Minimizing the impact of elevated prolactin in children and adolescents

Clinical features

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

Not all patients with hyperprolactinemia develop problems. Whether hyperprolactinemia secondary to antipsychotic treatment adversely affects bone density or sexual maturation is unknown. Furthermore, sexual side effects—such as a decrease or loss of libido, erectile dysfunction, impotence, and ejaculatory or orgasmic difficulties—do not show a strong correlation with PRL levels.¹¹

Effects of hyperprolactinemia may be more pronounced in adolescents because PRL synthesis and release are stimulated by estrogen. In adolescent females elevated estrogen levels can be related to:

• increased estrogen levels in menstruating females
• increased estrogen levels in females taking oral contraceptives.¹⁶

Therefore, adolescent females taking antipsychotics are at high risk for increased PRL levels and resultant effects. For example, the BMD of adolescent girls with 6 months of hypothalamic-pituitary-gonadal (HPG) axis dysfunction caused by hyperprolactinemia was reduced by 2 standard deviations (SDs) below the population mean.¹⁶ A BMD 1 SD below the mean age-population value may double the risk for fractures.¹⁶ Unfortunately, there are no studies that measure estrogen levels or BMDs of children taking psychotropics¹⁶ or that assess PRL in pubertal girls taking atypical antipsychotics or SSRIs.

Evaluation of hyperprolactinemia

Blood samples to measure PRL levels must be collected under standardized conditions. A morning fasting serum PRL level should be obtained between 8 am and 10 am (3 hours after waking up). It is best to avoid emotional stress or strenuous exercise for at least 30 minutes before the blood draw because these conditions can raise PRL. Avoid nipple stimulation for 24 hours before testing because this also can raise PRL levels. A woman having abnormal nipple discharge should not do anything to cause more discharge before the test. Serum PRL levels should be monitored every 6 months in pubertal girls taking psychotropics until they experience sexual maturity or regular menstrual cycles so that abnormalities can be identified early and irreversible BMD loss is minimized.¹⁶