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Hyperprolactinemia
D'Ann Somerall, DNP, FNP-BC
William E. Somerall Jr., MD, MEd
image BASICS
DESCRIPTION
Hyperprolactinemia is an abnormal elevation in the serum prolactin level with multiple possible etiologies.
EPIDEMIOLOGY
Prevalence
  • Predominant age: reproductive age
  • Predominant sex: female > male
  • More readily detected in females because a slight elevation in prolactin causes changes in menstruation and galactorrhea
ETIOLOGY AND PATHOPHYSIOLOGY
  • Prolactin, which is produced by lactotrophs in the anterior pituitary, is regulated by:
    • Inhibitory factors, primarily dopamine, produced in the hypothalamus and delivered via the hypothalamic-pituitary vessels in the pituitary stalk
    • Stimulatory factors, primarily thyrotropin-releasing hormone (TRH)
  • Causes of hyperprolactinemia include the following:
    • Physiologic
      • Pregnancy due to increased estrogen
      • Breastfeeding
      • Nipple stimulation
      • Stress, including postoperative state
    • Medications
      • Dopamine (D2) blockers: prochlorperazine, metoclopramide
      • Dopamine depleters: &agr;-methyldopa, reserpine
      • Antidepressants: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (SSRIs do not appear to cause clinically significant hyperprolactinemia)
      • Verapamil (but no other calcium channel blockers; thought to decrease hypothalamic synthesis of dopamine)
      • Antipsychotics: haloperidol, fluphenazine, risperidone
    • Hypothyroidism (due to elevated TRH)
    • Chest wall conditions:
      • Herpes zoster
      • After thoracotomy
      • Trauma
    • Prolactin-secreting adenoma (anterior pituitary), categorized:
      • Microadenoma: <1 cm
      • Macroadenoma: >1 cm
    • Pituitary stalk compression/disruption:
      • Craniopharyngioma
      • Rathke cleft cyst
      • Meningioma
      • Astrocytoma
      • Metastases
      • Head trauma
      • Infiltrative/inflammatory disorders
    • Diminished prolactin clearance:
      • Chronic renal failure
      • Cirrhosis
  • Cocaine
image DIAGNOSIS
PHYSICAL EXAM
  • Visual field testing
  • Cranial nerve exam
DIFFERENTIAL DIAGNOSIS
Macroprolactinemia: Macroprolactin, a polymer of several units of prolactin, is detected by immunologically based lab tests but is not biologically active. If patient is asymptomatic but found to have elevated prolactin (PRL), consider this diagnosis and notify the lab. No treatment is required.
DIAGNOSTIC TESTS & INTERPRETATION
  • Serum prolactin (most accurate results if checked fasting, in morning) <25 &mgr;g/L normal; >25 &mgr;g/L abnormal; >250 &mgr;g/L often indicates a prolactinoma (1)[A].
  • Pregnancy test
  • Thyroid-stimulating hormone (TSH)
  • Luteinizing hormone (LH)/follicle-stimulating hormone (FSH) if amenorrheic
  • Chemistry, renal function
  • LFTs
Initial Tests (lab, imaging)
A single measurement of serum prolactin; a level above the upper limit of normal confirms the diagnosis.
  • Pituitary MRI: single best imaging
  • CT scan if MRI is contraindicated
  • Levels should be drawn prior to breast exam.
Follow-Up Tests & Special Considerations
Formal visual field testing if pituitary adenoma is suspected
image TREATMENT
GENERAL MEASURES
  • Discontinue offending medications, if any (1)[A].
  • Treat underlying causes (1)[A].
  • For asymptomatic patients with mild PRL elevations, observation alone may be considered (1,2)[A]
  • Medications indicated for (1)[A]:
    • Symptoms of hypogonadism, such as decreased libido
    • Galactorrhea (if bothersome to patient)
    • Restoration of fertility
    • Pituitary adenoma
    • Prevention of osteoporosis
MEDICATION
Dopamine agonists: decrease serum prolactin concentrations and decrease the size of most lactotroph adenomas
  • Cabergoline (Dostinex): This is now a first-line choice due to efficacy and favorable side effect profile (1,3)[A]: dosed twice weekly. Cabergoline was more effective than bromocriptine in reducing persistent hyperprolactinemia, galactorrhea, and amenorrhea/oligomenorrhea (2)[A]. Has recently been reported to be associated with significant improvements in the body mass index, total HDL and LDL cholesterol levels, and insulin sensitivity; decrease in proinflammatory markers; and carotid intima media thickness, indicated with bromocriptine failure or resistance; has been shown to reduce erectile dysfunction in hyperprolactinemic men (1)[A]
    • Adverse effects (better tolerated if start with low dose, slow titration, given at night with food):
      • Nausea/vomiting
      • Headache
      • Dizziness
      • Fatigue
      • Light-headedness
      • Postural hypotension (2)[A]
  • Bromocriptine (Parlodel): This has the longest clinical history: dosed BID; preferred by some clinicians when infertility is an indication for treatment (2,4)[A].
  • Both are effective for reducing tumor size and improving symptoms (2)[A].
  • SE less with cabergoline than bromocriptine (2)[A]. Pergolide (Permax) is no longer used in the United States. If patient is still on med, do not withdraw abruptly.
P.515

ADDITIONAL THERAPIES
Patients with medically and surgically refractory prolactinomas; radiotherapy produced a reduction in prolactin levels in nearly all patients and normalization in over a quarter of patients with low complication rates (2)[A].
SURGERY/OTHER PROCEDURES
  • For adenomas, medical treatment will be successful in 80-90% of patients. In some cases, surgery is indicated (1).
  • Indications
    • Intolerance or resistance to medical treatment
    • Headache
    • Visual field loss
    • CSF leak due to tumor apoplexy or shrinkage
    • Cranial nerve deficit
  • Risks
    • High recurrence rate (up to 40%)
    • CSF leakage
    • Meningitis
    • Transient diabetes insipidus (5)
  • Pituitary insufficiency
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Depends on etiology
  • After at least 2 years of treatment, no tumor and prolactin levels normal may consider decreasing and stopping medication. Must be followed closely, as tumor may grow back (1).
  • Consider:
    • Formal visual field testing yearly (4)[A]
    • Serial MRIs if clinically indicated (4)[A]
Pregnancy Considerations
  • If pregnancy is desired in a woman with hyperprolactinemia, dopamine agonists are not approved during pregnancy and should be discontinued once pregnancy is confirmed, but their use is recommended if neurologic findings are present (1)[A].
  • With microprolactinoma: Treat with bromocriptine if symptomatic; monthly pregnancy tests; discontinue bromocriptine when pregnancy is confirmed.
  • With macroprolactinomas: a definitive, individualized plan is made. Options include discontinuation of bromocriptine at conception and careful monitoring of PRL levels and VS, with or without MRI scan evidence of tumor enlargement; prepregnancy transsphenoidal surgery with debulking of tumor; continuation of bromocriptine throughout gestation, with a risk to the fetus.
  • Careful monitoring of visual fields in each trimester. No need to monitor prolactin levels, as they are normally high due to pregnancy (1)[A].
PATIENT EDUCATION
  • Discuss risks of untreated hyperprolactinemia:
    • Headache
    • Visual field loss
    • Decreased bone density
    • Infertility
  • Patient guide to hyperprolactinemia diagnosis and treatment
PROGNOSIS
  • Tends to recur after discontinuation of medical therapy (1)
  • Over 10 years, 7% chance of progression of prolactin-secreting microadenoma (4)
REFERENCES
1. Hoffman AR, Melmed S, Schlechte J. Patient guide to hyperprolactinemia diagnosis and treatment. J Clin Endocrinol Metab. 2011;96(2):35A-36A.
2. Wang AT, Mullan RJ, Lane MA, et al. Treatment of hyperprolactinemia: a systematic review and metaanalysis. Syst Rev. 2012;1:33.
3. Wong A, Eloy JA, Couldwell WT, et al. Update on prolactinomas. Part 2: treatment and management strategies. J Clin Neurosci. 2015;22(10): 1568-1574.
4. Casanueva FF, Molitch ME, Schlechte JA, et al. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf). 2006;65(2):265-273.
5. Bloomgarden E, Molitch ME. Surgical treatment of prolactinomas: cons. Endocrine. 2014;47(3):730-733.
6. Sun GE, Pantalone KM, Gupta M, et al. Is chronic nipple piercing associated with hyperprolactinemia? Pituitary. 2013,16(3):351-353.
Additional Reading
&NA;
  • Inancli SS, Usluogullari A, Ustu Y, et al. Effect of cabergoline on insulin sensitivity, inflammation, and carotid intima media thickness in patients with prolactinoma. Endocrine. 2013;44(1):193-199.
  • Inder WJ, Castle D. Antipsychotic-induced hyperprolactinaemia. Aust N Z J Psychiatry. 2011;45(10):830-837.
  • Jackson J, Safranek S, Daugird A. Clinical inquiries. What is the recommended evaluation and treatment for elevated serum prolactin? J Fam Pract. 2006;54(10):897-899.
  • Klibanski A. Clinical practice. Prolactinomas. N Engl J Med. 2010;362(13):1219-1226.
  • 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. Pituitary gland: can prolactinomas be cured medically? Nat Rev Endocrinol. 2010;6(4): 186-188.
Codes
&NA;
ICD10
E22.1 Hyperprolactinemia
Clinical Pearls
&NA;
  • If a cause for hyperprolactinemia cannot be found by history, examination, and routine laboratory testing, an intracranial lesion might be the cause and brain MRI with specific pituitary cuts and intravenous contrast media should be performed.
  • Treatment of hyperprolactinemia should be targeted at correcting the cause (hypothyroidism, discontinuation of offending medications, etc.).
  • There is a difference among antipsychotics in influencing prolactin levels. In general, those with the highest potency D2 antagonism are most likely to elevate prolactin levels. Among the newer atypical antipsychotics, risperidone has been identified as more likely to elevate prolactin.
  • Chronic nipple piercing has not been shown to cause hyperprolactinemia (6).
  • High prolactin levels decrease testosterone by inhibiting gonadotropin-releasing hormone (GnRH), LH, and FSH secretion and by decreasing central dopamine activity, both of which are important in mediating sexual arousal.