdominal examination may give clues for cirrhosis as a possible etiology.
• Pregnancy testing is required unless the patient is postmenopausal or has had a hysterectomy.
• Patients with macroadenoma should be evaluated for possible hypopituitarism. Male patients should have testosterone levels checked.
• Many patients with acromegaly have prolactin co-secreted with growth hormone. Anyone thought to have acromegaly should be evaluated with an insulin-like growth factor-1 (IGF-1) level measurement and a glucose tolerance test for nonsuppressible growth hormone levels if needed.

Imaging Studies

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

Other Tests

These would be determined by any identified cause, (eg, visual-field testing especially if a pituitary macroadenoma is found or if optic nerve involvement is noted on imaging studies).

Treatment

Medical Care

Direct treatment is geared toward resolving hyperprolactinemic symptoms or reducing tumor size. Patients on medications that cause hyperprolactinemia should have them withdrawn if possible. Patients with hypothyroidism should be given thyroid hormone replacement therapy.

• When symptoms are present, medical therapy is the treatment of choice. Patients with hyperprolactinemia and no symptoms (idiopathic or microprolactinoma) can be monitored without treatment. Consider treatment for women with amenorrhea. In addition, duel energy radiographic absorptiometry scanning should be considered to evaluate bone density.
• The persistent hypogonadism associated with hyperprolactinemia can lead to osteoporosis. Treatment significantly improves the patient's quality of life. 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 monitored.³
• Radiation treatment is another option. However, the risk of hypopituitarism makes this a poor choice. It may be necessary for rapidly growing tumors, but its benefits in routine treatment have not been shown to outweigh the risks.
• Medication
  • The dopamine agonist, bromocriptine mesylate, is often the initial drug of choice. It lowers the prolactin level in 70-100% of patients. Agents other than bromocriptine have been used (eg, cabergoline, quinagolide). Cabergoline, in particular, probably is more effective and causes fewer adverse effects than bromocriptine. However, it is much more expensive. Cabergoline is often used in patients who cannot tolerate the adverse effects of bromocriptine or in those who do not respond to bromocriptine.^4,5
  • Pergolide, a drug previously used for the treatment of hyperprolactinemia was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to stop pergolide abruptly. Health care professionals should assess patients’ need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.
  • Response to therapy should be monitored by checking fasting serum prolactin levels and checking tumor size with MRI. Most women (approximately 90%) regain cyclic menstruation and achieve resolution of galactorrhea. Testosterone levels in men increase but may remain below normal.
  • 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 the normal range. After withdrawal, approximately one sixth of patients maintain normal prolactin levels.
    
    Kharlip et al looked at the recurrence of hyperprolactinemia after withdrawal of cabergoline therapy in 46 patients who had undergone long-term treatment with the drug.⁵  At the beginning of the investigation, the study's patients were normoprolactinemic and had experienced tumor volume reduction after at least 2 years of treatment with cabergoline.
    
    The overall recurrence rate of hyperprolactinemia following cabergoline withdrawal was 54%; it was estimated that the recurrence risk by 18 months after the drug's discontinuation was 63%. The authors also found that recurrence risk was related to the size of the tumor remnant remaining before therapy was discontinued, with an 18% risk increase for each millimeter of remnant. They concluded that withdrawal of cabergoline is safe in patients meeting the criteria used in the study but that close follow-up with these patients is essential, particular in the first year after the drug's discontinuation.
  • Bromocriptine is also used to shrink macroadenomas. Normalization of visual fields is observed in as many as 90% of patients. A failure to improve within 1-3 months is an indication for surgery. Tumors usually shrink to 50% of their original size in approximately 90% of patients treated for macroadenomas for 1 year. In patients with nonprolactinoma tumors (masses that are compressing 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 tumor shrinkage.

Surgical Care

General indications for pituitary surgery include patient drug intolerance, tumors resistant to medical therapy, patients who have persistent visual-field defects in spite of medical treatment, and patients with large cystic or hemorrhagic tumors.

Consultations

Physicians who are comfortable with the initial evaluation of a patient (without evidence of tumor mass effect) can easily initiate therapy and provide follow-up. However, given the time constraints of modern ambulatory medicine, consultation with an endocrinologist is often necessary.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Dopamine agonists

These agents directly stimulate postsynaptic dopamine receptors. Dopaminergic neurons in tuberoinfundibular processes modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor, believed to be dopamine.

Bromocriptine (Parlodel)

Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist; partial dopamine D1-receptor agonist. Inhibits prolactin secretion with no effect on other pituitary hormones. May be given with food to minimize possibility of GI irritation.

Dosing

Adult

1.25-2.5 mg PO initially; increase gradually every few days to approximately 5-10 mg daily in divided doses.

Pediatric

Not recommended

Interactions

Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects

Contraindications

Documented hypersensitivity; ischemic heart disease, uncontrolled hypertension, peripheral vascular disorders; breastfeeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or hepatic disease; generally stopped during pregnancy but can be restarted if symptoms recur; perform regular visual-field testing during pregnancy to monitor for tumor growth; should be given hs to minimize postural hypotension or nausea

Cabergoline (Dostinex)

Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist with low affinity for D1 receptors.

Dosing

Adult

0.25-1 mg PO twice/wk; start with a low dose and increase q4wk based on prolactin levels

Pediatric

Not recommended

Interactions

Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects

Contraindications

Documented hypersensitivity; ischemic heart disease, uncontrolled hypertension, peripheral vascular disorders; breastfeeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or hepatic disease; generally stopped during pregnancy but can be restarted if symptoms recur; perform regular visual-field testing during pregnancy to monitor for tumor growth; can be given hs to minimize postural hypotension or nausea

Quinagolide (Norprolac)

Pituitary selective dopamine-2 receptor agonist used in cases of bromocriptine resistance or intolerance. Used in the UK, not available in US.

Dosing

Adult

0.075 mg PO qd

Pediatric

Not recommended

Interactions

Not established

Contraindications

Documented hypersensitivity; decreased kidney or liver function

Precautions

Pregnancy

Precautions

May cause dizziness or hypotension

Follow-up

Further Outpatient Care

Once the diagnosis has been established and therapy initiated, fasting prolactin levels should be monitored monthly. Later, prolactin levels can be monitored every 3-6 months. Shrinkage of the tumor should be followed by formal visual-field testing and MRI.

Complications

Potential complications of hyperprolactinemia are primarily related to tumor size and the physiologic effects of the condition. These include blindness, hemorrhage, osteoporosis, and infertility.

Prognosis

• When monitored for longer than 7 years, 90-95% of 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 if the patient's basal prolactin level is less than 40 ng/mL.
• Surgery is often not curative for macroprolactinomas, with a recurrence rate of as high as 40% within 5 years.
• Recurrence rates of hyperprolactinemia are as high as 80%, and, subsequently, patients require long-term medical therapy.

Patient Education

• A decrease in prolactin levels may restore ovulation. Advice about birth control methods should be given when prolactin levels approach the normal range.
• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education article Amenorrhea.

Miscellaneous

Medicolegal Pitfalls

The primary reason physicians are sued is failure to diagnose, regardless of the diagnosis. The diagnosis of hyperprolactinemia is often made during the evaluation of the patient's complaints. This condition is easily diagnosed unless the physician fails to consider it in his or her differential.

References

1. Nilsson LA, Roepstorff C, Kiens B, et al. Prolactin suppresses malonyl-CoA concentration in human adipose tissue. Horm Metab Res. Jun 23 2009;[Medline].

2. Schlechte JA. Long-term management of prolactinomas. J Clin Endocrinol Metab. August 2007;92(8):2861-5. [Medline].

3. Sathyapalan T, Gonzalez S, Atkin SL. Effect of long-term, high-dose estrogen treatment on prolactin levels: a retrospective analysis. Climacteric. Jul 21 2009;1-4. [Medline].

4. Nachtigall LB, Valassi E, Lo J, McCarty D, Passeri J, Biller BM, et al. Gender effects on cardiac valvular function in hyperprolactinaemic patients receiving cabergoline: a retrospective study. Clin Endocrinol (Oxf). Apr 17 2009;[Medline].

5. Kharlip J, Salvatori R, Yenokyan G, Wand GS. Recurrence of hyperprolactinemia after withdrawal of long-term cabergoline therapy. J Clin Endocrinol Metab. Jul 2009;94(7):2428-36. [Medline].

6. Biller MKB, Daniels GH. Neuroendocrine regulation and diseases of the anterior pituitary and hypothalamus. In: Braunwald E, Isselbacher KJ, Wilson J, et al. Harrison's Principles of Internal Medicine. 14^th ed. New York, NY: McGraw-Hill; 1998:1974-8.

7. Blackwell RE. Hyperprolactinemia. Evaluation and management. Endocrinol Metab Clin North Am. Mar 1992;21(1):105-24. [Medline].

8. Conner P, Fried G. Hyperprolactinemia; etiology, diagnosis and treatment alternatives. Acta Obstet Gynecol Scand. Mar 1998;77(3):249-62. [Medline].

9. Davies PH. Drug-related hyperprolactinaemia. Adverse Drug React Toxicol Rev. Jun 1997;16(2):83-94. [Medline].

10. Hartog M, Hull MG. Hyperprolactinaemia. BMJ. Sep 17 1988;297(6650):701-2. [Medline].

11. Jones TH. The management of hyperprolactinaemia. Br J Hosp Med. Apr 19-May 2 1995;53(8):374-8. [Medline].

12. Kaye TB. Hyperprolactinemia. Causes, consequences, and treatment options. Postgrad Med. May 1996;99(5):265-8. [Medline].

13. Lancet. Management of prolactinoma. Lancet. Sep 15 1990;336(8716):661. [Medline].

14. Molitch ME. Medical treatment of prolactinomas. Endocrinol Metab Clin North Am. Mar 1999;28(1):143-69, vii. [Medline].

15. Prescrire International. Cabergoline and hyperprolactinaemia: new preparation. Better than bromocriptine. Prescrire Int. 2000;Feb;9(45):195-7. [Medline].

16. Serri O, Chik CL, Ur E, Ezzat S. Diagnosis and management of hyperprolactinemia. CMAJ. Sep 16 2003;169(6):575-81. [Medline].

17. Valdemarsson S. Macroprolactinemia. Risk of misdiagnosis and mismanagement in hyperprolactinemia. Lakartidningen. 2004;101(6):458-65. [Medline].

18. Wilson JD. Endocrine Disorders of the Breast. In: Braunwald E, Isselbacher KJ, Wilson J, et al,. Harrison's Principles of Internal Medicine. 1998. 14^th ed. New York, NY: McGraw-Hill; 2116-7.

Keywords

hyperprolactinemia, prolactin, prolactinoma, pituitary tumor, tumor pituitary, cabergoline, prolactin levels, macroprolactinomas, pituitary tumors, breast development, elevated serum prolactin level, pituitary adenoma, prolactin-secreting tumors, anterior pituitary gland, lactation, secondary amenorrhea, galactorrhea, oligomenorrhea, dopamine agonists, hypothyroidism

Contributor Information and Disclosures

Author

Donald Shenenberger, MD, FAAFP, Staff Dermatologist, Department of Dermatology, Naval Medical Center Portsmouth
Donald Shenenberger, MD, FAAFP is a member of the following medical societies: American Academy of Dermatology, American Academy of Family Physicians, Association of Military Dermatologists, and Uniformed Services Academy of Family Physicians
Disclosure: Nothing to disclose.

Medical Editor

David M Klachko, MBBCh, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri
David M Klachko, MBBCh is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, Endocrine Society, Missouri State Medical Association, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Yoram Shenker, MD, Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison
Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

The editors would like to thank Treyce Knee, MD, for previous contributions to this article.

Related eMedicine topics:
Luteinizing Hormone Deficiency
Ovarian Insufficiency
Pituitary Adenoma
Pituitary Disease and Pregnancy
Pituitary Macroadenomas
Pituitary Microadenomas
Prolactinoma

Clinical guidelines:
ACR Appropriateness Criteria® neuroendocrine imaging.
American College of Radiology - Medical Specialty Society.  1999 (revised 2006).  11 pages.  [NGC Update Pending] NGC:005121

Diagnosis of breast disease.
Institute for Clinical Systems Improvement - Private Nonprofit Organization.  1994 Jan (revised 2008 Jan).  47 pages.  NGC:006317

Stereotactic radiosurgery for patients with pituitary adenomas.
IRSA - Professional Association.  2004 Apr.  12 pages.  NGC:003598

Clinical trials:
Calcium and Vitamin D to Optimize Bone Mass in Boys With Risperidone-Induced Hyperprolactinemia

Substrate Metabolism and Insulin Sensitivity in Patients With Hyperprolactinemia Before and After Treatment

The Luveris In Vitro Fertilization Trial

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