Minimizing the impact of elevated prolactin in children and adolescents
Early identification, treatment can help lessen impaired development, other sequelae
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.
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 (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
Table 1
Causes of hyperprolactinemia
| Iatrogenic causes |
|---|
| 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) |
| Other causes |
| 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 Source: Reference 9 |
Table 2
Relative risk of hyperprolactinemia with common psychotropics
