Mark W. Ball, MD
Arthur L. Burnett, II, MD, MBA, FACS
BASICS
DESCRIPTION
• Hyperprolactinemia (HPRL) refers to serum prolactin levels that exceed the normal range <25 mg/L (∼500 mIU/L) in women and <20 mg/L (∼400 mIU/L) in men.
• It is the most common endocrine abnormality due to hypothalamic–pituitary disorders.
• It may result in hypogonadism, erectile dysfunction, infertility, galactorrhea, and osteoporosis.
• Most common causes are pregnancy, medications, hypothyroidism, and prolactin-secreting pituitary tumors (prolactinomas)
EPIDEMIOLOGY
Incidence
• Peak incidence occurs in women of age 25–34, at 23.9/100,000/yr.
• Incidence data in men is lacking
Prevalence
• Lifetime prevalence of prolactinoma is 30/100,000 in woman and 10/100,000 in men.
• Pituitary microadenomas are found in 10.9% of autopsies, with 44% prolactinomas.
• In men with sexual dysfunction, ∼1% have HPRL.
• 90% of prolactinomas occur in women of reproductive age.
• 40% of pituitary adenomas are prolactinomas
RISK FACTORS
• Female sex
• Pregnancy
• Prolactinomas
• Medications (antipsychotics, antidepressants, verapamil, opiates, GI motility drugs, estrogens)
• MEN-1 syndrome
Genetics
• Most prolactinomas are sporadic (1)
• Present in about 20% of adults with MEN-1, who have an autosomal dominant mutation in the MEN-1 tumor suppressor gene on chromosome 11
• Can rarely occur as part of familial isolated pituitary adenomas
PATHOPHYSIOLOGY
• Prolactin is produced in the anterior pituitary
• Secretion is pulsatile and increases with stress and sleep
• Tonically suppressed by dopamine via D2 receptors
– Medications that inhibit dopamine secretion raise prolactin levels
• Elevated prolactin suppresses GnRH, with subsequent reductions in LHRH, FSH, and sex steroid levels.
– Low testosterone can cause decreased libido, erectile dysfunction, infertility, and gynecomastia in men.
– Low estrogen can cause oligomenorrhea, decreased libido, anovulation, and galactorrhea in women
– Decreased bone mineral density can occur in both sexes secondary to low sex steroid levels.
• Prolactinomas: Pituitary microadenomas (<10 mm) and macroadenomas (>10 mm) can be seen in some patients as the cause of the elevated levels.
– Macroadenomas can have mass effect symptoms, including headache and visual disturbance by optic nerve compression
• Rarely, chest wall injury can increase prolactin levels.
• Macroprolactinemia is caused by an abnormal binding of the molecule to circulating IgG.
ASSOCIATED CONDITIONS
• Amenorrhea and/or galactorrhea in women
• Hypogonadism and/or ED in men
• Hypothyroidism: Increased thyrotropin-releasing hormone can stimulate prolactin secretion.
• Renal failure can result in reduced clearance.
• Cirrhosis
• Herpes zoster (particularly involving the chest wall)
GENERAL PREVENTION
Discontinuation of medication causing symptomatic HPRL (asymptomatic prolactin elevations need not be treated)
DIAGNOSIS
HISTORY
• Women: Often presents early in disease course.
– Infertility (including pregnancy history)
– Amenorrhea/menstrual irregularities
– Galactorrhea
• Men: Often presents late in disease course.
– Complaints of sexual dysfunction
Decreased libido
Erectile dysfunction (ED)
– Gynecomastia
• General
– Headache
– Visual field defects
• Psychiatric history and antipsychotic medication use
• Alcohol abuse
• Medication use:
– Antipsychotics: Butyrophenones (eg, haloperidol), phenothiazines (eg, chlorpromazine), thioxanthenes (eg, thiothixene), risperidone and others: Metoclopramide, sulpiride, pimozide, methyldopa, reserpine
– Others reported: Antiandrogens, cimetidine, cyproheptadine, danazol, estrogens, INH, tricyclic antidepressants, opiates, verapamil
PHYSICAL EXAM
• Breast exam for gynecomastia, galactorrhea
• Evidence of chest wall trauma or herpetic lesions
• Signs of hypogonadism
• Signs of hypothyroidism
• Visual field abnormalities
DIAGNOSTIC TESTS & INTERPRETATION
Lab (2)
• A single serum measurement > upper limit of normal makes the diagnosis of HPRL
• Serum PRL >500 μg/L is diagnostic of a macroprolactinoma
• Women of reproductive age should have a pregnancy test.
• In men presenting with ED, a testosterone level should be checked. If low, further evaluation of prolactin should be performed.
• With medication-induced HPRL, prolactin levels are usually <50 mg/L and almost always <100 mg/L.
• After stopping suspected medication, prolactin levels usually return to normal within 4 days.
Imaging
• Pituitary MRI is the test of choice. Should be obtained in all cases where prolactin is persistently elevated and no cause is apparent.
• DEXA scanning to evaluate for possible bone mineral density problems
• In women, pelvic US to assess for uterine or ovarian pathology
Diagnostic Procedures/Surgery
Formal visual field assessment should be done in patients with macroadenomas.
Pathologic Findings
Prolactinoma: Glands composed of cuboidal cells. May be either eosinophilic or chromophobic.
DIFFERENTIAL DIAGNOSIS
• Hypothyroidism
• Lab error or macroprolactinemia (abnormal prolactin molecule)
• Medication-induced
• Nonprolactin-secreting pituitary or hypothalamic tumor
• Polycystic ovary syndrome (PCOS)
• Pregnancy
• Prolactinoma
• Renal failure
TREATMENT
ALERT
Do not treat women until pregnancy is excluded.
GENERAL MEASURES (3)
• Women of reproductive age should have a pregnancy test 1st.
• Treat underlying cause or stop offending drug if possible
• Asymptomatic HPRL secondary to medication use does not require treatment.
MEDICATION
First Line
• Cabergoline or bromocriptine (dopamine agonists):
– Usually will lower prolactin levels, regardless of cause, and shrink prolactinomas
– In general, both cabergoline and bromocriptine are effective. Cabergoline is usually better-tolerated, more convenient, and more effective than bromocriptine, whereas bromocriptine is less expensive and has been used longer.
– Use dopamine agonists with caution in patients on psychotropic drugs that inhibit dopamine action.
Cabergoline dosing (0.5-mg tablets): Start with 0.25–0.5 mg once or twice weekly and increase the dose at monthly intervals until prolactin normalizes (>3 mg/wk is rarely needed).
Bromocriptine dosing (2.5-mg tablets): Start with 0.625 or 1.25 mg with food before bedtime and gradually increase at weekly intervals until prolactin level is controlled (usually 2.5 mg BID–TID).
– Side effects include nausea and postural hypotension
• Pregnancy considerations
– More experience with bromocriptine.
– Neither bromocriptine nor cabergoline has been associated with teratogenicity.
– Nevertheless, either drug is usually stopped at the 1st evidence of pregnancy, except in patients with macroadenomas in whom previous mass effects may recur if tumor enlarges.
– Significant enlargement of microadenomas is uncommon during pregnancy.
– Lactation: Dopamine agonists will inhibit lactation.
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Often performed transsphenoidally
• For microadenomas, generally reserved for patients intolerant of drug therapy. Tumors may recur.
• Only indicated for pituitary macroadenomas when medical therapy is ineffective, including persistent visual field abnormalities:
– Usually not curative
ADDITIONAL TREATMENT
Radiation Therapy
Usually only indicated for pituitary macroadenomas that have failed medical therapy, and where response to surgery is inadequate or surgery is contraindicated.
Additional Therapies
Men with ED or persistent hypogonadism may require additional therapies.
Complementary & Alternative Therapies
Vitex agnus-castus extract can be tried in cases of mild HPRL
ONGOING CARE
PROGNOSIS
• 90–95% of prolactin-secreting pituitary microadenomas will not grow further, even without medical therapy.
• Medical therapy is usually successful in normalizing prolactin levels, normalizing menses, reducing or stopping galactorrhea, inducing ovulation, and shrinking pituitary tumors.
• >90% of microadenomas do not grow significantly during pregnancy, even after medical therapy is stopped.
• Some microadenomas disappear with time (especially after menopause) or do not recur after medical therapy.
• Pituitary macroadenomas usually do not disappear completely with medical therapy and require continuous medical therapy.
COMPLICATIONS
• Dopamine agonists can worsen underlying psychiatric problems in patients taking psychotropic medications.
• Pituitary macroadenomas can secrete other hormones or become resistant to medical therapy.
FOLLOW-UP
Patient Monitoring
• Drug-induced HPRL:
– Prolactin should normalize after switching medications and no further follow-up is needed.
• Microadenomas:
– Some microadenomas resolve spontaneously.
– Measure prolactin every 6–12 mo to ensure continued drug efficacy.
– No need for repeat pituitary MRI unless prolactin increases markedly on therapy.
– Consider stopping dopamine agonist after at least a year of successful therapy; some microadenomas do not recur
• Macroadenomas:
– If prolactin normalizes, repeat pituitary MRI after 3–6 mo to ensure tumor shrinkage and establish new baseline.
– No consensus on frequency of further MRIs in patients whose prolactin is well-controlled medically.
– Repeat prolactin measurements every 3–6 mo.
– Follow visual fields in patients who have visual field defects at baseline.
– Some macroadenomas resolve spontaneously.
Patient Resources
Patient guide to hyperprolactinemia diagnosis and treatment. J Clin Endocrinol Metab. 2011;96:35A–36A.
REFERENCES
1. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–288.
2. Klibanski A. Clinical practice. Prolactinomas. N Engl J Med. 2010;362(13):1219–1226.
3. Casanueva FF, Molitch ME, Schlecte JA, et al. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf). 2006;65:265–273.
ADDITIONAL READING
• Klibanski A. Clinical practice. Prolactinomas. N Engl J Med. 2010;362(13):1219–1226.
• Mancini T, Casanueva FF, Giustina A. Hyperprolactinemia and prolactinomas. Endocrinol Metab Clin North Am. 2008;37:67–99.
• Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–288.
• Molitch ME. Drugs and prolactin. Pituitary. 2008;11:209–218.
• Schlecte JA. Long-term management of prolactinomas. J Clin Endocrinol Metab. 2007;92:2861–2865.
• Zeitlin S, Rajfer J. Hyperprolactinemia and erectile dysfunction. Rev Urol. 2000;2(1):39–42.
See Also (Topic, Algorithm, Media)
• Erectile Dysfunction
• Gynecomastia
CODES
ICD9
• 253.1 Other and unspecified anterior pituitary hyperfunction
• 256.39 Other ovarian failure
• 257.2 Other testicular hypofunction
ICD10
• E22.1 Hyperprolactinemia
• E28.39 Other primary ovarian failure
• E29.1 Testicular hypofunction
CLINICAL/SURGICAL PEARLS
• Women present early in the disease course, while men present late.
• Dopamine agonists are the 1st-line treatment of prolactinomas.
• Surgical excision is reserved for refractory cases.
• All women should be screened for pregnancy before initiating treatment.