Dr. Tébar Massó is an expert endocrinologist in Murcia specialized in thyroid, neuroendocrine tumors, diseases such as diabetes and obesity, expert in lipids and cardiovascular risks.
Definition of prolactin
Prolactin (PRL) is a hormone produced and secreted in the adenohypophysis, the anterior part of that small glandulite located at the base of the brain known as the pituitary gland. In its structure it has a certain resemblance to growth hormone (GH), also secreted in the adenohypophysis, and to placental lactogen (PLH), which, as its name suggests, is produced in the placenta. All 3 have a common precursor gene located on chromosome 6. PRL-producing cells are called lactotropic and GH-secreting cells somatotropic. Under certain circumstances, tumors develop from these cells which sometimes secrete only PRL, sometimes only GH and in many cases both hormones, receiving the name of lacto-somatotrophic pituitary adenomas.
In mammals, such as humans, the fundamental mission of PRL is to stimulate mammary growth before delivery, as well as milk production and the maintenance of this function after delivery to ensure breastfeeding. Similarly, during this period, PRL inhibits ovulation and reduces sexual desire to prevent pregnancy and prolong lactation. However, this inhibition has its flaws and can cause a woman to become pregnant during lactation. In men, an excess of prolactin decreases the concentration of testosterone and the production of sperm, which is accompanied by a decrease in fertility and sexual desire.
Definition of Hyperprolactinemia
Hyperprolactinemia (hyperPRL) is any increase in plasma PRL concentration whatever its cause. Normal plasma PRL concentrations range from 5 to 25 ng/ml (slightly less in men). Concentrations between 25 and 100 ng/ml are probably due to functional situations, but above 100 ng/ml we must think of a possible PRL-producing pituitary tumor, prolactinoma.
Among the causes of hyperPRL we have to highlight:
- Physiological: Pregnancy, lactation, sucking of the nipple for other reasons, thoracic trauma, sleep, stress, sexual intercourse, physical exercise, etc.
- Lesions of the hypothalamus, pituitary stalk and hypophysis: here the most frequent cause is prolactinoma, more frequent in its form smaller than 1cm in diameter (microprolactinoma) than in the macroprolactinma form. But this group also includes compressive lesions or lesions by section of the pituitary stalk, hyperPRL accompanying other brain tumors, hypophysitis, granulomas or trauma affecting this area.
- HyperPRL secondary to drugs. Also very frequent due to the enormous consumption of antipsychotic drugs, antiemetics, antidepressants, opioids and estrogens. Among them, sulpiride stands out.
- HyperPRL secondary to systemic disorders, such as chronic renal failure, hypothyroidism, cirrhosis or convulsions.
- It is worth mentioning the existence of a situation known as macroprolactinemia. Macroprolactin is the union of several PRL molecules to form a large molecule, of high weight, but unable to bind to the receptor and therefore without biological activity. In the analytical analysis we suspect it when there are very high concentrations of PRL, which do not correspond to hypothalamic-pituitary alterations or to the intake of drugs, etc.
All hyperPRL should be studied in order to be able to act etiologically on the cause.
Clinically, hyperPRL that is not very high may not be accompanied by striking symptoms, but it is usual for hyperPRL in women to present with oligomenorrhea or frank amenorrhea, infertility and galactorrhea, and in men with infertility, erectile dysfunction (impotence) and sometimes gynecomastia. In both, if the situation of hypogonadism is maintained, bone decalcification may appear. In the case that the HyperPRL is due to a pituitary tumor (prolactinoma), symptoms secondary to intracranial growth of a tumor will appear: headache and loss of vision fundamentally.
Once the existence of hyperPRL has been confirmed and the existence of macroprolactin has been ruled out, it is necessary to perform a pituitary MRI with contrast to establish whether or not there is a pituitary tumor or pathology in this area. If there is not, we will make differential studies of the other etiological situations described above and if it is not found, we would say that it is a functional hyperPRL, which means a greater hypothalamic-pituitary sensitivity for the production of PRL, perhaps due to a lower dopaminergic effect.
Definition of prolactinoma
Prolactinoma is the most frequent pituitary tumor among pituitary adenomas (40%), occurring in 10 out of every 100,000 men and 30 out of every 100,000 women.
Prolactinomas can be diagnosed as microprolactinomas (1cm). The former remain circumscribed to the sella turcica, giving no compressive symptoms, whereas macroadenomas go beyond the limits of the sella turcica and can compress the pituitary stalk, invade the cavernous sinuses, etc. Only 5% of microadenomas progress to macroadenomas, even 30% of microadenomas cease PRL production spontaneously. Prolactinoma can be part of the serious process known as Multiple Endocrine Neoplasia type I.
Due to the mass effect they are common to men and women; thus we will find:
- Headache, vision alterations (bitemporal hemianopsia, blurred vision, decreased visual acuity), paralysis or paresis of cranial nerves, hydrocephalus, epileptic seizures, hydrocephalus, and a serious complication which is pituitary apoplexy.
The clinical manifestations of hyperPRL are different in men and women:
- In men: decreased libido, impotence and oligozoospermia (due to secondary hypogonadism). Rarely galactorrhea.
- In women: oligomenorrhea/amenorrhea, infertility, loss of libido and galactorrhea.
In children and pubescent girls its presentation is rare, but if present: Growth retardation, pubertal delay and primary amenorrhea are the data of suspicion.
The diagnosis of prolactinoma requires confirming hyperPRL, ruling out other causes of hyperPRL, ruling out macroprolactin, documenting complications and documenting pituitary adenoma with gadolinium MRI.
What is the treatment?
Treatment is primarily medical and rarely surgical.
Medical treatment is specifically based on the use of dopaminergic agonists, of which cabergoline and bromocriptine are the most commonly used, especially the former, while bromocriptine is preferred by some in pregnancy and quinagolide remains as an alternative to the former.
- Cabergoline: the initial dose can be 0.25 to 0.50 mg twice a week, a dose which usually normalizes the function and therefore the PRL figures. But for the tumor to decrease in size, doses of 0.50 to 1 mg 3 times per week are required. Sometimes the tumor disappears with these doses and when treatment is interrupted there is no functional or tumor recurrence.
- Bromocriptine: it was the first agonist we had on the market. It is used at higher doses than cabergoline and its side effects are greater than those of cabergoline. Bromocriptine 2.5 mg every 8 hours controls practically 100% of hyperPRL. To reduce tumor size, doses higher than 15 to 25 mg/day are needed, with considerably more side effects than cabergoline.
- Quinagolide is a non-ergotamine agonist, generally better tolerated than bromocriptine, but not as effective as cabergoline.
In the pregnant woman, we know today that safety with cabergoline is the same as with bromocriptine and that the experience with these drugs is that their studies have shown that they are not accompanied by more miscarriages, pre-term deliveries, multiple pregnancies or congenital malformations than expected in the general population. If dopaminergic agonists are withdrawn at the diagnosis of pregnancy the possibility of tumor growth is negligible in microadenomas, but they grow in up to 23% of macroadenomas. For this reason the current recommendation is to suspend treatment with agonists if the pregnant woman has microprolactinoma and perhaps to maintain agonists if she has macroprolactinoma, in any case treatment should be individualized for each pregnant woman. The controls to see how the prolactinoma is going, if necessary, should be better with MRI than with analytical tests.