The main symptoms of hyperprolactinemia are galactorrhea and amenorrhea, the latter caused by alterations in normal gonadotropin-releasing hormone release.
Pathologic causes of hyperprolactinemia include pharmacologic agents, hypothyroidism, chronic renal disease, chronic neurostimulation of the breast, hypothalamic disease, and pituitary tumors.
Most macroadenomas enlarge with time; almost all microadenomas do not.
The dopamine agonist of choice is cabergoline because of increased efficacy and fewer side effects.
Surgical treatment of prolactinomas is recommended only for patients who fail to respond or do not comply with medical management.
Prolactin (PRL) is a polypeptide hormone containing 198 amino acids and with a molecular weight (MW) of 22 kDa. It circulates in different molecular sizes : a monomeric (small) form (MW = 22 kDa), a polymeric (big) form (MW = 50 kDa), and an even larger polymeric (big-big) form (MW >100 kDa). Big PRL is presumed to be a dimer, and big-big PRL may represent an aggregation of monomeric molecules. The larger forms also contain added sugar moieties (glycosylation), which decreases biologic activity. The small form is biologically active, and approximately 80% of the hormone is secreted in this form.
PRL is synthesized and stored in the pituitary gland in chromophobe cells called lactotrophs, which are located mainly in the lateral areas of the gland. PRL is encoded by its gene (10 kb) on chromosome 6. At the molecular level, it is stimulated and suppressed by a number of factors. The principal stimulating factor is thyroid-releasing hormone (TRH), and the major inhibiting factor is dopamine , which has been suggested to be the prolactin-inhibiting factor (PIF). Estrogen also improves PRL secretion by enhancing the effects of TRH and inhibiting the effects of dopamine. A potential direct effect may also be mediated via galanin. The principal receptor with which dopamine interacts is D2, which is the target for various dopamine agonists used in the treatment of hyperprolactinemia .
PRL is normally present in measurable amounts in serum, with mean levels of approximately 8 ng/mL in adult women. It circulates in an unbound form, has a 20-minute half-life, and is cleared by the liver and kidney. The main function of PRL is to stimulate the growth of mammary tissue and to produce and secrete milk into the alveoli; thus it has mammogenic and lactogenic functions. Specific receptors for PRL are present in the plasma membrane of mammary cells and in many other tissues.
PRL is synthesized in decidualized stroma of endometrial tissue. From these tissues, PRL is secreted into the circulation and, in the event of pregnancy, into the amniotic fluid. The control of decidual PRL is different from that of the pituitary and does not respond to dopamine.
PRL synthesis and release from the lactotrophs are controlled by central nervous system neurotransmitters, which act on the pituitary via the hypothalamus. The major control mechanism is inhibition, because pituitary stalk section results in increased PRL secretion. It appears that the major physiologic inhibitor of PRL release is the neurotransmitter dopamine (PIF), which acts directly on the pituitary gland. There are specific dopamine receptors on the lactotrophs, and dopamine inhibits PRL synthesis and release in pituitary cell cultures. Although a hypothalamic prolactin-releasing factor (PRF) has not been isolated, it is known that the neurotransmitter serotonin and thyrotropin-releasing factor stimulate PRL release. Because the latter stimulates PRL release only minimally unless infused, it appears that serotonin is a PRF or is responsible for its secretion. The rise in PRL levels during sleep appears to be controlled by serotonin.
PRL is secreted episodically and serum levels fluctuate throughout the day and throughout the menstrual cycle, with peak levels occurring at midcycle. Although changes in PRL levels are not as marked as the pulsatile episodes of luteinizing hormone (LH), estrogen stimulates PRL production and release. Under the influence of estrogen, PRL levels increase in girls at the time of puberty; there is a slight decline in levels after menopause.
During pregnancy, as estrogen levels increase, there is a concomitant hypertrophy and hyperplasia of the lactotrophs. The maternal increase in PRL levels occurs soon after implantation, concomitant with the increase in circulating estrogen. Circulating levels of PRL steadily increase throughout pregnancy, reaching approximately 200 ng/mL in the third trimester; the rise is directly related to the increase in circulating levels of estrogen; however, there is a wide range of values of PRL in pregnancy, and values as high as 400 ng/mL can be found in normal pregnancy. Despite the elevated PRL levels during pregnancy, lactation does not occur because estrogen inhibits the action of PRL on the breast, most likely blocking PRL’s interaction with its receptor. A day or two after delivery of the placenta, estrogen and PRL levels decline rapidly and lactation is initiated. PRL levels reach basal levels in nonnursing women in 2 to 3 weeks. Although basal levels of circulating PRL decline to the nonpregnant range approximately 6 months after parturition in nursing women, after each act of suckling, PRL levels increase markedly and stimulate milk production for the next feeding.
Nipple and breast stimulation also increase PRL levels in a woman who is not pregnant, as does trauma to the chest wall. Other physiologic stimuli that increase PRL release are exercise, sleep, and stress. In addition, PRL levels normally rise after ingestion of the midday meal. Thus PRL levels normally fluctuate throughout the day, with maximal levels occurring during the night while asleep and a smaller increase occurring in the early afternoon. When the amount measured in the circulation in a woman who is not pregnant exceeds a certain level, usually 20 to 25 ng/mL, the condition is called hyperprolactinemia. The optimal time to obtain a blood sample for assay to diagnose hyperprolactinemia is in the fasting state.
The most common cause of slightly elevated PRL levels is stress , particularly the stress caused by visiting the physician’s office. All women with initial PRL levels lower than 50 ng/mL should have subsequent samples drawn 60 minutes after resting in a quiet room to determine whether true pathologic hyperprolactinemia is present. Fig. 37.1 depicts normalization of PRL only in those with stress-related elevations, which occurred during a 60-minute rest period (referred to in the study as a “test”).
Hyperprolactinemia can produce disorders of gonadotropin sex steroid function, resulting in menstrual cycle derangement (oligomenorrhea and amenorrhea) and anovulation, as well as inappropriate lactation, or galactorrhea. The mechanism whereby elevated PRL levels interfere with gonadotropin release appears to be related to abnormal gonadotropin-releasing hormone (GnRH) release. Women with hyperprolactinemia have abnormalities in the frequency and amplitude of LH pulsations, with a normal or increased gonadotropin response after GnRH infusion.
This abnormality of GnRH cyclicity thus inhibits gonadotropin release but not its synthesis. The reason for this abnormal secretion of GnRH is an inhibitory effect of dopamine and opioid peptides at the level of the hypothalamus. In addition, elevated PRL levels have been shown to interfere with the positive estrogen effect on midcycle LH release. It has also been shown that elevated levels of PRL directly inhibit basal and gonadotropin-stimulated ovarian secretion of estradiol and progesterone; however, this mechanism is probably not the primary cause of anovulation because women with hyperprolactinemia can have ovulation induced with various agents, including pulsatile GnRH.
The clinician should measure serum PRL levels in all women with galactorrhea, as well as those with oligomenorrhea and amenorrhea not explained by another reason such as ovarian failure (elevated levels of follicle-stimulating hormone [FSH]). Hyperprolactinemia has been reported to be present in 15% to 20% of women who present with menstrual disturbances.
Special cases in the measurement of prolactin: Hook effect and macroprolactin
Because of possible aggregation of molecular forms of PRL when levels are high, if a tumor (adenoma) is suspected and values of PRL are only mildly elevated, the test should be repeated in a diluted sample. This has been called the hook effect and is explained by high endogenous levels of PRL binding up all the assay antibody, leaving an inadequate quantity for the assay ( ). The laboratory should be asked to dilute the sample before assay when PRL levels are unexpectedly low.
The opposite occurrence was mentioned earlier, when PRL is found to be elevated in a woman who is normal clinically. This is due to “clumping” of glycosylated PRL with immunoglobulin and can be corrected by gel electrophoresis or merely by adding polyethylene glycol to the serum, which precipitates the abnormal forms ( ).
Galactorrhea is defined as the nonpuerperal secretion of watery or milky fluid from the breast that contains neither pus nor blood. The fluid may appear spontaneously or after palpation. To determine whether galactorrhea is present, the clinician should palpate the breast, moving from the periphery toward the nipple in an attempt to express any secretion. The diagnosis of galactorrhea can be confirmed by observing multiple fat droplets in the fluid when examined under low-power magnification ( Fig. 37.2 ). The incidence of galactorrhea in women with hyperprolactinemia has been reported to range from 30% to 80%, and these differences probably reflect variations in the techniques used to detect mammary excretion. Unless there has been continued breast stimulation after a pregnancy, the presence of galactorrhea serves as a biologic indicator that the PRL level is abnormally elevated.
Causes of hyperprolactinemia
Pathologic causes of hyperprolactinemia, in addition to a PRL-secreting pituitary adenoma ( prolactinoma ) and other pituitary tumors that produce acromegaly and Cushing disease, include hypothalamic disease, various pharmacologic agents, hypothyroidism, chronic renal disease, and any chronic type of breast nerve stimulation, such as may occur with thoracic operation, herpes zoster infection, or chest trauma. Box 37.1 lists the causes of hyperprolactinemia.
Empty sella syndrome
Nonsecreting pituitary adenomas
Pituitary stalk section
See Box 37.2
Chest wall lesions
Spinal cord lesions
Chronic renal failure
Polycystic ovary syndrome
One of the most common causes of galactorrhea and hyperprolactinemia is the ingestion of pharmacologic agents, particularly tranquilizers, narcotics, and antihypertensive agents ( Box 37.2 ). Of the tranquilizers, the phenothiazines and diazepam can produce hyperprolactinemia by depleting the hypothalamic circulation of dopamine or by blocking its binding sites and thus decreasing dopamine action.
Anesthetics, including cocaine
Dopamine receptor antagonists
SSRIs, Selective serotonin reuptake inhibitors.
The tricyclic antidepressants block dopamine uptake, and propranolol, haloperidol, phentolamine, and cyproheptadine block hypothalamic dopamine receptors. The antihypertensive agent reserpine depletes catecholamines, and methyldopa blocks the conversion of tyrosine to dihydroxyphenylalanine (dopa). Ingestion of oral contraceptive steroids can also mildly increase PRL levels, with a greater incidence of hyperprolactinemia occurring with older, higher-estrogen formulations. Nevertheless, galactorrhea does not usually occur during oral contraceptive ingestion because the exogenous estrogen blocks the binding of PRL to its receptors.
Primary hypothyroidism can also produce hyperprolactinemia and galactorrhea because of decreased negative feedback of thyroxine (T 4 ) on the hypothalamic-pituitary axis. The resulting increase in TRH stimulates PRL secretion and thyroid-stimulating hormone (TSH) secretion from the pituitary. Approximately 3% to 5% of individuals with hyperprolactinemia have hypothyroidism. Therefore TSH, the most sensitive indicator of hypothyroidism, should be measured in all individuals with hyperprolactinemia .
Hyperprolactinemia can occur in those with abnormal renal disease resulting from decreased metabolic clearance and increased production rate. The cause of the latter is unknown.
Mild hyperprolactinemia (30 to 40 ng/mL) may occur in women with polycystic ovary syndrome (PCOS). This occurs in up to 30% of women and may be related to the chronic state of unopposed estrogen stimulation.
Central nervous system disorders
Diseases of the hypothalamus that produce alterations in the normal portal circulation of dopamine can result in hyperprolactinemia. These include craniopharyngioma and infiltration of the hypothalamus by sarcoidosis, histiocytosis, leukemia, or carcinoma. All these conditions are rare, with craniopharyngioma being the most common. These tumors arise from remnants of Rathke’s pouch along the pituitary stalk. Grossly they can be cystic, solid, or mixed, and calcification is usually visible on a radiograph. They are most often diagnosed during the second and third decades of life and usually result in impairment of secretion of several pituitary hormones.
Various types of pituitary tumors, lactotroph hyperplasia, and the empty sella syndrome can be associated with hyperprolactinemia. It has been estimated that as many as 80% of all pituitary adenomas secrete PRL. The most common pituitary tumor associated with hyperprolactinemia is the prolactinoma, arbitrarily defined as a microadenoma if its diameter is less than 1 cm and as a macroadenoma if it is larger ( Fig. 37.3 ). Hyperprolactinemia has been reported to occur in approximately 25% of those with acromegaly and 10% of those with Cushing disease, indicating that these pituitary adenomas, which mainly secrete growth hormone (GH) and adrenocorticotropic hormone (ACTH), often also secrete PRL. Hyperplasia of lactotrophs has been reported to occur in approximately 8% of pituitary glands examined at autopsy. Individuals with hyperplasia of the lactotrophs cannot be distinguished from those having a microadenoma by any clinical, laboratory, or radiologic method. The diagnosis can be made only at the time of surgical exploration of the pituitary gland. Pituitary enlargement with suprasellar extension caused by lactotroph hyperplasia has been reported. Functional hyperprolactinemia is the term used for the clinical diagnosis of cases of elevated PRL levels without imaging evidence of an adenoma.