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W.a. Daniel - One of the best experts on this subject based on the ideXlab platform.
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The Role of the Nervous System in the Regulation of Liver Cytochrome P450
Current drug metabolism, 2011Co-Authors: Jacek Wójcikowski, W.a. DanielAbstract:The central and peripheral nervous systems are important factors influencing the functioning of liver cytochrome P450 (CYP). It has been shown that changes in the brain monoaminergic systems affect liver cytochrome P450 (CYP) expression (CYP1A, CYP2B, CYP2C11 and CYP3A). The brain dopaminergic system has been established as an important center regulating the liver CYP. This regulation proceeds via the Tuberoinfundibular Pathway and the dopaminergic D2 receptors of the pituitary, as well as the mesolimbic Pathway engaging the D2 receptors of the nucleus accumbens (conveying a message to the paraventricular nucleus of the hypothalamus). These two dopaminergic Pathways stimulate the secretion of pituitary hormones, which directly (GH) or indirectly (ACTH, TSH) activate hepatic nuclear/ cytosolic receptors controlling CYP genes. Recent preliminary studies with selective noradrenaline or serotonin neurotoxins suggest also involvement of the brain noradrenergic and serotonergic systems in the regulation of liver CYP. Moreover, the influence of the peripheral nervous system involving several neurotransmitters (acetylcholine, noradrenaline, adrenaline, dopamine, serotonin) on liver function may also be important for the physiological regulation of hepatic CYP activity. The hypothalamus controls liver function not only by releasing hormones from the pituitary gland but also by stimulating the autonomic sympathetic and parasympathetic projections to the liver. In addition to direct neural connections, the autonomic nervous system can indirectly affect liver function via the hypothalamus-adrenal axis and the hypothalamus- pancreas axis. Therefore, the estimation of neuroactive drug action on hepatic CYP requires an in vivo model which allows the central neuroendocrine and peripheral autonomic regulation of genes coding for CYP isoforms.
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The brain dopaminergic system as an important center regulating liver cytochrome P450 in the rat.
Expert opinion on drug metabolism & toxicology, 2009Co-Authors: Jacek Wójcikowski, W.a. DanielAbstract:This paper reviews evidence that changes in the functioning of the brain dopaminergic system affect liver cytochrome P450 (CYP) expression (CYP1A, CYP2B, CYP2C11 and CYP3A in the case of the Tuberoinfundibular Pathway or CYP1A and CYP3A in the case of the mesolimbic Pathway), as well as blood plasma concentration of the respective pituitary hormones in the rat. Thus, the brain dopaminergic system has been established as an important center regulating the liver CYP. This regulation proceeds through the dopaminergic D(2) receptors of the pituitary (activated by the Tuberoinfundibular Pathway) and the D(2) receptors of the nucleus accumbens (activated by the mesolimbic Pathway and conveying a message from the nucleus accumbens to the paraventricular nucleus of the hypothalamus). These receptors directly (GH) or indirectly (CRH --> ACTH --> corticosterone; TRH --> TSH --> T(3)) stimulate the secretion of hormones, which activate nuclear/cytosolic receptors controlling CYP genes. Thus, the prediction of neuroactive drug action on hepatic CYP and drug-drug interactions on the basis of in vitro studies only is not sufficient, because such an experimental model does not allow the central neuroendocrine regulation of the enzyme.
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Regulation of liver cytochrome P450 by activation of brain dopaminergic system: physiological and pharmacological implications.
Biochemical pharmacology, 2008Co-Authors: Jacek Wójcikowski, Krystyna Gołembiowska, W.a. DanielAbstract:The aim of the present study was to investigate the influence of activation of brain dopaminergic system by different dopaminomimetics on the level and activity of liver cytochrome P450 (CYP) isoforms. Studies into the identification of hormones and cytokines which are known to mediate liver CYP expression were also simultaneously carried out. Stimulation of dopaminergic receptors in the pituitary, a target for the Tuberoinfundibular Pathway, by dopamine (a D(1)/D(2) receptor agonist) administered intraperitoneally caused a significant increase in the activities and protein levels of CYP2B, CYP2C11 and CYP3A, a substantial increase in the blood plasma level of growth hormone (GH) and a significant decrease in triiodothyronine (T(3)) level. Local stimulation of dopaminergic receptors in the nucleus accumbens, a target for the mesolimbic Pathway, by apomorphine (a D(1)/D(2) receptor agonist), amphetamine (an indirect D(1)/D(2) dopaminemimetic) and quinpirole (a D(2) receptor agonist) produced a substantial rise in CYP3A activity and protein level, caused a large increase in corticosterone concentration and a moderate drop in T(3) level. SKF82958 (a D(1) receptor agonist) did not significantly affect the CYP isoforms or hormones studied. In both cases (activation of the Tuberoinfundibular or mesolimbic Pathway), the activity and the protein level of CYP1A considerably decreased. Plasma levels of thyroxine, testosterone, interleukin-2 and interleukin-6 were not changed after activation of the two Pathways. The obtained results establish the brain dopaminergic system as a physiological centre regulating cytochrome P450 (engaging D(2) receptors and pituitary hormones) and demonstrate new pharmacological aspects of neuroactive drugs that affect this system.
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Identification of factors mediating the effect of the brain dopaminergic system on the expression of cytochrome P450 in the liver.
Pharmacological reports : PR, 2008Co-Authors: Jacek Wójcikowski, W.a. DanielAbstract:Our earlier study showed that damage to brain dopaminergic Pathways causes decreases in CYP2B, CYP2C11 and CYP3A, as well as increases in CYP1A protein levels and activities in the liver. The aim of the present study was to investigate the influence of lesions of brain dopaminergic Pathways on hormones and cytokines that are thought to mediate the effect of the dopaminergic system on liver CYP expression. At 48 h or 7 days after lesion of the Tuberoinfundibular Pathway, growth hormone level was significantly decreased, while the concentration of triiodothyronine was considerably increased. Fourteen days after lesion of the mesolimbic Pathway, triiodothyronine level was significantly elevated, while corticosterone concentration was visibly reduced. The plasma levels of thyroxine, testosterone, interleukin-2, and interleukin-6 were not changed after lesion of the Tuberoinfundibular or the mesolimbic Pathways. The present study suggests that liver CYP is regulated by the dopaminergic Tuberoinfundibular Pathway via growth hormone and triiodothyronine, while the mesolimbic Pathway influences this enzyme via corticosterone and triiodothyronine. Cytokines are not involved in the observed down-regulation of CYP isoforms after lesion of either dopaminergic Pathway.
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The regulation of liver cytochrome P450 by the brain dopaminergic system
Current drug metabolism, 2007Co-Authors: Jacek Wójcikowski, Krystyna Gołembiowska, W.a. DanielAbstract:Genes encoding different cytochrome P450 (CYP) isoforms are regulated by endogenous hormones (e.g. pituitary hormones, thyroid hormones, glucocorticoids) which are all under control of the central nervous system. The aim of the present study was to investigate the influence of lesions of brain dopaminergic Pathways on the level and the activity of CYP isoforms (1A, 2A, 2B, 2C6, 2C11, 2D, 3A) in rat liver. At 48 h after lesion of the Tuberoinfundibular Pathway, only the activity and the protein level of CYP2B were significantly decreased. Seven days after lesion of the above-mentioned Pathway, significant inhibition of CYP2B, CYP2C11 and CYP3A activities and a decrease in CYP protein levels were observed. At the same time, the activity and the protein level of CYP1A considerably increased. Fourteen days after damage of the mesolimbic Pathway, the activity and the protein level of CYP3A were significantly reduced, while those of CYP1A were substantially elevated. In contrast, lesion of the nigrostriatal Pathway did not affect any CYP isoforms studied. The obtained results provide the first direct evidence for the influence of brain dopaminergic system on the level and the activity of CYP in the liver, which is Pathway- and isoform-dependent. Hence stimulation or inhibition of the brain dopaminergic system (e.g. by dopamine receptor-blocking neuroleptics) may cause changes in CYP activity of physiological, pharmacological and toxicological significance, since CYP isoforms that are regulated by the dopaminergic system catalyze the metabolism of endogenous substances (e.g. steroids), clinically important drugs (e.g. psychotropics, calcium channel antagonists, antibiotics) and toxins.
Jacek Wójcikowski - One of the best experts on this subject based on the ideXlab platform.
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The Role of the Nervous System in the Regulation of Liver Cytochrome P450
Current drug metabolism, 2011Co-Authors: Jacek Wójcikowski, W.a. DanielAbstract:The central and peripheral nervous systems are important factors influencing the functioning of liver cytochrome P450 (CYP). It has been shown that changes in the brain monoaminergic systems affect liver cytochrome P450 (CYP) expression (CYP1A, CYP2B, CYP2C11 and CYP3A). The brain dopaminergic system has been established as an important center regulating the liver CYP. This regulation proceeds via the Tuberoinfundibular Pathway and the dopaminergic D2 receptors of the pituitary, as well as the mesolimbic Pathway engaging the D2 receptors of the nucleus accumbens (conveying a message to the paraventricular nucleus of the hypothalamus). These two dopaminergic Pathways stimulate the secretion of pituitary hormones, which directly (GH) or indirectly (ACTH, TSH) activate hepatic nuclear/ cytosolic receptors controlling CYP genes. Recent preliminary studies with selective noradrenaline or serotonin neurotoxins suggest also involvement of the brain noradrenergic and serotonergic systems in the regulation of liver CYP. Moreover, the influence of the peripheral nervous system involving several neurotransmitters (acetylcholine, noradrenaline, adrenaline, dopamine, serotonin) on liver function may also be important for the physiological regulation of hepatic CYP activity. The hypothalamus controls liver function not only by releasing hormones from the pituitary gland but also by stimulating the autonomic sympathetic and parasympathetic projections to the liver. In addition to direct neural connections, the autonomic nervous system can indirectly affect liver function via the hypothalamus-adrenal axis and the hypothalamus- pancreas axis. Therefore, the estimation of neuroactive drug action on hepatic CYP requires an in vivo model which allows the central neuroendocrine and peripheral autonomic regulation of genes coding for CYP isoforms.
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The brain dopaminergic system as an important center regulating liver cytochrome P450 in the rat.
Expert opinion on drug metabolism & toxicology, 2009Co-Authors: Jacek Wójcikowski, W.a. DanielAbstract:This paper reviews evidence that changes in the functioning of the brain dopaminergic system affect liver cytochrome P450 (CYP) expression (CYP1A, CYP2B, CYP2C11 and CYP3A in the case of the Tuberoinfundibular Pathway or CYP1A and CYP3A in the case of the mesolimbic Pathway), as well as blood plasma concentration of the respective pituitary hormones in the rat. Thus, the brain dopaminergic system has been established as an important center regulating the liver CYP. This regulation proceeds through the dopaminergic D(2) receptors of the pituitary (activated by the Tuberoinfundibular Pathway) and the D(2) receptors of the nucleus accumbens (activated by the mesolimbic Pathway and conveying a message from the nucleus accumbens to the paraventricular nucleus of the hypothalamus). These receptors directly (GH) or indirectly (CRH --> ACTH --> corticosterone; TRH --> TSH --> T(3)) stimulate the secretion of hormones, which activate nuclear/cytosolic receptors controlling CYP genes. Thus, the prediction of neuroactive drug action on hepatic CYP and drug-drug interactions on the basis of in vitro studies only is not sufficient, because such an experimental model does not allow the central neuroendocrine regulation of the enzyme.
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Regulation of liver cytochrome P450 by activation of brain dopaminergic system: physiological and pharmacological implications.
Biochemical pharmacology, 2008Co-Authors: Jacek Wójcikowski, Krystyna Gołembiowska, W.a. DanielAbstract:The aim of the present study was to investigate the influence of activation of brain dopaminergic system by different dopaminomimetics on the level and activity of liver cytochrome P450 (CYP) isoforms. Studies into the identification of hormones and cytokines which are known to mediate liver CYP expression were also simultaneously carried out. Stimulation of dopaminergic receptors in the pituitary, a target for the Tuberoinfundibular Pathway, by dopamine (a D(1)/D(2) receptor agonist) administered intraperitoneally caused a significant increase in the activities and protein levels of CYP2B, CYP2C11 and CYP3A, a substantial increase in the blood plasma level of growth hormone (GH) and a significant decrease in triiodothyronine (T(3)) level. Local stimulation of dopaminergic receptors in the nucleus accumbens, a target for the mesolimbic Pathway, by apomorphine (a D(1)/D(2) receptor agonist), amphetamine (an indirect D(1)/D(2) dopaminemimetic) and quinpirole (a D(2) receptor agonist) produced a substantial rise in CYP3A activity and protein level, caused a large increase in corticosterone concentration and a moderate drop in T(3) level. SKF82958 (a D(1) receptor agonist) did not significantly affect the CYP isoforms or hormones studied. In both cases (activation of the Tuberoinfundibular or mesolimbic Pathway), the activity and the protein level of CYP1A considerably decreased. Plasma levels of thyroxine, testosterone, interleukin-2 and interleukin-6 were not changed after activation of the two Pathways. The obtained results establish the brain dopaminergic system as a physiological centre regulating cytochrome P450 (engaging D(2) receptors and pituitary hormones) and demonstrate new pharmacological aspects of neuroactive drugs that affect this system.
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Identification of factors mediating the effect of the brain dopaminergic system on the expression of cytochrome P450 in the liver.
Pharmacological reports : PR, 2008Co-Authors: Jacek Wójcikowski, W.a. DanielAbstract:Our earlier study showed that damage to brain dopaminergic Pathways causes decreases in CYP2B, CYP2C11 and CYP3A, as well as increases in CYP1A protein levels and activities in the liver. The aim of the present study was to investigate the influence of lesions of brain dopaminergic Pathways on hormones and cytokines that are thought to mediate the effect of the dopaminergic system on liver CYP expression. At 48 h or 7 days after lesion of the Tuberoinfundibular Pathway, growth hormone level was significantly decreased, while the concentration of triiodothyronine was considerably increased. Fourteen days after lesion of the mesolimbic Pathway, triiodothyronine level was significantly elevated, while corticosterone concentration was visibly reduced. The plasma levels of thyroxine, testosterone, interleukin-2, and interleukin-6 were not changed after lesion of the Tuberoinfundibular or the mesolimbic Pathways. The present study suggests that liver CYP is regulated by the dopaminergic Tuberoinfundibular Pathway via growth hormone and triiodothyronine, while the mesolimbic Pathway influences this enzyme via corticosterone and triiodothyronine. Cytokines are not involved in the observed down-regulation of CYP isoforms after lesion of either dopaminergic Pathway.
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The regulation of liver cytochrome P450 by the brain dopaminergic system
Current drug metabolism, 2007Co-Authors: Jacek Wójcikowski, Krystyna Gołembiowska, W.a. DanielAbstract:Genes encoding different cytochrome P450 (CYP) isoforms are regulated by endogenous hormones (e.g. pituitary hormones, thyroid hormones, glucocorticoids) which are all under control of the central nervous system. The aim of the present study was to investigate the influence of lesions of brain dopaminergic Pathways on the level and the activity of CYP isoforms (1A, 2A, 2B, 2C6, 2C11, 2D, 3A) in rat liver. At 48 h after lesion of the Tuberoinfundibular Pathway, only the activity and the protein level of CYP2B were significantly decreased. Seven days after lesion of the above-mentioned Pathway, significant inhibition of CYP2B, CYP2C11 and CYP3A activities and a decrease in CYP protein levels were observed. At the same time, the activity and the protein level of CYP1A considerably increased. Fourteen days after damage of the mesolimbic Pathway, the activity and the protein level of CYP3A were significantly reduced, while those of CYP1A were substantially elevated. In contrast, lesion of the nigrostriatal Pathway did not affect any CYP isoforms studied. The obtained results provide the first direct evidence for the influence of brain dopaminergic system on the level and the activity of CYP in the liver, which is Pathway- and isoform-dependent. Hence stimulation or inhibition of the brain dopaminergic system (e.g. by dopamine receptor-blocking neuroleptics) may cause changes in CYP activity of physiological, pharmacological and toxicological significance, since CYP isoforms that are regulated by the dopaminergic system catalyze the metabolism of endogenous substances (e.g. steroids), clinically important drugs (e.g. psychotropics, calcium channel antagonists, antibiotics) and toxins.
Krystyna Gołembiowska - One of the best experts on this subject based on the ideXlab platform.
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Regulation of liver cytochrome P450 by activation of brain dopaminergic system: physiological and pharmacological implications.
Biochemical pharmacology, 2008Co-Authors: Jacek Wójcikowski, Krystyna Gołembiowska, W.a. DanielAbstract:The aim of the present study was to investigate the influence of activation of brain dopaminergic system by different dopaminomimetics on the level and activity of liver cytochrome P450 (CYP) isoforms. Studies into the identification of hormones and cytokines which are known to mediate liver CYP expression were also simultaneously carried out. Stimulation of dopaminergic receptors in the pituitary, a target for the Tuberoinfundibular Pathway, by dopamine (a D(1)/D(2) receptor agonist) administered intraperitoneally caused a significant increase in the activities and protein levels of CYP2B, CYP2C11 and CYP3A, a substantial increase in the blood plasma level of growth hormone (GH) and a significant decrease in triiodothyronine (T(3)) level. Local stimulation of dopaminergic receptors in the nucleus accumbens, a target for the mesolimbic Pathway, by apomorphine (a D(1)/D(2) receptor agonist), amphetamine (an indirect D(1)/D(2) dopaminemimetic) and quinpirole (a D(2) receptor agonist) produced a substantial rise in CYP3A activity and protein level, caused a large increase in corticosterone concentration and a moderate drop in T(3) level. SKF82958 (a D(1) receptor agonist) did not significantly affect the CYP isoforms or hormones studied. In both cases (activation of the Tuberoinfundibular or mesolimbic Pathway), the activity and the protein level of CYP1A considerably decreased. Plasma levels of thyroxine, testosterone, interleukin-2 and interleukin-6 were not changed after activation of the two Pathways. The obtained results establish the brain dopaminergic system as a physiological centre regulating cytochrome P450 (engaging D(2) receptors and pituitary hormones) and demonstrate new pharmacological aspects of neuroactive drugs that affect this system.
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The regulation of liver cytochrome P450 by the brain dopaminergic system
Current drug metabolism, 2007Co-Authors: Jacek Wójcikowski, Krystyna Gołembiowska, W.a. DanielAbstract:Genes encoding different cytochrome P450 (CYP) isoforms are regulated by endogenous hormones (e.g. pituitary hormones, thyroid hormones, glucocorticoids) which are all under control of the central nervous system. The aim of the present study was to investigate the influence of lesions of brain dopaminergic Pathways on the level and the activity of CYP isoforms (1A, 2A, 2B, 2C6, 2C11, 2D, 3A) in rat liver. At 48 h after lesion of the Tuberoinfundibular Pathway, only the activity and the protein level of CYP2B were significantly decreased. Seven days after lesion of the above-mentioned Pathway, significant inhibition of CYP2B, CYP2C11 and CYP3A activities and a decrease in CYP protein levels were observed. At the same time, the activity and the protein level of CYP1A considerably increased. Fourteen days after damage of the mesolimbic Pathway, the activity and the protein level of CYP3A were significantly reduced, while those of CYP1A were substantially elevated. In contrast, lesion of the nigrostriatal Pathway did not affect any CYP isoforms studied. The obtained results provide the first direct evidence for the influence of brain dopaminergic system on the level and the activity of CYP in the liver, which is Pathway- and isoform-dependent. Hence stimulation or inhibition of the brain dopaminergic system (e.g. by dopamine receptor-blocking neuroleptics) may cause changes in CYP activity of physiological, pharmacological and toxicological significance, since CYP isoforms that are regulated by the dopaminergic system catalyze the metabolism of endogenous substances (e.g. steroids), clinically important drugs (e.g. psychotropics, calcium channel antagonists, antibiotics) and toxins.
Julie L Fudge - One of the best experts on this subject based on the ideXlab platform.
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From Galactorrhea to Osteopenia: Rethinking Serotonin–Prolactin Interactions
Neuropsychopharmacology, 2004Co-Authors: Ana B F Emiliano, Julie L FudgeAbstract:The widespread use of the selective serotonin reuptake inhibitors (SSRIs) has been accompanied by numerous reports describing a potential association with hyperprolactinemia. Antipsychotics are commonly known to elevate serum prolactin (PRL) through blockade of dopamine receptors in the pituitary. However, there is little awareness of the mechanisms by which SSRIs stimulate PRL release. Hyperprolactinemia may result in overt symptoms such as galactorrhea, which may be accompanied by impaired fertility. Long-term clinical sequelae include decreased bone density and the possibility of an increased risk of breast cancer. Through literature review, we explore the possible Pathways involved in serotonin-induced PRL release. While the classic mechanism of antipsychotic-induced hyperprolactinemia directly involves dopamine cells in the Tuberoinfundibular Pathway, SSRIs may act on this system indirectly through GABAergic neurons. Alternate Pathways involve serotonin stimulation of vasoactive intestinal peptide (VIP) and oxytocin (OT) release. We conclude with a comprehensive review of clinical sequelae associated with hyperprolactinemia, and the potential role of SSRIs in this phenomenon.
Fasiha Haq - One of the best experts on this subject based on the ideXlab platform.
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Antipsychotic-induced euprolactinemic galactorrhea in an adolescent girl: a case report.
The primary care companion for CNS disorders, 2012Co-Authors: Woo Jin Kwak, Shakeel Raza, Fasiha Haq, Ankit Patel, Fatima Siddiqui, Mohammad Younis, Radhika GholkarAbstract:To the Editor: We describe a case report of galactorrhea with prolactin level within normal limits in a healthy 16-year-old African American girl after administration of quetiapine. Prolactin is an endogenous hormone from the anterior pituitary gland that promotes lactation. Dopamine predominantly inhibits prolactin. Antipsychotic medications block the dopamine-2 (D2) receptor via the Tuberoinfundibular dopamine Pathway, which can result in hyperprolactinemia.1 Serotonin is an indirect modulator of prolactin secretion.2 Hyperprolactinemia can cause galactorrhea, gynecomastia, sexual dysfunction, menstrual irregularities, infertility, hirsutism, and acne in women due to hypoestrogenism; hypogonadism and impaired growth and sexual maturation in adolescents; and potential osteoporosis.3,4 Women have greater prolactin elevations from antipsychotics than do men.5,6 Children and adolescents may also have greater prolactin elevations in response to antipsychotics.7 Conventional antipsychotics, risperidone, zotepine, and amisulpride are known to elevate prolactin more than other atypical antipsychotic medications.4,8–10 The median time to onset of galactorrhea is 20 days (range, 7–75 days) after commencement of an antipsychotic medication.8 Compared to typical antipsychotics with tighter D2 receptor binding, most atypical antipsychotics are less likely to cause hyperprolactinemia and thus galactorrhea. Quetiapine is known to have overall weaker dopamine binding activity; positron emission tomography scans showed transiently high striatal D2 receptor occupancy. Quetiapine’s transient association with the D2 receptor is postulated to allow normal dopaminergic neurotransmission in the Tuberoinfundibular Pathway and thus avoid hyperprolactinemia. This may explain only a temporary elevation of prolactin levels. D2 receptor occupancy decreases to 0%–27% in 12 hours.11 Quetiapine is less likely to elevate serum prolactin levels than risperidone.10,12 Fluoxetine also has been described to cause hyperprolactinemia and galactorrhea, possibly by stimulating prolactin release from pituitary lactotrophs.13 Hyperprolactinemia and galactorrhea from selective serotonin reuptake inhibitor use tended to correlate with above average dosages.14 Our patient was taking fluoxetine at 15 mg daily. Oral fluoxetine at 60 mg daily for 6 days increased prolactin levels in various studies.14,15 Case report. Mary, a 16-year-old African American adolescent girl, presented to the adolescent inpatient unit in 2011 for a chief complaint of “hearing voices and seeing spirits that tell her to kill herself.” As a child, she had delays in meeting her milestones in walking, talking, and toileting. She denied any substance abuse history. Her urine drug screen was negative. Her medical history was unremarkable except for previous diagnosis of schizoaffective disorder. Mary started hearing voices at 12 years of age. Previously, the voices commanded her to hurt others. She was in the 11th grade and receiving special education for behavior issues when she lost her grandfather and started hearing voices again. This time, the voices consisted of the voice of her deceased grandfather, the voice of her aunt, and an unidentified male voice. The voices were instructing her to kill herself now. She had multiple attempts of suicide by cutting herself. Sometimes, she “blacked out” in severe distress from the voices. She reported memory lapses and recalls poor choices and actions made during such episodes. Her medications at admission included oral fluoxetine 10 mg daily and oral ziprasidone 60 mg twice daily. After reviewing her history, symptoms, and medication trials, we decided to treat her with oral fluoxetine 15 mg daily and oral quetiapine extended release (XR) 100 mg daily. Ziprasidone was discontinued because it was not effective. She reported bilateral mastalgia, breast enlargement, and “milk discharge” from her breasts 3 days after starting quetiapine. Galactorrhea was confirmed by physical examination. She denied having headaches and vision changes. Her serum prolactin level was 19.9 ng/mL (reference range is 3.4 to 24.1 ng/mL) 6 days after starting fluoxetine and quetiapine XR. Prolactin levels > 100 ng/mL are characteristic of tumors secreting prolactin.4 We checked her serum prolactin level on 2 different occasions; findings of both serum prolactin assays were not elevated beyond a normal reference range (reference range for a 13- to 15-year-old girl is < 60 ng/mL16). Both prolactin assays were obtained in a fasting state. Quetiapine XR was discontinued at this time. Her serum prolactin level was 19.2 ng/mL 7 days after stopping quetiapine XR. It can take 3 days to 3 weeks for serum prolactin levels to normalize after stopping antipsychotic medications.4 Mary stated that her menstrual cycle was regular over the last 3 months. She did endorse vaginal discharge. The pelvic examination showed pelvic tenderness. Urinalysis confirmed elevated white blood cells and nitrites. We tested her for gonorrhea and chlamydia, and the results were negative. We treated her with doxycycline and azithromycin. Her urine culture was positive for diphtheroid bacilli. Her urine pregnancy test was negative, and her serum beta human chorionic gonadotropin test was also negative. Her thyroid-stimulating hormone and free T4 levels were within normal limits. Euprolactinemic galactorrhea has been associated with thyroid abnormalities.17 Her blood urea and creatinine levels were within normal limits. Prolactin can be high in patients with chronic renal failure.18 Gonadotropin-associated protein and acetylcholine have been identified as prolactin-inhibiting factors in animals.19 A computed tomography scan of the head, performed after hospital discharge, showed no mass lesion in the brain. Mary exhibited hostile behavior and mood alterations with other females that were problematic. These behaviors can be a clinical manifestation of hyperprolactinemia,20 but our patient had prolactin levels within normal limits. Quetiapine was discontinued, and after 2 weeks her galactorrhea resolved. Prolactin levels can be high in patients with chronic renal failure.17 Her serum prolactin level was checked again 2 weeks after discontinuation of quetiapine, and it was still within the normal range. Drug-induced hyperprolactinemia is postulated to occur through various mechanisms. One mechanism decreases dopamine, another increases serotonin. Prolactin can be increased by various medications and mechanisms. Lithium acts on serotoninergic Pathways to elevate prolactin. Estrogen potentiation of vasoactive intestinal peptide mediates hypothalamic synthesis of prolactin. Estrogen also has actions on the pituitary lactotroph cells to stimulate prolactin release. Opiates can inhibit dopamine synthesis and raise prolactin. H2 antagonists can inhibit dopamine release. Alprazolam raises prolactin levels through an unclear mechanism. Most psychotropic medications increase prolactin by inhibiting dopaminergic Pathways.2,4 Thyrotropin-releasing hormone promotes prolactin release.21 There is a trend to apply atypical antipsychotics to treat a broad spectrum of psychiatric diseases. Quetiapine has a lower affinity for dopamine D2 receptors and appears to be selective for mesolimbic and mesocortical dopamine receptors, with relative sparing of the Tuberoinfundibular system.22 Quetiapine has also been used to correct olanzapine-induced galactorrhea.23 However, there is a case report documenting dose-dependent quetiapine-induced galactorrhea.24 Female adolescents are more vulnerable to the side effect of galactorrhea caused by antipsychotic medications. In this case, typical and atypical antipsychotic medications most likely contributed to the galactorrhea, although fluoxetine may have contributed as well. Our patient had a serum prolactin level within normal limits despite the galactorrhea. Our patient was reluctant to reveal that she had galactorrhea; clinicians should screen female adolescents for galactorrhea when prescribing psychotropic medications and administer atypical antipsychotics cautiously.
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Ziprasidone-induced galactorrhea in an adolescent female: a case report.
Primary care companion to the Journal of clinical psychiatry, 2010Co-Authors: Shakeel Raza, Fasiha HaqAbstract:To the Editor: Prolactin is a lactogenic hormone, and its release is tonically inhibited by hypothalamic dopamine. Dopamine-2 (D2) receptor blockage in the Tuberoinfundibular Pathway releases prolactin.1 Second-generation neuroleptics are not particularly associated with hyperprolactinemia. With the exception of risperidone,2 it is assumed that hyperprolactinemia with second-generation antipsychotics (SGAs) is rare and transient.3–5 The rise in serum prolactin is directly associated with the degree of dopamine receptor blockage.6 Ziprasidone is considered to be a weak blocker of the D2 receptor.7 Significant prolactin elevation was not reported as being associated with ziprasidone use.8 To our knowledge, there are at least 5 case reports of ziprasidone-induced galactorrhea in the literature.9–13 Chronic elevation in prolactin in females can lead to loss of libido, galactorrhea, gynecomastia, amenorrhea, oligomenorrhea, hirsutism, disturbance of normal ovarian cycle, or increased risk of chronic osteoporosis. Case report. Ms A, a 16-year-old African American girl, has a history of neglect; sexual, physical, and emotional abuse; and multiple losses. She presented in 2009 with multidimensional symptomatology, which included attention-deficit/hyperactivity disorder (ADHD)–like symptoms (hyperactivity, impulsivity, and inattention); posttraumatic stress disorder–like symptoms (nightmares, flashbacks, numbing, avoidance, and sexually acting out behavior); psychotic symptoms (auditory hallucinations, eg, “voices asking me to do bad stuff”; paranoia, ie, “people are gossiping about me”); bipolar spectrum symptoms (eg, rapid mood swings, anger control issues, impulsivity, and decreased sleep); and oppositional defiant behavior. There was no past history of illicit substance abuse or alcohol drinking. She has a longstanding history of self-mutilating behavior (cutting her wrists) and overdosing on pills, which required multiple psychiatric hospitalizations, including long-term placement in a residential treatment facility. Prior to her current hospitalization, she had been treated with divalproex, quetiapine, and fluoxetine. During the hospitalization, she was started on ziprasidone 80 mg bid and divalproex 500 mg po twice daily was continued. Two weeks after ziprasidone treatment began, she developed galactorrhea and her blood prolactin level was 68.6 ng/mL (laboratory reference value, 1.40–24.20 ng/mL). Ziprasidone was discontinued and aripiprazole 2 mg/d was started. Three weeks later, galactorrhea had stopped and her serum prolactin level was within the normal range. She had no medical condition that could explain the elevated prolactin and galactorrhea levels. Some other known causes of galactorrhea were excluded, eg, chronic renal failure, pregnancy and lactation, and primary hypothyroidism. On a mental status examination, she reported a dysphoric mood and her affect was mood congruent. She had clear speech and had no suicidal or homicidal ideation. There were no hallucinations, but she reported paranoid ideations. Among atypical antipsychotics, ziprasidone has the highest serotonin (5-HT) receptor–dopamine receptor (5-HT2A/D2, 5-HT2C/D2, and 5-HT1A/D2) affinity ratios. Although ziprasidone is a weaker blocker of D2 receptors than conventional antipsychotics, ziprasidone-induced symptomatic hyperprolactinemia has been reported in literature.9–13 At a dose of 120 mg/d, 60% D2 receptor occupancy was obtained.14 Patients with the DRD2A1 allele had a 40% higher level of prolactin as compared to patients without this allele.15 Antipsychotic-induced hyperprolactinemia is not an uncommon condition, but it remains underdiagnosed and undertreated. In conclusion, physicians should routinely inquire about symptoms of hyperprolactinemia, eg, galactorrhea, gynecomastia, menstrual irregularities, and sexual dysfunction, in patients taking neuroleptics. If not treated, these symptoms could lead to noncompliance. Prolactin level can be elevated even in the absence of galactorrhea.
