INTRODUCTION — The clinical manifestations of hyperprolactinemia are relatively few and usually easy to recognize. Once the presence of prolactin excess is identified, further evaluation to establish the underlying cause is usually straightforward. The clinical manifestations and evaluation of hyperprolactinemia are reviewed here. The causes and treatment of hyperprolactinemia are discussed elsewhere. (See "Causes of hyperprolactinemia" and "Management of hyperprolactinemia".)
CLINICAL PRESENTATION — Hyperprolactinemia causes typical symptoms in premenopausal women and in men, but not in postmenopausal women.
Premenopausal women — Hyperprolactinemia in premenopausal women causes hypogonadism, with symptoms that include infertility, oligomenorrhea, or amenorrhea [1,2] and less often galactorrhea. In a retrospective study of 104 patients with hyperprolactinemia ages 30 to 44 years, the most commonly reported symptoms were infertility, headache, and oligomenorrhea in 48, 39, and 29 percent, respectively [3]. Galactorrhea was slightly less common (24 percent).
Menstrual cycle dysfunction — Excluding pregnancy, hyperprolactinemia accounts for approximately 10 to 20 percent of cases of amenorrhea. The mechanism appears to involve inhibition of luteinizing hormone (LH), and perhaps follicle-stimulating hormone (FSH) secretion, via inhibition of the release of gonadotropin-releasing hormone (GnRH). As a result, serum gonadotropin concentrations are normal or low, as in other causes of secondary hypogonadism.
The symptoms of hypogonadism due to hyperprolactinemia in premenopausal women correlate with the magnitude of the hyperprolactinemia. In most laboratories, a serum prolactin concentration above 15 to 20 ng/mL (15 to 20 mcg/L SI units) is considered abnormally high in women of reproductive age.
●A serum prolactin concentration greater than 100 ng/mL (100 mcg/L SI units) is typically associated with overt hypogonadism, subnormal estradiol secretion, and its consequences, including amenorrhea, hot flashes, and vaginal dryness.
●Moderate degrees of hyperprolactinemia, eg, serum prolactin values of 50 to 100 ng/mL (50 to 100 mcg/L SI units), cause either amenorrhea or oligomenorrhea.
●Mild degrees of hyperprolactinemia, eg, serum prolactin values of 20 to 50 ng/mL (20 to 50 mcg/L SI units), may cause only insufficient progesterone secretion and, therefore, a short luteal phase of the menstrual cycle [4,5]. Mild hyperprolactinemia can cause infertility even when there is no abnormality of the menstrual cycle; these women account for approximately 20 percent of those evaluated for infertility.
Bone density — Women with amenorrhea secondary to hyperprolactinemia have a lower spine and forearm bone mineral density compared with normal women or women with hyperprolactinemia and normal menses [6,7]. Restoration of menses following therapy results in an increase in bone density, although it may not return to normal [6,7]. Adolescents, when compared with adults with prolactinomas, have lower bone density at the time of diagnosis and less improvement after two years of dopamine agonist therapy [8].
Galactorrhea — Hyperprolactinemia in premenopausal women can also cause galactorrhea [9], but most premenopausal women who have hyperprolactinemia do not have galactorrhea (see 'Premenopausal women' above). Many women who have galactorrhea have normal serum prolactin concentrations [9]. (See 'Galactorrhea without hyperprolactinemia' below and "Nipple discharge".)
Postmenopausal women — Postmenopausal women, by definition, are already hypogonadal, and hyperprolactinemia does not change that situation. Because postmenopausal women are also markedly hypoestrogenemic, galactorrhea is rare. Hyperprolactinemia in these women is recognized only in the relatively unusual situation when a lactotroph adenoma becomes so large as to cause headaches or impair vision or is detected as an incidental finding when a magnetic resonance imaging (MRI) study is performed for an unrelated reason.
Men — Hyperprolactinemia in men also causes hypogonadotropic hypogonadism, which is manifested by decreased libido, impotence, infertility, gynecomastia, or, rarely, galactorrhea [10,11]. As in women, there is a rough correlation between the presence of any of these symptoms and the degree of hyperprolactinemia.
●Hypogonadotropic hypogonadism – Hyperprolactinemia causes decreased testosterone secretion and low serum testosterone concentrations that are not associated with an increase in LH secretion [10]. As in women, the effect of prolactin must be on the pituitary or hypothalamus. The consequences of the hypogonadism are similar to those of hypogonadism due to other causes and include, in the short term, decreased energy and libido, and in the long term, decreased muscle mass, decreased body hair, and osteoporosis. In one study of 20 men, for example, 16 had osteopenia in the spine and six in the hip [12]. (See "Causes of secondary hypogonadism in males", section on 'Hyperprolactinemia'.)
●Erectile dysfunction – Hyperprolactinemia appears to cause erectile dysfunction by a mechanism unrelated to hypogonadism because correcting the hyperprolactinemia with a dopamine agonist drug corrects the impotence. One report suggests that correcting the hypogonadism by the administration of testosterone does not correct the impotence, which corresponds to the author's clinical observations [10]. (See "Epidemiology and etiologies of male sexual dysfunction", section on 'Epidemiology'.)
●Infertility – Although hyperprolactinemia can cause infertility in men, probably by decreasing LH and perhaps FSH secretion, it is not a common finding among men who present for evaluation of infertility. In a study of 171 infertile men, as an example, only seven (4 percent) had hyperprolactinemia [11]. (See "Causes of male infertility", section on 'Endocrine and systemic disorders (hypogonadotropic hypogonadism)'.)
●Galactorrhea – Men with hyperprolactinemia may develop galactorrhea. This occurs less often than in women, presumably because the glandular breast tissue in men has not been made sensitive to prolactin by preceding stimulation by estradiol and progesterone.
DIAGNOSIS — The diagnosis of hyperprolactinemia is made by a serum prolactin concentration that is well above the normal range (>20 ng/mL [20 mcg/L]) in men and postmenopausal women and >30 ng/mL in premenopausal women. Because meals may stimulate prolactin secretion slightly, if an initial serum prolactin concentration is only slightly elevated (21 to 40 ng/mL [21 to 40 mcg/L SI units]), the test should be repeated on a fasting sample before the patient is considered to have hyperprolactinemia. (See 'Evaluation of hyperprolactinemia' below.)
Hyperprolactinemia is a potential cause of oligomenorrhea, amenorrhea, galactorrhea, and infertility in women and hypogonadism and/or erectile dysfunction in men. Therefore, serum prolactin should be measured in a patient who presents with any of these symptoms [13].
Serum prolactin concentrations — The usual normal range for serum prolactin is approximately 5 to 20 ng/mL (5 to 20 mcg/L). The measurement can be performed at any time since usual daily activities have little effect on prolactin secretion. However, serum prolactin concentrations may increase slightly during sleep, strenuous exercise, and occasionally with emotional or physical stress, intense breast stimulation, and high-protein meals. Therefore, if an initial prolactin level is only borderline high, the test should be repeated (see 'Evaluation of hyperprolactinemia' below). Normal values are higher in women than men, and dynamic testing is not needed.
Pitfalls in diagnosis
Hook effect — Caution should be exercised in interpreting serum prolactin concentrations between 20 and 200 ng/mL (20 to 200 mcg/L SI units) in the presence of a macroadenoma because of possible artifactually low values due to the "hook effect" [14-16]. This effect occurs when a very high serum prolactin, eg, 5000 ng/mL (5000 mcg/L SI units), saturates both the capture and signal antibodies used in immunoradiometric and chemiluminescent assays, preventing the binding of the two in a "sandwich." The result is an apparent prolactin concentration that is only modestly elevated, suggesting that the macroadenoma is clinically nonfunctioning. The artifact can be avoided by repeating the assay using a 1:100 dilution of serum [13].
Macroprolactin — Macroprolactin causes hyperprolactinemia through decreased prolactin clearance. Macroprolactin is native prolactin that is bound to immunoglobulin G (IgG) and is usually 150 to 170 kDa in size, compared with 23 kDa for monomeric prolactin [17]. This entity is not of clinical significance directly, but patients can be misdiagnosed and treated as ordinary hyperprolactinemia. Misdiagnosis can be avoided by asking the laboratory to pretreat the serum with polyethylene glycol to precipitate the macroprolactin before the immunoassay for prolactin in the supernatant. This entity is discussed in greater detail separately. (See "Causes of hyperprolactinemia", section on 'Macroprolactinemia'.)
EVALUATION OF HYPERPROLACTINEMIA — Because meals may stimulate prolactin secretion slightly, if an initial serum prolactin concentration is only slightly elevated (21 to 40 ng/mL [21 to 40 mcg/L SI units]), the test should be repeated on a fasting sample before the patient is considered to have hyperprolactinemia. If serum prolactin is elevated on the second sample, hyperprolactinemia is confirmed, and the next step is to determine the cause. Most patients with hyperprolactinemia have a lactotroph adenoma. Therefore, the evaluation is aimed at (1) exclusion of pharmacologic or extrapituitary causes of hyperprolactinemia and (2) neuroradiologic evaluation of the hypothalamic-pituitary region [18]. (Related Lab Interpretation Monograph(s): "High prolactin in adults".) (See "Causes of hyperprolactinemia".)
History — A search for the cause of the hyperprolactinemia should begin with the history. One should inquire about pregnancy (physiologic hyperprolactinemia) and medications that can cause hyperprolactinemia (such as estrogens, neuroleptic drugs such as risperidone, metoclopramide, antidepressant drugs, cimetidine, methyldopa, and verapamil). One should also inquire about headache, visual symptoms, symptoms of hypothyroidism, and a history of renal disease.
Physical examination — The physical examination should be directed toward testing for a chiasmal syndrome (eg, bitemporal field loss) and looking for chest wall injury and signs of hypothyroidism or hypogonadism.
Laboratory/imaging tests — Studies should be performed to test for hypopituitarism, primary hypothyroidism, and renal insufficiency.
Magnetic resonance imaging (MRI) of the pituitary with and without contrast should be performed in a patient with any degree of hyperprolactinemia to look for a mass lesion in the hypothalamic-pituitary region, unless the patient is taking a medication known to cause hyperprolactinemia or has marked renal impairment. (See 'Chronic kidney disease' below.)
If a mass lesion is found in the region of the sella turcica, secretion of other pituitary hormones should also be evaluated. Only a pituitary adenoma can cause hypersecretion of other pituitary hormones, but any mass lesion in the area of the sella can cause hyposecretion of one or more pituitary hormones. To evaluate for hypersecretion, we suggest measurements of:
●Serum prolactin (lactotroph adenomas)
●Insulin-like growth factor-1 (IGF-1) (somatotroph adenomas)
●Plasma corticotropin (ACTH) (corticotroph adenomas)
Additional endocrine testing is needed when a gonadotroph or thyrotroph adenoma is suspected (luteinizing hormone [LH], follicle-stimulating hormone [FSH], total or free thyroxine [T4], and thyroid-stimulating hormone [TSH], respectively).
Although not generally useful in the differential diagnosis of a sellar mass, the possibility of hormonal hyposecretion should be evaluated in all patients who have a sellar mass in order to identify and replace hormone deficiencies. (See "Causes, presentation, and evaluation of sellar masses", section on 'Hormonal evaluation' and "Diagnostic testing for hypopituitarism".)
If the MRI shows a normal hypothalamic-pituitary region and there are no obvious causes of hyperprolactinemia, the diagnosis is idiopathic hyperprolactinemia. This syndrome may, in some patients, be due to microadenomas that are too small to be seen on imaging. (See "Causes of hyperprolactinemia".)
MRI in drug-induced hyperprolactinemia — The degree of elevation that can be attributed to a drug depends upon the drug. Most drugs do not cause an elevation to over 100 ng/mL, but the antipsychotic drug risperidone can cause an elevation up to 300 or even 400 ng/mL [19]. Therefore, we recommend ordering magnetic resonance imaging (MRI) if the serum prolactin concentration is greater than 100 ng/mL in patients taking a drug known to elevate the prolactin concentration but greater than 300 ng/mL in those taking risperidone. There are no stimulatory or suppressive endocrine tests that distinguish between the causes of hyperprolactinemia. Similarly, the prolactin measurement need not be repeated in these patients. (See "Causes of hyperprolactinemia".)
Chronic kidney disease — Hyperprolactinemia in chronic kidney disease (CKD) is due to decreased clearance of prolactin. Serum prolactin concentrations are typically elevated to as much as 10-fold normal in patients with end-stage kidney disease requiring dialysis [20]. Prolactin levels of this magnitude in the setting of end-stage kidney disease (eg, CKD 4 or 5) and in the absence of other pituitary hormone abnormalities or symptoms suggestive of pituitary tumor (eg, visual loss) typically need no further pituitary evaluation. It is unclear at which threshold of kidney dysfunction prolactin begins to rise. Therefore, in the setting of lesser degrees of renal impairment, the need for pituitary imaging is uncertain. Very mild degrees of renal impairment probably do not elevate prolactin. The decision to obtain an MRI of the pituitary is based on the magnitude of the prolactin elevation, the degree of renal impairment, and on other findings, such as visual impairment and other pituitary hormone abnormalities. MRI for a patient with any degree of renal impairment should be ordered without gadolinium.
Ectopic prolactin secretion — Secretion of prolactin from an ectopic source is uncommon but has been reported from several types of tumors [21]. An ectopic source should be suspected in a patient who has hyperprolactinemia that is not associated with a large sellar mass and is completely resistant to cabergoline.
GALACTORRHEA WITHOUT HYPERPROLACTINEMIA
Incidence — The serum prolactin concentration is often normal in women who present with galactorrhea. In the largest series of patients presenting with galactorrhea, prolactin was normal in 46 percent [9]. The likelihood that the prolactin is normal is even higher if menses are normal. No cause of this phenomenon has been documented, but often it represents persistent milk secretion following resolution of a previously elevated prolactin, most commonly after nursing or drug-induced hyperprolactinemia. Galactorrhea in the absence of hyperprolactinemia is not the result of any ongoing disease. (See "Nipple discharge".)
Diagnosis — The first step in diagnosis is to be sure the breast secretion is clear or milky. Green or black fluid also usually represents milk, which can be confirmed by staining the fluid for fat. Blood in the fluid is a reason for referral for evaluation of a breast tumor. If the fluid is milk, the next step is to measure the serum prolactin concentration. If the prolactin is elevated, the cause should be sought, as described above. If the prolactin is not elevated, there is no ongoing disease and no further tests are needed. Other causes of nipple discharge are discussed elsewhere. (See "Nipple discharge".)
Treatment — Galactorrhea in the absence of hyperprolactinemia usually does not need to be treated, because it is not associated with ongoing disease and it is usually not bothersome. For the unusual patient whose galactorrhea occurs spontaneously and to a degree that causes staining of the clothes, treatment with a low dose of dopamine agonist, such as 0.25 mg of cabergoline twice a week, will reduce the prolactin concentration to below normal and reduce or eliminate the galactorrhea. (See "Management of hyperprolactinemia", section on 'Initial therapy (dopamine agonists)'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperprolactinemia/prolactinoma".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Prolactinoma (The Basics)")
●Beyond the Basics topics (see "Patient education: High prolactin levels and prolactinomas (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Clinical manifestations
•Premenopausal women – The clinical manifestations of hyperprolactinemia in premenopausal women are mainly those of hypogonadism. In women, these include menstrual cycle dysfunction (oligomenorrhea or amenorrhea) and infertility (luteal phase abnormalities or anovulation). Less often, galactorrhea occurs. Hyperprolactinemia accounts for approximately 10 to 20 percent of cases of amenorrhea. (See 'Premenopausal women' above.)
The symptoms of hypogonadism due to hyperprolactinemia in premenopausal women correlate with the magnitude of the hyperprolactinemia. (See 'Menstrual cycle dysfunction' above.)
Most premenopausal women with hyperprolactinemia do not have galactorrhea; among women who present with galactorrhea as an isolated finding, nearly 50 percent have normal serum prolactin concentrations. (See 'Galactorrhea without hyperprolactinemia' above.)
•Postmenopausal women - Postmenopausal women are already hypogonadal, so hyperprolactinemia in them is recognized only when a lactotroph adenoma becomes large enough to cause headaches or impair vision or is detected as an incidental sellar mass by magnetic resonance imaging (MRI). In the setting of estrogen deficiency, hyperprolactinemia rarely causes galactorrhea. (See 'Postmenopausal women' above.)
•Men – Hyperprolactinemia also causes hypogonadotropic hypogonadism in men, resulting in decreased libido and infertility. Other manifestations of hyperprolactinemia are erectile dysfunction, gynecomastia, and, rarely, galactorrhea. As in women, there is a rough correlation between the presence of any of these symptoms and the degree of hyperprolactinemia. (See 'Men' above.)
●Evaluation
•Prolactin – Women with oligomenorrhea, amenorrhea, or galactorrhea and men with symptoms of hypogonadism, impotence, or gynecomastia should have a serum prolactin determination. The usual normal range for serum prolactin is up to 20 ng/mL (20 mcg/L) in men and postmenopausal women and up to 30 ng/mL (30 mcg/L) in premenopausal women.
If the prolactin concentration is only slightly high (21 to 40 ng/mL [21 to 40 mcg/L SI units]), it should be repeated before the patient is considered to have hyperprolactinemia. If the repeat value is still elevated, the next step is to determine the cause. (See "Causes of hyperprolactinemia".)
Serum prolactin values above 200 ng/mL usually indicate the presence of a lactotroph adenoma (figure 1). (See 'Serum prolactin concentrations' above.)
•Pituitary MRI – MRI of the pituitary should be performed in patients with any degree of hyperprolactinemia to look for a mass lesion in the hypothalamic-pituitary region, unless the patient is taking a medication known to cause hyperprolactinemia. (See 'Laboratory/imaging tests' above.)
We recommend ordering an MRI if the serum prolactin concentration is greater than 100 ng/mL in patients taking a drug known to elevate the prolactin concentration but greater than 300 ng/mL in those taking risperidone. (See 'MRI in drug-induced hyperprolactinemia' above.)
If a mass lesion is found in the region of the sella turcica, secretion of other pituitary hormones should also be evaluated. Only a pituitary adenoma can cause hypersecretion of other pituitary hormones, but any mass lesion >1 cm in diameter in the area of the sella can cause hyposecretion of one or more pituitary hormones. (See "Causes, presentation, and evaluation of sellar masses", section on 'Hormonal evaluation' and "Clinical manifestations of hypopituitarism".)
