Approach
Hyperprolactinemia can manifest clinically in many different ways, varying significantly depending on the patient's characteristics, as well as the cause and magnitude of prolactin (PRL) excess. It is normally unmasked during the evaluation of presenting complaints, such as amenorrhea, galactorrhea, erectile dysfunction, or headaches.
Once the diagnosis of hyperprolactinemia has been confirmed through detection of serum PRL levels above the normal reference range (for the particular laboratory), its underlying cause is evaluated in a stepwise manner. A single measurement of PRL is generally adequate in patients with a consistent clinical picture, a sellar mass and substantial PRL increase.[47][48] However, repeat testing to exclude stress or unusual pulsatility as a cause is recommended in patients with mild raised prolactin (less than five times the upper limit of normal).[49][48] Dynamic tests for PRL secretion are not needed.[48] In patients with symptomatic nonphysiological hyperprolactinemia, recommended first steps are excluding medication use, renal failure, hypothyroidism, and parasellar tumors as possible causes.[3][48]
On detection of hyperprolactinemia:
A detailed history should be obtained and a thorough physical exam performed (to aid diagnosis of the underlying cause).
History and exam should try to exclude physiologic causes.
Medications known to cause hyperprolactinemia should be replaced or withdrawn if possible (may require consultation with a specialist physician, such as a psychiatrist or cardiologist, depending on the offending drug). In particular, antipsychotic medication that is associated with high risk of hyperprolactinemia (e.g., risperidone, chlorpromazine) should be changed to prolactin-sparing drugs (e.g., aripiprazole, quetiapine).[50]
Laboratory tests to help identify the underlying cause:
Liver and renal function tests
Thyroid function tests
Pregnancy test
Macroprolactin levels (measured in asymptomatic or atypical presentations).[48]
Imaging studies:
Magnetic resonance imaging (MRI) scan of the pituitary gland is performed once physiologic, drug-induced, and secondary hyperprolactinemias have been excluded.
If a macroadenoma is present, the patient should be investigated for hypopituitarism.
If no lesion is detected on MRI, idiopathic hyperprolactinemia is diagnosed.
When there is a discrepancy between a large pituitary tumor on imaging and mildly elevated PRL, serial dilution of serum samples can be used to eliminate an artifact that can occur with some immunoradiometric assays, which can lead to a falsely low PRL reading.[48]
Clinical history and exam
During the evaluation of a patient with hyperprolactinemia, a detailed past medical, drug, and family history should be obtained, and a thorough physical exam performed, focusing on signs and symptoms indicative of PRL excess.
The predominant clinical consequence of hyperprolactinemia, in both men and women, is hypogonadotropic hypogonadism, which is due to an interruption in the pulsatile secretion of gonadotropin-releasing hormone by the elevated PRL. This leads to decreased levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and a concomitant reduction in estrogen and testosterone concentrations that manifest with characteristic clinical features.
Hyperprolactinemia presents with a variety of signs and symptoms depending on its severity and underlying cause:
In both men and women, prolactinomas, particularly macroprolactinomas (>10 mm in diameter), produce signs and symptoms of a "mass effect." These include headaches, visual loss or visual field defects, cranial nerve neuropathies, and seizures. Hypopituitarism may also occur as a result of compression of the hypothalamic-pituitary stalk or other pituitary cells.[1][2][3] Hypopituitarism may involve any or all of the endocrine axes regulated by the pituitary. In order of frequency, it leads to growth hormone (GH) deficiency, secondary hypogonadism, secondary hypothyroidism, and secondary adrenal failure. It may also cause diabetes insipidus.[51]
In women, moderate PRL excess (i.e., 51-75 micrograms/L) is usually associated with oligomenorrhea, whereas mild PRL elevation (i.e., 31-50 micrograms/L) results in a short luteal phase and decreased fertility and libido.[2]
Hyperprolactinemia also presents with different signs and symptoms depending on the age and sex of the patient:
Premenopausal women usually have PRL levels >100 micrograms/L and present with galactorrhea, oligo/amenorrhea, infertility, menstrual disturbances, decreased libido, sexual dysfunction, hirsutism, vaginal dryness with dyspareunia, habitual abortions, and the possibility of pregnancy.
Postmenopausal women usually present with signs and symptoms of a mass effect, and galactorrhea occurs only in the presence of estrogen replacement therapy.[1]
Other clinical manifestations in postmenopausal women include osteopenia and osteoporosis (loss of height and back pain, but without an increased risk of pathologic fractures) secondary to hypoestrogenemia resulting from elevated PRL levels, as well as hirsutism and acne, which may be due to increased secretion of dehydroepiandrosterone sulfate (DHEAS) from the adrenal glands, also known as hyperandrogenemia.[1][2][3][52][53]
Men present with infertility (due to reduced sperm production), impotency (due to erectile dysfunction), decreased libido, galactorrhea, gynecomastia, reduced bone density, and signs and symptoms of a mass effect.[1][2][3]
Children present with delayed puberty and signs and symptoms of a mass effect in both sexes, and primary amenorrhea and galactorrhea in girls.[54]
The patient should also be evaluated for signs and symptoms related to possible underlying causes of hyperprolactinemia such as hypothyroidism (fatigue; sensitivity to cold; constipation; menstrual abnormalities; muscle cramps; weight gain; thyroid goiter; cool, rough, and dry skin; puffy face and hands; husky voice; slow reflexes; thin and brittle nails; carotenemic skin color) and other systemic diseases, including chronic renal failure (signs of uremia: hypertension, yellow skin, uremic fetor, decreased mental status) and cirrhosis (hepatosplenomegaly, weight loss, ascites, jaundice, peripheral edema, encephalopathy, pyrexia, dilatation of superficial veins). Hyperprolactinemia has also been associated with preclinical atherosclerosis (assessed by carotid intima media thickness), metabolic abnormalities (such as increased insulin resistance), and systemic inflammation (assessed by increased levels of high-sensitivity C-reactive protein).[55][56][57]
A comprehensive medical history is required to reveal the presence of drugs known to raise PRL levels. Such drugs should be replaced or withdrawn if possible (may require consultation with a specialist physician, such as a psychiatrist or cardiologist, depending on the offending drug).
Physiologic causes of hyperprolactinemia, such as pregnancy, lactation, hypoglycemia, myocardial infarction, surgery, psychological stress, exercise, food ingestion, sexual intercourse, and sleep, should also be excluded.
The physical exam should include evaluation of the chest wall, abdomen, and breast searching for signs of cirrhosis, as well as trauma (e.g., burns, bruising), and surgical scars. Palpation of the thyroid gland (to identify a goiter), ophthalmologic assessment (with particular attention to the visual fields), and assessment for the presence of hypogonadism (e.g., testicular size and texture, pattern of body hair growth) should also be carried out.
Investigations
The initial diagnostic focus should be on identification of a plausible nontumor etiology, as this will avoid the associated risks and expense of unnecessary computed tomography (CT) and MRI scans.
Blood tests
When PRL values are not diagnostic, levels should be re-evaluated on another day, at least 1 hour after the patient has awakened or eaten. To avoid pulsatile secretion, 2 to 3 samples separated by at least 15 to 20 minutes, are required (although some trials have shown no significant difference between such values).[1][19] Stress is a confounding parameter that can cause pseudohyperprolactinemia. In these cases, PRL measurement drawn from an indwelling antecubital intravascular catheter, either as a repeated sample or after 120-minute bed rest, can quite reliably solve these problems. A resting sample may be considered if random PRL values are below 94 micrograms/L (2000 milliunits/L).[58] Drugs known to elevate PRL levels should be replaced or withdrawn if possible, with appropriate advice from a specialist physician, such as a psychiatrist or cardiologist, before a second sample is taken.[29] The duration of withdrawal depends on the half-life of the drug but is usually between 48 and 72 hours. There is no need to suspend oral contraceptives or estrogen-progesterone hormone therapy.[19]
Renal, liver, and thyroid function should be tested with measurement of electrolytes, blood urea nitrogen, and urinalysis; liver function tests and albumin; and thyroid function tests (thyroid-stimulating hormone [TSH], free thyroxine [T4]) and prothrombin time, respectively.
A pregnancy test to rule out pregnancy-related hyperprolactinemia should also be performed.[1][2][3][19]
In asymptomatic or atypical presentations, or when menstrual disorders can be attributed to other causes, such as polycystic ovary syndrome, macroprolactinemia should be measured via polyethylene glycol (PEG) precipitation and excluded. Harmonization of PEG precipitation process and reporting by laboratories may improve diagnostic accuracy. Gel filtration chromatography is another method, but it is time consuming, expensive, and not used routinely in clinical laboratories. Assessment of PRL concentrations after separation of PRL macroforms and the use of a more appropriate reference range for PRL can help to differentiate true hyperprolactinemia and pseudohyperprolactinemia.[1][2][3][6][19][39][59]
PRL stimulation tests including thyrotropin-releasing hormone and antidopamine (metoclopramide, domperidone) tests have been proposed, but their sensitivity and diagnostic value in determining the need for subsequent imaging techniques are low.[19]
Imaging studies
After exclusion of physiologic, pharmacologic, and other secondary causes of hyperprolactinemia, MRI of the head with selective pituitary cuts is required to evaluate patients for a mass lesion. MRI is preferred to CT, as CT may miss small lesions while exposing the patient to large doses of radiation.[1][2][3]
A CT scan is indicated in cases of calcified sellar or suprasellar tumors such as craniopharyngiomas, or when bony structures are involved.
In the absence of symptoms, the clinical utility of finding a pituitary adenoma with MRI is questionable, as up to 10% of imaging studies on asymptomatic patients yield abnormal pituitary findings suggestive of adenoma known as an incidentaloma.[60]
Some investigators suggest evaluation with MRI only if PRL levels are >100 micrograms/L, whereas others recommend it for all patients with persistently elevated PRL levels in the absence of an identifiable secondary cause for the hyperprolactinemia.[3][61][62]
The optimal PRL cutoff value that distinguishes between prolactinoma and nonfunctioning pituitary adenoma (NFPA) has not been established. However, 98.7% of patients with NFPA with suprasellar extension have PRL levels below 94 micrograms/L (2000 milliunits/L), suggesting that serum PRL levels of up to 100 micrograms/L may be a useful cutoff (based upon 25 micrograms/L PRL as the upper limit of normal for women).[1][63] Similarly, a retrospective review found that only 4.2% of patients with NFPA had PRL levels >90 micrograms/L.[64]
If a macroadenoma is detected, the patient should be further screened for hypopituitarism through evaluation of the levels of the other pituitary and end-organ hormones (adrenocorticotropic hormone, LH, FSH, GH, TSH, free T4, glucose tolerance test, cortisol, testosterone, estradiol, DHEAS, insulin-like growth factor 1).[1][2][3] Some clinicians perform initial basal determinations of these hormones to rule out associated hypersecretion and to establish baseline reference values for comparison following future interventions.[65]
If a macroadenoma is detected in the presence of mild hyperprolactinemia, the most likely diagnosis is a non-PRL-producing pituitary adenoma or other sellar mass causing the "stalk effect".[2]
Some cases of giant prolactinomas (large macroadenomas >2 cm) present with factitiously normal or even low PRL levels, a phenomenon known as the "hook effect". This effect is due to saturation of anti-PRL antibodies in an assay (normally immunoradiometric) tube causing artificially low results. Further measurement of PRL following a 1/100 dilution results in diagnosing this situation.[1][19]
If physiologic, drug-induced, and secondary hyperprolactinemias have been excluded, and no lesion is detected on MRI, the diagnosis of idiopathic hyperprolactinemia is made.
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