What is prolactin

Prolactin is a hormone produced by the anterior pituitary gland, a grape-sized organ found at the base of the brain and controlled by the hypothalamus that is in charge of milk production, and also contributes to breast development. The major chemical controlling prolactin secretion is dopamine, which inhibits prolactin secretion from the pituitary. Prolactin is released from the pituitary in response to thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide (VIP), oxytocin and galanin and PHM-27 ¹. Normally present in low amounts in men and non-pregnant women, prolactin’s primary role is to promote lactation (breast milk production). Prolactin secretion is regulated and inhibited by the brain chemical dopamine. Additionally, gamma-aminobutyric acid (GABA) as well as other unidentified prolactin-release-inhibiting factors may play a role as an inhibitor ¹. The prolactin level is usually high throughout pregnancy and just after childbirth. During pregnancy, the hormones prolactin, estrogen, and progesterone stimulate breast milk development. Following childbirth, prolactin helps initiate and maintain breast milk production in nursing women. If a woman does not breastfeed, her prolactin level soon drops back to pre-pregnancy levels. If she does nurse, suckling by the infant plays an important role in the release of prolactin. There is a feedback mechanism between how often the baby nurses and the amount of prolactin secreted by the pituitary as well as the amount of milk produced.

Prolactin is the principal hormone that controls the initiation and maintenance of lactation. In normal individuals, prolactin concentrations increase in response to physiologic stimuli such as sleep, stress, exercise, sexual intercourse, and hypoglycemia, and are also elevated during pregnancy, lactation, postpartum, and in the newborn infant.

Hyperprolactinemia (abnormally high prolactin levels) is the most common hypothalamic-pituitary disorder encountered in clinical endocrinology. Pathologic causes of hyperprolactinemia include prolactin-secreting pituitary adenoma (prolactinoma, which is more frequent in females than males and accounts for approximately 40% of all pituitary tumors), functional and organic disease of the hypothalamus, primary hypothyroidism, compression of the pituitary stalk, chest wall lesions, renal insufficiency, polycystic ovarian disease, and ectopic tumors. Prolactinoma a tumor of the pituitary gland that causes excess production of prolactin is the most common type of pituitary tumor and is usually benign. They develop more frequently in women but are also found in men. Problems resulting from them can arise both from the unintended effects of excess prolactin, such as milk production in a woman who is not pregnant or nursing and, rarely, in a man (galactorrhea) and from the size and location of the tumor.

Hyperprolactinemia often results in loss of libido, galactorrhea, oligomenorrhea or amenorrhea, and infertility in premenopausal females, and loss of libido, impotence, infertility, and hypogonadism in males. Postmenopausal and premenopausal women, as well as men, can also suffer from decreased muscle mass and osteoporosis.

Prolactinomas may rarely present in childhood or adolescence. In girls, disturbances in menstrual function and galactorrhea may be seen, whereas in boys, delayed pubertal development and hypogonadism are often present. The treatment options are the same as in adult patients.

If the anterior pituitary gland and/or the prolactinoma tumor enlarge significantly, it can put pressure on the optic nerve, causing headaches and visual disturbances, and it can interfere with the other hormones that the pituitary gland produces. In women, prolactinomas can cause infertility and irregularities in menstruation while in men, these tumors can cause a gradual loss in sexual function and libido. If left untreated, prolactinomas may eventually damage the surrounding tissues.

Figure 1. The pituitary gland location

Figure 2. The hypothalamus and pituitary gland (anterior and posterior) endocrine pathways and target organs

Prolactin synthesis and regulation

Prolactin is synthesized by lactotrophs in the anterior pituitary gland. The number of lactotrophs will increase during pregnancy in response to the physiological need to develop breast tissues and to prepare for milk production. Prolactin production is regulated at the gene transcription level. Factors that stimulate prolactin secretion to upregulate prolactin gene transcription while factors that inhibit prolactin secretion downregulate prolactin gene transcription. The 2 most important factors that regulate prolactin secretion are: thyrotropin-releasing hormone (TRH) and dopamine both secreted by the hypothalamus. Thyrotropin-releasing hormone (TRH) has a stimulatory effect on thyroid-stimulating hormone (TSH) as well as prolactin; whereas, dopamine has an inhibitory effect on prolactin. In the absence of pregnancy (i.e., high estrogen) or lactation, prolactin is tonically inhibited by dopamine and the effect of dopamine trumpets the effect of thyrotropin-releasing hormone (TRH). Prolactin has a negative feedback on its own production by stimulating the release of dopamine in the hypothalamus. Medications that antagonize dopamine production, for example, an antipsychotic block, the tonic inhibition of dopamine result in symptoms of excessive prolactin. Conversely, medications that are dopamine agonists such as bromocriptine or cabergoline inhibit prolactin secretion. Thus, these medications are used in the treatment of prolactinoma. Estrogen in high levels, as the case with pregnancy, stimulate prolactin release directly from the anterior pituitary. Interestingly, suckling stimulates sensory nerves in the nipple that carries the signal via the spinal cord to arcuate nucleus which inhibits dopamine release by removing the inhibitory action of dopamine on prolactin. At the same time, the afferent signal from the nipple activates supraoptic and paraventricular nuclei to increase the production of oxytocin which allows for milk ejection. Prolactin also has an inhibitory effect on the release of gonadotropin-releasing hormone (GnRH) produced by the hypothalamus-inhibiting follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release from the anterior pituitary. This leads to inhibition of the ovulatory cycle in females which explains the lactational amenorrhea. This mechanism serves as a natural contraceptive and may play a role in spacing out pregnancies. Similarly, prolactin in males inhibits gonadotropin-releasing hormone (GnRH) release resulting in decreased spermatogenesis and infertility.

Prolactin function

The main 2 functions of prolactin are to stimulate milk production and to develop breast tissues. Prolactin plays a role in breast development with estrogen and progesterone by stimulating further breast growth and enlargement of the alveoli in preparation for lactation. In addition to breast tissues development, prolactin is an essential player in milk production. Prolactin stimulates milk production by inducing the enzyme that synthesizes the constituents of milk, such as lactose (the carbohydrate of milk), casein (the protein of milk), and lipids. Prolactin is involved in the biosynthesis of milk constituents by binding to the cell membrane and inducing the transcription cascade to make the necessary enzymes for milk production. Lactogenesis does not occur, however; until after parturition because high estrogen and progesterone during pregnancy down regulate prolactin receptors in the breasts. After parturition, the estrogen and progesterone levels fall precipitously. Thus, the inhibitory effects on the breast are removed. As long as suckling is maintained, prolactin level stays elevated after the pregnancy with each episode of feeding producing peak prolactin levels. If the mother does not nurse her baby, prolactin levels fall to non-pregnant levels after 1 to 2 weeks.

Prolactin test

Prolactin levels may be used for several reasons. It is important to exclude two causes of hyperprolactinemia: hypothyroidism and the ingestion of drugs that either deplete central dopamine or block dopamine receptors. Having excluded these two important causes, and any hypothalamic lesion, three common diagnostic possibilities remain: the patient may have a microadenoma, a macroadenoma or no tumor at all. If patients do not harbor an identifiable tumor, they are described as having idiopathic hyperprolactinemia. It is likely, however, that patients with this condition may harbor small microprolactinomas, which were undetected with less sensitive imaging tools used in the past, and even with MRI.

Prolactin testing may be used, along with other hormone tests, to help:

• Determine the cause of breast milk production not associated with pregnancy or breast-feeding (galactorrhea)
• Diagnose the cause of infertility and erectile dysfunction in men
• Diagnose the cause of menstrual irregularities and/or infertility in women
• Detect and diagnose tumors that produce excess prolactin (prolactinomas), monitor their treatment, and detect recurrences
• Evaluate anterior pituitary function or other pituitary disorder

Serum prolactin measurements are not recommended during pregnancy in patients with prolactinomas. The test results are uninterpretable in this setting and may lead to unnecessary testing triggered by higher than normal prolactin levels.

For assays employing antibodies, the possibility exists for interference by human antianimal antibodies (ie, heterophile antibodies) in the patient sample. Patients who have been regularly exposed to animals or have received immunotherapy or diagnostic procedures utilizing immunoglobulins or immunoglobulin fragments may produce antibodies, (e.g, HAMA), that interfere with immunoassays. This may falsely elevate or falsely decrease the results.

Interference due to extremely high titers of antibodies to analyte-specific antibodies, streptavidin or ruthenium can occur.

When is prolactin test ordered?

Prolactin testing may be ordered when:

• A person has symptoms of a prolactinoma, such as unexplained headaches, visual impairment, and/or unexplained breast nipple discharge
• A woman is experiencing infertility or irregular menstrual periods
• A man has symptoms such as decreased sex drive (libido), nipple discharge, or infertility or has a low testosterone level

When a person has a prolactinoma, prolactin levels may be ordered periodically to monitor the progress of the tumor and its response to treatment. They may also be ordered at regular intervals to monitor for prolactinoma recurrence.

Prolactin levels may be ordered, along with other hormone levels such as growth hormone, when a health practitioner suspects that a person has a pituitary disorder such as hypopituitarism.

When a person has a condition or is taking medications that may affect dopamine production, prolactin concentrations may sometimes be monitored.

Normal prolactin levels

Males:

• <18 years: not established
• > or =18 years: 4.0-15.2 ng/mL

Females:

• <18 years: not established
• > or =18 years: 4.8-23.3 ng/mL

Prolactin is secreted in a pulsatile manner, with a distinct circadian pattern ². Circulating prolactin levels are lowest at midday (noon), with a modest increase occurring during the afternoon. Prolactin levels increase shortly (60-90 min) after onset of sleep, peaking in the early morning. Prolactin levels also rise in response to stress, food, serotonin, acetylcholine, opiates, estrogens, thyrotropin-releasing hormone, and angiotensin 2.

What does abnormal prolactin test result mean?

Men and non-pregnant women will normally have only small amounts of prolactin in their blood. Prolactin levels do, however, need to be evaluated based on the time of day that they are collected. The levels will vary over a 24-hour period, rising during sleep and peaking in the morning. Ideally, a person’s blood sample should be drawn 3 to 4 hours after waking.

A high level of prolactin (hyperprolactinemia) is normal during pregnancy and after childbirth while the mother is nursing.

A high level may also be seen with:

• Tumors that produce and release prolactin (prolactinomas)
• The eating disorder anorexia nervosa
• Diseases of the hypothalamus
• Hypothyroidism
• Kidney disease
• Liver disease
• Polycystic ovary syndrome (PCOS)
• Other pituitary diseases and tumors
• Hyperprolactinemia has been reported in several autoimmune conditions such as systemic lupus erythematosus (SLE), antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, autoimmune thyroid disease, and celiac disease ³.

Levels of prolactin that are below normal are not usually treated but may be indicative of a general decrease in pituitary hormones caused by a pituitary disorder such as hypopituitarism.

Is there anything else I should know?

Stress from illness, chest wall trauma, seizures, lung cancer, and use of marijuana can cause moderate increases in prolactin.

Drugs that can cause an elevated prolactin include estrogen, tricyclic antidepressants, risperidone, opiates, amphetamines, hypertension drugs (reserpine, verapamil, methyldopa) and some drugs that are used to treat gastroesophageal reflux (cimetidine). Nipple stimulation may cause a moderate increase in prolactin blood level.

Low prolactin levels may be caused by drugs such as dopamine, levodopa, and ergot alkaloid derivatives.

Prolactinomas are often small. Along with prolactin levels, a health practitioner may do an MRI (magnetic resonance imaging) of the brain to locate and determine the size of the tumor as well as the size of the pituitary gland.

High prolactin levels

The causes of hyperprolactinemia may be considered, in a simplified fashion, as resulting from four basic abnormalities. In some patients, however, it is not possible to elucidate the cause of hyperprolactinemia.

Hypothalamic Dopamine Deficiency

Diseases of the hypothalamus, such as tumors, arterio-venous malformations, and inflammatory processes such as sarcoidosis result in either diminished synthesis or release of dopamine. Furthermore, certain drugs (e.g. alpha-methyldopa and reserpine) are capable of depleting the central dopamine stores.

Defective Transport Mechanisms

Section of the pituitary stalk results in impaired transport of dopamine from the hypothalamus to the lactotrophs. Pituitary or stalk tumors with abnormal blood supplies, or their pressure effects, may interfere with the circulatory pathway from the hypothalamus down the pituitary stalk to the normal lactotrophs, or a tumor, producing effective dopamine deficiency due to a functional stalk section.

Lactotroph Insensitivity to Dopamine

Dopamine receptors have been found on human pituitary lactotroph adenoma cells. Receptor sensitivity to dopamine could be diminished, which would explain the lack of response to increased endogenous dopamine stimulation. However, an obvious response of the receptors to pharmacologic dopamine agonists (DA) makes this possibility less likely. Certain drugs act as dopamine-receptor-blocking agents, including phenothiazines (e.g. chlorpromazine), butyrophenones (haloperidol), and benzamides (metoclopramide, sulpiride, and domperidone). These drugs block the effects of endogenous dopamine and thus release lactotrophs from their hypothalamic inhibition. This sequence of events results in hyperprolactinemia.

Stimulation of Lactotrophs

Hypothyroidism may be associated with hyperprolactinemia. If hypothyroidism results in increased TRH production, then TRH (which can act as a PRF) could lead to hyperprolactinemia. Estrogens act directly at the pituitary level, causing stimulation of lactotrophs, and thus enhance prolactin secretion. Furthermore, estrogens increase the mitotic activity of lactotrophs, increasing cell numbers. Injury to the chest wall can also lead to hyperprolactinemia. This results from abnormal stimulation of the reflex associated with the rise in prolactin that is seen normally in lactating women during suckling.

High prolactin causes

In general, serum prolactin concentrations parallel tumor size in patients with prolactinomas. Macroadenomas (>10 mm in diameter) are typically associated with serum prolactin concentrations above 250 ng/mL, and a concentration above 500 ng/mL is diagnostic of a macroprolactinoma. Moderately increased concentrations of serum prolactin are not a reliable guide for determining whether a prolactin-producing pituitary adenoma is present. If the patient has a macroadenoma and a serum prolactin level of less than 200ng/mL (4000mU/L), consideration should be given to the possibility that a nonfunctioning pituitary adenoma (pseudo-prolactinoma) is present, the hyperprolactinemia resulting from deprivation of some lactotrophs of dopaminergic inhibition. However, a laboratory artifact may lead to a wrong differential diagnosis between macroprolactinomas and pseudoprolactinomas.

Prolactin-secreting macroadenomas (>10 mm in diameter) can sometimes produce exceedingly high serum prolactin concentrations that may paradoxically result in falsely low prolactin concentrations when measured by immunometric assays. In such situations, very high concentrations of prolactin saturate both the capture and signal antibodies in the assay, block formation of the capture antibody-prolactin-signal antibody “sandwich,” and result in falsely decreased prolactin results (referred to as the “high-dose hook effect”). Therefore, patients bearing macroprolactinomas with extremely high serum prolactin levels (generally >1,000 ng/ml [>180,000 mU/L]) may present falsely low levels, e.g. 30-120 ng/ml (600-2,400 mU/L) range, causing the patient to be misdiagnosed as harboring a nonfunctioning pituitary adenoma. With such tumors, serum prolactin levels may be falsely decreased into the normal reference interval, potentially resulting in inappropriate patient management. In order to avoid unnecessary surgery (treatment of choice for nonfunctioning tumors), prolactin assays with serum dilution, which eliminates the analytic artifact in these cases, are recommended in patients with macroadenomas who may harbor a prolactinoma.

Another laboratory pitfall concerns the presence of high serum prolactin levels in subjects with few or no symptoms related to prolactin excess. Human prolactin circulates as monomeric prolactin and as larger forms which are indistinguishable by routine assays. Monomeric prolactin is the most common form, but serum prolactin can be elevated due to the presence of aggregates with low biological activity, such as big-big prolactin, leading to so-called macroprolactinemia.

A microadenoma is described as having a maximum diameter of up to 10mm (the maximal diameter of the normal pituitary gland). A microadenoma is often visualized using magnetic resonance imaging (MRI). Usually, the serum prolactin level is below 200ng/mL (4000mU/L) in patients with microadenomas.

In patients where a discrepancy between pituitary tumor size and prolactin elevation is observed, a test for false-low serum prolactin (hook effect) should be performed by serial dilution. The Roche Cobas Prolactin II assay should demonstrate no high-dose hook effect at prolactin concentrations up to approximately 12,500 ng/mL ⁴.

After initiation of medical therapy of prolactinomas, prolactin levels should decrease substantially in most patients; in 60% to 80% of patients, normal levels should be reached. Failure to suppress prolactin levels may indicate tumors resistant to the usual central-acting dopamine agonist therapies; however, a subset of patients will show tumor shrinkage despite persistent hyperprolactinemia. Patients who show neither a decrease in prolactin levels nor tumor shrinkage might require additional therapeutic measures.

Multiple medications can cause increased prolactin concentration including estrogens, dopamine receptor blockers (eg, phenothiazines), dopamine antagonists (eg, metoclopramide, domperidone), alpha-methyldopa, cimetidine, opiates, antihypertensive medications, and other antidepressants and antipsychotics.

In patients with asymptomatic hyperprolactinemia, assessment for macroprolactin (prolactin bound to immunoglobulin) is suggested. Macroprolactin is detected by differing degrees depending on the immunoassay used to measure prolactin. The Roche Cobas Prolactin II assay shows low reactivity with most forms of macroprolactin. Macroprolactin should be evaluated in asymptomatic hyperprolactinemic subjects or when pituitary imaging studies are not informative.

Elevated prolactin key points

• Hyperprolactinemia is the most common hypothalamic-pituitary dysfunction, being an important cause of irregular menses and infertility amongst young women
• Clinical and laboratorial investigation is crucial to determine hyperprolactinemia cause and to indicate the proper treatment
• Prolactinoma is the most common cause of pathological hyperprolactinemia
• Macroprolactinemia is a laboratorial pitfall and must be ruled out in asymptomatic hyperprolactinemic individuals. Usually, treatment is not necessary
• Hook effect is another laboratorial pitfall that underestimates prolactin levels and may confound diagnosis between macroprolactinomas and pseudoprolactinomas
• Clinical treatment with dopamine agonists are effective in 80 to 90% of hyperprolactinemic patients leading to normal serum prolactin levels and tumor reduction. Normoprolactinemia after dopamine agonist withdrawal is possible in around 20% of cases.
• Surgical treatment may be indicate in resistant/intolerant patients and symptomatic apoplectic tumors
• Radiotherapy is rarely indicated and must be reserved to control tumor growing in aggressive cases
• Temozolomide is an alternative of treatment for resistant/aggressive prolactinomas not responding to high doses of dopamine agonists, multiple surgeries and radiotherapy
• Bromocriptine is still the dopamine agonist of choice for inducing pregnancy

What other tests may be done to evaluate high prolactin levels?

Other tests that may be done include testosterone (levels will usually be low in a male when prolactin is high), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) (to help evaluate ovulation and fertility), an MRI of the brain (to show pituitary enlargement and help locate a tumor), and an eye examination (to evaluate visual disturbances). Elevated prolactin levels require further laboratory tests to ensure that the elevation is not due to macroprolactin.

If I have high prolactin, why is my doctor testing my thyroid?

Increased levels of prolactin are often seen in people with hypothyroidism (although they do not cause it). If you have hyperprolactinemia, your doctor will most likely test you for hypothyroidism.

How are prolactinomas treated?

Prolactinomas may be treated with medications that act like dopamine (such as bromocriptine or cabergoline) to decrease prolactin production. Treatment can reduce prolactin levels and symptoms and restore fertility, but the medications may have to be taken for several months or years. Surgery is sometimes necessary if the prolactinomas are large or not responding to treatment. This surgery is delicate and requires an experienced surgeon. Sometimes, despite medication and/or surgery, the prolactinoma recurs.

What is macroprolactin?

A number of otherwise healthy people have elevated prolactin levels because some of the prolactin in their blood is in a different form called macroprolactin. Macroprolactin is prolactin that is bound to a protein (immunoglobulin), is not active in the body, and does not indicate the presence of disease. If an elevated prolactin is found, further laboratory tests may be done to make sure that this is not due to macroprolactin.

Precipitation with polyethylene glycol (PEG) is an excellent screening method. Chromatography confirms the presence of macroprolactin but is an expensive and time-consuming method; it is performed only when PEG precipitation results are inconclusive. Macroprolactinemia is a common finding, some reporting it as frequently as 8 to 42% of all cases; other centers find that it is extremely rare. Big-big prolactin biological activity is still controversial in the literature. Studies in vitro with rat Nb2 cells bioassays show either the presence or the absence of biological activity. A recent study using a human prolactin receptor-mediated assay compared with rat Nb2 cells assay showed that the activity displayed by macroprolactin toward the rat receptor may be inappropriate because it is not observed in the human prolactin receptor-mediated assay, consistent with the apparent absence of bioactivity in vivo. Most patients with macroprolactinemia do not manifest clinical features related to hyperprolactinemia, and do not need any treatment. Therefore, in order to avoid unnecessary medical or even surgical procedures, macroprolactin screening is important to consider when clinical features and serum prolactin assay results are not consonant with one another.

High prolactin symptoms

The symptoms associated with hyperprolactinemia may be due to several factors: the direct effects of excess prolactin, such as the induction of galactorrhea or hypogonadism, the effects of the structural lesion causing the disorder (i.e. the pituitary tumor), leading to, for example, headaches, visual field defects, or external ophthalmoplegia; or associated dysfunction of secretion of other anterior pituitary hormones.

The incidence of galactorrhea in hyperprolactinemic patients is between 30% and 80%, depending on the skill of the examiner and the degree of estrogen deficiency. Approximately 50% of women with galactorrhea, however, have normal prolactin. As mentioned below, it is particularly those patients with very high prolactin levels, i.e. greater than 100ng/mL (2000mU/L), who often have no galactorrhea. Thus, galactorrhea is an inconsistent marker of hyperprolactinemia.

Women with hyperprolactinemia usually present with menstrual abnormalities – amenorrhea or oligomenorrhea – or regular cycles with infertility. Occasionally, patients may present with menorrhagia. Menstrual disorders are often not seen with mild hyperprolactinemia but it is unusual for there to be no menstrual problems if the prolactin is greater than 180 ng/l (3,600 mU/L).

In contrast, men often present late in the course of the disease with symptoms of expansion of their pituitary tumor (i.e. headaches, visual defects, and external ophthalmoplegia) or symptoms from secondary adrenal or thyroid failure. These men, however, have usually been impotent for many years before their presentation. Because the disease is occult for many years, men present late in the course of their disease. In contrast to women in whom microprolactinomas are most commonly seen, macroprolactinomas are usually found in men and the serum prolactin levels are usually much higher than those in women.

Occasionally, the syndrome may occur in prepubertal or peripubertal children, when it may present with delayed or arrested puberty or with headache and/or visual field defects or with growth arrest. Children and adolescents often present with aggressive prolactinomas, perhaps reflecting a different mechanism(s) of tumorigenesis rather than disease duration; it should not be forgotten that the rate of cell proliferation at this stage of the life cycle is greater.

High prolactin treatment

Therapeutic strategy must consider several aspects, such as the patient’s clinical presentation, the differences between microadenomas and macroadenomas concerning their natural history, the desire for pregnancy, and the patient’s treatment preference, if applicable. Medical treatment with DA drugs is currently the gold standard approach both for microprolactinomas and macroprolactinomas. Pituitary surgery, usually by the transsphenoidal approach is generally reserved for prolactinomas resistant to dopamine drugs ¹. For microadenomas, the results in the hands of most experienced surgeons are similar, with about 80% having serum prolactin normalization. However ~25% develop recurrence of hyperprolactinemia by five years after surgery even with the most experienced transsphenoidal surgeons. Surgical results in macroprolactinomas are much poorer, mainly in big and/or invasive tumors. Radiotherapy for prolactinomas generally bring poor results, and is currently reserved only for macroadenomas refractory both to medical and surgical treatment.

Dopamine agonist drug therapy

The first dopamine ergot compound to be used in clinical practice was bromocriptine, a peptide ergot. It was introduced in the early 1970s in Europe and thus there is more than 40 years of experience of the use of such compounds in the treatment of hyperprolactinemia. Bromocriptine has the advantage of having a long duration of action compared to dopamine itself or oral compounds such a levo-dopa (L-dopa).

Bromocriptine has a similar mode of action to dopamine in stimulating dopamine receptors on the prolactin-secreting pituitary cells – D2 receptors. Stimulation of these receptors leads to inhibition of both prolactin secretion and synthesis. Subsequently a variety of other compounds have been developed which are useful additions. These include pergolide mesylate, quinagolide, and cabergoline.

Cabergoline has an extremely long biological half-life and thus, generally only needs to be administered either once or twice per week, with a weekly dose of 0.5 to 2.0 mg ¹. This dose may be increased in refractory cases. In addition to its long biological half-life, cabergoline is generally better tolerated than bromocriptine, so increasing the patient’s adherence ¹. Therefore, cabergoline is currently considered the first choice drug for the treatment of prolactinomas, except for patients wishing pregnancy in the short-term ¹. In a study comparing bromocriptine (2.5 to 5.0 mg twice daily) to cabergoline (0,5 to 1.0 mg twice weekly) in 459 hyperprolactinemic women with amenorrhea, stable normoprolactinemia was achieved in 83% of patients on cabergoline and in 59% patients on bromocriptine ¹. Ovulatory cycles or pregnancy occurred in 72% of cases on cabergoline and in 52% of cases on bromocriptine ¹. Drug withdrawal due to adverse effects was reported in 3% of cases on cabergoline and in 12% of cases on bromocriptine. Regarding tumor size, a decrease in at least 50% was obtained in 64% of patients on bromocriptine and in 93% of patients on cabergoline ¹. This important beneficial effect of dopamine treatment can rapidly relieve mass effects symptoms such as visual impairment, without the need of surgical decompression.

Surgical therapy of large prolactin-secreting pituitary tumors is unsatisfactory since it is only capable of normalizing serum prolactin levels or gonadal function in fewer than 20% of patients, particularly those with high prolactin levels, so there is a need for another approach to the problem. Three major lines of evidence suggest that medical therapy may help in the treatment of these large tumors.

Dopamine agonist drug therapy side effects

Side effects of dopamine therapy usually occur at the start of treatment and frequently disappear with continued therapy. If treatment is started with full doses or increased too quickly, dizziness, nausea, and postural hypotension may occur. To avoid such effects, dopamine must always be taken during a meal. Administration should be started at night, with a snack, when the patient retires to bed.

Cabergoline and pergolide were associated with a higher risk of cardiac valvopathy in patients with Parkinson´s disease. These dopamine also have an agonist effect on serotonin receptor 5HT2B, present in fibroblast of cardiac valves and cordoalha tendinea. Fibroblasts proliferation occurs after this receptor activation, leading to valve insufficiency, specially of tricuspid and pulmonary valves. This proposed mechanism was already described in carcinoid syndrome. Nevertheless, mean cabergoline dose for Parkinson patients is 3 mg a day, much higher than the usual dose for hyperprolactinemia. To date, 17 observational studies addressed the issue of valvopathy risk in hyperprolactinemic patients on cabergoline: only one of them pointed to a moderate tricuspid regurgitation associated with cabergoline.

Nevertheless, as this issue is not completely elucidated, echocardiographic evaluations is recommended before and during dopamine treatment at the physician’s discretion.

Regarding pergolide, it was withdrawn from the market.

Can dopamine agonist drug be withdrawn without recurrence of hyperprolactinemia?

One of the drawbacks of medical treatment of prolactinomas is the need for long-term therapy. As a matter of fact, treatment with bromocriptine and other dopamine drugs generally is considered as “symptomatic”, since bromocriptine discontinuation leads to recurrence of hyperprolactinemia in most patients and to tumor regrowth, at least after short-term use ¹.

Concerning long-term therapy with bromocriptine, a recent retrospective study showed that 25.8% of 62 patients with microprolactinomas and 15.9% of 69 patients with macroprolactinomas treated with bromocriptine for a median time of 47 months had persistent normoprolactinemic after a median time of 44 months after drug withdrawal ¹. Another study encompassed a large cohort of hyperprolactinemic patients on cabergoline. The drug was discontinued in patients who attained normoprolactinemia, with at least 50% of tumor reduction or disappearance on image, with at least 2 years of follow-up after cabergoline withdrawal. Serum prolactin remained normal in 76%, 70% and 64% of patients with “idiopathic” hyperprolactinemia, microprolactinomas and macroprolactinomas, respectively ¹. This great discrepancy between results with bromocriptine and cabergoline was not confirmed by a recent metanalysis, including 743 patients from nineteen studies: the pooled proportion of patients with remission was 21% ¹. Stratifying those results, remission was obtained in 32% for idiopathic hyperprolactinemia, 21% for micro and 16% for macroprolactinomas. The probability of success was higher when dopamine treatment lasted at least two years. A trend of cabergoline superiority over bromocriptine was observed albeit with no statistical significance.

Although the exact mechanism of prolactinomas remission is not completely understood, which could also be linked to the natural history of the disease ¹. Periodic withdrawal of dopamine is recommended, especially in cases with normal serum prolactin levels and tumor reduction.

Prolactinomas resistant to dopamine agonists

About 15% of patients with prolactinomas are resistant to dopamine therapy ¹. The main mechanism is reduction of D2R tumoral expression. If a patient has been responsive and then becomes unresponsive, a pituitary carcinoma should be ruled out. The approach to the resistant prolactinoma includes pituitary surgery, radiotherapy and drugs as temozolomide. Pituitary surgery, usually by transsphenoidal approach, aims for complete tumor removal or at least a vast debulking, which may lead to serum prolactin normalization with dopamine reintroduction in partially resistant cases. Surgery is more effective in microadenomas and non-invasive macroadenomas. In a metanalsysis a surgical remission rate of 74.7% in micro and 34% in macroadenomas was shown. Nevertheless, the recurrence rate was 18% and 23% in micro and macroadenomas, respectively, leading to an even lower long-term remissison rate. Radiotherapy is indicated in aggressive cases not controlled by surgery or drugs ¹. The alkilating agent temozolomide has proved efficacy in aggressive pituitary adenomas and carcinomas, mainly the prolactin secreting ones.

Low prolactin levels

In the vast majority of prolactin deficiency states, the deficiency occurs secondary to general anterior pituitary dysfunction. The most commonly associated condition is postpartum pituitary necrosis (Sheehan syndrome); however, prolactin deficiency can also be caused by anterior pituitary impairment secondary to pituitary (or extrapituitary) tumor or treatment of tumor, parasellar diseases, head injury, infection (eg, tuberculosis, histoplasmosis), or infiltrative diseases (e.g, sarcoidosis, hemochromatosis, lymphocytic hypophysitis) ⁵. Sheehan syndrome is characterized by infarction of the anterior pituitary following postpartum. The pathophysiology of Sheehan syndrome involves a significant blood loss during childbirth which compromises the blood supply to the enlarged anterior pituitary causing it to undergo ischemic necrosis ⁶. This results in failure to produce the hormones made by the anterior pituitary such as prolactin. The signs and symptoms might not occur until months after the blood loss. The most common presenting symptom of Sheehan syndrome is the failure to lactate (agalactorrhea). Other symptoms are related to the functions of the hormones made by the anterior pituitary such as amenorrhea and decreased sex drive. Sheehan syndrome represents one of the pathology scenarios where prolactin deficiency is apparent.

Partial isolated prolactin deficiency is rare, and case reports of total isolated prolactin deficiency are rarer still and may have a genetic component (i.e, familial puerperal alactogenesis) ⁷. Although the endocrine and metabolic function of prolactin is not fully understood, the clinical manifestation of prolactin deficiency is probably limited to puerperal alactogenesis ⁷.

While there is evidence that women who smoke tend to breast feed for shorter periods, there is a wide variation of breast-feeding rates in women who do smoke. This suggest that psychosocial factors rather than physiological mechanisms (e.g., nicotine suppressing prolactin levels) are responsible for the lower rates of breast feeding in women who do smoke ⁸.

Low prolactin causes

The most common causes of prolactin deficiency include postpartum pituitary necrosis (Sheehan syndrome) ⁹ and all other causes of anterior pituitary dysfunction ¹⁰. Prolactin deficiency can be secondary to other causes that primarily affect the anterior pituitary. Anterior pituitary function to produce hormone such as prolactin can be impaired due to mass effect (tumor) or infections such as tuberculosis and histoplasmosis, or infiltrative process such as; sarcoidosis and hemochromatosis ¹¹.

Classically, the typical sequence in loss of pituitary hormones is the following:

• Gonadotropins (LH, FSH)
• Growth hormone
• Thyrotropin-stimulating hormone
• Corticotropin
• Prolactin (deficiency uncommon except with pituitary infarction [Sheehan syndrome])

Another cause can be medication (ie, dopamine infusion, ergot preparation, pyridoxine, diuretics). Nicotine also diminishes the amount of prolactin released in response to the suckling stimulus. This may explain the decreased milk yield in mothers who smoke; they have been found to lactate for a shorter time than do comparable groups of mothers who do not smoke. Although plasma prolactin levels are usually within the reference range in anorexia, bulimic patients have been reported to have either reference-range or low prolactin levels.

Retained placental fragments in the peripartum interval can also suppress prolactin.

Prolactin deficiency is associated with G-protein mutations, such as Albright hereditary osteodystrophy. In this case, it may be found with olfactory dysfunction in type I pseudohypoparathyroidism.

Prolactin deficiency is found in a rare hereditary disorder called multiple pituitary hormone deficiency. This familial occurrence has been associated with mutation of the PROP1 gene or Pit1 gene (also called POU1F1) ¹². These genes encode transcription factors that are necessary for the differentiation of lactotrophs, as well as of somatotrophs and thyrotrophs. Multiple pituitary hormone deficiency is associated not only with prolactin deficiency, but usually with somatotropin (growth hormone [GH], thyrotropin [also known as thyroid-stimulating hormone, or TSH]) deficiencies as well.

Hypoprolactinemia can result from autoimmune disease ¹³, hypopituitarism ¹⁴, growth hormone deficiency, hypothyroidism, excessive dopamine action in the tuberoinfundibular pathway and/or the anterior pituitary, and ingestion of drugs that activate the D2 receptor, such as direct D2 receptor agonists like bromocriptine and pergolide, and indirect D2 receptor activators like amphetamines (through the induction of dopamine release) ¹⁵.

Usually, no workup is necessary, because supplemental prolactin is not yet available for treatment ¹⁶; however, suspicion of the disease can be confirmed by administering thyrotropin-releasing hormone (TRH) or an antidopaminergic agent (eg, metoclopramide) and measuring prolactin levels. Failure to respond (rise in the level of prolactin) in the setting of the challenge is diagnostic.

The following tests can also be performed: prolactin assay in the third trimester or in peripartum women; LH, FSH, thyrotropin, and free thyroxine; and other tests as necessary to diagnose anterior hypopituitarism.

The most important historical finding in prolactin deficiency is the lack of breast milk production following childbirth. A history of anterior pituitary dysfunction is also important.

• Menstrual disorders, delayed puberty, infertility, and subfertility are important historically, secondary to their association with hypoprolactinemia.
• Inadequate lactation is speculated to be secondary to a partial prolactin deficiency and can be considered a historical marker.

No specific physical findings are associated with hypoprolactinemia other than the lack of breast milk production following childbirth. The most common symptom complex of anterior pituitary dysfunction in men and women is secondary hypogonadism caused by deficiencies of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

Currently, no medication exists to treat prolactin deficiency; however, experimental recombinant human prolactin has been formulated and has been shown to be effective in correcting lactational performance in rats treated with bromocriptine ¹⁷.

Inadequate lactation may respond to antidopaminergic agents that block the dopamine-induced hypothalamic inhibitory control of prolactin. Metoclopramide has been shown in prospective, placebo-controlled studies to significantly increase milk yield in patients with inadequate lactation ¹⁸. Subfertility caused by hypoprolactinemia may be treated with clomiphene citrate (50 mg/d for 5 d) or with gonadotropins (LH, FSH; dose varies).

In one study, normal sperm characteristics were restored when prolactin levels were raised to normal values in hypoprolactinemic men ¹⁹.

References

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