Impulse Control Disorders in Patients with Pituitary Tumors Treated with Dopamine Agonists: A Systematic Review.

BACKGROUND: The increased prevalence of Impulse Control Disorders (ICDs) in dopamine agonist (DA) treated patients with Parkinson's disease is well described. Despite the frequent use of DAs in the management of pituitary tumors, the relationship between DAs and prevalence of ICDs in patients with pituitary tumours is unclear. AIMS: To establish the prevalence of ICDs in patients with prolactinoma or acromegaly and determine whether prevalence differs in those on DAs to those treated without. METHODS: Systematic review of the literature (registered a priori) reporting prevalence of ICDs in patients with prolactinoma or acromegaly (conducted June 2023). A narrative synthesis describing prevalence of ICDs according to assessment method was performed. Prevalence comparisons between patients with prolactinoma or acromegaly treated with DAs, to patients treated without, were summarised. RESULTS: Studies were largely retrospective, observational and heterogenous, with few patients with prolactinoma and acromegaly treated without DA. Prevalence of ICDs varied between 0-60% in patients with prolactinoma, and from 5-23% in studies with at least five patients with acromegaly. In most studies comparing DA exposed to non-DA exposed cases, DA use was not associated with ICDs. CONCLUSIONS: Reported prevalence of ICDs in patients with prolactinoma and acromegaly varies considerably. Given ICDs were reported to be highly prevalent in some studies, clinicians should be mindful of these potentially serious disorders. ICD screening tools validated for use in patients with pituitary tumors combined with prospective studies including appropriate controls, are necessary to accurately establish prevalence of ICDs and true impact of DAs in their development.

Long-term Discontinuation of Dopamine Agonist Treatment in Patients with Prolactinomas Revisited.

The most common type of functioning pituitary adenomas is prolactinomas; unlike other types, they are treated medically with dopamine agonists (DA). This treatment aims to normalize PRL levels and decrease tumor size by 50% or more. These objectives are typically achieved by 90% of patients with microprolactinoma, two-thirds of those with macroprolactinomas, and about half of those with giant prolactinomas. Life-long pharmacological treatment implies costs, discomfort, and the possibility of side effects, therefore, it has been suggested that DA discontinuation could be attempted in some patients. Long-term remission seems more likely in who, after 2 years of therapy achieve clinical, biochemical, and imaging remission criteria: no evidence of hypogonadism, a normal PRL level (preferably <5 ng/mL), and a >50% of tumor size reduction. Long-term remission seems to be more likely if the patient has been treated with cabergoline (CBG) for a minimum of 2 years, the PRL levels have normalized, tumor size has decreased by at least 50%, and the DA dose can gradually be tapered down to 0.25-0.5 mg per week. After treatment withdrawal, about 65% of patients experience a recurrence of hyperprolactinemia within the first 12 months of DA discontinuation. Although in most patients in whom DA discontinuation has been attempted, the hyperprolactinemia will recur, not all of them will require re-initiation of treatment. A good clinical judgement is crucial to identify those patients who need life-long treatment.

Effect of Dopaminergic Therapy on Impulse Control Disorders in Patients With a Prolactinoma.

BACKGROUND: Studies have reported an increase in the incidence of impulse control disorders (ICDs) in patient groups treated with dopamine agonists (DAAs), especially in Parkinson disease (PD). However, very few studies have reported on ICDs in individuals with a prolactinoma who were treated with DAAs. OBJECTIVE: To see whether a DAA by itself causes ICDs in individuals with a prolactinoma by controlling the susceptibility to impulsivity by excluding individuals with other risk factors for ICDs. METHOD: We compared the performance of 31 individuals with a prolactinoma receiving DAA therapy (DAA+) on various behavioral scales and the Iowa gambling task (IGT), a neuropsychological instrument that measures risky decision-making, with the performance of 20 individuals with a prolactinoma who were not on DAA therapy (DAA-) and 30 healthy controls (HC). RESULTS: There was no significant difference among the groups concerning performance on the Zuckerman Sensation Seeking Scale-V, Minnesota Impulse Disorders Interview, Barratt Impulsiveness Scale-11, or IGT. No correlation was found between the scores on these scales and the duration or dose of DAA in the DAA+ group. The incidence of ICDs was 25.8% in the DAA+ group, 15% in the DAA- group, and 16.7% in the HC. The differences among the groups did not reach statistical significance. CONCLUSION: Individuals who are under treatment with low-dose, D 2 -selective DAAs for a prolactinoma do not face an increased risk for ICDs, especially when they are carefully screened for any psychiatric comorbidity that may also display impulsivity.

TLR4 inhibition suppresses growth in oestrogen-induced prolactinoma models.

Prolactinomas have harmful effects on human health. Bromocriptine is the only commercially available drug in China, but about 25% of prolactinoma patients do not respond to it in clinic, its pathogenesis remains unknown. Thus, its pathogenesis needs to be determined to develop new therapeutic methods for prolactinomas. The expression of ERß, TLR4, and prolactin (PRL) in the pituitary gland of C57BL/6 mice and human prolactinoma specimen was examined by immunofluorescence or immunohistochemistry. The role of TLR4 in prolactinoma was determined using estradiol-induced models of C57BL/6 wild-type and TLR4-/- mice. MMQ cells were treated with estradiol, fulvestrant, and lipopolysaccharide (LPS) or transfected with TLR4 siRNA to study the expression of ERß, TLR4, and PRL in these cells. Furthermore, the interaction between ERß and TLR4 was investigated by immunoprecipitation analysis. The expression of PRL and TLR4 was co-located and increased in the pituitary gland of mice and human prolactinoma specimen compared to that in the control specimen. Meanwhile, TLR4 knockout or treatment with the TLR4 inhibitor TAK242 not only significantly inhibited tumor overgrowth but also decreased the expression of PRL in estradiol-treated mice through p38 MAPK pathway regulation. However, MMQ treated with estradiol and LPS enhanced PRL expression than treated with estradiol or LPS alone. Finally, ERß or TLR4 inhibition prevented the estradiol-induced PRL increase by regulating the TLR4/p38 MAPK pathway in vitro. Estradiol promoted prolactinoma development by activating the TLR4/p38 MAPK pathway through ERß, and TLR4 is a potential therapeutic target for prolactinoma treatment.

The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas.

BACKGROUND: Prolactinoma is a functional pituitary adenoma that secretes excessive prolactin. Dopamine agonists (DAs) such as bromocriptine (BRC) are the first-line treatment for prolactinomas, but the resistance rate is increasing year by year, creating a clinical challenge. Therefore, it is urgent to explore the molecular mechanism of bromocriptine resistance in prolactinomas. Activation of the P38 MAPK pathway affects multidrug resistance in tumours. Our previous studies have demonstrated that inhibiting MAPK14 can suppress the occurrence of prolactinoma, but the role of MAPK11/12/13/14 (p38 MAPK) signalling in dopamine agonist-resistant prolactinomas is still unclear. METHODS: A prolactinoma rat model was established to determine the effect of bromocriptine on MAPK11/12/13/14 signalling. DA-resistant GH3 cells and DA-sensitive MMQ cells were used, and the role of MAPK11/12/13/14 in bromocriptine-resistant prolactinomas was preliminarily verified by western blot, RT-qPCR, ELISA, flow cytometry and CCK-8 experiments. The effects of MAPK11 or MAPK14 on bromocriptine-resistant prolactinomas were further verified by siRNA transfection experiments. RESULTS: Bromocriptine was used to treat rat prolactinoma by upregulating DRD2 expression and downregulating the expression level of MAPK11/12/13/14 in vivo experiments. The in vitro experiments showed that GH3 cells are resistant to bromocriptine and that MMQ cells are sensitive to bromocriptine. Bromocriptine could significantly reduce the expression of MAPK12 and MAPK13 in GH3 cells and MMQ cells. Bromocriptine could significantly reduce the expression of MAPK11, MAPK14, NF-κB p65 and Bcl2 in MMQ but had no effect on MAPK11, MAPK14, NF-κB p65 and Bcl2 in GH3 cells. In addition, knockdown of MAPK11 and MAPK14 in GH3 cells by siRNA transfection reversed the resistance of GH3 cells to bromocriptine, and haloperidol (HAL) blocked the inhibitory effect of bromocriptine on MAPK14, MAPK11, and PRL in MMQ cells. Our findings show that MAPK11 and MAPK14 proteins are involved in bromocriptine resistance in prolactinomas. CONCLUSION: Bromocriptine reduces the expression of MAPK11/12/13/14 in prolactinomas, and MAPK11 and MAPK14 are involved in bromocriptine resistance in prolactinomas by regulating apoptosis. Reducing the expression of MAPK11 or MAPK14 can reverse bromocriptine resistance in prolactinomas.

PBK/TOPK Inhibitor Suppresses the Progression of Prolactinomas.

Background: Prolactinoma is the most common type of pituitary tumors, and its resultant tumor occupying and hormone disturbance greatly damage the health of patients. In this study, we investigated a protein kinase-PDZ Binding Kinase (PBK)/T-LAK Cell-Originated Protein Kinase (TOPK) as a candidate protein regulating prolactin (PRL) secretion and tumor growth of prolactinomas. Methods: Downloaded prolactinoma transcriptome dataset from Gene Expression Omnibus (GEO) database, and screened differentially expressed genes (DEGs) between normal pituitary tissues and prolactinoma tissues. Then, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed, a protein-protein interaction (PPI) network was constructed and the hub genes were identified. After a literature search, TOPK was presumed as an candidate target regulating the prolactinoma. We found a specific inhibitor of TOPK to investigate its effects on the proliferation, migration, apoptosis and PRL secretion of pituitary tumor cells. Finally, the regulation of TOPK inhibitor on its downstream target-p38 Mitogen Activated Protein Kinase (p38 MAPK) was detected to explore the potential mechanism. Results: A total of 361 DEGs were identified, and 20 hub genes were screened out. TOPK inhibitor HI-TOPK-032 could suppress the proliferation & migration and induce apoptosis of pituitary tumor cells in vitro, and reduce PRL secretion and tumor growth in vivo. HI-TOPK-032 also inhibited the phosphorylation level of the downstream target p38 MAPK, suggesting that TOPK inhibitors regulate the development of prolactinoma by mediating p38 MAPK. Conclusion: Our study of identification and functional validation of TOPK suggests that this candidate can be a promising molecular target for prolactinoma treatment.

Patients with acromegaly might not be at higher risk for dopamine agonist-induced impulse control disorders than those with prolactinomas.

OBJECTIVE: To evaluate the prevalence of impulse control disorders (ICD) and psychiatric symptoms in patients with acromegaly receiving dopamine agonists (DA) in comparison with those with prolactinoma, nonfunctioning pituitary adenomas (NFA), and healthy controls (HC). DESIGN: Forty patients with acromegaly, 40 with prolactinoma, 38 with NFA, and 32 HCs were included. All patients and controls were evaluated using the revised version of the Minnesota Impulsive Disorders Interview (MIDI-R), Symptom Check List (SCL-90-R) questionnaire, Barratt Impulsiveness Scale (BIS-11), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). RESULTS: We detected ICD associated with DAs in two patients with acromegaly (5%) and three patients (7.5%) with prolactinoma. All patients' symptoms resolved after discontinuation of the drug. While the mean DA dose was higher in patients with acromegaly than prolactinomas (p < 0.05), no difference was detected in terms of ICD prevalence between two groups (p > 0.05). SCL-90 depression and interpersonal sensitivity subscale positivity was higher in patients with NFA than HCs. Patients with prolactinoma had higher obsession and interpersonal sensitivity positivity and those with NFA had higher somatization, interpersonal sensitivity, and depression positivity as compared to patients with acromegaly (p < 0.05 for all). CONCLUSIONS: Although DA dose was significantly higher in patients with acromegaly, there was no significant difference in the prevalence of DA-related ICD. The higher prevalence of positive screening in SCL-90 in patients with NFA in comparison to HCs supports the hypothesis that the presence of a pituitary adenoma per se might cause significant psychiatric symptoms.

Hormonal imbalance and pituitary adenoma during antipsychotic treatment in an adolescent with bipolar affective disorder.

In this paper we present the case of a female teenager patient who was diagnosed with bipolar affective disorder and during psychotropic treatment with risperidone, the prolactin levels ranged between 55 ng/mL and 85 ng/mL at monthly repeated dosing. During this period, the patient presented somatic alterations in her state of health. The patient benefited from brain imaging, which revealed that in sella turcica is distinguished a well-defined and relatively homogeneous formation, measuring approximately 11/8 mm, suggestive of a pituitary adenoma. After changing the antipsychotic treatment, the pituitary formation resolved to a subsequent imaging re-evaluation.

Isolation and characterisation of CD9-positive pituitary adult stem/progenitor cells in rats.

S100ß protein and SOX2-double positive (S100ß/SOX2-positive) cells have been suggested to be adult pituitary stem/progenitor cells exhibiting plasticity and multipotency. The aim of the present study was to isolate S100ß/SOX2-positive cells from the adult anterior lobes of rats using a specific antibody against a novel membrane marker and to study their characteristics in vitro. We found that cluster of differentiation (CD) 9 is expressed in the majority of adult rat S100ß/SOX2-positive cells, and we succeeded in isolating CD9-positive cells using an anti-CD9 antibody with a pluriBead-cascade cell isolation system. Cultivation of these cells showed their capacity to differentiate into endothelial cells via bone morphogenetic protein signalling. By using the anterior lobes of prolactinoma model rats, the localisation of CD9-positive cells was confirmed in the tumour-induced neovascularisation region. Thus, the present study provides novel insights into adult pituitary stem/progenitor cells involved in the vascularisation of the anterior lobe.

Characteristics of pericytes in diethylstilbestrol (DES)-induced pituitary prolactinoma in rats.

Prolactinomas are the most common tumor of the human pituitary. They result in excessive prolactin secretion and important changes in the vasculature. Pericytes are perivascular cells associated with capillaries and have crucial roles in physiological and pathological neovascularization. We previously reported that pericytes produce type I and III collagens in the anterior pituitary of adult rats. In addition, pituitary pericytes contained well-developed cell organelles and actively synthesized collagens during early postnatal development. However, the characteristics of pericytes in pituitary tumors are unclear. In this study, we used diethylstilbestrol (DES)-treated rats as an animal model of prolactinoma. Using five common pericyte markers, more pericytes were observed in rats treated with DES for 3 months (prolactinoma) compared to the control. Transmission electron microscopy revealed that attached and semidetached pericytes exhibited active cell organelles. Moreover, we identified pericyte migration between capillaries. Although the fine structure of pituitary pericytes was active in prolactinoma, expressions of type I and III collagen mRNAs were greatly diminished. In sum, the characteristics and functions of pericytes were altered in pituitary tumors. This study is the first to clarify fine structural changes of pericytes in rat prolactinomas and improves our understanding of the function of pericytes under pathological conditions.

Effects of inhibiting connexin43 on expression of fibroblast growth factor in prolactinomas in rats.

OBJECTIVE: The aim of this study was to investigate the effect of connexin43(Cx43) on basic fibroblast growth factor (bFGF) expression by inhibiting Cx43 expression in prolactinomas in rats. METHODS: An experimental rat model of prolactinoma induced by estradiol (E2) treatment was used. Gap junction inhibitor was applied in through the arachnoid space by injection of carbenoxolone (CBX). Cx43 and bFGF expression was examined by both western blotting, respectively. RESULTS: Pituitaries treated with E2 were hypertrophic, but this was reduced by CBX treatment. Estradiol induced Cx43 and bFGF expression, which decreased following CBX treatment. CONCLUSIONS: Altered Cx43 expression modulates bFGF expression, which correlates with prolactinoma development.

Autoimmune Fibrotic Adverse Reactions in One-Year Treatment with Cabergoline for Women with Prolactinoma.

AIM: Cabergoline is related to an elevated risk of fibrotic adverse reactions including cardiac valvular and pleuropulmonary fibrosis. We investigated pulmonary and cardiac valve fibrosis and immunological markers before and after 3 and 12 months of treatment with cabergoline in women with prolactinoma. MATERIAL-METHODS: The study included thirty-two women with newly diagnosed prolactinoma and 28 healthy women. CAB cumulative dose was 7.8±5.5 mg after 3-month therapy, and 31±22 mg after 12-month follow-up. The risk of autoimmune adverse fibrotic reactions related to CAB treatment including cardiac valvulopathy and pulmonary fibrosis were assessed by a transthoracic echocardiography and pulmonary function tests, respectively. Immunological markers including Antistreptolysin O, Rheumatoid factor, Immunglobuline E, Antinuchlear antibody were also evaluated. RESULTS: Before the start of CAB therapy, the total prevalence of trace grade of mitral, aortic, pulmonic, and tricuspid valve regurgitations were found as 34%, 3%, 6.3%, and 39 % respectively in women with prolactinoma. After improving of prolactin levels with CAB treatment, no change was found in the prevalence of the all valve regurgitations. There was no deterioration in pulmonary function tests. Rheumatoid factor was found higher in newly diagnosed women with prolactinoma than in healthy women (p=0.01), and this was improved by CAB therapy (p=0.005). CONCLUSION: The prospective study indicated that sufficient cabergoline doses for a period of one year treatment of prolactinoma were not found to be related to fibrotic adverse reactions including cardiac valvular and pulmonary fibrosis or increased levels of immunological marker, apart from rheumatoid factor. For the first time Rf was found higher in newly diagnosed women with prolactinoma and was improved after cabergoline therapy.

[Expression of nNOS and ultrastructural changes in the penile tissue of rats with prolactinoma-induced erectile dysfunction].

OBJECTIVE: To study the expression of nNOS and ultrastructural changes in the penile tissue of rats with prolactinoma-induced erectile dysfunction (ED). METHODS: We established the model of prolactinoma in 20 male Westar rats by peritoneal injection of diethylstilbestrol (DES) and treated the control rats with normal saline (n = 10) or sterilized arachis oil (n = 10). After 8 weeks, we performed the apomorphine test and measured the weight of the pituitary gland and the levels of serum prolactin (PRL) and testosterone (T) to confirm the successful construction of the prolactinoma-induced ED model. Then we determined the expression of nNOS in the penile tissue by immunohistochemistry and examined the ultrastructural changes of the penile cavernosum under the transmission electron microscope. RESULTS: The prolactinoma-induced ED model was successfully established in 15 rats. The weight of the pituitary gland was significantly increased in the rats treated with DES as compared with the normal saline and sterilized arachis oil controls ([46.7 ± 15.5] vs [11.7 ± 2.4] and [12.4 ± 2.3] mg, both P < 0.05). The level of serum PRL was markedly higher while that of T remarkably lower in the former than in the latter two groups ([1,744.9 ± 304.5] vs [11.5 ± 2.4] and [10.6 ± 1.9] ng/ml, both P < 0.0l; [1.54 ± 0.46] vs [3.11 ± 1.08] and [3.04 ± 1.11] ng/ml, both P < 0.05). The rate of penile erection was significantly reduced in the prolactinoma-induced ED model rats in comparison with the normal saline and arachis oil controls (16.7% vs 100% and 87.5%, both P < 0.05), and so was the expression of nNOS in the penile tissue (0.024 ± 0.011 vs 0.066 ± 0.019 and 0.058 ± 0.021, both P < 0.05). Transmission electron microscopy manifested significant ultrastructural changes in the endothelial and smooth muscle cells of the cavernous tissue in the prolactinoma-induced ED models. CONCLUSION: The ultrastructural changes of the penile cavernous tissue and the reduced expression of nNOS in penile tissue may be the most important mechanisms of prolactinoma-induced ED in rats.

Pituitary gene expression differs in D-galactose-induced cell senescence and steroid-induced prolactinomas.

In general, pituitary tumors are benign with low mitotic activity. Premature senescence has been considered to be a significant mechanism underlying this uniquely benign pituitary tumor. The present study aims to compare the expression of the associated proteins involved in premature senescence pathways among normal, aging and pituitary adenoma cells. We successfully induced the aging pituitary using continuous D­galactose (D­gal) injection as well as a prolactin­secreting pituitary tumor via diethylstilbestrol implants. Compared with normal pituitary cells, the aging pituitary tissues revealed increased expression of IL­6, C/EBPß, p53, p21 and p16 and decreased expression of pituitary tumor transforming gene. In contrast, the expression of IL­6, p21 and p16 was decreased in pituitary tumor cells compared with normal pituitary tissues. Taken together, multiple pathways including IL­6/C/EBPß, p53/p21 and p16 were activated in aging pituitary cells in response to D­gal treatment. However, all these pathways were immune to pituitary tumors treated by chronic estrogen. The findings and the involvement of cytokines in a highly prevalent natural disease model (pituitary adenomas) indicate a potential use of this pathway as a target for effective therapy for tumor silencing and prevention of adenoma progression towards malignancy.

Diagnosis of prolactinoma in two male-to-female transsexual subjects following high-dose cross-sex hormone therapy.

Male-to-female transsexual persons use oestrogens + antiandrogens to adapt their physical bodies to the female sex. Doses are usually somewhat higher than those used by hypogonadal women receiving oestrogen replacement. Particularly in cases of self-administration of cross-sex hormones, doses may be very high. Oestrogens are powerful stimulators of synthesis and release of prolactin and serum prolactin levels are usually somewhat increased following oestrogen treatment. Prolactinomas have been reported in male-to-female transsexual persons, both after use of high and conventional doses of oestrogens but remain rare events. We report two new cases of prolactinomas in male-to-female transsexual persons, one in a 41-year-old subject who had used nonsupervised high-dose oestrogen treatment since the age of 23 years and another one in a 42 year old who had initiated oestrogen treatment at the age of 17 years. Their serum prolactin levels were strongly increased, and the diagnosis of a pituitary tumour was confirmed by imaging techniques. Both cases responded well to treatment with cabergoline treatment whereupon serum prolactin normalised. Our two cases are added to the three cases of prolactinomas in the literature in persons who had used supraphysiological doses of oestrogens.

Effects of silencing connexin43 on expression of pituitary tumor-transforming gene in prolactinomas.

OBJECTIVES: Pituitary tumor transforming gene (PTTG) is thought to play an important role in prolactinomas, and its overexpression is influenced by estrogen action in the pituitary. Changes in estrogen levels in the rat anterior pituitary increase the number of gap junctions (GJs) increasing both Connexin43 (Cx43) expression and intercellular communication, contributing to pituitary tumor growth. The aim of this study was to investigate the effect of Cx43 on PTTG expression by silencing Cx43 expression using RNA interference (RNAi) in vivo. METHODS: An experimental rat model of prolactinoma induced by estradiol (E2) treatment was used. Connexin43 RNAi was applied in vivo through the arachnoid space by injection of double-stranded RNA (dsRNA). Pituitary Cx43 immunostaining was examined using immunofluorescence and Cx43 and PTTG expression by both reverse-transcription-PCR (RT-PCR) and western blotting, respectively. RESULTS: (1) Pituitaries treated with E2 were hypertrophic, but this was reduced by dsRNA treatment. (2) Pituitary Cx43 immunofluorescence increased following E2 treatment, but returned to normal levels following dsRNA treatment. (3) Estradiol induced Cx43 and PTTG expression, which decreased following dsRNA treatment. DISCUSSION: Altered Cx43 expression modulates PTTG expression, which correlates with prolactinoma development. Thus, inhibiting gap junction intercellular communication (GJIC) as a means of weakening the pathologic role PTTG in prolactinomas may be of therapeutic interest.

The effects of hypokalaemia on the hormone exocytosis in adenohypophysis and prolactinoma cell culture model systems.

The extracellular ion milieu determines the exocytosis mechanism that is coupled to spontaneous electrical activity. The K(+) ion plays crucial role in this mechanism: as the potassium current is associated with membrane hyperpolarization and hormone release through protein cascade activation. The primary aim of this study was to investigate the response mechanisms of normal adenohypophysis and adenohypophyseal prolactinoma cell populations at different extracellular K(+) levels with an otherwise isoionic milieu of all other essential ions. We focused on prolactin (PRL) and adrenocorticotrophic hormone (ACTH) release.In our experimental study, female Wistar rats (n=20) were treated with estrone-acetate (150 µg/kg b.w./week) for 6 months to induce prolactinomas in the adenohypophysis. Primary, monolayer cell cultures were prepared by enzymatic and mechanical digestion. PRL and ACTH hormone presence was measured by radioimmunoassay or immuno-chemiluminescence assay. Immunocytochemistry was used to assess the apoptotic cells.Differences between the effects of hypokalaemia on normal adenohypophysis cultures and prolactinoma cell populations were investigated. Significant alteration (p<0.001, n=10) in hormone exocytosis was detected in K(+) treated adenohypophyseal and prolactinoma cell cultures compared to untreated groups. Immunocyto-chemistry showed that Bcl-2 expression was reduced under hypokalaemic conditions.The decrease in hormone exocytosis was tightly correlated to the extracellular K(+) in both cell types, leading to the conclusion that external K(+) may be the major factor for the inhibition of hormone release. The significant increase in hormone content in supernatant media suggests that hypokalaemia may play important role in apoptosis.

Thrombospondin-1 (TSP-1) analogs ABT-510 and ABT-898 inhibit prolactinoma growth and recover active pituitary transforming growth factor-ß1 (TGF-ß1).

Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-ß1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT-898, in addition to their described antiangiogenic effects, increased active TGF-ß1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas.

CEBPD suppresses prolactin expression and prolactinoma cell proliferation.

Hyperprolactinemia, usually caused by a pituitary lactotroph tumor, leads to galactorrhea and infertility. Increased prolactin (PRL) levels may be due to enhanced PRL expression or proliferation of PRL-secreting cells. We hypothesize that PRL expression and PRL-secreting cell proliferation are linked. Using microarray-based gene expression profiling, we identified CCAAT-enhancer-binding protein δ (CEBPD) transcription factor as a critical gene that regulates both PRL expression and lactotroph cell proliferation. CEBPD expression levels are decreased approximately 7-fold in experimental rat prolactinoma cells. Forced expression of this transcription factor in PRL-secreting cells (GH3 and MMQ) inhibited PRL expression and cellular proliferation, and CEBPD knockdown by small interfering RNA leads to increased PRL expression in both cell lines. To determine mechanisms underlying this observation, we determined binding of CEBPD to the PRL promoter and also showed marked suppression (96%) of PRL promoter activity. CEBPD and Pit1 interact and attenuate each other's binding to the PRL promoter. CEBPD also suppresses expression of proliferation-related genes, including c-Myc, survivin, as well as cyclins B1, B2, and D1. These results show that PRL expression and cell proliferation are controlled in part by CEBPD.