Hyperprolactinemia: Monitoring children on long-term risperidone
How to address evidence of potential for developmental effects with sustained use.
Elevated serum prolactin inhibits the hypothalamus’ pulsatile release of gonadotrophin-releasing hormone (GnRH), which in turn decreases the pituitary’s secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In women, prolactin also blocks the feedback effect of estradiol on LH secretion (Figure). The prolactin level that triggers gonadal hypofunction appears to vary substantially among individuals.9
Symptoms of elevated prolactin can occur as a direct result of prolactin’s physiologic effect on breast tissue or indirectly through hypogonadism related to decreased FSH and LH. Symptoms of hyperprolactinemia—which can be seen more readily in sexually mature adolescents than in children—include:
- amenorrhea or oligorrhea
- breast enlargement or engorgement in females and males
- galactorrhea (females > males)
- decreased libido
- erectile dysfunction.
Although evidence is inconclusive, other problems may be associated with increased prolactin in children and adolescents. These include failure to enter or progress through puberty,8 increased risk of benign breast tumors,22 and reduced bone density.10
Bone changes. Decreased estrogen related to hyperprolactinemia may inhibit bone mineralization, causing osteopenia, osteoporosis, and increased fracture risk.10 The mechanism of bone density loss may be estrogen’s osteoclast activating and osteoblast inhibiting action. The level and duration of prolactin elevation that can hamper bone growth has not been defined, although evidence suggests a pervasive effect:
- 65% of a group of 38 premenstrual patients developed osteoporosis or osteopenia when taking risperidone or typical antipsychotics for schizophrenia for a mean of 8 years.11
- Bone loss has persisted 2 years after prolactin normalized in adolescents with prolactinomas.12
Prolactin secretion is controlled by stimulatory and inhibitory influences (A). Antipsychotic blockade of dopamine’s inhibitory influence (B) increases serum prolactin and its effect on mammary tissue (C). In the brain, hyperprolactinemia inhibits the release of gonadotropin-releasing hormone (GnRH) by the hypothalamus, which results in decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion by the pituitary (D). FSH and LH are important determinants of male and female gonadal maturation by their direct action on testes and ovaries within the hypothalamic-pituitary-gonadal axis.
Source: Developed by Manpreet Khemka, MBBS, and Jeffrey Ali, MD, MSc. Current Psychiatry Illustration by Rob Flewell
Hyperprolactinemia in children and adolescents
We suggest that children and adolescents receiving prolonged risperidone treatment can present with symptoms similar to those associated with hyperprolactinemia secondary to other causes, including:
- prolactinomas (the most common cause)13
- thyrotropin-releasing hormone stimulation in primary hypothyroidism
- hypoglycemia
- inherited endocrine syndromes
- physiologic stress
- medications.
The most common presenting symptoms of prolactinomas are headache, amenorrhea, and galactorrhea. A few patients have delayed puberty.13 In a review of hyperprolactinemia in children, Massart and Saggese14 proposed a correlation between elevated serum prolactin and underlying pathology:
- >100 ng/mL usually suggests organic pathology and requires MRI or CT confirmation
- <100 ng/mL usually indicates functional pathology.
What the evidence says. Using the key words “risperidone and hyperprolactinemia in children and adolescents” in a PubMed search, we identified 7 prospective, cross-sectional, and retrospective studies.14-20 We then analyzed these studies in terms of subjects’ age, sex, primary psychiatric disorder, dosage of risperidone used, prolactin elevation pattern, reported clinical consequences, and interventions used to ameliorate asymptomatic or symptomatic hyperprolactinemia.
Prolactin and antipsychotics. In a cross-sectional study, Staller15 compared serum prolactin at baseline and after 6 months in 50 children treated with atypical antipsychotics. Patients taking risperidone showed greater increases in prolactin than those taking quetiapine or olanzapine. Saito et al16 reached a similar conclusion in a prospective study of 40 children treated with atypical antipsychotics for 4 to 15 weeks.
Ups and downs. Prolactin levels increase sharply in the first weeks of risperidone treatment, peak at around 6 to 8 weeks, and then trend downward toward normal.17 In a post hoc analysis of pooled data from 5 clinical trials totaling 700 patients age 5 to 15, Findling et al17 reported that mean serum prolactin:
- peaked in the first 1 to 2 months of patients’ starting risperidone, 0.02 to 0.06 mg/kg/d
- returned to within or close to normal range by 3 to 5 months.
No correlation was seen between prolactin elevation and side effects that could be attributed to prolactin.
In a 2-part study, Anderson et al18 examined the short- and long-term effects of risperidone treatment on prolactin in children age 5 to 17 with autism. In the initial double-blind, placebo-controlled trial, 101 children were randomly assigned to risperidone 1.8 mg/d, or placebo. After 8 weeks, 63 children continued with open-label risperidone, mean dose 1.96 mg/d, for up to a total 22 months. Serum prolactin was measured at baseline (9.3±7.5 ng/ mL) and then at 2, 6, and 22 months.
