**6. Pathological causes**

Pathological hyperprolactinemia can be caused by: lactotroph hyperplasia, lactotroph cells adenoma (prolactinoma) and miscellaneous.

#### 1. Lactotroph hyperplasia

Lactotroph hyperplasia derives, in most cases, from the decrease of the dopamine inhibitory tone over the lactotroph cells. Hypothalamic and pituitary stalk lesions can cause light or moderated hyperprolactinemia, normally less than 150 ng/ml (18-19, 23).

Physiological and Pathological Hyperprolactinemia: Can We Minimize Errors in the Clinical Practice? 223

Sometimes, it takes part of the type one multiple endocrine neoplasms (MEN). It is the only

The prolactinoma natural history shows that over 90% of the microadenomas do not grow and they do not progress to macroadenomas, that suggest that these have a different biological behavior to the microadenomas (19, 24-27), Most of the times the lactotroph cells are the only ones affected but up to a 10% can alter, as well, the somatotropes or the mamosomatotropes, and a prolactin and growth hormone (GH) co-secretion is


1. Its efficiency: even small tumors, smaller than 1 cm, can produce significant

2. Its proportionality: usually, the prolactin serum concentration rises in direct relation to

1. Big tumors with light hyperprolactinemia: they are usually atipic prolactinomas, worse differentiated and, so, less sensitive to therapy with dopaminergic agonists and more

2. Hook effect: very high levels of prolactin secreted by the macroadenoma saturate the assays and lead to an apparently low value (between 20 and 200 ng/ml), which could confuse the macroprolactinoma with a non-secretory macroadenoma. It is produced by interferences in the enzime inmunoassays for prolactin and it can be settled by serum dilution to 1:100, which will show the real prolactin serum values secreted by the tumor

The hyperprolactinemia appears in most of the patients with CRI and dialysated. When these patients take medication that can alter the hypothalamic regulation of the

pituitary tumor with an effective medical treatment.

produced.

Prolactinoma can lead to:

hypogonadism.

hyperprolactinemia.

the adenoma size:

Discrepancies are frequent:

(19, 28-29).

**7. Miscellaneous** 





Prolactin secretion by the prolactinoma is characterized by:


susceptible to surgical treatment.

1. Decrease of the prolactin clearing:

a. Chronic renal insufficiency. (CRI)

The most common cause of hyperprolactinemia are the drugs. Any substance that acts over the central nervous system can, potentially, change the prolactin serum levels. Generally, the serum prolactin concentration increase a few hours or days after the drug administration and it gets normal from 2 to 4 days after its suspension.

Drugs can be divided in two big groups: drugs that act over the hypothalamus altering the dopamine metabolism and the drugs that act directly over the hypophysis. These last ones are more powerful and its action mechanism is dopamine antagonist, displacing it from its receptor in the lactotroph cell. Examples of these are the metoclopramide, sulpiride and domperidone. The Antihypertensives as reserpine and methyldopa act in the hypothalamus. Cimetidine and similar substances stimulate the receptor H2 and provoke the hyperprolactinemia.

The hyperprolactine grade depends on the drug, for example, haloperidol can provoke rises lower than 20 ng/ml, but the risperidone can raise it over 100 ng/ml (19).

Estrogens rise the prolactin secretion and explain the higher response of prolactin in women in the presence of the different physiological stimulus.

Besides, up to a 30% of the patients with polycystic ovary syndrome show a light hyperprolactinemia, and the treatment with dopaminergic agonists can, in some cases, normalize the menstrual cycle.

The primary hypothyroidism is associated with a slight increase of the prolactin serum concentration in a 40% of the patients, but values over 25 ng/ml appear in less of the 10% (19, 23).

2. Lactotroph cells adenoma: prolactinoma

It is the most frequent secretory pituitary tumor and it represents a 60% of the operating tumors. The 90% of the prolactinomas are intrasellar microadenomas (<10 nm).

In women, over 90% are microadenomas, especially between 20 and 40 years old (2, 3). In male, the 60% are macroadenomas and it is because the poor symptoms, the delay of the medical visit for erectile dysfunction or a higher growth rate (19).

Prolactinomas are the most common pituitary tumors and they are, normally, benign. They are more frequent in women, but they can also appear in men. The symptoms that they cause, if the symptoms appear, are related to prolactin excess and so, the milk production in non-pregnant women, which is called galactorrhea.

Prolactinoma, the same as other pituitary neoplasms, comes from a monoclonal expansion of a cell that has mutated (18, 19, 23). It is usually sporadic and benign and it is rarely malign and metastatic.

Sometimes, it takes part of the type one multiple endocrine neoplasms (MEN). It is the only pituitary tumor with an effective medical treatment.

The prolactinoma natural history shows that over 90% of the microadenomas do not grow and they do not progress to macroadenomas, that suggest that these have a different biological behavior to the microadenomas (19, 24-27), Most of the times the lactotroph cells are the only ones affected but up to a 10% can alter, as well, the somatotropes or the mamosomatotropes, and a prolactin and growth hormone (GH) co-secretion is produced.

Prolactinoma can lead to:

222 Prolactin

1. Lactotroph hyperplasia

Lactotroph hyperplasia derives, in most cases, from the decrease of the dopamine inhibitory tone over the lactotroph cells. Hypothalamic and pituitary stalk lesions can cause light or moderated hyperprolactinemia, normally less than 150 ng/ml (18-19, 23). The most common cause of hyperprolactinemia are the drugs. Any substance that acts over the central nervous system can, potentially, change the prolactin serum levels. Generally, the serum prolactin concentration increase a few hours or days after the drug

Drugs can be divided in two big groups: drugs that act over the hypothalamus altering the dopamine metabolism and the drugs that act directly over the hypophysis. These last ones are more powerful and its action mechanism is dopamine antagonist, displacing it from its receptor in the lactotroph cell. Examples of these are the metoclopramide, sulpiride and domperidone. The Antihypertensives as reserpine and methyldopa act in the hypothalamus. Cimetidine and similar substances stimulate the

The hyperprolactine grade depends on the drug, for example, haloperidol can provoke

Estrogens rise the prolactin secretion and explain the higher response of prolactin in

Besides, up to a 30% of the patients with polycystic ovary syndrome show a light hyperprolactinemia, and the treatment with dopaminergic agonists can, in some cases,

The primary hypothyroidism is associated with a slight increase of the prolactin serum concentration in a 40% of the patients, but values over 25 ng/ml appear in less of the

It is the most frequent secretory pituitary tumor and it represents a 60% of the operating

In women, over 90% are microadenomas, especially between 20 and 40 years old (2, 3). In male, the 60% are macroadenomas and it is because the poor symptoms, the delay of

Prolactinomas are the most common pituitary tumors and they are, normally, benign. They are more frequent in women, but they can also appear in men. The symptoms that they cause, if the symptoms appear, are related to prolactin excess and so, the milk

Prolactinoma, the same as other pituitary neoplasms, comes from a monoclonal expansion of a cell that has mutated (18, 19, 23). It is usually sporadic and benign and it is rarely

tumors. The 90% of the prolactinomas are intrasellar microadenomas (<10 nm).

the medical visit for erectile dysfunction or a higher growth rate (19).

production in non-pregnant women, which is called galactorrhea.

rises lower than 20 ng/ml, but the risperidone can raise it over 100 ng/ml (19).

women in the presence of the different physiological stimulus.

administration and it gets normal from 2 to 4 days after its suspension.

receptor H2 and provoke the hyperprolactinemia.

normalize the menstrual cycle.

2. Lactotroph cells adenoma: prolactinoma

10% (19, 23).

malign and metastatic.


Prolactin secretion by the prolactinoma is characterized by:


Discrepancies are frequent:


#### **7. Miscellaneous**

	- a. Chronic renal insufficiency. (CRI)

The hyperprolactinemia appears in most of the patients with CRI and dialysated. When these patients take medication that can alter the hypothalamic regulation of the prolactin, this can take to serum values over 2000 ng/ml. It is produced by a decrease of the glomerular filter, although a pituitary primary defect associated to a renal failing cannot be dismissed.

Physiological and Pathological Hyperprolactinemia: Can We Minimize Errors in the Clinical Practice? 225

Because the secretion of the prolactin is pulsatile, it is advisable to determine the serum

To the most of the clinical laboratories, the normal serum concentration is less than 25 ng/ml

The determination should be done, ideally, in a basal situation, under rest conditions and







It is convenient to insist in the importance of differentiate between the big pituitary nonsecretory macroadenomas, that apply compression to the pituitary stalk and can curse with prolactin serum values that are not too high, generally lower than 200 ng/ml (pseudoprolactinoma) from the real macroprolactinomas, which usually show prolactin serum

The first ones are susceptible of surgical treatment, while the prolactinomas are treated, most of them, with medical treatment. In a same way, low prolactin serum concentrations can coexist with uncovered small tumors in an incidental way, and they can lead to false

Nevertheless, values between 20 and 200 ng/ml, in presence of a macro-lesion, obliged to reassess the samples using a dilution of 1:100 to dismiss the hook effect described previously and according to it very high values of serum prolactin saturate the assays and lead to an

**8. Assessment and diagnosis of the hyperprolactinemia** 

(Note: conversion factor: mU/l × 0,0472 =ng/ml; ng/ml × 21,2 = mU/l.)

after suppression of any medication that can interfere in its quantification.

The clinical records are determinant to the hyperprolactinemia treatment:


Values of serum prolactin can lead to the diagnosis (figure 6):

cataloguing the hyperprolactinemia state.

less frequently in some microprolactinomas.


extrapituitary hyperprolactinemia.

characteristic of a prolactinoma.

diagnosis of microprolactinoma (19, 33).

concentrations over 200 ng/ml.

prolactin in, at least, 2 times or more.

in women and 20 ng/ml in men.

adrenal dysfunction.

tumor presence.

b. Macroprolactinemia.

In some patients with hyperprolactinemia without a perceptible cause or idiopathic, this could be due to an excess of macromolecules of prolactin, known as macroprolactin or big prolactin. The macroprolactin is a complex of prolactin joined to an IgG antibody with a low bioactivity but with a higher mean life than normal prolactin, of 23 kDa, which condition its lower clearing and the consequent accumulation of high serum concentrations.

To distinguish it from other causes, some samples of serum with polyethylene glycol should be precipitated (13, 19-20).

This prolactin variety can be present in over 10% of the patients with hyperprolactinemia, and its presence should be suspected in every hyperprolactinemia without a defined etiology, with poor or nonexistent symptomatology, despite of the high prolactin serum concentrations and with poor or nonexistent response to normal therapy with dopaminergic agonists (13,19-20, 28-30).

This situation can lead to unsuitable diagnosis and treatments in patients with hyperprolactinemia, but usually without clinical significance. Every hyperprolactinemia assay should consider the possible presence of macroprolactinemia (19, 30).

When the cause is not found and the imaging tests are negative, the hyperprolactinemia is defined as idiopathic. In most of the cases they are small microadenomas. A 10% of them will be visible between 2 and 6 years. In other cases it is a transitory and selflimited disorder that can be solved spontaneously (19,31).

2. Hyperprolactinemia related to psychotropic drugs

Prolactin determinations will not be needed in individual under psychotropic treatment, but if there is indicative clinical symptoms of hyperprolactinemia.

However, in a patient with hyperprolactinemia under psychotropic drugs, among others, subsequent studies (hormonal and imaging) will be performed only if:


The assessment of the new patient should be done ideally 3 months after the medication suppression or, if not possible, the possibility of a substitutive medication that does not provoke hyperprolactinemia should be assessed, always under psychiatric control.

It is normally not recommended the dopaminergic agonists use in a combined form to psychotropic or dopaminergic antagonist drugs because of the undesirable effects. (19,20).
