Physiology

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”).

Serum prolactin levels (mean plus or minus standard error [±SE]) in women with prolactinoma (N = 20) and idiopathic (N = 30) and stress-related ( N = 20) hyperprolactinemia (H) before (pretest I and II) and during hyperprolactinemia test. Differences (* P < .01) are in relation to time zero values. (Mean prolactin values among groups were also significantly different [ P < .01] at all times.)

(From Muneyyirci-Delale O, Goldstein D, Reyes FI, et al. Diagnosis of stress-related hyperprolactinemia: evaluation of the hyperprolactinemia rest test. N Y State J Med. 1989;89(4):205-208.)

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.

Galactorrhea

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.

Fat droplets seen under microscope from a patient with galactorrhea.

(From Kletzky OA, Davajan V. Hyperprolactinemia: diagnosis and treatment. In: Mishell DR, Davajan V, Lobo RA, eds. Infertility, Contraception and Reproductive Endocrinology. 3rd ed. Cambridge, MA: Blackwell Scientific; 1991.)

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.

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.

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

Hypothalamic causes

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.

Pituitary causes

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.

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