Astrid L. Libman, Julio Libman 

Galactorrhea and amenorrhea syndrome is a clinical picture characterized by menstrual disturbances, infertility and / or galactorrhea that occurs outside the normal lactation period, due to increased prolactin production.

Pathophysiology

Prolactin is a protein hormone secreted by eosinophilic cells of the anterohypophysis. Its secretion is increased by a variety of stimuli: stress, periods of deep tension, exercise, hypoglycemia, intercourse in women, and nipple sucking. The response to nipple and breast stimulation requires an intact afferent neural pathway from these structures to the CNS. Its plasma level varies throughout the day, with a nadir between 10 and 12 hours and a marked increase around 2 hours after initiating sleep.

The main functions of prolactin are the initiation and maintenance of lactation. The development of the normal non-lactating female breast depends primarily on estradiol, which induces the growth, division, and elongation of the ducts and the maturation of the nipple. The development of the alveoli requires the synergistic action of progesterone and estrogens. For the formation of milk, the preparation of the breast by these two hormones is necessary, the permissive action of glucocorticoids, GH, insulin and thyroxine, and the action of specific lactogenic hormones, including prolactin, which plays a role. critical in initiating and maintaining breastfeeding, whether normal or inappropriate. In humans, prolactin is necessary for the development of the breast, but by itself it is not sufficient for its maturation; This generally means that men and women with hyperprolactinemia do not have clinical signs of breast enlargement. The fact that milk production requires exposure of the breast to appropriate levels of estrogen means that a significant proportion of women and men with hyperprolactinemia do not have galactorrhea. In this sense, and regarding the inhibitory effect of hyperprolactinemia on the reproductive axis in both sexes, prolactin seems to inhibit the production of GnRH in the hypothalamus, preventing the release of LH and FSH, and would also block ovarian steroidogenesis. it causes a significant proportion of women and men with hyperprolactinemia to be free from galactorrhea. In this sense, and regarding the inhibitory effect of hyperprolactinemia on the reproductive axis in both sexes, prolactin seems to inhibit the production of GnRH in the hypothalamus, preventing the release of LH and FSH, and would also block ovarian steroidogenesis. it causes a significant proportion of women and men with hyperprolactinemia to be free from galactorrhea. In this sense, and regarding the inhibitory effect of hyperprolactinemia on the reproductive axis in both sexes, prolactin seems to inhibit the production of GnRH in the hypothalamus, preventing the release of LH and FSH, and would also block ovarian steroidogenesis.

Prolactin is the only pituitary hormone whose secretion is subject to a predominantly inhibitory tone by the hypothalamus, and in this sense, dopamine is the main physiological inhibitor. This explains, on the one hand, the frequent appearance of hyperprolactinemia in diseases of the hypothalamus or in processes that injure the pituitary stalk, and on the other, its production as a result of the administration of drugs that affect dopaminergic neurotransmission. Reserpine, which is a catecholamine depletor, alpha methyldopa, which is a false neurotransmitter, and haloperidol, metoclopramide, and chlorpromazine, all dopamine antagonists, cause hyperprolactinemia. Estrogens, including the small amount found in oral contraceptives, stimulate prolactin secretion.

The observation that TRH stimulates prolactin secretion shows the relationship between prolactin and thyroid function. In hypothyroidism, there is a discrete hyperplasia of prolactin cells, which explains the association of galactorrhea and thyroid hypofunction. Pituitary adenomas are associated with hyperprolactinemia and galactorrhea, either because the adenoma produces the hormone or because it compresses the hypothalamic-pituitary portal system, with decreased dopaminergic inhibition.

Symptoms and signs

Galactorrhea can be unilateral or bilateral, spontaneous or by expression of the breast. One-fifth of women with prolactin-producing pituitary adenomas do not have galactorrhea, which is due to concomitant estrogen deficiency in these patients. A relatively large proportion of women with oligohypomenorrhea or secondary amenorrhea have hyperprolactinemia. If galactorrhea and menstrual alterations coexist, hyperprolactinemia will be found in 80% of cases. A galactorrhea with normal ovulatory cycles is usually associated with statistically normal prolactin levels; In other cases of galactorrhea with normal ovulatory cycles that are associated with elevated prolactins by RIA, a high molecular weight prolactin has been found, very little biologically active, but that reacts in the RIA with the specific antibody. In an appreciable number of patients it is not possible to find a demonstrable cause of hyperprolactinemia, which is attributed to hypothalamic functional alterations.

On the other hand, if it is a pituitary microadenoma, the symptoms and signs of pituitary tumor syndrome usually do not exist. In this sense, men with prolactinic adenomas present, at the time of diagnosis, larger tumors and higher levels of prolactin, perhaps because they consult the doctor later for psychological reasons and / or because of the less striking onset of endocrine manifestations (for eg: impotence and sterility).

In a patient with galactorrhea and / or amenorrhea and / or sterility, in whom hyperprolactinemia is found, a careful questioning should be made about the intake of drugs and contraceptives.

Study methodology

Endocrine evaluation. Basal prolactin. Baseline prolactin quantification is probably one of the best methods to differentiate tumor hyperprolactinemia from functional hyperprolactinemia. Due to its pulsatile secretion and the numerous factors that can influence its plasma levels, it is essential to obtain three samples separated by 30-minute intervals (prolactin pool) or over the course of several days. Normal values ​​are below 25 ng / ml in women and 20 ng / ml in men. The majority of patients with prolactins greater than 100 ng / ml, and practically 100% with figures above 250 ng / ml, have pituitary adenomas. Although a significant proportion of patients with concentrations between 25 and 100 ng / ml have pituitary tumors, the majority of functional or drug-induced hyperprolactinemias fall within this range.

Thyroxine (T4) and thyrotrophin (TSH) dosage. They should be routine in all patients with hyperprolactinemia, since the manifestations of hypothyroidism can be very subtle and go unnoticed.

Neuroradiological evaluation. MRI provides an adequate image of the hypothalamus and pituitary to determine the presence of a microadenoma, macroadenoma or other lesions at the hypothalamic level. In general, there tends to be a good correlation between adenoma size and prolactin levels. The coexistence of a large adenoma with not greatly increased prolactin concentrations suggests that it is not a hormone-producing tumor and that the increase in prolactin is attributable to compression of the pituitary stalk.