Elevated Serum Prolactin Research Articles

Global profiling of prolactin-modulated transcripts in breast cancer in vivo

BackgroundProlactin (PRL) is essential for normal mammary gland development. PRL promotes mammary tumor formation in rodents and elevated serum prolactin is associated with increased risk of estrogen-receptor positive breast cancer in women. On the other hand, PRL may also exert pro-differentiation effects and act to suppress invasive features of established breast cancer. Previously published limited global transcript profiling analyses of prolactin-regulated gene expression in human breast cancer cells have exclusively been performed in vitro. The present study aimed to shed new light on how PRL modulates estrogen receptor (ER)-positive breast cancer through global transcript profiling of a human breast cancer xenograft model in vivo.MethodsThe prolactin-responsive human T47D breast cancer cell line was xenotransplanted into nude mice and global transcript profiling was carried out following treatment with or without human PRL for 48 h. A subset of PRL-modulated transcripts was further validated using qRT-PCR and immunohistochemistry.ResultsThe in vivo analyses identified 130 PRL-modulated transcripts, 75 upregulated and 55 downregulated, based on fold change >1.6 and P-value <0.05. From this initial panel of transcripts, a subset of 18 transcripts with established breast cancer-relevance were selected and validated by qRT-PCR. Some but not all of the transcripts were also PRL-modulated in vitro. The selected PRL-modulated transcripts were tested for dependence on Stat5, Jak1 or Jak2 activation, and for co-regulation by 17β-estradiol (E2). The protein encoded by one of the PRL-regulated transcripts, PTHrP, was examined in a panel of 92 human breast cancers and found by in situ quantitative immunofluorescence analysis to be highly positively correlated with nuclear localized and tyrosine phosphorylated Stat5. Gene Ontology analysis revealed that PRL-upregulated genes were enriched in pathways involved in differentiation. Finally, a gene signature based on PRL-upregulated genes was associated with prolonged relapse-free and metastasis-free survival in breast cancer patients.ConclusionsThis global analysis identified and validated a panel of PRL-modulated transcripts in an ER-positive human breast cancer xenotransplant model, which may have value as markers of relapse-free and metastasis-free survival. Gene products identified in the present study may facilitate ongoing deciphering of the pleiotropic effects of PRL on human breast cancer.

Hyperprolactinemia as a cause of female primary infertility and its prevalence in Gezira State, Central Sudan

Background: Hyperprolactinemia is a condition of elevated serum prolactin. Prolactin is a 198-amino acid protein (23-kD) produced in the lactotrophs cells of the anterior pituitary gland. Hyperprolactinemia is the most common hypothalamo-pitiutary disorder; it can also occur secondary to use of some drugs, chronic illnesses like hypothyroidism, chronic liver and kidney disease, stress and neurogenic disorders. Idiopathic Hyperprolactinemia refers to elevation of serum prolactin in the absence of the above conditions. Objective: The aim of this study is to explain scientifically hyperprolactinemia as a cause of female primary infertility and its prevalence in GeziraState, Central Sudan. Method: Serum prolactin, FSH and LH levels were estimated using commercially specific enzyme immunoassay (EIA) technique in serum from 200 women (150 primary infertile and 50 fertile non-pregnant and non-lactating) attending Wad Medani teaching hospital in Wad Medani city, Central Sudan, from 2011 till 2013. Results: Hyperprolactinemia was found in 33.3%, irregular menstrual cycle 66%, amenorrhea 6.7%, oligomenorrhoea 59.3%, normal menorrhea (33,3%) and galactorrhoea 3.3% of primary infertile women. Conclusion: The prevalence of hyperprolactinemia was about one-third of primary infertile women in GeziraState (Central Sudan). The mainaetiology ofprimary infertility was anovulatory cycle due to high level of prolactin.

High incidence of mammary intraepithelial neoplasia development in Men1‐disrupted murine mammary glands

Mutations of the MEN1 tumour suppressor gene predispose patients to the development of multiple endocrine neoplasia type 1 (MEN1) syndrome, which is characterized by multiple endocrine tumours, including prolactinomas. The recent findings of the interaction between menin, encoded by the MEN1 gene, and the oestrogen receptor, as well as the observation of rare cases of mammary carcinomas in our heterozygous Men1 mutant mice, led us to investigate a putative tumour suppressor function of the Men1 gene in mouse mammary cells by disrupting the gene in luminal epithelial cells. A significantly higher incidence of mammary intraepithelial neoplasia (MIN) was observed in mutant WapCre-Men1(F/F) mice (51.5%) than in WapCre-Men1(+/+) (0%) or Men1(F/F) (7.1%) control mice. The majority of MIN observed in the mutant mice displayed complete menin inactivation. Because of the leakage of WapCre transgene expression, prolactinomas were observed in 83.3% of mutant mice, leading to premature death. As there was no correlation between MIN development and elevated serum prolactin levels, and phospho-STAT5 expression was decreased in mammary lesions, the increased incidence of MIN lesions was most likely due to Men1 disruption rather than to prolactinoma development. Interestingly, in MIN lesions, we found a decrease in membrane-associated E-cadherin and beta-catenin expression, the latter of which is a menin partner. Finally, reduced menin expression was found in a large proportion of two independent cohorts of patients with breast carcinomas. Taken together, the current work indicates a role of Men1 inactivation in the development of mammary pre-cancerous lesions in mice and a potential role in human mammary cancer.

What is the best way to diagnose clinically suspected prolactinomas of the pituitary?

Evidence-Based Answer In patients with a single elevated serum prolactin level (SPL), the test should be confirmed with a repeat morning measurement followed by a clinical evaluation for secondary causes (SOR: C, consensus guidelines). Patients with persistently elevated SPL and no clear cause should undergo gadolinium-enhanced magnetic resonance imaging (MRI) to identify possible pituitary adenomas, regardless of the degree of SPL elevation (SOR: B, retrospective cohort study).

Growth hormone deficiency, secondary hypothyroidism, and empty sella following treatment of childhood macroprolactinoma

Macroprolactinoma are rare in childhood, especially in the first decade. A 9-year-old girl presented with headache, vomiting, and decreased vision for 8 months. A diagnosis of macroprolactinoma was made following documentation of elevated serum prolactin (958 ng/ml) with a contrast enhancing macroadenoma (30 × 27 × 28 mm) on magnetic resonance imaging of pituitary. Anterior pituitary function was normal. Cabergoline therapy resulted in resolution of all symptoms in 2-8 months. Revaluation at 10 months of cabergoline therapy revealed normal serum prolactin (14 ng/ml), normal pituitary function, with 91% decrease in adenoma size (11.5 × 13.6 × 12.7 mm). Evaluation at 36 months of cabergoline therapy for growth arrest and weight gain for past 6 months revealed low serum prolactin, growth hormone deficiency, and secondary hypothyroidism with empty sella. She had biochemical as well as structural resolution of prolactinoma. This report highlights the development of multiple pituitary hormone deficiency with empty sella, an uncommon side effect of cabergoline therapy for macroprolactinoma.

Evaluation of Serum Prolactin Levels in Intellectually Disabled Patients Using Antipsychotic Medications

BackgroundPatients with intellectual disabilities may be treated with antipsychotic medications for a variety of diagnoses. Use of this category of medication can increase prolactin levels and place the patient at risk for sexual dysfunction and lower bone mineral density. The proposed mechanism of action is affinity for the dopamine receptor. Use of bromocriptine, a dopamine receptor antagonist, was proposed to attenuate hyperprolactinemia.ObjectivesThe objectives of this study were to (1) review serum prolactin (PRL) elevations associated with the use of antipsychotic (AP) medications in an intellectually disabled adult population and (2) determine if any association existed between the level of elevation and AP used.Patients and MethodsMedical records for adult patients at two Oklahoma facilities for the intellectually disabled were reviewed to evaluate prolactin levels for individuals prescribed antipsychotics. A linear regression model was used to evaluate the relationship between prolactin levels with intellectual disability level, bromocriptine use, demographics, and antipsychotic.Results73 (n = 53 males, n = 20 females) patients met criteria. The average age was 41.2 years. Nearly 70% of the patients had severe to profound levels of disability. 77% were prescribed second generation antipsychotics; 19% received first generation agents. Two variables, gender and bromocriptine use, were found to be significant predictors of prolactin levels. Mean prolactin level for females was 44 ng/mL (normal range: 4-30 ng/mL, males = 4-23 ng/mL). Patients who did not receive bromocriptine had mean levels of 23 ng/mL. No significant difference in prolactin levels was found for type of AP.ConclusionsMean prolactin levels for females were significantly higher than for males. Both sexes were found to have higher-than-normal levels. Use of bromocriptine was associated with higher prolactin levels. In this population of patients, the type of AP used had no significance on prolactin levels.

Invasive Giant Prolactinoma Presenting as a Nasal Polyp

A previously healthy, 14-year-old obese boy (body mass index 33 kg/m2) presented with progressive weight gain, nasal stuffiness, snoring, and a polypoid mass in his left nostril. Imaging studies revealed a homogenously enhancing mass extending from the floor of sella to the nasopharynx, measuring 8.7 × 7.6 cm transversely, 9.9 × 5.4 cm sagittally, and 5.5 × 8.0 cm coronally. The mass occupied the entire nasopharynx and extended bilaterally into inferior orbital fissures and pterygopalatine fossae (Figure). It abutted the basilar artery, temporal lobe parenchyma, and the inferior margin of the sella turcica, and it elevated the anterior pituitary lobe. It also invaded the cavernous sinuses, clivus, and sphenoid bones. The initial prolactin level was markedly elevated at 29 415 ng/mL (normal range 3-18). Biopsy was consistent with pituitary adenoma, with further staining confirming it to be a prolactinoma. His prolactin level was reduced to 12 059 ng/mL while on cabergoline, 0.5 mg/wk for 2 weeks, and subsequently to a present value of 316 ng/mL, on a cabergoline dose of 12 mg/wk. There has also been a significant reduction in the tumor size in 5 years (Figure). Invasive giant prolactinomas present with extrasellar extension and massive serum prolactin elevations.1Symon L. Jakubowski J. Kendall B. Surgical treatment of giant pituitary adenomas.J Neurol Neurosurg Psychiatry. 1979; 42: 973-982Crossref PubMed Scopus (111) Google Scholar Giant prolactinomas (≥4 cm) constitute only 0.5%-4.4% of all pituitary tumors.2Corsello S.M. Ubertini G. Altomare M. Lovicu R.M. Migneco M.G. Rota C.A. et al.Giant prolactinomas in men: efficacy of cabergoline treatment.Clin Endocrinol (Oxf). 2003; 58: 662-670Crossref PubMed Scopus (101) Google Scholar, 3Shrivastava R.K. Arginteanu M.S. King W.A. Post K.D. Giant prolactinomas: clinical management and long-term follow up.J Neurosurg. 2002; 97: 299-306Crossref PubMed Scopus (128) Google Scholar, 4Yu C. Wu Z. Gong J. Combined treatment of invasive giant prolactinomas.Pituitary. 2005; 8: 61-65Crossref PubMed Scopus (35) Google Scholar Clinical and imaging in our case raised the suspicion of nasopharyngeal carcinoma, rhabdomyosarcoma, small round blue cell tumor, and esthesioneuroblastoma. This case highlights the importance of assessing serum prolactin in erosive skull base tumors, as prolactinomas respond to cabergoline obviating the need for extensive surgical resection.

Is chronic nipple piercing associated with hyperprolactinemia?

Literature on hyperprolactinemia in the setting of a nipple piercing is limited to individuals with concomitant breast/chest wall infection. It is unclear if chronic nipple stimulation from a piercing alone can cause sustained elevations of serum prolactin. Nipple piercing is emerging as a more mainstream societal form of body art, and the answer to this clinical question would potentially alter patient management. Our aim was to assess serum prolactin levels in subjects with nipple piercing. Inclusion criteria were as follows: men and women ≥ 18 years old with nipple piercing(s) present > 6 months. Exclusion criteria included: women who are pregnant, lactating or < 6 months postpartum; subjects on medications known to increase prolactin levels; chest wall/breast infection at the time of phlebotomy or conditions known to be associated with hyperprolactinemia. Three men and eight women were enrolled. Median (range) ages for men and women were 33 (24-42) and 27 years (23-42), respectively. All except one subject had bilateral piercings. The median interval from nipple piercing to blood draw was 4.0 (2.0-12.0) years. None of the subjects had hyperprolactinemia. Median (range) prolactin levels for men and women were 5.6 ng/mL (3.8-7.4) and 8.0 ng/mL (2.8-10.9), respectively. Our results suggest that in the absence of any concomitant infection, chronic nipple piercing is not associated with hyperprolactinemia.

Paliperidone Palmitate for Schizophrenia

Paliperidone palmitate, a long-acting, intramuscular formulation of paliperidone, is now available for clinical use. Paliperidone is an active metabolite of risperidone and it is also available in an oral formulation for daily use.To compare the effects of paliperidone palmitate with any other treatment for people with schizophrenia and schizophrenia-like illnesses.We searched the Cochrane Schizophrenia Group's Register (November 2009) and inspected references of identified studies for further trials. We contacted the manufacturers of paliperidone palmitate, the Food and Drug Administration, and authors of relevant trials for additional material.We included randomised controlled trials (RCTs).We independently selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate, we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to benefit/harm statistic (NNB/H). We calculated mean differences (MD) for continuous data.Five studies with 2215 participants compared paliperidone palmitate with placebo. Fewer people left studies early if they were randomised to paliperidone palmitate (n = 2183, 5 RCTs, RR 0.76 CI 0.70 to 0.84, NNTB 9 CI 7 to 14) and those receiving any dose of paliperidone palmitate were significantly less likely to show no improvement in global state (n = 1696, 4 RCTs, RR 0.79 CI 0.74 to 0.85, NNTB 7 CI 5 to 9). People randomised to paliperidone palmitate were less likely to experience a recurrence of psychosis (n = 312, 1 RCT, RR 0.28 CI 0.17 to 0.48, NNTB 5 CI 4 to 6) than those allocated to placebo in a single trial specifically designed to study recurrence. In the other studies where recurrence was recorded only as an adverse event, we found that people who received paliperidone palmitate were also less likely to experience a recurrence of psychotic symptoms (n = 1837, 4 RCTs, RR 0.55 CI 0.44 to 0.68, NNTB 10 CI 8 to 14). Paliperidone palmitate was associated with fewer reports of agitation or aggression (n = 2180, 5 RCTs, RR 0.65 CI 0.46 to 0.91, NNTB 39 CI 25 to 150) and of using anxiolytic medications (n = 2170, 5 RCTs, RR 0.89 CI 0.83 to 0.96, NNTB 16 CI 11 to 44). A consistent, significant elevation in serum prolactin (ng/mL) was found for both men and women receiving paliperidone palmitate, but the data were too heterogenous to sum. We found no evidence of sexual dysfunction in these short-term trials. People receiving paliperidone palmitate had a significantly greater increase in weight (n = 2052, 5 RCTs, MD 1.34 CI 0.97 to 1.70) in comparison with people who received placebo.Two studies with 1969 participants compared flexibly-dosed paliperidone palmitate with flexibly-dosed risperidone long-acting injection. The mean doses of paliperidone palmitate in these trials were 73.3 and 104.6 mg every four weeks compared with risperidone long-acting injection at mean doses, respectively, of 35.3 and 31.7 mg every two weeks. We found no differences between paliperidone palmitate and risperidone long-acting injection for leaving these studies early for any reason (n = 1969, 2 RCTs, RR 1.12 CI 1.00 to 1.25). Those receiving paliperidone palmitate were statistically no more likely to have a recurrence of psychotic symptoms than those receiving risperidone long-acting injection (n = 1961, 2 RCTs, RR 1.23 CI 0.98 to 1.53). While we found no significant difference in the occurrences of deaths in the pooled trials (n = 1967, 2 RCTs, RR 3.62 CI 0.60 to 21.89), we note that a total of six deaths occurred in these two trials, with five deaths among people who received paliperidone palmitate and one death among people who received risperidone long-acting injection. Although death is the most serious of adverse events, the small number of these events in these trials makes it unclear if this finding is meaningful. We found that participants randomised to paliperidone palmitate were significantly less likely to use anticholinergic medications in these trials (n = 1587, 2 RCTs, RR 0.67 CI 0.55 to 0.82, NNTB 13 CI 10 to 24). We found no data regarding paliperidone palmitate relating to services use, quality of life, behaviour, patient satisfaction, cognitive functioning or cost.In short-term studies, paliperidone palmitate is an antipsychotic drug that is more efficacious than placebo. We found its adverse effects to be similar to those of its related compounds, paliperidone and risperidone, with extrapyramidal movement disorders, weight gain, and tachycardia all more common with paliperidone palmitate than placebo. While no difference was found in the incidence of reported adverse sexual outcomes, paliperidone palmitate is associated with substantial increases in serum prolactin. When flexibly dosed with a mean doses of approximately 70 to 110 mg every four weeks, paliperidone palmitate appears comparable in efficacy and tolerability to risperidone long-acting injection flexibly dosed with mean doses of approximately 35 mg every two weeks.

An Analysis of Potentially Prolactin-Related Adverse Events and Abnormal Prolactin Values in Randomized Clinical Trials with Paliperidone Palmitate

Paliperidone palmitate has been associated with serum prolactin elevations in some patients. However, few individuals with elevated prolactin levels (hyperprolactinemia) have symptomatic potentially prolactin-related adverse events (PPR-AEs). To quantify rates of hyperprolactinemia in subjects treated with the newly marketed paliperidone palmitate long-acting injection (PP-LAI) in randomized clinical trials, summarize rates of PPR-AEs in those trials by sex and dose, and determine how many PPR-AEs required treatment. Numbers and rates of investigator-reported hyperprolactinemia and PPR-AEs were obtained from the sponsor's clinical trial database and have been included in regulatory filings. Results were tabulated for males, females, and overall, and by dose administered, using descriptive statistics. Those requiring treatment were described as well. There were 3173 subjects (61.4% males) exposed to PP-LAI in 10 clinical trials; 2831 (89.2%) patients had recorded prolactin levels, including 1759 males (90.3% of exposed males) and 1072 females (87.5% of exposed females). Overall, at any time, prolactin levels were elevated for 38.8% of the subjects (39.5% for males and 37.7% for females; p = 0.354 between sexes). However, there was no significant correlation between monthly dose and proportion of subjects with elevated prolactin levels (p = 0.109). There were 115 PPR-AEs in 107 patients (3.4%); 51 (44.3% of PPR-AEs) cases represented asymptomatic hyperprolactinemia. The remaining 64 symptomatic PPR-AEs affected 2.0% of the total number of subjects. Fifteen events in 13 participants (0.41% of patients or 4.7 events/1000 patients) required treatment. Clinicians should periodically assess patients on paliperidone palmitate for any PPR-AEs and carefully assess the benefits and risks when managing these effects.

Not only dopamine D2 receptors involved in Peony-Glycyrrhiza Decoction, an herbal preparation against antipsychotic-associated hyperprolactinemia

Clinical studies have demonstrated the effectiveness of an herbal preparation called Peony-Glycyrrhiza Decoction (PGD) in alleviating antipsychotic-induced hyperprolactinemia (hyperPRL). In the present study, we further examined the pharmacological action of PGD on prolactin (PRL) secretion using in vitro and in vivo models, with specific attention to the role of dopaminergic mediators and other sex hormones. Treatment with PGD at 1-5mg/ml significantly suppressed PRL secretion and synthesis in MMQ cells, a model of hyperPRL derived from pituitary adenoma cells. The suppressive effects were completely abolished by pretreatment with 10μM haloperidol, a dopamine D(2) receptor antagonist. Consistent with a D(2)-action, PGD did not affect PRL in rat pituitary lactotropic tumor-derived GH3 cells that lack the D(2) receptor expression but significantly increased the expression of D(2) receptors and dopamine transporters (DAT) in PC12 cells. In a rat model of hyperPRL, produced by repeated injection of the dopamine blocker metoclopramide (MCP), chronic PGD (2.5-10g/kg daily) significantly reduced elevated serum PRL. The reduction in magnitude was similar to that elicited by bromocriptine (BMT), a dopamine D(2) receptor agonist currently used for treatment of hyperPRL. Neither PGD nor BMT altered serum estradiol, but PGD reversed decreased serum progesterone to control level, whereas BMT did not. These results indicate that the anti-hyperPRL effects of PGD are associated not only with D(2) receptor and DAT modulation, but also with a normalization of other sex hormone dysfunction. This experimental evidence supports clinical use of PGD as an effective treatment of antipsychotic-induced hyperPRL.

Paliperidone palmitate for schizophrenia

Paliperidone palmitate, a long-acting, intramuscular formulation of paliperidone, is now available for clinical use. Paliperidone is an active metabolite of risperidone and it is also available in an oral formulation for daily use. To compare the effects of paliperidone palmitate with any other treatment for people with schizophrenia and schizophrenia-like illnesses. We searched the Cochrane Schizophrenia Group's Register (November 2009) and inspected references of identified studies for further trials. We contacted the manufacturers of paliperidone palmitate, the Food and Drug Administration, and authors of relevant trials for additional material. We included randomised controlled trials (RCTs). We independently selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate, we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to benefit/harm statistic (NNB/H). We calculated mean differences (MD) for continuous data. Five studies with 2215 participants compared paliperidone palmitate with placebo. Fewer people left studies early if they were randomised to paliperidone palmitate (n = 2183, 5 RCTs, RR 0.76 CI 0.70 to 0.84, NNTB 9 CI 7 to 14) and those receiving any dose of paliperidone palmitate were significantly less likely to show no improvement in global state (n = 1696, 4 RCTs, RR 0.79 CI 0.74 to 0.85, NNTB 7 CI 5 to 9). People randomised to paliperidone palmitate were less likely to experience a recurrence of psychosis (n = 312, 1 RCT, RR 0.28 CI 0.17 to 0.48, NNTB 5 CI 4 to 6) than those allocated to placebo in a single trial specifically designed to study recurrence. In the other studies where recurrence was recorded only as an adverse event, we found that people who received paliperidone palmitate were also less likely to experience a recurrence of psychotic symptoms (n = 1837, 4 RCTs, RR 0.55 CI 0.44 to 0.68, NNTB 10 CI 8 to 14). Paliperidone palmitate was associated with fewer reports of agitation or aggression (n = 2180, 5 RCTs, RR 0.65 CI 0.46 to 0.91, NNTB 39 CI 25 to 150) and of using anxiolytic medications (n = 2170, 5 RCTs, RR 0.89 CI 0.83 to 0.96, NNTB 16 CI 11 to 44). A consistent, significant elevation in serum prolactin (ng/mL) was found for both men and women receiving paliperidone palmitate, but the data were too heterogenous to sum. We found no evidence of sexual dysfunction in these short-term trials. People receiving paliperidone palmitate had a significantly greater increase in weight (n = 2052, 5 RCTs, MD 1.34 CI 0.97 to 1.70) in comparison with people who received placebo.Two studies with 1969 participants compared flexibly-dosed paliperidone palmitate with flexibly-dosed risperidone long-acting injection. The mean doses of paliperidone palmitate in these trials were 73.3 and 104.6 mg every four weeks compared with risperidone long-acting injection at mean doses, respectively, of 35.3 and 31.7 mg every two weeks. We found no differences between paliperidone palmitate and risperidone long-acting injection for leaving these studies early for any reason (n = 1969, 2 RCTs, RR 1.12 CI 1.00 to 1.25).Those receiving paliperidone palmitate were statistically no more likely to have a recurrence of psychotic symptoms than those receiving risperidone long-acting injection (n = 1961, 2 RCTs, RR 1.23 CI 0.98 to 1.53).While we found no significant difference in the occurrences of deaths in the pooled trials (n = 1967, 2 RCTs, RR 3.62 CI 0.60 to 21.89), we note that a total of six deaths occurred in these two trials, with five deaths among people who received paliperidone palmitate and one death among people who received risperidone long-acting injection. Although death is the most serious of adverse events, the small number of these events in these trials makes it unclear if this finding is meaningful. We found that participants randomised to paliperidone palmitate were significantly less likely to use anticholinergic medications in these trials (n = 1587, 2 RCTs, RR 0.67 CI 0.55 to 0.82, NNTB 13 CI 10 to 24). We found no data regarding paliperidone palmitate relating to services use, quality of life, behaviour, patient satisfaction, cognitive functioning or cost. In short-term studies, paliperidone palmitate is an antipsychotic drug that is more efficacious than placebo. We found its adverse effects to be similar to those of its related compounds, paliperidone and risperidone, with extrapyramidal movement disorders, weight gain, and tachycardia all more common with paliperidone palmitate than placebo. While no difference was found in the incidence of reported adverse sexual outcomes, paliperidone palmitate is associated with substantial increases in serum prolactin. When flexibly dosed with a mean doses of approximately 70 to 110 mg every four weeks, paliperidone palmitate appears comparable in efficacy and tolerability to risperidone long-acting injection flexibly dosed with mean doses of approximately 35 mg every two weeks.

Remarkable Cystic Expansion of Microprolactinoma Causing Diabetes Insipidus during Pregnancy

A 26-yr-old woman with galactorrhea had an elevated serum prolactin (PRL) level (75 ng/ml). Magnetic resonance imaging (MRI) revealed a 4-mm intrasellar tumor, suggesting a PRL-producing microadenoma. Cabergoline was prescribed and ameliorated the patient’s galactorrhea. No tumor growth was observed for 1 yr after MRI (Fig. 1), and cabergoline administration was discontinued when the patient became pregnant. At 24 wk gestation, she was admitted to the obstetrics department for intrauterine growth retardation. She developed polyuria (7700 ml/d) at 29 wk gestation and had a low serum arginine vasopressin (AVP) level (0.5 pg/ml). MRI revealed a 2-cm cystic lesion with suprasellar extension (Fig. 2). Her serum PRL level robustly increased (461 ng/ml), but visual field testing results were normal. Diabetes insipidus caused by cystic expansion of a prolactinoma was consid-

Serum Prolactin Concentrations in Relation to Hypopituitarism and Obesity in Children with Optic Nerve Hypoplasia

Background/Aims: The majority of children with optic nerve hypoplasia (ONH) develop hypopituitarism and many also become obese. These associated conditions are a major cause of morbidity and are possibly due to hypothalamic dysfunction. Because mild hyperprolactinemia often occurs in subjects with disorders of the hypothalamus, we examined whether hyperprolactinemia was present in children with ONH during the first 3 years of life and whether it was a marker for hypopituitarism and/or obesity. Methods: Data were retrospectively analyzed from a registry study of children with ONH. The initial serum prolactin was obtained prior to age 36 months (n = 125) and compared with pituitary function and body mass index at age 5. Results: 72% of subjects had an elevated initial serum prolactin and 60% had hypopituitarism. An elevated initial prolactin was associated with hypopituitarism (OR 2.58; 95% CI 1.16, 5.73), specifically with growth hormone deficiency (OR 2.77; 95% CI 1.21, 6.34). 31% of subjects had a body mass index ≥85th percentile, but this did not correlate with initial hyperprolactinemia. Conclusions: Early hyperprolactinemia correlates with the presence of hypopituitarism in children with ONH, but it is not a reliable prognosticator of hypopituitarism. Additionally, hyperprolactinemia does not predict future weight excess.

Severe oligozoospermia in a patient with myxedema coma

A case of severe oligozoospermia with myxedema coma is herein presented. The patient was referred to a male infertility clinic with a 5-year history of primary infertility. Decreased serum testosterone and elevated serum prolactin without abnormal MRI findings in the hypothalamus, and decreased semen volume and sperm motility were noted. A GnRH test revealed a decreased luteinizing hormone response, whereas the HCG test showed a normal testosterone increase. Because a urinalysis after ejaculation indicated retrograde ejaculation, imipramine administration was started. However, the semen quality deteriorated, so the patient was referred to an ART clinic. Twenty-one months from the initial visit, the patient developed a loss of consciousness and edema due to myxedema coma, a life-threatening state of hypothyroidism. The patient recovered after 1 month of thyroid hormone replacement therapy (HRT) with corticosteroids. Three months after the myxedema coma, a semen analysis showed a decreased semen volume (0.2 mL) and severe oligozoospermia (two spermatozoa/ejaculate). Elevated prolactin and decreased testosterone levels were still present. These parameters gradually improved after restoration of euthyroidism by HRT. In conclusion, physicians should confirm the thyroid function in the management of male infertility, especially in patients with elevated prolactin levels.

A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole for the treatment of acute manic or mixed episodes in Asian patients with bipolar I disorder (the AMAZE study)

Objectives. To investigate the efficacy and safety of aripiprazole in Asian patients with manic or mixed episodes associated with bipolar I disorder. Methods. Subjects were randomised to aripiprazole (24 mg/day; reduced to 12 mg/day if needed for tolerability; n = 128) or placebo (n = 130) for 3 weeks in this multicentre, double-blind study. The primary efficacy measure was mean change from baseline in Young Mania Rating Scale (YMRS) Total score. Results. A total of 136 patients (aripiprazole 56.3%; placebo 49.2%) completed the study. The majority of patients (92.6%) received aripiprazole 24 mg/day. Aripiprazole produced statistically significant mean improvements in YMRS Total scores compared with placebo from Day 4 through to Week 3 (–11.3 vs. –5.3; P < 0.001). The most common adverse events (> 15% of patients; aripiprazole vs. placebo) were akathisia (22.0 vs. 5.6%) and insomnia (16.3 vs. 9.6%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight from baseline (–0.4 vs. –0.7 kg; P = 0.231). Aripiprazole was not associated with an elevated serum prolactin level. Conclusions. Aripiprazole had significantly greater efficacy than placebo for the treatment of acute manic or mixed episodes associated with bipolar I disorder in Asian patients. Treatment was generally safe and well tolerated.

Quetiapine-Induced Galactorrhea With Normal Prolactin Level in an Adult Female Patient

To the Editor: Quetiapine is an atypical antipsychotic agent with less propensity than other atypical antipsychotics to induce antipsychotic-associated hyperprolactinemia in standard recommended therapeutic dosages,1,2 and when it does induce the condition at all, the rise in serum prolactin level is only transient.3 Accordingly, quetiapine has been recommended as an alternative in patients who develop galactorrhea associated with other antipsychotics.4–6 However, hyperprolactinemia with related side effects may rarely be encountered in a few susceptible individuals.7 We describe a case of quetiapine-induced galactorrhea without an increase in blood prolactin level in an adult female patient. We then discuss the implications of quetiapine with respect to such an adverse effect. Case report. Ms A, a 45-year-old white woman, was diagnosed with DSM-IV-TR bipolar disorder at the age of 23 years and experienced repeated episodes of both depression and mania over the years. Treatment with lithium carbonate and sodium valproate was tried without much success. She recently presented to the psychiatric emergency department with an acute manic episode (DSM-IV-TR). The patient was agitated and refused to sit during the interview. She paced back and forth, talked or mumbled incessantly, and occasionally busted into laughter and cursed during the interview. Around the time of admission, her symptoms comprised irritability, psychomotor agitation, pressured speech, flight of ideas, insomnia, grandiose and aggressive behavior, sexual disinhibition, and lack of insight. She denied any auditory and visual hallucinations. Upon her admission to the hospital, a drug screen was negative. Findings of a head computed tomography scan were within normal limits. Results of other routine investigations including complete blood count, complete metabolic profile, thyroid function tests, liver function tests, and prolactin level were within normal limits. Treatment with quetiapine was initiated for both therapeutic as well as prophylactic purposes; she responded well, and her manic symptoms subsided. She was discharged from the hospital after 1 week. After 2 months of continued treatment, she reported breast enlargement, “milk” discharge from her breast, and bilateral breast pain and amenorrhea. Galactorrhea was confirmed by physical examination. Surprisingly, her serum prolactin level at this stage was again found to be within normal range (13 ng/mL; normal range, 2.80–20 ng/mL) instead of being high. Pregnancy test was negative. Thyroid function tests revealed no abnormalities and excluded hypothyroidism from being the cause of galactorrhea. Physical examination revealed no other abnormality. She neither complained of visual disturbance nor described symptoms suggestive of raised intracranial pressure. A brain scan was not performed as the serum prolactin elevation was within normal limits. Since we assumed quetiapine was one of the possible causes of galactorrhea, quetiapine was stopped, which led to dramatic resolution of symptoms within 72 hours. Ms A, however, took another 2 months to resume her normal menstrual cycle. A PubMed search for the years 1996 to 2011 with the keywords antipsychotics, quetiapine, and galactorrhea was performed; other articles were obtained via a Google Scholar search that included the same time span and keywords. To the best of our knowledge, this is the first case reporting galactorrhea without hyperprolactinemia in the medical literature. However, several studies have shown that quetiapine does not increase prolactin level to the same extent as do other antipsychotic medications. The newly accepted explanation for the prolactin-sparing property of quetiapine and other atypical antipsychotic agents is the poor occupancy of dopamine D2 receptors on lactotrope cells in the anterior pituitary gland compared to striatal dopamine D2 occupancy.8 This contrasts with the property of all conventional antipsychotics and some atypical agents like risperidone in blocking dopamine D2 receptors on prolactin-secreting cells in the pituitary gland, removing the main inhibitory effect on prolactin secretion.9 A study on the incidence of hyperprolactinemia and prolactin-related side effects in children and adolescents treated with antipsychotics showed that there is no significant increase in prolactin level after the long-term use (2 years) of quetiapine.10 In 2006, a 12-week randomized, double-blind study of quetiapine, risperidone, or fluphenazine on sexual functioning in people with schizophrenia showed that, overall, quetiapine was associated with normal prolactin levels.11 Treatment with quetiapine and olanzapine caused prolactin levels to be elevated just temporarily. However, no correlation between prolactin levels and dosage could be found in these subjects under treatment.12 Detailed endocrine-metabolic studies performed on 5 women showed isolated galactorrhea with normal serum prolactin levels.13 To our knowledge, 2 case reports7,14 have been published on subjects who developed hyperprolactinemic galactorrhea with quetiapine. However, no case reports have been published about quetiapine-induced galactorrhea with normal level of prolactin as was seen in our subject. Although quetiapine is considered to be a prolactin-sparing atypical antipsychotic, quetiapine-induced galactorrhea may rarely be encountered as a side effect in susceptible individuals, and therefore physicians should routinely inquire about quetiapine as one of the possible causes of galactorrhea even when the prolactin level is within normal limits.

Central Prolactin Modulates Insulin Sensitivity and Insulin Secretion in Diabetic Rats

Background: Prolactin secretion is self-regulating as it acts upon hypothalamic dopaminergic systems which inhibit prolactin release from the anterior pitutary. Circulating prolactin improves glucose homeostasis by increasing insulin action and secretion, but central prolactin effects on glucose homeostasis have not been examined. Here, we determined that chronic central infusion of prolactin modulates insulin resistance and β-cell function and mass in 90% of pancreatectomized diabetic male rats. Methods: Diabetic rats were divided into three groups according to the dose of intracerebroventricular infusion of prolactin during 4 weeks: (1) low-dose prolactin (Low-PRL; 0.1 µg/h), (2) high-dose prolactin (High-PRL; 1 µg/h) and (3) vehicle only (cerebrospinal fluid). Nondiabetic rats were centrally infused with the vehicle. Results: Chronic intracerebroventricular infusion of Low-PRL lowered body weight and epididymal fat pads by increasing hypothalamic dopamine levels that reduced serum prolactin levels and potentiated leptin signaling. However, High-PRL slightly exacerbated energy dysregulation, decreased hypothalamic dopamine levels, and elevated serum prolactin levels. Both dosages promoted β-cell mass but in a different manner: Low-PRL decreased β-cell apoptosis, whereas High-PRL increased its proliferation. However, only Low-PRL enhanced first-phase insulin secretion and improved insulin sensitivity at a hyperglycemic state in comparison to the control. Low-PRL also increased glucose infusion rates and decreased hepatic glucose output in hyperinsulinemic states, signifying an improvement in hepatic insulin sensitivity. However, High-PRL exacerbated hepatic insulin resistance compared with the control diabetic rats. Conclusions: In contrast to the exacerbation of insulin resistance caused by High-PRL, Low-PRL may improve energy and glucose metabolism by increasing hypothalamic dopamine levels in diabetic rats.

Gamma knife stereotactic radiosurgery for drug resistant or intolerant invasive prolactinomas

We evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas. Twenty-two patients with cavernous sinus invasive prolactinoma underwent GKSR between 1994 and 2009. Thirteen patients were dopamine agonist (DA) resistant. Six patients were intolerant to DA. Three patients chose GKSR as their initial treatment modality in hopes they might avoid life long suppression medication. The median tumor volume was 3.0 cm3 (range 0.3–11.6). The marginal tumor dose (median= 15 Gy, range 12–25 Gy) prescribed was based on the dose delivered to the optic apparatus. The median follow-up interval was 36 months (range, 12–185). Endocrine normalization was defined as a normal serum prolactin level off DA (cure) or on DA. Endocrine improvement was defined asa decreased but still elevated serum prolactin level. Endocrine deterioration was defined as an increased serum prolactin level. Endocrine normalization was achieved in six(27.3%) patients. Twelve (54.5%) patients had endocrine improvement. Four patients (18.2%) developed delayed increased prolactin. Imaging-defined local tumor control was achieved in 19 (86.4%) patients, 12 of whom had tumor regression. Three patients had a delayed tumor progression and required additional management. One patient developed a new pituitary axis deficiency after GKSR. Invasive prolactinomas continue to pose management challenges. GKSR is a non invasive adjunctive option that may reduce prolactin levels in patients who are resistant to or intolerant of suppression medication. In a minority of cases, patients may no longer require long term suppression therapy.

Antipsychotic-Induced Euprolactinemic Galactorrhea in an Adolescent Girl

Antipsychotic-Induced Euprolactinemic Galactorrhea in an Adolescent Girl