Prolactinomas are noncancerous tumors made up from lactotrophs in the pituitary gland. The most common symptom of a prolactinoma is galactorrhea. Diagnosis is by measurement of prolactin levels and imaging tests. Treatment involves tumor inhibition with dopamine agonist drugs and sometimes removal or destruction of the adenoma.
Galactorrhea involves secretion of breast milk. A discussion of nipple discharge in general is provided elsewhere.
Etiology of Prolactinoma
Prolactinomas are noncancerous tumors composed of lactotrophs, which are prolactin-secreting adenomas. Prolactin is produced in cells called lactotrophs that constitute about 30% of the cells of the anterior pituitary. In humans, the major function of prolactin is stimulating milk production. Prolactin is the hormone most frequently produced in excess by pituitary tumors. In contrast to other anterior pituitary hormones, prolactin is regulated primarily by suppression by dopamine, and not by negative feedback from peripheral hormones.
Galactorrhea is generally due to a prolactin-secreting pituitary adenoma (prolactinoma) but may result from any cause of hyperprolactinemia (see table Causes of Hyperprolactinemia). Most tumors in women are microadenomas (< 10 mm in diameter), but a small percentage are macroadenomas (> 10 mm) when diagnosed. The frequency of microadenomas is much lower in men, perhaps because of later recognition; however, for reasons that are unclear, prolactin secreting adenomas have more aggressive growth and cause more severe symptoms of mass effect (eg headaches or visual complaints) and fewer symptoms related to hormone deficiency in men. Nonfunctioning pituitary mass lesions also can increase prolactin levels by compressing the pituitary stalk and thus interrupting the action of dopamine, which normally suppresses prolactin secretion.
Hyperprolactinemia and galactorrhea also may be caused by ingestion of certain medications, including phenothiazines and some other antipsychotics, certain antihypertensives (especially alpha-methyldopa and verapamil), and opioids. Primary hypothyroidism can cause hyperprolactinemia and galactorrhea because increased levels of thyroid-releasing hormone increase secretion of prolactin as well as thyroid-stimulating hormone (TSH). Prolactin levels may rise in circulation as a consequence of renal insufficiency due to impaired renal clearance of prolactin. Nipple stimulation and pregnancy are physiologic causes of increased prolactin secretion. Hyperprolactinemia may be associated with hypogonadotropism and hypogonadism probably through inhibition of gonadotrophin-releasing hormone (GnRH) release or action on the pituitary gonadotropes (see table Causes of Hyperprolactinemia).
Причини гіперпролактинемії
Cause | Example |
|---|---|
Physiologic | Early infancy (up to 3 months) Food ingestion Nipple stimulation in women Pregnancy Postpartum period Sexual intercourse in some women Sleep Stress |
Hypothalamic disorders | Head trauma Hypothalamic tumors Idiopathic galactorrhea (presumed abnormality in dopamine secretion) Nontumerous hypothalamic infiltration: Sarcoidosis, tuberculosis, Langerhans cell histiocytosis Postencephalitis |
Pituitary disorders | Prolactin-secreting pituitary tumors Surgical pituitary stalk section and other stalk lesions Tumors causing pituitary stalk compression |
Other endocrine disorders | Primary hypothyroidism |
Disorders of other systems | Ectopic production of prolactin: Bronchogenic carcinoma (not squamous cell; mostly small cell undifferentiated) Hypernephroma Liver disease |
Chest wall lesions | Surgical scars Trauma Tumors |
Pharmacologic | Antihypertensive medications: Alpha-methyldopa, atenolol, clonidine, labetalol, reserpine, verapamil H2-antagonists Oral contraceptives and estrogens Opioids Psychoactive medications, eg, benzamides (metoclopramide, sulpiride), butyrphenones (haloperidol), phenothiazines, tricyclic and some other antidepressants Thyrotropin-releasing hormone |
Data from Rebar RW: Practical evaluation of hormonal status. In Reproductive Endocrinology: Physiology, Pathophysiology and Clinical Management, edited by SSC Yen and RB Jaffe. Philadelphia, WB Saunders Company, 1978, p. 493. | |
Symptoms and Signs of Prolactinoma
Abnormal lactation is not defined quantitatively; it is milk release that is inappropriate, persistent, or worrisome to the patient. Spontaneous lactation is more unusual than milk released in response to manual expression. The milk is white, and fat globules can be seen when a sample is examined with a microscope. Women with galactorrhea commonly also have amenorrhea or oligomenorrhea. Women with galactorrhea and amenorrhea may also have symptoms and signs of estrogen deficiency, including dyspareunia and reduced libido, due to inhibition of pulsatile luteinizing hormone and follicle-stimulating hormone release by high prolactin levels. However, estrogen production may be normal, and signs of androgen excess, including hirsutism, have been observed in some women with hyperprolactinemia. Hyperprolactinemia may occur with other menstrual cycle disturbances besides amenorrhea, including infrequent ovulation and corpus luteum dysfunction.
Men with prolactin-secreting pituitary tumors typically have headaches or visual difficulties. About two thirds of affected men have loss of libido and erectile dysfunction.
Diagnosis of Prolactinoma
Prolactin levels
Thyroxine (T4) and thyroid-stimulating hormone (TSH) levels
CT or MRI
Diagnosis of galactorrhea due to a prolactin-secreting pituitary adenoma is based on elevated prolactin levels (typically > 5 times normal, sometimes much higher.) Decrease in lesion size in response to drug treatment may confirm the diagnosis when prolactin levels are elevated to an equivocal range. In general, prolactin levels correlate with the size of a pituitary tumor and can be used to follow patients over time. With a nonfunctioning pituitary mass, prolactin levels are not usually elevated > 3 to 4 times normal. A trial of dopamine agonist therapy can help distinguish between prolactin-secreting and nonfunctioning lesions; in both types of lesion, prolactin levels decrease after treatment, but prolactin-secreting lesions decrease in size, whereas nonfunctioning lesions do not.
Serum gonadotropin and estradiol levels are either low or in the normal range in women with hyperprolactinemia, and testosterone levels may be low in men. Primary hypothyroidism is easily ruled out by absence of elevated TSH. In the setting of a known pituitary tumor, TSH and free thyroxine levels should be measured to evaluate for possible central hypothyroidism.
MRI with contrast is the method of choice in identifying microadenomas. High-resolution CT may be used when MRI is contraindicated or unavailable. Visual field examination is indicated in all patients with macroadenomas and in any patient who elects surveillance only.
Treatment of Prolactinoma
Depends on sex, cause, symptoms, and other factors
When indicated, initial treatment is usually with a dopamine agonist
Мікроаденоми
Microprolactinomas can be treated in multiple ways. Asymptomatic patients who have prolactin levels < 100 mcg/L (4,348 pmol/L) and normal CT or MRI results or who have only microadenomas can probably be observed; serum prolactin often normalizes within years. Patients with hyperprolactinemia should be monitored with quarterly measurement of prolactin levels and undergo sellar MRI or CT annually for at least an additional 2 years. The frequency of sellar imaging can then be reduced if prolactin levels do not increase.
In women, indications for treatment include
Desire for pregnancy
Amenorrhea or significant oligomenorrhea (because of the risk of osteoporosis)
Hirsutism
Low libido
Troublesome galactorrhea
In men, galactorrhea itself is rarely troublesome enough to require treatment; indications for treatment include
Hypogonadism (because of the risk of osteoporosis)
Erectile dysfunction
Low libido
Troublesome infertility
The initial treatment for both sexes is usually a dopamine agonist such as bromocriptine 1.25 to 5 mg orally twice a day or the longer-acting cabergoline 0.25 to 1.0 mg orally once or twice a week, which lower prolactin levels. Cabergoline is the treatment of choice because it is more easily tolerated (has a lower frequency of adverse effects) and more potent than bromocriptine. Women trying to become pregnant should stop cabergoline or bromocriptine use at the time of a positive pregnancy test result.
Quinagolide, a nonergot-derived dopamine agonist, is also an option for hyperprolactinemia. It is started at 25 mcg orally once a day and titrated over 7 days up to the usual maintenance dose of 75 mcg once a day (can increase weekly in 75- to 150-mcg increments to maximum dose 600 mcg once a day). Quinagolide should not be used by women contemplating pregnancy.
Patients with concomitant hypogonadism who elect to not use dopamine agonist therapy can be treated with estrogen (with or without a progestin, as indicated) or testosterone. Women with a microadenoma who are clinically hypoestrogenic or have low estradiol levels, can be given exogenous estrogen. Exogenous estrogen is unlikely to cause tumor expansion.
Макроаденоми
Patients with macroadenomas generally should be treated initially with dopamine agonists even in cases of large tumors invading and compressing the optic chiasm. Dopamine agonists usually shrink a prolactin-secreting tumor. Dopamine agonists will not shrink a nonfunctioning tumor that is causing pituitary stalk compression, although prolactin levels will decrease. If prolactin levels fall and symptoms and signs of compression by the tumor abate, no other therapy may be necessary. However, typically, larger, nonfunctioning lesions need additional treatment, usually surgery. Although dopamine agonist treatment usually needs to be continued long-term, prolactin-secreting tumors sometimes remit, either spontaneously or perhaps aided by the drug therapy. Sometimes, therefore, dopamine agonists can be stopped without a recurrence of the tumor or a rise in prolactin levels; remission is more likely with microadenomas than macroadenomas. Remission is also more likely after pregnancy.
High doses of dopamine agonists, particularly cabergoline and pergolide, are thought to have caused valvular heart disease in some patients with Parkinson disease. Studies evaluating the lower doses of dopamine agonists used for hyperprolactinemia have not demonstrated an increased risk of valvular heart disease, but the possibility should be discussed with patients, and echocardiographic surveillance should be considered, especially when doses > 3 mg per week are used. The risk may be less with bromocriptine or quinagolide. Dopamine agonists in the doses used for hyperprolactinemia also sometimes cause behavioral and psychiatric changes, characterized by increased impulsivity and occasionally psychosis, and this limits their use in some patients.
Surgery is second-line therapy in patients whose tumor is resistant to dopamine agonists or in patients who are intolerant of medical therapy.
Radiation therapy should be used only in patients with progressive disease who do not respond to other forms of therapy. With irradiation, hypopituitarism often develops several years after therapy. Monitoring endocrine function and sellar imaging are indicated yearly for life.
Лікування вагітних пацієнток
Women should stop dopamine agonists (cabergoline or bromocriptine) at the time of a positive pregnancy test result because reduction in prolactin levels is no longer required, and there is little risk of clinically significant pituitary tumor growth. Stopping medication allows prolactin levels to naturally rise during pregnancy. However, if the tumor is invasive or abutting the optic chiasm, it may be prudent to continue dopamine agonist therapy throughout pregnancy. During pregnancy, about 30% of macroadenomas enlarge; and normal pituitary tissue expands. If patients have clinical evidence of tumor expansion (headaches and/or visual field loss) and enlargement is confirmed by MRI, then dopamine agonist therapy probably should be re-started. The Endocrine Society guidelines (1) recommend using bromocriptine, but many experts use cabergoline, particularly if it was used before the pregnancy; there is no evidence of adverse outcomes to either fetus or mother.
Довідкові матеріали щодо лікування
1. Melmed S, Casanueva FF, Hoffman AR, et al: Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 96(2): 273–288, 2011.
Ключові моменти
Galactorrhea is the most common sign of a prolactinoma.
The most common cause of galactorrhea is a pituitary adenoma, but many drugs, and endocrine, hypothalamic, or other disorders may be responsible.
Measure prolactin levels and do central nervous system imaging to detect a causative tumor.
For microprolactinomas, give a dopamine agonist if certain troublesome symptoms are present.
For macroadenomas, give a dopamine agonist and consider surgical ablation or sometimes radiation therapy when drugs fail to achieve treatment goals.
Додаткова інформація
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