Current p SYCHIATRY How to prevent hyperprolactinemia in patients taking antipsychotics Atypical antipsychotics elevate serum prolactin levels at least transiently, and this effect depends on each compound’s dopamine-binding properties. W. Victor R. Vieweg, MD ntipsychotics have long been linked with hyperpro- 1 Professor of psychiatry and internal medicine lactinemia. This phenomenon was first considered Medical College of Virginia A a drug class effect, but the arrival of clozapine, bet- Virginia Commonwealth University, Richmond ter deliniation of dopamine receptor subtypes, and identifica- Antony Fernandez, MD tion of the four principal CNS dopamine pathways revealed that hyperprolactinemia was not a universal consequence of Assistant clinical professor of psychiatry Medical College of Virginia antipsychotic use. Virginia Commonwealth University We now know that most atypical antipsychotics are less Psychiatry Service McGuire VA Medical Center, Richmond likely to induce hyperprolactinemia than older antipsy- chotics, but we don’t know why. The most likely explanation is that most of the newer agents block dopamine D2 mini- mally in the hypothalamic tuberoinfundibular pathway.2 Evidence is emerging that atypical agents elevate serum pro- lactin levels at least transiently—but usually less than typical antipsychotics—and this effect varies, depending on each compound’s dopamine-binding properties. continued on page 58 VOL. 2, NO. 2 / FEBRUARY 2003 57 Hyperprolactinemia Figure 1 CHANGES IN PROLACTIN LEVELS OVER TIME Reproductive period post-reproductive 200 Breast feeding 100 Mean serum prolactin concentrations Peak 30 minutes from puberty until menopause. after suckling For nursing women, the length of the arrows depicts the increase in serum Non-lactating prolactin concentration associated with 20 each episode of suckling. The Y-axis expresses serum prolactin concentration 10 Prolactin (ng/ml or mg/l) in both ng/ml and mg/l. 5 Pregnancy Puerperium Source: Adapted and reprinted with permission from Friesen HG. Human prolactin. Ann R Coll Phys Surg Female Can 1978;11:275-81. Male 12 50 60 Age (years) Prolactin physiology ing in higher prolactin levels in premenopausal women than Prolactin—a large peptide containing 198 amino acids—was in men. the first anterior pituitary gland hormone to be isolated in pure form.3 Despite its molecular weight of approximately Prolactin secretion 23,000, the hormone easily crosses the blood-brain barrier.4 Normally, prolactin is secreted in pulses—approximately 14 Similar to other anterior in a 24-hour period, with an interpulse interval of about 80 pituitary hormones, prolactin is minutes.5 A bimodal daily pattern of secre- secreted episodically. Its secretion is tion is superimposed upon this pattern, with inhibited by dopamine release from the The hypothalamus peak levels at night and trough levels at hypothalamus and enhanced by different noon. Stress—including surgery and gener- prolactin-releasing factors. Prolactin is the blunts prolactin al anesthesia, exercise, and hypoglycemia— only anterior pituitary hormone that is pro- secretion primarily via may transiently increase prolactin levels. duced by tuberoinfundibular neurons governed dopamine release Endocrine regulation. Estrogen modulates by dopamine.5 Dopamine stimulates lactotrope the response of hypothalamic factors that D2 receptors and inhibits adenylate cyclase, control prolactin production. It stimulates resulting in reduced prolactin synthesis and decreased prolactin response to dopamine and release. increased response to thyrotropic-releasing hormone. Serum prolactin concentrations change Insulin also stimulates prolactin secretion—probably by during various life stages (Figure 1).6 Estrogen’s effects on inducing hypoglycemia. Serum insulin level changes within prolactin gene expression regulate prolactin synthesis, result- physiologic ranges appear to affect prolactin regulation. 58 Current VOL. 2, NO. 2 / FEBRUARY 2003 p SYCHIATRY Current p SYCHIATRY Neuroendocrine regulation. The hypothalamus Table 1 blunts prolactin secretion primarily via COMMON CLINICAL EFFECTS IN PATIENTS dopamine release. This modulation occurs prin- WITH HYPERPROLACTINEMIA cipally within the tuberoinfundibular dopamine pathway. The D2 subtype is the only dopamine Organ or syndrome Clinical effects receptor in the anterior pituitary gland: • a decrease in dopamine levels reaching the Behavior Direct effects anterior pituitary gland increases the num- Secondary effects due to ber of D2 receptors hypogonadism • to a lesser extent, estrogen decreases the Possible cognitive impairment number of D2 receptors. Bones Decreased bone mineral density due Dopamine-modulated reductions in action to testosterone or estrogen deficits potential discharge from lactotrophs and in cal- cium flux leads to decreased intracellular calci- Breast Engorgement um and decreased prolactin secretion.5 Lactation unrelated to breast feeding Most hormones are target-organ agents and are regulated via a feedback loop that includes Cardiovascular system Possible adverse effects due to low the peripheral circulation. Prolactin, however, is levels of testosterone or estrogen not considered to have a specific target organ. It Menstrual function Absence of ovulation is its own inhibiting factor, using an autoregula- Amenorrhea tory, pituitary-to-hypothalamus short-loop feed- back circuit. Sexual function Reduced libido For example, prolactin-secreting tumors or Reduced arousal drugs that elevate hormone levels lead to an Orgasmic dysfunction increase in dopamine. In contrast, hypophysec- tomy decreases dopamine. In this setting, pro- Source: Adapted and reprinted with permission from Dickson RA, Glazer WM. Neuroleptic- induced hyperprolactinemia. Schizophr Res 1999;35(suppl):S75-S86. lactin injections will restore normal dopamine levels. Prolactin-releasing factors include thy- rotropic-releasing hormone, vasoactive intestinal peptide, Diagnosis of hyperprolactinemia and serotonin. Pathologic hyperprolactinemia is defined as consistently ele- vated serum prolactin concentration (>20 ng/ml) in the Prolactin’s actions absence of pregnancy or postpartum lactation. Because of the Many tissues—including breast, liver, ovary, testis, and pulsatile nature of prolactin secretion, a definitive diagnosis prostate—have prolactin receptors. These receptors are stim- of hyperprolactinemia requires three serum prolactin levels ulated with equal potency by prolactin and growth hormone. taken on different mornings. The principal site of prolactin action is the mammary Clinical presentation. Hyperprolactinemia—the most com- gland, where the hormone initiates and maintains lactation mon hypothalamic-pituitary disturbance—usually presents after childbirth. Major stimuli for breast development are with clinical features of gonadal dysfunction (Table 1).8 estrogen, progesterone, prolactin, and placental mammotrop- Symptoms and signs related to a brain mass—headache, ic hormones. Other stimuli include insulin, cortisol, and thy- visual field disturbances, ophthalmoplegia, and reduced visu- roid hormone.7 al acuity—may predominate with a large pituitary tumor. Gonadotropin secretion is influenced by prolactin via The patient may first present to a primary care physician or the hypothalamus. Prolactin-mediated inhibition of luteiniz- to a clinical specialist, such as a gynecologist, neurologist, ing hormone-releasing hormone secretion impairs ophthalmologist, pediatrician, psychiatrist, or urologist. gonadotropin release and inhibits gonadal function. Thirty to 80% of women with hyperprolactinemia devel- VOL. 2, NO. 2 / FEBRUARY 2003 59 Hyperprolactinemia op galactorrhea,9 although some women with galactorrhea have long-term effects on bone density. Trabecular bone mass have normal prolactin levels. Men with hyperprolactinemia has been found to be reduced in young women with amenor- usually have gonadal dysfunction, which unfortunately is rhea secondary to hyperprolactinemia. This trabecular often attributed to “psychogenic” causes. Particularly in men, osteopenia is reversible—spinal bone density decreases pro- prolactin is implicated in the control of libido. gressively without treatment and improves when hyperpro- Causes. Hyperprolactinemia may be caused by any process lactinemia is treated. Menstrual function appears to best pre- that inhibits dopamine synthesis, the neurotransmitter’s dict risk of progressive spinal osteopenia in women with transport to the anterior pituitary gland, or its action at the hyperprolactinemia. Estradiol level is a stronger predictor of lactotrope dopamine receptors (Table 2).9 In this article, we clinical course than is the prolactin level.10 will limit our discussion to antipsychotic drugs. Estrogen and prolactin. During pregnancy, the rise in estro- Antipsychotic drugs and hyperprolactinemia gen levels probably stimulates an increase in prolactin. Among the four principal dopamine pathways in the brain, Increased prolactin levels are also found in women taking the tuberoinfundibular pathway is a system of short axons at the base of the hypothalamus that Table 2 releases dopamine into the portal CAUSES OF PATHOLOGIC HYPERPROLACTINEMIA veins of the pituitary gland. Terminals in the median eminence Hypothalamic disease Tumor, infiltrative disease, pseudotumor of the hypothalamus release cerebri, cranial radiation dopamine that travels down the pituitary stalk in the portal veins. Pituitary disease Prolactinoma, acromegaly, Cushing’s Typical antipsychotics block disease,