Influence of CYP2D6 Metabolizer Status on Risperidone and Paliperidone Tolerability in Children and Adolescents.

Background: Risperidone and, to a lesser extent, paliperidone are metabolized by CYP2D6; however, there are limited data related to variation in CYP2D6 phenotypes and the tolerability of these medications in children and adolescents. Furthermore, the impact of CYP2D6 on the association of risperidone and paliperidone with hyperprolactinemia in youth is not well understood. Methods: A retrospective chart review was performed in psychiatrically hospitalized children and adolescents prescribed risperidone (n = 263, age = 3-18 years, mean age = 13 ± 3 years, 49% female) or paliperidone (n = 124, age = 5-18 years, mean age = 15 ± 2 years, 44% female) who had CYP2D6 genotyping performed as part of routine care. CYP2D6 phenotypes were determined based on Clinical Pharmacogenetics Implementation Consortium guidelines and CYP2D6 inhibitors causing phenoconversion. Adverse effects were obtained from a review of the electronic health record, and patients were selected, in part, to enrich non-normal metabolizers. Results: Among risperidone-treated patients, 45% experienced an adverse effect, whereas 36% of paliperidone-treated patients experienced adverse effects. Discontinuation of risperidone due to lack of efficacy was more frequent in the CYP2D6 normal metabolizers and ultrarapid metabolizers compared with intermediate metabolizers (IMs) and phenoconverted poor metabolizers (pPMs) (54.5% vs. 32.7%, p < 0.001). Discontinuation due to weight gain was more common among risperidone- than paliperidone-treated patients (17% vs. 7%, p = 0.011). Among those taking paliperidone, CYP2D6 was associated with discontinuation due to side effects (p = 0.008), and youth with slower CYP2D6 metabolism (i.e., pPMs and IMs) were more likely to discontinue. Hyperprolactinemia was found in 10% of paliperidone-treated patients and 5% of risperidone-treated patients, and slower CYP2D6 metabolizers required higher risperidone doses to cause hyperprolactinemia (p = 0.011). Conclusions: CYP2D6 phenotype is associated with discontinuation of risperidone due to lack of efficacy and the dose of risperidone that induced hyperprolactinemia, as well as discontinuation of paliperidone due to adverse effects. Future studies should evaluate exposure-response and toxicity relationships in risperidone- and paliperidone-treated youth.

[Association of the Level of Serum Prolactin with Polymorphic Variants of the GRIN2A, GPM3, and GPM7 Genes in Patients with Schizophrenia Taking Conventional and Atypical Antipsychotics].

The dopamine, serotonin and glutamate systems are jointly involved in the pathogenesis and pharmacotherapy of schizophrenia. We formulated a hypothesis that polymorphic variants of the GRIN2A, GRM3, and GRM7 genes may be associated with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics as basic treatment. 432 Caucasian patients diagnosed with schizophrenia were examined. DNA was isolated from peripheral blood leukocytes using the standard phenol-chloroform method. For pilot genotyping, 12 SNPs in the GRIN2A gene, 4 SNPs in the GRM3 gene, and 6 SNPs in the GRM7 gene were selected. Allelic variants of the studied polymorphisms were determined by real-time PCR. The level of prolactin was determined by enzyme immunoassay. Among persons taking conventional antipsychotics, there were statistically significant differences in the distribution of genotype and allele frequencies in groups of patients with normal and elevated prolactin levels for the GRIN2A rs9989388 and GRIN2A rs7192557 polymorphic variants, as well as differences in serum prolactin levels depending on the genotype of the GRM7 rs3749380 polymorphic variant. Among persons taking atypical antipsychotics, statistically significant differences were found in the frequencies of genotypes and alleles of the GRM3 rs6465084 polymorphic variant. An association of polymorphic variants of the GRIN2A, GRM3, and GRM7 genes with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics has been established for the first time. The identified associations of polymorphic variants of the GRIN2A, GRM3 and GRM7 genes with the development of hyperprolactinemia in patients with schizophrenia taking conventional and atypical antipsychotics have been established for the first time. These associations not only confirm the close connection of the dopaminergic, serotonergic, and glutamatergic systems in the development of schizophrenia, but also demonstrate the potential of taking into account the genetic component during therapy.

Effects of sustained hyperprolactinemia in late gestation on the mammary parenchymal tissue transcriptome of gilts.

BACKGROUND: Gilts experiencing sustained hyperprolactinemia from d 90 to 109 of gestation showed an early onset of lactogenesis coupled with premature mammary involution. To better understand the molecular mechanisms underlying the premature mammary involution observed in these gilts, a transcriptomic analysis was undertaken. Therefore, this study aimed to explore the effect of hyperprolactinemia on the global transcriptome in the mammary tissue of late gestating gilts and identify the molecular pathways involved in triggering premature mammary involution. METHODS: On d 90 of gestation, gilts received daily injections of (1) canola oil until d 109 ± 1 of gestation (CTL, n = 18); (2) domperidone (to induce hyperprolactinemia) until d 96 ± 1 of gestation (T7, n = 17) or; (3) domperidone (until d 109 ± 1 of gestation (T20, n = 17). Mammary tissue was collected on d 110 of gestation and total RNA was isolated from six CTL and six T20 gilts for microarray analysis. The GeneChip® Porcine Gene 1.0 ST Array was used for hybridization. Functional enrichment analyses were performed to explore the biological significance of differentially expressed genes, using the DAVID bioinformatics resource. RESULTS: The expression of 335 genes was up-regulated and that of 505 genes down-regulated in the mammary tissue of T20 vs CTL gilts. Biological process GO terms and KEGG pathways enriched in T20 vs CTL gilts reflected the concurrent premature lactogenesis and mammary involution. When looking at individual genes, it appears that mammary cells from T20 gilts can simultaneously upregulate the transcription of milk proteins such as WAP, CSN1S2 and LALBA, and genes triggering mammary involution such as STAT3, OSMR and IL6R. The down-regulation of PRLR expression and up-regulation of genes known to inactivate the JAK-STAT5 pathway (CISH, PTPN6) suggest the presence of a negative feedback loop trying to counteract the effects of hyperprolactinemia. CONCLUSIONS: Genes and pathways identified in this study suggest that sustained hyperprolactinemia during late-pregnancy, in the absence of suckling piglets, sends conflicting pro-survival and cell death signals to mammary epithelial cells. Reception of these signals results in a mammary gland that can simultaneously synthesize milk proteins and initiate mammary involution.

Pharmacogenomics in clinical practice to prevent risperidone-induced hyperprolactinemia in autism spectrum disorder.

Autism spectrum disorder (ASD) is a global challenge that may disrupts family and social life significantly. There is robust evidence for the association of a pharmacokinetic gene variant (e.g., CYP2D6) with risperidone-induced hyperprolactinemia in ASD. Association of a pharmacodynamic gene variant (e.g., DRD2) with risperidone-induced hyperprolactinemia in ASD is also evident from multiple studies. In addition to genetic factors, dose, duration and drug-drug interactions of risperidone might also increase the serum prolactin level. There are several difficulties, such as reimbursement, knowledge and education of healthcare providers, in implementing risperidone pharmacogenomics into clinical practice. However, preparation of national and international pharmacogenomics-based dosing guidelines of risperidone may advance precision medicine of ASD.

Bu-Shen-Zhu-Yun decoction induces PRLR deubiquitination and JAK2/STAT5 activation via CSN5 in vitro.

PURPOSE: To determine the effect of Bu-Shen-Zhu-Yun Decoction (BSZY-D) on the kisspeptin through JAK2/STAT5 signaling pathway in hyperprolactinemia (HPRL) infertility. METHOD: SD rats were treated with BSZY-D for cerebrospinal fluid (CSF) extraction. GT1-7 cells were subjected to different treatments. The phosphorylation levels of JAK2 and STAT5, and the expressions of PRLR and kisspeptin of GT1-7 cells in different groups were detected by western blot, RT-qPCR and immunofluorescence. The expressions of CSN5 and GATA1 and other molecular features were checked by western blot, RT-PCR, co-immunoprecipitation and renilla luciferase activity. RESULTS: The phosphorylation levels of JAK2 and STAT5, and the expressions of PRLR and kisspeptin in the HPRL group were significantly decreased, and these changes could be reversed after BSZY-D treatment. In addition, the presence of PRLR deubiquitination was detected in the HPRL group, which could be reversed by shRNA-CSN5, suggesting that BSZY-D played a role through targeting CSN5. The binding level of GATA1 and CSN5 promoter in the HPRL group was significantly decreased, but elevated in the HPRL (BSZY-D/CSF) group (P < 0.05). CONCLUSION: BSZY-D improved the transcription activity of GATA1 and increased the binding of GATA1 and CSN5. BSZY-D was involved in the deubiquitination of PRLR, which contributes to alleviating the symptoms of HPRL infertility.

Hyperprolactinemia in a male pituitary androgen receptor knockout mouse is associated with female-like lactotroph development.

BACKGROUND: Circulating prolactin concentration in rodents and humans is sexually dimorphic. Oestrogens are a well-characterised stimulator of prolactin release. Circulating prolactin fluctuates throughout the menstrual/oestrous cycle of females in response to oestrogen levels, but remains continually low in males. We have previously identified androgens as an inhibitor of prolactin release through characterisation of males of a mouse line with a conditional pituitary androgen receptor knockout (PARKO) which have an increase in circulating prolactin, but unchanged lactotroph number. OBJECTIVES: In the present study, we aimed to specify the cell type that androgens act on to repress prolactin release. MATERIALS AND METHODS: PARKO, lactotroph-specific, Pit1 lineage-specific and neural-specific conditional androgen receptor knockout male mice were investigated using prolactin ELISA, pituitary electron microscopy, immunohistochemistry and qRT-PCR. RESULTS: Lactotroph-specific, Pit1 lineage-specific and neural-specific conditional AR knockouts did not duplicate the high circulating prolactin seen in the PARKO line. Using electron microscopy to examine ultrastructure, we showed that pituitary androgen receptor knockout male mice develop lactotrophs that resemble those seen in female mice. Castrated PARKO males have significantly reduced circulating prolactin compared to intact males. When expression of selected oestrogen-regulated anterior pituitary genes was examined, there were no differences in expression level between controls and knockouts. DISCUSSION: The cell type that androgens act on to repress prolactin release is not the lactotroph, cells in the Pit1-lineage, or the dopaminergic neurons in the hypothalamus. PARKO males develop a female-specific lactotroph ultrastructure that this is likely to contribute to the increase in circulating prolactin. Castrated PARKO males have significantly reduced circulating prolactin compared to intact males, which suggests that removal of both circulating oestrogens and androgens reduces the stimulation of pituitary prolactin release. CONCLUSION: Further investigation is needed into prolactin regulation by changes in androgen-oestrogen balance, which is involved sexual dimorphism of development and diseases including hyperprolactinemia.

Hyperprolactinemia using domperidone in prepubertal gilts: Effects on hormonal status, mammary development and mammary and pituitary gene expression.

Objectives of this experiment were to determine if the domperidone protocol previously used for gestating gilts can also lead to hyperprolactinemia in growing gilts, and to assess the effects of such a protocol on hormonal status, mammary development and gene expression in mammary and pituitary tissue of gilts at puberty. The impact on future lactation performance was also determined. At 75 ± 3 kg body weight (BW), gilts were divided between: 1) controls (CTL), receiving daily intramuscular (IM) injections of canola oil (1.1 mL) for 29 d (n = 41), and 2) treated (DOMP), receiving daily IM injections with 0.5 mg/kg BW of the dopamine receptor antagonist domperidone for 29 d (n = 40). In addition to that daily injection, treated gilts also received twice daily IM injections with 0.5 mg/kg BW of domperidone over the first 3 d of treatment. Fifteen gilts per treatment were sacrificed at 210 ± 5 d of age to collect mammary glands (for compositional analysis and gene expression) and the anterior pituitary (for gene expression). Remaining gilts were bred and allowed to farrow. Blood was sampled at the onset of treatment and on days 14 and 30. Gilts that farrowed were also blood sampled on days 3 and 20 of lactation. Blood was assayed for prolactin (PRL), leptin, insulin-like growth factor 1 (IGF-1), urea, free fatty acids and glucose. Concentrations of PRL increased after 14 d and 30 d of treatment (P < 0.01) and were lesser on day 3 of lactation in DOMP than CTL gilts (P < 0.01). At puberty, there were tendencies (P < 0.10) for total parenchymal protein and DNA to be greater in DOMP than CTL gilts. Treatment did not affect mRNA abundance of PRL or the long form of the PRL receptor genes in the pituitary gland at puberty but expression level of the dopamine receptor D2 and PRL genes was much lower in pubertal than late-pregnant gilts (P < 0.001). Furthermore, many genes related with PRL had a much greater expression level in late pregnancy than at puberty. On day 20 of lactation, CTL sows had greater concentrations of urea than DOMP sows (P < 0.01). The growth rate of litters was not affected by treatment nor was milk composition (P > 0.10). Even though PRL concentrations were increased with treatment, the absence of effect on mammary development was either due to timing relative to developmental stage, whereby treatment was initiated when gilts were too young, or was because all PRL receptors may have been saturated thereby preventing biological action of additional PRL.

Association of ANKK1 polymorphism with antipsychotic-induced hyperprolactinemia.

OBJECTIVE: Schizophrenia is a severe highly heritable mental disorder. Genetic polymorphisms of dopaminergic pathways are related to pathogenesis of drug response. Hyperprolactinemia (HPRL), a common adverse effect of antipsychotics, is attributed to blockade of dopamine D2 receptors. Ankyrin Repeat and Kinase Domain containing 1 (ANKK1) gene is closely related to Dopamine Receptor D2 type (DRD2) gene functioning. We examined whether the functional polymorphism rs2734849 in the ANKK1 gene is associated with antipsychotic-induced HPRL. METHODS: We recruited 446 patients with schizophrenia from among the Russian population of the Siberian region. The polymorphism rs2734849 in the ANKK1 gene was genotyped with The MassARRAY® Analyzer 4 by Agena Bioscience™, using the kit SEQUENOM Consumables iPLEXGold 384. Genotype and allele frequencies were compared between groups of schizophrenia patients with and without HPRL using the χ2 test. RESULTS: A comparison between schizophrenia patients with and without HPRL revealed significantly higher frequency of the C allele of the polymorphic variant rs2734849 in the ANKK1 gene in patients with HPRL as compared to the patients without it (χ2 = 3.70; p = .05; odds ratio [OR] = 1.30 [0.99-1.69]). CONCLUSION: The functional polymorphism rs2734849 in the ANKK1 gene was associated with HPRL in patients with schizophrenia.

Association between 8 P-glycoprotein (MDR1/ABCB1) gene polymorphisms and antipsychotic drug-induced hyperprolactinaemia.

INTRODUCTION: Hyperprolactinaemia, a common adverse effect of antipsychotic drugs, is primarily linked to blockade of dopamine D2 receptors in the pituitary gland. Certain antipsychotic drugs, such as, for example risperidone and paliperidone, are more likely to induce hyperprolactinaemia compared to others. This effect is probably caused by a relatively high blood/brain concentration ratio, a consequence of being a substrate of P-glycoprotein. Genetic variants of P-glycoprotein with changed functional activity might influence the potential of risperidone and paliperidone to cause hyperprolactinaemia as the altered blood/brain concentration ratio would lead to a reduced therapeutic drug level within essential brain areas making dose adaptations necessary. This increases exposure of dopamine D2 receptors within the pituitary gland. AIMS: To investigate possible associations between MDR1/ABCB1 gene polymorphisms and antipsychotic drug-induced hyperprolactinaemia in Russian patients with schizophrenia and to determine possible differences between risperidone/paliperidone and other antipsychotics. METHODS: In total, 446 patients with schizophrenia were included from 3 psychiatric hospitals in Siberia. Blood samples were obtained in a cross-sectional study design for DNA extraction and prolactin measurement. Associations between hyperprolactinaemia and 8 MDR1/ABCB1 gene-polymorphisms were assessed using logistic regression analysis accounting for covariates. The analysis was repeated in a patient subgroup using risperidone or paliperidone. RESULTS: We did not observe an association between any of the 8 single nucleotide polymorphisms and the prevalence of antipsychotic-induced hyperprolactinaemia in the total patient population. However, in the risperidone/paliperidone subgroup, the single nucleotide polymorphism rs2032582 (G2677T) was found to be negatively associated with risperidone/paliperidone-induced hyperprolactinaemia. CONCLUSION: This study revealed a significant association between the ABCB1 gene polymorphism rs2032582 (G2677T) and risperidone/paliperidone-induced hyperprolactinaemia.

The effect of CYP2D6 variation on antipsychotic-induced hyperprolactinaemia: a systematic review and meta-analysis.

Hyperprolactinemia is a known adverse drug reaction to antipsychotic treatment. Antipsychotic blood levels are influenced by cytochrome P450 enzymes, primarily CYP2D6. Variation in CYP450 genes may affect the risk of antipsychotic-induced hyperprolactinemia. We undertook a systematic review and meta-analysis to assess whether CYP2D6 functional genetic variants are associated with antipsychotic-induced hyperprolactinemia. The systematic review identified 16 relevant papers, seven of which were suitable for the meta-analysis (n = 303 participants including 134 extreme metabolisers). Participants were classified into four phenotype groups as poor, intermediate, extensive, and ultra-rapid metabolisers. A random effects meta-analysis was used and Cohen's d calculated as the effect size for each primary study. We found no significant differences in prolactin levels between CYP2D6 metabolic groups. Current evidence does not support using CYP2D6 genotyping to reduce risk of antipsychotic-induced hyperprolactinemia. However, statistical power is limited. Future studies with larger samples and including a range of prolactin-elevating drugs are needed.

New insights into human prolactin pathophysiology: genomics and beyond.

PURPOSE OF REVIEW: To briefly summarize what is known regarding hyperprolactinemia and prolactin-secreting tumors, and review recent findings. RECENT FINDINGS: Prolactin was previously thought to inhibit secretion of gonadotropin-releasing hormone (GnRH) by directly inhibiting the firing of GnRH neurons, resulting in hypogonadotropic hypogonadism and infertility. However, kisspeptin has recently been implicated as the mediator of hyperprolactinemia-induced infertility, by acting upstream of the GnRH neurons as an integrator of endocrine signals.Macroprolactin is generally considered to be inactive and clinically insignificant, but new studies have suggested that patients with macroprolactinemia may have reproductive manifestations as well as sexual dysfunction.Several mutations and polymorphisms in the prolactin receptor have been described, which could describe a genetic cause for prolactinomas and characterize cases of isolated familial hyperprolactinemia.Kisspeptin and tyrosine kinase inhibitors have emerged as potential new therapeutic targets for the treatment of hyperprolactinemia and dopamine-resistant prolactinomas. SUMMARY: Molecular studies are shedding light on the pathophysiology of hyperprolactinemia and the effects of excess prolactin production on the reproductive system. Similarly, genetic studies have begun to reveal how differences in prolactin receptor function may account for some of the previously 'idiopathic' cases of hyperprolactinemia and bring to light new causes of prolactinomas. Further elucidation of the transcriptional pathways affected by these genetic changes may help to create new therapeutic targets.

A pharmacogenetic study of patients with schizophrenia from West Siberia gets insight into dopaminergic mechanisms of antipsychotic-induced hyperprolactinemia.

BACKGROUND: Hyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland. Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within the adenohypophysis. Nevertheless, due to competition for pituitary DRD2s by high dopamine levels may limit antipsychotic-induced HPRL. Moreover, the activity of prolactin-producing lactotrophs also depends on other hormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters, enzymes of neurotransmitter metabolism and other factors. Polymorphic variants in the genes coding for these receptors and proteins can have functional significance and influence on the development of hyperprolactinemia. METHODS: A set of 41 SNPs of genes for dopamine receptors DRD1, DRD2, DRD3, DRD4, the dopamine transporter SLC6A3 and dopamine catabolizing enzymes MAOA and MAOB was investigated in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) with and without HPRL who were treated with classical and/or atypical antipsychotic drugs. Additive genetic model was tested and the analysis was carried out in the total group and in subgroup stratified by the use of risperidone/paliperidone. RESULTS: One statistically significant association between polymorphic variant rs1799836 of MAOB gene and HPRL in men was found in the total group. Furthermore, the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be associated with HPRL in the subgroup of patients using the risperidone/paliperidone, but not with HPRL induced by other antipsychotic drugs. CONCLUSIONS: Our results indicate that genetic variants of MAOB and SLC6A3 may have consequences on the modulation of prolactin secretion. A further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.

Prolactin - a pleiotropic factor in health and disease.

The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expressed in a wide array of tissues, and a growing number of biological processes continue to be attributed to prolactin. In this Review, we focus on the newly discovered roles of prolactin in human health and disease, particularly its involvement in metabolic homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone, the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour. New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will also be presented and discussed.

Acute Suppression of LH Secretion by Prolactin in Female Mice Is Mediated by Kisspeptin Neurons in the Arcuate Nucleus.

Hyperprolactinemia causes infertility, but the specific mechanism is unknown. It is clear that elevated prolactin levels suppress pulsatile release of GnRH from the hypothalamus, with a consequent reduction in pulsatile LH secretion from the pituitary. Only a few GnRH neurons express prolactin receptors (Prlrs), however, and thus prolactin must act indirectly in the underlying neural circuitry. Here, we have tested the hypothesis that prolactin-induced inhibition of LH secretion is mediated by kisspeptin neurons, which provide major excitatory inputs to GnRH neurons. To evaluate pulsatile LH secretion, we collected serial blood samples from diestrous mice and measured LH levels by ultrasensitive ELISA. Acute prolactin administration decreased LH pulses in wild-type mice. Kisspeptin neurons in the arcuate nucleus and in the rostral periventricular area of the third ventricle (RP3V) acutely responded to prolactin, but prolactin-induced signaling in kisspeptin neurons was up to fourfold higher in the arcuate nucleus when compared with the RP3V. Consistent with this, conditional knockout of Prlr specifically in arcuate nucleus kisspeptin neurons prevented prolactin-induced suppression of LH secretion. Our data establish that during hyperprolactinemia, suppression of pulsatile LH secretion is mediated by Prlr on arcuate kisspeptin neurons.

Variant Prolactin Receptor in Agalactia and Hyperprolactinemia.

A loss-of-function variant in the gene encoding the prolactin receptor ( PRLR) was reported previously in a woman with persistent postpartum galactorrhea; however, this paradoxical phenotype is not completely understood. Here we describe a 35-year-old woman who presented with idiopathic hyperprolactinemia that was associated with a complete lack of lactation after each of her two deliveries. She is a compound heterozygote for loss-of-function variants of PRLR. Her unaffected parents are heterozygotes. These findings are consistent with previous work showing that mice deficient in functional Prlr do not lactate.

UGT1A1 polymorphisms associated with prolactin response in risperidone-treated children and adolescents with autism spectrum disorder.

The aim of this study was to investigate the association of drug-metabolizing enzyme and transporter (DMET) polymorphisms with the risperidone-induced prolactin response using an overlapping gene model between serum prolactin level and hyperprolactinemia in autism spectrum disorder (ASD) patients. Eighty-four ASD patients who were receiving risperidone for at least 1 month were recruited and then assigned to either the normal prolactin group or the hyperprolactinemia group based on their serum prolactin level. The genotype profile of 1936 (1931 single nucleotide polymorphisms (SNPs) and 5 copy number variation (CNVs) drug metabolism markers was obtained using the Affymetrix DMET Plus GeneChip microarray platform. Genotypes of SNPs used to test the accuracy of DMET genotype profiling were determined using TaqMan SNP Genotyping Assay kits. Eighty-four patients were selected for the allelic association study after microarray analyses (51 in the normal prolactin group, and 33 in the hyperprolactinemia group). An overlapping allelic association analysis of both analyses discovered five DMET SNPs with a suggestive association (P < 0.05) with risperidone-induced prolactin response. Three UGT1A1 SNPs (UGT1A1*80c.-364C > T, UGT1A1*93 c.-3156G > A, and UGT1A1 c.-2950A > G, showed a suggestive association with the risperidone-induced prolactin response and found to be in complete linkage disequilibrium (D' value of 1). In this DMET microarray platform, we found three UGT1A1 variants with suggestive evidences of association with the risperidone-induced prolactin response both measured by hyperprolactinemia and by prolactin level. However, due to the lack of validation studies confirmation and further exploration are needed in future pharmacogenomic studies.

Children with MEN1 gene mutations may present first (and at a young age) with Cushing disease.

OBJECTIVE: Cushing disease (CD) is a rare entity caused by ACTH-secreting pituitary tumours, leading to prolonged hypercortisolism. Most cases are sporadic but can rarely occur in the context of familial predisposition, due to germline mutations in genes such as MEN1, leading to multiple endocrine neoplasia type 1, MEN1. We have reported previously that CD can be the first and only presenting manifestation of MEN1. In this report, we describe a cohort of paediatric patients who presented with CD as the first manifestation of MEN1. MATERIALS AND METHODS: A retrospective analysis of paediatric patients admitted to the National Institutes of Health (NIH) Clinical Center for evaluation of hypercortisolism, between 1997 and 2017. MEN1 was diagnosed on a clinical, familial and/or genetic basis. RESULTS: Of a total of 238 children with CD, six patients were subsequently diagnosed with MEN1, three males and three females with a mean age at diagnosis of CD at 13.4 ± 2.9 years. Five of the six patients had familial MEN1 and one patient was a sporadic case. Additional manifestations of MEN1 included primary hyperparathyroidism in three patients and hyperprolactinemia in two patients. DISCUSSION: This report describes a paediatric patient population with MEN1 in whom CD was the initial manifestation, confirming a previous observation that paediatric patients with MEN1 may present first with an ACTH-producing adenoma. Therefore, germline MEN1 mutations should be sought in paediatric CD and tested for when there is a suggestive family history and/or other manifestations.

Impact of NTRK2, DRD2 and ACE polymorphisms on prolactin levels in antipsychotic-treated patients with first-episode psychosis.

BACKGROUND: Hyperprolactinemia is a common side-effect of antipsychotics (APs), which may trigger serious secondary problems and compromise the adherence to treatment which is crucial for prognosis, especially in patients presenting with a first-episode of psychosis (FEP). AIMS: We evaluated, in some cases for the first time, the effect of polymorphisms in multiple candidate genes on serum prolactin (PRL) levels in an AP-treated FEP cohort recruited in the multicenter PEPs study (Phenotype - genotype and environmental interaction; Application of a predictive model in first psychotic episodes). METHODS: PRL concentration was measured in serum from 222 patients. A total of 167 polymorphisms were selected in 23 genes. Genetic association analysis was performed in the whole sample and also in homogenous subgroups of patients treated with APs with a high (N = 101) or low risk (N = 95) of increasing PRL release, which showed significant differences in their PRL levels. RESULTS: After Bonferroni correction, polymorphisms in NTRK2, DRD2 and ACE genes were associated with PRL concentration. CONCLUSION: Our results give more support to the impact of DRD2, but also of other genes related to dopamine availability such as ACE. Moreover, this study provides the first evidence for the involvement of NTRK2, which suggests that pathways other than the ones related to dopamine or serotonin may participate in the AP-related PRL levels.