Minimizing the impact of elevated prolactin in children and adolescents
Early identification, treatment can help lessen impaired development, other sequelae
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Hyperprolactinemia—increased levels of prolactin (PRL) in the blood that may be caused by hypothyroidism, pituitary disorders, atypical antipsychotics, or other conditions and medications—has numerous physiologic manifestations, including amenorrhea, infertility, abnormal bone resorption, increased risk of breast cancer, and compromised immunity. Evaluation of hyperprolactinemia in patients taking psychotropics—particularly children and adolescents, in whom hyperprolactinemia’s adverse effects may be more pronounced—should include an examination for signs and symptoms of hyperprolactinemia and assessment to rule out other potential causes. This article reviews hyperprolactinemia’s causes, symptoms, evaluation, and treatment, with an emphasis on younger patients.
Causes of hyperprolactinemia
PRL is a circulating autocrine or paracrine factor (Box 1).1,2 Its primary biologic activities can be broadly divided into 4 areas: reproductive, metabolic, osmoregulatory, and immunoregulatory (Box 2).1,3-8
- prolactinomas, which usually present as incidental findings on a brain CT or MRI or with symptoms of tumor mass
- a craniopharyngioma or other tumor that compresses the pituitary stalk or hypothalamus and interrupts the hypothalamic-dopa minergic inhibition of PRL release.10
Primary thyroid failure (hypothyroidism) can produce a compensatory increase in the discharge of central hypothalamic thyrotropin-releasing hormone, resulting in increased stimulation of PRL secretion.10
Conventional antipsychotics. The anti-psychotic potency of phenothiazines, thioxanthenes, butyrophenones, and dibenzoxazepines generally parallels their potency in increasing PRL levels.9 Although a dose-response relationship between PRL concentrations and conventional antipsychotics is likely, immediate and pronounced increases in PRL can occur even with low doses.
Prospective studies have shown that 3 to 9 weeks of treatment with an antipsychotic such as chlorpromazine increased mean baseline PRL levels up to 10-fold, even at therapeutic doses.11 Conventional antipsychotics can cause marked increases in PRL, probably by blocking dopamine receptors in the tuberoinfundibular tract.12 The blockage of D2 receptors removes the main inhibitory influence on PRL secretion and is associated with increased PRL release.12
Atypical antipsychotics cause less elevation in PRL levels than conventional anti-psychotics. This may be because of their:
- highly selective mesolimbic and meso-cortical dopamine receptor antagonism, which spares dopamine blockade within the tuberoinfundibular tract
- relatively lower D2 receptor affinity.11
Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) have a high affinity for D2 receptors and thus have potent D2 antagonistic effects.12,13 At dosages of 8 mg/d to 11.8 mg/d, risperidone and paliperidone are associated with the greatest increase in PRL levels among atypical antipsychotics.14
The rate of risperidone metabolism depends on the patient’s cytochrome P (CYP) 2D6 liver enzyme genotype. “Extensive” CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas “poor” CYP2D6 metabolizers convert it much more slowly. Six percent to 8% of white individuals and a very low percentage of Asians have little or no CYP2D6 activity and are “poor metabolizers.” CYP2D6 also is inhibited by various substrates and nonsubstrates, notably quinidine. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of the active moiety after single and multiple doses are similar in extensive and poor metabolizers.15
Clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole are associated with a much lower risk of PRL elevation than risperidone. In an 8-week open-label trial, aripiprazole (mean dose 9.4±4.2 mg/d), did not increase serum PRL in 15 children and adolescents.2
Ziprasidone may cause only transient PRL elevation.16 PRL abnormalities may be least likely with clozapine and quetiapine, possibly because of their relatively lower D2 receptor affinity. Amenorrhea, galactorrhea, or inhibition of ejaculation have not been reported with the use of these 2 antipsychotics.16 Patients who developed hyperprolactinemia on conventional anti-psychotics have been treated subsequently with clozapine without hyperprolactinemia recurrence.16 Iloperidone has been associated with decreased PRL levels.17
Antidepressants that work by blocking catecholamine reuptake also cause hyperprolactinemia. This increase may be related to the antidopaminergic, stimulatory effects of estrogen. Numerous cases of galactorrhea and amenorrhea have been reported with the use of selective serotonin reuptake inhibitors (SSRIs).16 Galactorrhea has been reported in women who took venlafaxine.12 Less is known about the effects of nefazodone or bupropion on serum PRL. Mirtazapine can decrease serum PRL in men, probably through indirect 5-HT1 agonist and 5-HT2 and 5-HT3 antagonist activity.16
PRL elevation is greater in children and adolescents than adults because of increased density of D2 receptors in the developing striatum and differential D2 receptor sensitivity in the tuberoinfundibular tract.16 Unfortunately, few studies have examined the consequences of elevated PRL in children and adolescents.
What controls production of prolactin?
Prolactin (PRL) is a lactogenic polypeptide hormone with a structure that resembles human growth hormone and human placental lactogen. A single gene on chromosome 6 encodes PRL, which is composed of 199 amino acids.1
PRL is produced primarily by lactotroph cells in the anterior pituitary gland, but also is produced and is active in breast tissue and mammary glands, placenta and decidua, bone marrow cells, lymphocytes (T cells and B cells), and other tissues. It has >300 biologic activities.1
PRL acts primarily through receptors that belong to the large class-1 cytokine receptor superfamily. PRL receptors have multiple isoforms in many different tissues.
Like most anterior pituitary hormones, PRL is under dual regulation by hypothalamic hormones delivered via the hypothalamic-pituitary portal circulation. Its production is stimulated and inhibited by several molecular factors. Under most conditions the predominant signal for PRL secretion from the pituitary is under inhibitory control. This is primarily mediated by the neurotransmitter dopamine, which is a tonic inhibitor of PRL expression and thus prevents its release. Other inhibitors of PRL are triiodothyronine (T3) and somatostatin.2 Molecular stimulators of PRL production include thyrotropin-releasing factor, vasoactive intestinal peptide, peptide histidine isoleucine, gonadotropin-releasing hormone, and estrogen. These 5 molecular stimulators all enhance the growth of PRL-producing cells.1 The balance between these stimulatory and inhibitory signals determines the amount of PRL released from the anterior pituitary.
Prolactin: A versatile hormone with many roles
Prolactin (PRL) is best known for its regulatory role in reproductive processes. It inhibits secretion of the pituitary hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), which are responsible for gonadal function. PRL also influences normal breast development, lactation following childbirth, and corpus luteum development. It plays a critical role in inducing and maintaining mammary epithelial cell growth and differentiation.1
A recently observed correlation between elevated plasma PRL and breast cancer development suggests a mitogenic action in breast tissue. A prospective, case-control study of 851 women from the Nurses’ Health Study cohort found a “modestly” increased relative risk of postmenopausal breast cancer associated with PRL plasma concentrations (1.34; 95% confidence interval, 1.02 to 1.76).3
PRL also acts as a physiologic sensor during lactation. It regulates ductal side branching and directly controls lobuloalveolar development and lactogenesis (synthesis of milk) in breast tissue. PRL is stimulated by suckling; it responds to demands for milk production by partitioning nutrients such as calcium away from adipose tissue and into the mammary glands.1,4
In reproduction, PRL can have a luteotropic or luteolytic action, depending on the stage of the reproductive cycle. It negatively modulates LH and FSH secretion by suppressing gonadotropin-releasing hormone and as a result suppresses ovulation during lactation.3 PRL also maintains luteal vascularization in early pregnancy.1
PRL also has a role in bone development and bone mass maintenance. It has a direct inhibitory effect on osteoblast function, possibly through an effect on estrogen.5 Although the mechanism is unclear, sustained plasma PRL elevation decreases bone formation, leading to reduced bone mineral density and increased risk of hip fracture.6
PRL is a stimulatory modulator of immune function and may be a “stress hormone.” It is widely produced by lymphocytes. PRL and its receptors are expressed on diverse bone marrow-derived human cell types, including B cells, T cells, monocytes, natural killer cells, and cluster of differentiation 34 (CD34) human stem cells.7 The widespread expression of PRL receptors on hematopoietic and immune cells implies a role in immunohematopoietic system development.
Other functions of PRL include regulation of pancreatic islets growth and function during the perinatal period; osmoregulation in mammary glands, amniotic membranes, and the intestinal epithelial membrane; and maintenance of positive calcium deposition.1 As a potent platelet aggregation co-activator, prolactin also may be a risk factor for both arterial and venous thrombosis.8
Causes of hyperprolactinemia
Conventional antipsychotics (phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines)
Atypical antipsychotics (risperidone, olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole, paliperidone)
SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram)
Antiretroviral agents (ritonavir, indinavir, zidovudine)
Gastrointestinal agents (omeprazole, ranitidine, cimetidine, famotidine)
Other medications (oral contraceptives, verapamil, methyldopa, reserpine, triptorelin, bendroflumethiazide)
Tumors (prolactinoma, craniopharyngioma, other cerebral tumor)
Ectopic prolactin synthesis (bronchial carcinoma, acromegaly, empty sella syndrome, polycystic ovarian syndrome)
Chronic renal failure
Primary thyroid failure
Physiological causes (pregnancy, lactation, stress, sleep, sexual intercourse, head injury, surgery)
SSRIs: selective serotonin reuptake inhibitors
Relative risk of hyperprolactinemia with common psychotropics
Effect on prolactin serum levels
0: no hyperprolactinemia effect; +/-: increased but not to abnormal levels; +: increased to abnormal in small percentage of patients; ++: increased to abnormal in >50% of patients; CR: isolated case reports of hyperprolactinemia but generally no increase to abnormal
Adenomas. Primary hyperprolactinemia related to excessive secretion from the pituitary and other tissues causes multiple clinical effects, including:
- amenorrhea, oligomenorrhea, anovulatory cycles, galactorrhea, breast pain, breast enlargement, infertility, hirsutism, and loss of libido in females
- impotence, loss of libido, decrease in seminal fluid volume, galactorrhea, and gynecomastia in males.12
Preclinical studies of risperidone suggested an association with pituitary adenomas in female mice.18 To determine if there was a similar association in humans, Szarfman et al18 retrospectively evaluated data on 7 antipsychotics—aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol—and found 77 pituitary tumors associated with use of these medications. Risperidone was associated with 54 of the pituitary tumors—including 3 in adolescents age 14 to 16. No pituitary tumors were reported with aripiprazole. Approximately one-half of the pituitary tumors were benign. Symptoms included visual field defects, headaches, pituitary hemorrhage, convulsions, and coma.
Other adverse effects reported in the study were hyperprolactinemia, galactorrhea, amenorrhea, and gynecomastia. The incidence of adverse effects with risperidone was >10-fold higher than with haloperidol or olanzapine and >25-fold higher than with clozapine, ziprasidone, quetiapine, and aripiprazole.
Hyperprolactinemia secondary to macroadenoma or microadenoma in children and adolescents is rare and difficult to diagnose because typically it is suspected only when symptoms of tumor expansion occur. The usual initial symptoms of microadenomas are menstrual disturbances and galactorrhea in girls and galactorrhea and gynecomastia in boys.19
Decreased bone mass. Long-term hyperprolactinemia may lead to delayed puberty, primary amenorrhea, short stature, infertility, and osteopenia and/or osteoporosis due to decreased bone mass density (BMD).16 The risk of osteoporosis and/or osteopenia is directly related to the duration of hyperprolactinemia. A serum PRL level twice the upper limit of normal can result in osteopenia.
Breast cancer risk may be increased in hyperprolactinemia because of the effects of PRL on breast tissue and mammary gland development. A study of premenopausal (n=235) and postmenopausal women (n=851) reported a positive correlation between elevated PRL levels and breast cancer risk.3 “Crosstalk” between PRL and estradiol in activating AP-1 activity may promote carcinogenesis. Furthermore, tamoxifen, a common treatment for breast cancer, lowers PRL concentrations.3