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Background and objectiveCognitive impairments have been reported in patients with hyperprolactinemia; however, there is a lack of knowledge of brain structure alterations relevant to hyperprolactinemia in prolactinomas. Thus, we aimed to identify changes in brain structure in prolactinomas and to determine whether these changes are related to cognitive performance and clinical characteristics.MethodsParticipants were 32 female patients with prolactinomas and 26 healthy controls (HC) matched for age, sex, education, and handedness. All participants underwent magnetic resonance imaging brain scans, neuropsychological assessments, and clinical evaluations. Voxel-based morphometry analysis was used to identify changes in gray matter volume (GMV). Partial correlation analysis and multiple linear regression were performed to determine the relationship between GMV, cognition, and clinical characteristics.ResultsCompared to HC, patients with prolactinomas demonstrated a decrease in GMV in the left hippocampus, left orbitofrontal cortex, right middle frontal cortex (MFC), and right inferior frontal cortex (IFC). In addition, patients performed worse than controls on tests for verbal memory and executive function, and this was significantly related to the GMV of the left hippocampus and right MFC, respectively. Moreover, in the patients, we found a negative relationship between serum prolactin levels and the GMV of the left hippocampus and right IFC, whereas a positive relationship was found between the GMV of the left hippocampus and serum levels of estradiol and luteinizing hormone.ConclusionIn patients with prolactinomas, specific brain structure abnormalities have been identified and are associated with cognitive impairments and dysfunctional hormones. This study enhances our understanding of brain structure changes that may occur with prolactinomas and provides novel and fundamental evidence for previous behavioral findings relevant to hyperprolactinemia.

The present study aimed to investigate the function of the prolactin/adenoma maximum diameter (PRL/MD) and the prolactin/adenoma volume (PRL/V) in the differential diagnosis of prolactinomas and other types of pituitary adenomas. A total of 118 patients with pituitary adenoma, hyperprolactinemia and a plasma PRL <250 µg/l were enrolled. Clinical data from these patients were retrospectively analyzed. A receiver operating characteristic curve was plotted. The function of PRL, PRL/MD and PRL/V in the differential diagnosis of prolactinomas and other types of pituitary adenomas was compared. The results revealed that a PRL of 55.65 µg/l was the most accurate [sensitivity (SE), 0.800; specificity (SP), 0.716; positive predictive value (PPV), 0.857; negative predictive value (NPV), 0.933; and Youden index (YI), 0.516]. The PRL/MD with the highest diagnostic value was 4.03 µg/(l x mm) (SE, 0.800; SP, 0.898; PPV, 0.727; NVP, 0.929; and YI, 0.698). The PRL/V with the highest diagnostic value was 54.00 µg/(l x cm³) (SE, 0.900; SP, 0.966; PPV, 0.900; NVP, 0.966; and YI, 0.866). The PRL/MD tended to be of higher diagnostic accuracy than PRL, but this difference was not statistically significant (P=0.097). The differentiation ability of PRL/V was significantly stronger than that of PRL (P=0.028). Thus, serum PRL, PRL/MD and PRL/V levels may be able to differentiate prolactinomas from other types of hyperprolactinemia-causing pituitary adenomas prior to treatment. PRL/V may be better than the PRL level in achieving a differential diagnosis, and the optimal PRL/V ratio for differentiating prolactinomas from other types of hyperprolactinemia-causing pituitary adenomas was 54.00 µg/(l x cm³). [ABSTRACT FROM AUTHOR]

Cell cycle control can prevent excessive proliferative response in the pituitary homeostasis. Cyclin dependent kinases (Cdks) are modulated by cyclins or Cdk inhibitors, such as p21 and p27, which can regulate cell cycle progression from the G1 to S phases. This study was conducted to evaluate the levels and the promoter region methylation status of p21 and p27 in prolactinomas (PRL) and analyze their association with clinicopathologic features. We found high-p21 level cases were featured by 5/23 and H-scores 142.3 ± 23.7 in invasive-PRL specimens, and 19/25 and 221.3 ± 45.4 in non-invasive specimens (x2 = 14.11, p = 0.000), while high-p27 level cases were featured by 6/23 and H-scores 129.8 ± 31.1 in invasive-PRL specimens, and 18/25 and 197.1 ± 46.6 in non-invasive specimens (x2 = 10.11, p = 0.001). A similar trend was also observed for p21 and p27 protein levels in PRL specimens through western-blot (P < 0.01, respectively). The Ki-67 index was much higher in invasive specimens than in non-invasive specimens (x2 = 10.10, p = 0.001). Average 33 CpG sites per sample were analyzed by using MALDI-TOF Mass array, and 7/33 CpG sites methylation levels of p27 were higher than 50%. There existed significant differences in 4 CpG sites between invasive specimens and non-invasive specimens (p < 0.01). We found that D2 receptor was closely correlated with p21 levels (P < 0.05, r = 0.567) and p27 levels (P < 0.05, r = 0.591). In PRL, the deficiency in p21 and p27 contributed to the tumor proliferation and migration and Cdk inhibitors may be used as a new therapeutic approach. [ABSTRACT FROM AUTHOR]

Background and objective: Cognitive impairments have been reported in patients with hyperprolactinemia; however, there is a lack of knowledge of brain structure alterations relevant to hyperprolactinemia in prolactinomas. Thus, we aimed to identify changes in brain structure in prolactinomas and to determine whether these changes are related to cognitive performance and clinical characteristics. Methods: Participants were 32 female patients with prolactinomas and 26 healthy controls (HC) matched for age, sex, education, and handedness. All participants underwent magnetic resonance imaging brain scans, neuropsychological assessments, and clinical evaluations. Voxel-based morphometry analysis was used to identify changes in gray matter volume (GMV). Partial correlation analysis and multiple linear regression were performed to determine the relationship between GMV, cognition, and clinical characteristics. Methods: Participants were 32 female patients with prolactinomas and 26 healthy controls (HC) matched for age, sex, education, and handedness. All participants underwent magnetic resonance imaging brain scans, neuropsychological assessments, and clinical evaluations. Voxel-based morphometry analysis was used to identify changes in gray matter volume (GMV). Partial correlation analysis and multiple linear regression were performed to determine the relationship between GMV, cognition, and clinical characteristics. Conclusion: In patients with prolactinomas, specific brain structure abnormalities have been identified and are associated with cognitive impairments and dysfunctional hormones. This study enhances our understanding of brain structure changes that may occur with prolactinomas and provides novel and fundamental evidence for previous behavioral findings relevant to hyperprolactinemia. [ABSTRACT FROM AUTHOR]

Fetal alcohol exposure (FAE) is known to increase prolactin (PRL) secretion from the pituitary lactotropes. In this study, we determined whether microRNAs (miRs) are involved in FAE-induced alteration in PRL release. We employed a rat animal model of FAE involving feeding pregnant Fisher 344 rats with a liquid diet containing 6.7% alcohol between gestational days 7-21 (AF). Both cyclic and estradiol-implanted FAE females showed increased levels of plasma PRL and pituitary Prl mRNA but reduced levels of pituitary dopamine D2 receptor (D2r) and its short spliced form (D2s). FAE increased the expression levels of miR-9 and miR-326 and did not produce any significant changes in miR-153 or miR-200a levels in the pituitary. Effects of FAE on miR-9 and miR-326 were associated with reduced levels of D2r and D2s, increased levels of Prl in the pituitary, and in plasma. These effects of FAE on D2r, D2s and Prl were enhanced following estradiol treatment. In PRL-producing MMQ cells, ethanol increased miR-9 but not miR-326, reduced levels of D2r and D2s and increased levels of Prl. Treatment of MMQ cells with an anti-miR-9 oligo reduced ethanol effects on miR-9, D2r, D2s and Prl. miR-9 mimic oligos reduced the luciferase activity of reporter vector containing D2r 3'UTR, but failed to reduce the mutant luciferase activity. These data suggest that FAE programs the pituitary to produce increased amounts of miR-9 expression that represses the D2r gene and its spliced variant D2s by targeting its 3'UTR leading to an increase in PRL production and secretion. [ABSTRACT FROM AUTHOR]

Serum prolactin (PRL) levels exhibit a gradual rise both in male and female rats from birth to adulthood, with females consistently displaying higher levels compared to age-matched males. This pattern has traditionally been attributed to the development and maturation of endocrine and neuroendocrine networks responsible for regulating PRL synthesis and secretion. However, the effect of dopamine (DA), which acts as an inhibitory factor on lactotroph function, also increases from birth to puberty, particularly in females. Nonetheless, the secretion of PRL remains higher in females compared to males. On the other hand, the observed sex differences in serum PRL levels during early postnatal development cannot be attributed to the influence of estradiol (E2). While serum E2 levels gradually increase after birth, only after 45 days of life do the disparities in E2 levels between females and males become evident. These observations collectively suggest that neither the maturation of hypothalamic DA regulation nor the rise in E2 levels can account for the progressive and sustained elevation in serum PRL levels and the observed sexual dimorphism during postnatal development. This review highlights the importance of recent discoveries in animal models that shed light on inhibitory mechanisms in the control of PRL secretion within the pituitary gland itself, that is intrapituitary mechanisms, with a specific emphasis on the role of transforming growth factor β1 and activins in PRL secretion., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Prolactin (PRL) is an anterior pituitary hormone which has its principle physiological action in initiation and maintenance of lactation. In human reproduction, pathological hyperprolactinemia most commonly presents as an ovulatory disorder and is often associated with secondary amenorrhea or oligomenorrhea. Galactorrhea, a typical symptom of hyperprolactinemia, occurs in less than half the cases. Out of the causes of hyperprolactinemia, pituitary tumors may be responsible for almost 50% of cases and need to be investigated especially in the absence of history of drug induced hyperprolactinemia. In women with hyperprolactinemic amenorrhea one important consequence of estrogen deficiency is osteoporosis, which deserves specific therapeutic consideration. Problem in diagnosing and treating hyperprolactinemia is the occurrence of the ′big big molecule of prolactin′ that is biologically inactive (called macroprolactinemia), but detected by the same radioimmunoassay as the biologically active prolactin. This may explain many cases of very high prolactin levels sometimes found in normally ovulating women and do not require any treatment. Dopamine agonist is the mainstay of treatment. However, presence of a pituitary macroadenoma may require surgical or radiological management.

Os macroprolactinomas são tumores benignos hipofisários, secretores de prolactina, manifestando-se com amenorréia, galactorréia e disfunção gonadal. O tratamento de primeira escolha é clínico, com agonistas dopaminérgicos. O tratamento cirúrgico é reservado para os raros casos que não respondem ao tratamento clínico, intolerância à medicação ou nos casos agudos quando ocorre a hemorragia intra-tumoral. Descrevemos o caso de uma paciente portadora de macroprolactinoma submetida a duas ressecções cirúrgicas e resistente ao tratamento clínico, com evolução não usual.Macroprolactinomas are benign prolactin-secreting pituitary tumors, causing amenorrhea, galactorrhea and gonadal dysfunction. Clinical treatment with dopamine agonists is the first-choice therapy. Surgery is indicated for the rare cases that are resistant to clinical treatment, when there is intolerance to the medication, or intratumoral hemorrhage is detected. We describe the case of a female patient with macroprolactinoma submitted to two surgical procedures and resistant to clinical treatment, with unusual evolution.

Relatamos nossa experiência com 38 casos de prolactinomas. Os adenomas foram divididos em três grupos. Os adenomas mono-hormonais tendem a ser microadenomas e manifestam-se com as alterações típicas deste tipo de tumor. Os bi- hormonais, em que a prolactina se associa principalmente ao GH ou sub unidade alfa tendem a apresentar sintomas visuais, assim como os pluri-hormonais. O tratamento dos prolactinomas é inicialmente clínico e a indicação cirúrgica está relacionada com intolerância a medicação ou a alterações visuais. O resultado cirúrgico com ressecção total do tumor foi possível em 50% dos casos.We report our experience with 38 cases of prolactin secreting pituitary adenomas. The adenomas were divided in three different groups. The adenomas producing only prolactin tend to be microadenoma and they show the typical alterations of this type of tumor. The GH-PRL, GH-alpha subunit, the other combinations, and the pluri hormonal adenomas tend to present with visual symptoms. The treatment of the prolactinomas is initially clinical and the surgical indication for this type of adenomas is related to intolerance to the medication or to visual alterations. Surgical result with total resection of the tumor was possible in 50% of the cases.

The authors present an update on the various treatment modalities and discuss management strategies for prolactinomas. Prolactinomas are the most common type of functional pituitary tumor. Effective hyperprolactinemia treatment is of great importance, due to its potential deleterious effects including infertility, gonadal dysfunction and osteoporosis. Dopamine agonist therapy is the first line of treatment for prolactinomas because of its effectiveness in normalizing serum prolactin levels and shrinking tumor size. Though withdrawal of dopamine agonist treatment is safe and may be implemented following certain recommendations, recurrence of disease after cessation of the drug occurs in a substantial proportion of patients. Concerns regarding the safety of dopamine agonists have been raised, but its safety profile remains high, allowing its use during pregnancy. Surgery is typically indicated for patients who are resistant to medical therapy or intolerant of its adverse side effects, or are experiencing progressive tumor growth. Surgical resection can also be considered as a primary treatment for those with smaller focal tumors where a biochemical cure can be expected as an alternative to lifelong dopamine agonist treatment. Stereotactic radiosurgery also serves as an option for those refractory to medical and surgical therapy. [ABSTRACT FROM AUTHOR]

Purpose: Pediatric prolactinomas are rare, especially in children under 14 years of age. In this study, we evaluated the clinical presentation and microsurgical outcome of prolactinomas in prepubertal children. Methods: Nine patients with prolactinomas who had undergone surgical removal of the tumor before the age of 14 years were included in this retrospective study. Data on their clinical presentation, medications, physical and laboratory evaluations, radiological findings, and long-time follow-up were obtained from their medical records. Results: The main presenting symptom in the four female patients was galactorrhea ( n = 4, 100 %), whereas the five male patients most commonly presented with headache ( n = 4, 80 %) and growth retardation ( n = 3, 60 %). Six (66.6 %) of the patients who had undergone transsphenoidal surgery were medication-free postoperatively. In three (33.3 %) patients with giant adenomas, complete resection of the tumor was not achieved. One (11.1 %) patient received radiotherapy after failed surgical and medical treatment. Postoperatively, electrolyte disturbances occurred in five (55.6 %) patients, diabetes insipidus in two (22.2 %), and thyroid dysfunction in two (22.2 %). These complications resolved spontaneously. During follow-up, growth and puberty were usually normal. Conclusions: Tumor compressive symptoms and/or gonadal and growth arrest may be the primary clinical presentations of pediatric prolactinoma. Patients who are not candidates for dopamine agonist therapy are best treated surgically, based on the low mortality and high cure rates. Hypopituitarism is a rare complication and may resolve spontaneously. Following successful treatment of a prolactinoma, growth and puberty in these children are normal. [ABSTRACT FROM AUTHOR]

Background: Dopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25-30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. However, tumors are resistant to therapy in 5-18% of patients. Methods: The exomes of six responsive prolactinomas and six resistant prolactinomas were analyzed by whole-exome sequencing. Results: Using stringent variant calling and filtering parameters, ten somatic variants that were mainly associated with DNA repair or protein metabolic processes were identified. New resistant variants were identified in multiple genes including PRDM2, PRG4, MUC4, DSPP, DPCR1, RP1L1, MX2, POTEF, C1orf170, and KRTAP10-3. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT-qPCR) in 12 prolactinomas and 3 normal pituitary glands. The mRNA levels of PRDM2 were approximately five-fold lower in resistant prolactinomas than in responsive tumors (p < 0.05). PRDM2 protein levels were lower in resistant prolactinomas than in responsive tumors, as determined by Western blotting and immunohistochemical analysis (p < 0.05). Overexpression of PRDM2 upregulated dopamine receptor D2 (D2DR) and inhibited the phosphorylation of ERK1/2 in MMQ cells. PRDM2 showed a synergistic effect with BRC on the inhibition of prolactin (PRL) secretion and MMQ cell viability, and low PRDM2 expression was associated with tumor recurrence. Conclusions: PRDM2 downregulation may play a role in dopamine-agonist resistance and tumor recurrence in prolactinomas. [ABSTRACT FROM AUTHOR]

Background Prolactinomas are the most common secretory pituitary adenomas. The first line of treatment involves dopamine agonists (DAs); however, a subset of patients is resistant to such therapy. Recent studies suggest that dopamine can up-regulate TGF-β1 synthesis in rat pituitary lactotrophs whereas estradiol down-regulates TGF-β1. To date, the role of TGF-β/Smad signaling in DAs-resistant prolactinomas has not been explored. Methods High-content screening (HCS) techniques, qRT-PCR, Western blot, immunofluorescence and ELISA, were performed to determine the role of TGF-β/Smad signaling in DAs-resistant prolactinomas. Results We reported a significant down-regulation of TGF-β/Smad signaling cascade in DAs-resistant prolactinomas compared to normal human anterior pituitaries. Following treatment with TGF-β1, the dopamine agonist, bromocriptine, and the estrogen antagonist (ER), fulvestrant in GH3 cells, we found that TGF-β1 and fulvestrant caused significant cytotoxicity in a dose- and time-dependent manner and activated Smad3 was detected following exposure to TGF-β1 and fulvestrant. In addition, treating GH3 cells with fulvestrant increased active TGF-β1 levels and decreased PRL levels in a dose-dependent manner. Conclusion TGF-β/Smad signaling pathway may play an important role in DA-resistant prolactinomas and has the potential to be a viable target for the diagnosis and treatment of prolactinomas, particularly in patients who are resistant to DAs. [ABSTRACT FROM AUTHOR]

Recent studies have reported a higher prevalence of pituitary tumors than previously thought. Among these tumors, prolactinomas occur in up to 66% of cases. Since the mid-1980s, the widespread use of dopamine agonists has facilitated the management of the majority of prolactinomas, allowing biological and tumoral control in most cases. The less frequent cases of resistant prolactinomas remain challenging despite a multimodal therapy approach. The understanding of genetic alterations in familial and aggressive pituitary tumors provides new perspectives in the management of some prolactinomas. Genetic screening should be considered, particularly in familial cases but also in young patients with macroprolactinomas, as some mutations can predict potential aggressiveness. [ABSTRACT FROM AUTHOR]

Objective: To identify the genes involved in prolactinoma by bioinformatics methods and provide new potential biomarkers for prolactinoma. Materials and Methods: The gene-expression profile data, GSE36314, including 4 prolactinoma samples and 3 controls, was downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the limma package in R and were then classified into different functional groups by COG (Clusters of Orthologous Groups) annotation based on BLASTX (Basic Local Alignment Search Tool). Transcriptional factors (TFs) were screened out by employing the Transcription Factor (TRANSFAC) database. An interaction network among DEGs and TFs was constructed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) software. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis were then performed for the genes in this network. Results: A total of 52 genes were identified as being significantly different between prolactinomas and normal samples which were classified into 29 COG functional categories. Three TFs, ZIC3 (Zic family member 3), NGFIC (nerve growth factor-induced protein C) and SP1 (Specificity Protein 1) were screened out, which can regulate part of DEGs. Two down-regulated genes, FSHB (follicle stimulating hormone ß subunit) and LHB (luteinizing hormone ß subunit) were involved in GnRH (gonadotropin-releasing hormone) signaling pathway. Conclusion: Several DEGs between prolactinoma and normal samples were identified in our study and candidate agents such as LHB and FSHB may provide the groundwork for a targeted therapy approach for prolactinomas. [ABSTRACT FROM AUTHOR]

Aim: The aim of this article is to investigate the phenotype and etiology of prolactinoma-associated headache as well as present and discuss the plausible pain-relieving effect of dopamine agonist treatment.Methods: In this case-based audit we included 11 patients with prolactinomas and one patient with idiopathic hyperprolactinemia presenting with headache that subsequently improved or resolved after dopamine agonist treatment.Results: A significant ipsilateral location of tumor mass and reported headache symptoms was observed (p = 0.018). After dopamine agonist treatment seven out of 12 patients became pain free within 2.5 months; after one year of treatment 11 out of 12 reported headache improvement or resolution. Average tumor volume reduction after treatment was 47 ± 22% during 9.5 ± 8.4 months of follow-up. There was no significant association between headache relief and tumor shrinkage (p = 0.43) or normalization of serum prolactin (p = 1.00), respectively.Conclusions: 1) The significant association between lateralization of tumor and headache suggests a mechanical origin of the headache, 2) headache responded to dopamine agonist treatment in most patients, and 3) our observations encourage future prospective controlled trials to investigate the role of hyperprolactinemia in the pathogenesis of headache as well as the therapeutic effects of dopamine agonists. [ABSTRACT FROM AUTHOR]

Prolactin (PRL) is an anterior pituitary hormone which has its principle physiological action in initiation and maintenance of lactation. In human reproduction, pathological hyperprolactinemia most commonly presents as an ovulatory disorder and is often associated with secondary amenorrhea or oligomenorrhea. Galactorrhea, a typical symptom of hyperprolactinemia, occurs in less than half the cases. Out of the causes of hyperprolactinemia, pituitary tumors may be responsible for almost 50% of cases and need to be investigated especially in the absence of history of drug induced hyperprolactinemia. In women with hyperprolactinemic amenorrhea one important consequence of estrogen deficiency is osteoporosis, which deserves specific therapeutic consideration. Problem in diagnosing and treating hyperprolactinemia is the occurrence of the 'big big molecule of prolactin' that is biologically inactive (called macroprolactinemia), but detected by the same radioimmunoassay as the biologically active prolactin. This may explain many cases of very high prolactin levels sometimes found in normally ovulating women and do not require any treatment. Dopamine agonist is the mainstay of treatment. However, presence of a pituitary macroadenoma may require surgical or radiological management. [ABSTRACT FROM AUTHOR]

Summary: Estrogens as well as certain growth factors strongly influence the development and growth of prolactinomas. However, the molecular mechanisms by which extracellular factors trigger prolactinomas are not well known. Amplified in breast cancer 1 (AIB1), also known as steroid receptor co-activator 3 (SRC-3), belongs to the p160/SRC family of nuclear receptor co-activators and is a major co-activator of the estrogen receptor. Here, we report that the estrogen receptor coactivator AIB1 is overexpressed in human prolactinomas and correlates with the detection of aromatase and estrogen receptor α (ERα). Of the 87 pituitary tumors evaluated in women, 56%, corresponding to hyperoprolactinemic women, contained an enriched population of prolactin-positive cells and hence were further classified as prolactinomas. All prolactinomas stained positive for both ERα and AIB1. Moreover, AIB1 sub-cellular distribution was indicative of the cell-cycle status of tumors; the nuclear expression of AIB1 was correlated with proliferative markers whereas the cytoplasmic localization of AIB1 coincided with active caspase-3. Thus, our results demonstrate for the first time that AIB1 is expressed in prolactinomas and suggest its participation in the regulation of proliferation and apoptosis of tumoral cells. Because aromatase expression is also enhanced in these prolactinomas and it is involved in the local production of estradiol, both mechanisms, ER-AIB1 and aromatase could be related. [Copyright &y& Elsevier]

Evaluation of health-related quality of life (QoL) in people with pituitary tumours has received much attention over the last 10-15 years. Most of them show impaired QoL, but little is known about how to prevent impairment or how to improve QoL. Our aim is to review what is known about QoL in pituitary tumours patients and to highlight the areas worth improving, for the patient's well being. The article has four sections: acromegaly, Cushing's syndrome, prolactinomas and non-functioning adenomas. Control of comorbidities is usually an important factor to prevent QoL impairment; however, each disease has specific characteristics that should be properly addressed in order to obtain full patient recovery after successful therapy. [ABSTRACT FROM AUTHOR]

_c_Background: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are rare types of trigeminal autonomic cephalalgias (TACs). Objective: To describe a series of patients with SUNCT and SUNA including relationship to pituitary tumors. Method: All patients diagnosed with SUNCT or SUNA in the Calgary Headache Assessment and Management Program were reviewed. Results: Six patients (five SUNCTs and one SUNA) were identified. The pain was severe, sharp, showed fixed-laterality, involved mainly the orbito-fronto-temporal region and was associated with autonomic symptoms. Attack duration ranged from 3 to 300 seconds and frequency was 1-200 paroxysms/day. MRI showed ipsilateral pituitary adenomas to the pain in five out of five of the SUNCT patients. Patients with adenomas underwent surgery. Pathology included three prolactinomas, and one mixed adenoma and gangliocytoma. One patient has remained headache free for 4 years after surgery. One was pain free for a year, and then headaches returned with tumor recurrence. Another had major improvement, and two have not improved. Patients were generally refractory to medications. Conclusion: All five of our patients with typical SUNCT had pituitary tumors, with headache ipsilateral to the pituitary tumors in all cases. Tumor removal provided major improvement in three out of five patients. Medical treatment was only partially effective. [ABSTRACT FROM AUTHOR]

Dopamine agonists (DA) are the mainstay of treatment for patients with prolactinomas. To describe the efficacy of treatment and the outcomes of DA withdrawal. Retrospective review of electronic medical records of patients with prolactinomas from 1985 to 2009. Seventy-nine patients (17 men/62 women), aged 35.3 ± 1.6 years at diagnosis were studied. The mean follow-up time was 84.7 ± 9.2 months (range 0-336). The mean initial size of microadenomas was 0.74 ± 0.10 cm (range 2.41 ± 0.39) and of macrodenomas 2.41 ± 0.39 cm (range 1.1-8) and serum prolactin (PRL) levels were 112 ± 19 and 263 ± 59 ng/ml, respectively (normal range 0-40). Fifty-one (65%) prolactinomas were micro- and 28 (35%) were macroadenomas. DA led to a decrease in adenoma size in 71% of them, while 53% of microadenomas were not visible during follow-up. In 26 patients, DA withdrawal was decided. After therapy of >24 months and a mean follow-up time of 49 ± 11 months (range 3-168), 15 subjects (58%) showed no recurrence of hyperprolactinemia. Higher remission rates, although not statistically significant, were observed with cabergoline (75%). The mean PRL levels before DA discontinuation were 12.2 ± 2.3 ng/ml (range 0.5-44.7) and after discontinuation they were significantly lower than pre-treatment values. Recurrence of hypeprolactinemia was evident during the first year in all but one patient. Remission rates were not associated with age or size of adenoma at diagnosis, initial or before DA discontinuation PRL levels and duration of treatment. DA withdrawal was followed by remission of hyperprolactinamia in about half of patients after >2 years of treatment. [ABSTRACT FROM AUTHOR]

Therapy with dopamine agonists has been associated with valvular heart disease (VHD) in Parkinson's disease, raising concern about the safety of these drugs. In hyperprolactinemic patients, the studies have mainly focused on the cardiac effects of cabergoline (CBG), with little information on bromocriptine (BRC). The aim of the present study was to evaluate the prevalence of VHD in patients with prolactinomas treated with CBG and BRC. The CBG group consisted of 51 patients (37 female; age 42.3 ± 13.5 years) who had been taking CBG for at least 1 year (mean 37.8 ± 21.3 months; cumulative doses 16-1,286.8 mg). The BRC group consisted of 19 patients (14 female; age 41.8 ± 11.5 years) who were on BRC for at least 1 year (mean 54.8 ± 30.2 months; cumulative doses 4,687.5-23,478.8 mg). The controls (CTR) were 59 healthy subjects matched for age, sex, and prevalence of arterial hypertension. Participants were subjected to transthoracic echocardiography and the valvular regurgitation was graduated as absent (grade 0), trace (1), mild (2), moderate (3) or severe (4). Compared to CTR, trace mitral (Mi) regurgitation (49% vs. 27.1%; P = 0.02), trace tricuspid (Tri) regurgitation (45.1% vs. 20.3%; P = 0.0003) and mild Tri regurgitation (7.8% vs. 0%; P = 0.0003) were more prevalent with CBG, while trace Tri regurgitation (73.7% vs. 20.3%; P = 0.0004) were more prevalent with BRC. Mitral tenting area was significantly higher in CBG than in BRC and CTR. None of the valvar abnormalities was associated with symptoms. In conclusion, patients with prolactinomas treated with either CBG or BRC showed higher prevalence of trace and mild Tri or Mi regurgitation, but these findings were not clinically significant. [ABSTRACT FROM AUTHOR]

Integrative genomics approaches associating DNA structure and transcriptomic analysis should allow the identification of cascades of events relating to tumor aggressiveness. While different genome alterations have been identified in pituitary tumors, none have ever been correlated with the aggressiveness. This study focused on one subtype of pituitary tumor, the prolactin (PRL) pituitary tumors, to identify molecular events associated with the aggressive and malignant phenotypes. We combined a comparative genomic hybridization and transcriptomic analysis of 13 PRL tumors classified as nonaggressive or aggressive. Allelic loss within the p arm region of chromosome 11 was detected in five of the aggressive tumors. Allelic loss in the 11q arm was observed in three of these five tumors, all three of which were considered as malignant based on the occurrence of metastases. Comparison of genomic and transcriptomic data showed that allelic loss impacted upon the expression of genes located in the imbalanced region. Data filtering allowed us to highlight five deregulated genes (DGKZ, CD44, TSG101, GTF2H1, HTATIP2), within the missing 11p region, potentially responsible for triggering the aggressive and malignant phenotypes of PRL tumors. Our combined genomic and transcriptomic analysis underlines the importance of chromosome allelic loss in determining the aggressiveness and malignancy of tumors. [ABSTRACT FROM AUTHOR]

Despite the fact that consensus guidelines recommend long-term dopamine agonist (DA) therapy as a first-line approach to the treatment of small prolactinoma, some patients continue to prefer a primary surgical approach. Concerns over potential adverse effects of long-term medical therapy and/or the desire to become pregnant and avoid long-term medication are often mentioned as reasons to pursue surgical removal. In this retrospective study, 34 consecutive patients (30 female, 4 male) preferably underwent primary pituitary surgery without prior DA treatment for small prolactinomas (microprolactinoma 1-10 mm, macroprolactinoma 11-20 mm) at the Department of Neurosurgery, University of Bern, Switzerland. At the time of diagnosis, 31 of 34 patients (91%) presented with symptoms. Patients with microprolactinomas had significantly lower preoperative prolactin (PRL) levels compared to patients with macroprolactinomas (median 143 μg/l vs. 340 μg/l). Ninety percent of symptomatic patients experienced significant improvement of their signs and symptoms upon surgery. The postoperative PRL levels (median 3.45 μg/l) returned to normal in 94% of patients with small prolactinomas. There was no mortality and no major morbidities. One patient suffered from hypogonadotropic hypogonadism after surgery despite postoperative normal PRL levels. Long-term remission was achieved in 22 of 24 patients (91%) with microprolactinomas, and in 8 of 10 patients (80%) with macroprolactinomas after a median follow-up period of 33.5 months. Patients with small prolactinomas can safely consider pituitary surgery in a specialized centre with good chance of long-term remission as an alternative to long-term DA therapy. [ABSTRACT FROM AUTHOR]

Aims and Objectives: To report hormonal outcome after surgery in a special subgroup of prolactinomas in whom medical therapy is not effective or not indicated. Patients and Methods: All patients who underwent surgery for prolactinomas, between December 2002 and December 2009, were analyzed retrospectively. The study group consisted of patients who were either intolerant or noncompliant to dopamine agonist (DA) therapy or those in whom medical treatment could not be given due to various reasons. The surgical results were assessed according to whether patients had microadenoma (<1 cm diameter), macroadenoma (>1 cm diameter), or giant prolactinoma (>4 cm diameter). Initial and final hormonal remission was defined as normalization of serum prolactin levels (<25 ng/ml) at 7 days after surgery and at last follow up, respectively. Results: Of the 172 patients, 133 (77%) were operated by primary transsphenoidal approach and 25 (14.5%) were operated transcranially and 14 patients required reoperation, either transsphenoidally (6 patients) or transcranially (8 patients). Overall, at last follow-up, hormonal remission could be achieved in 44% patients (83% microadenomas, 48% macroadenomas, and 16% of giant adenomas). There were three deaths (1.7%), 12 patients (7%) had single/multiple postoperative treatable complications. 59% of those patients, who did not achieve remission after surgery, finally attained normoprolactinemia with either DA therapy or radiotherapy, at last follow-up. Conclusions: Medical treatment of prolactinomas with DA should be considered as treatment of choice for these tumors. However, there is a major subgroup of patients who respond better to surgery rather than protracted medical therapy. [ABSTRACT FROM AUTHOR]

Prolactinomas are the most common secretory pituitary tumors; however, their pathogenesis is unclear. In order to explore the pathogenesis of prolactinomas, we used fiber-optic BeadArray to examine gene expression profiles in five prolactinomas compared with three normal pituitaries. Three down-regulated genes and one up-regulated gene were chosen for validation by quantitative real-time reverse-transcription polymerase chain reaction. We then performed pathway analysis on the identified differentially expressed genes using the Kyoto Encyclopedia of Genes and Genomes. Array analysis showed significant increases in the expression of 27 genes and 3 expressed sequence tags (ESTs), and decreases in 182 genes and 9 ESTs, including HIG1 domain family, member 1B, S100 calcium binding protein A9, angiopoietin 2, interleukin 8, hydroxyprostaglandin dehydrogenase 15-(NAD), suppression of tumorigenicity18, and WNT inhibitory factor 1. Pathway analysis showed that the P53 and GnRH signaling pathways may play an important role in tumorigenesis of prolactinomas. Our data suggest fiber-optic BeadArray combined with pathway analysis of differential gene expression profile appears to be a valid approach for investigating the pathogenesis of tumors. [ABSTRACT FROM AUTHOR]

Dopamine agonists are the treatment of choice for prolactinomas. However, there are still controversies concerning dose, treatment duration and criteria for drug withdrawal in different clinical situations. The aim of this study was to assess diagnostic and therapeutic approaches to prolactinomas among members of the Brazilian Society of Endocrinology and Metabolism (SBEM). SBEM members answered a questionnaire sent by e-mail that included 18 questions related to controversial issues about the management of prolactinomas. Among SBEM members, 721 (approximately 24% of total) answered the questionnaire. Concerning the diagnosis, 38% of the respondents stated that prolactin levels < 100 ng/ml would exclude the presence of a prolactinoma. Most of them favored the screening for macroprolactin in asymptomatic individuals instead of a routine screening (74% vs. 26%). Regarding the treatment, 70% of the respondents chose cabergoline as the drug of choice to treat macroprolactinomas whereas similar proportions advised cabergoline or bromocriptine as the best treatment for microprolactinomas (52% vs. 48%). Only 20% and 34% of respondents favored treatment withdrawal 2–3 years after prolactin normalization in patients with macroprolactinomas and microprolactinomas, respectively. In case of pregnancy, only 58 and 70% of respondents advocated discontinuation of treatment with dopamine agonists in patients with macroprolactinomas and microprolactinomas, respectively. Finally, only 36% would allow breast-feeding without restriction, 44% would restrict it to patients with microprolactinomas and 20% would not recommend it for women with prolactinomas There are several points of disagreement among SBEM members regarding the management of prolactinomas. [ABSTRACT FROM AUTHOR]

Abstract: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by the occurrence of tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene, consists of 10 exons that encode a 610-amino acid protein referred to as Menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division and proliferation. Germ-line mutations usually result in MEN1 or occasionally in an allelic variant referred to as Familial Isolated Hyperparathyroidism (FIHP). MEN1 tumours frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumour suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumours. To date, over 1300 mutations have been reported, and the majority (>70%) of these are predicted to lead to truncated forms of Menin. The mutations are scattered throughout the >9 kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83–84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210–211) have been reported to occur frequently in 4.5%, 2.7%, 2.6% and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype–genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of Menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. [ABSTRACT FROM AUTHOR]

In previous studies, we assessed the effects of intrapituitary injection of a recombinant adenoviral vector (RAd) harboring the cDNA for rat insulin-like growth factor type I (RAd-IGF-I) on the lactotrope and somatotrope populations in estrogen-induced prolactinomas. In the present study, we aimed to confirm these findings and further analyze the effect of transgenic RAd-IGF-I on the other pituitary cell populations in female rats. All animals except the intact group (no estrogen and no stereotaxic injection) received subcutaneous estrogen for 30 days, and the groups which received RAd-IGF-I or RAd expressing green fluorescent protein (control) were additionally treated with the appropriate vectors on experimental day 0. The RAd-IGF-I group showed a significant decrease in serum growth hormone and prolactin levels and lactotrope and somatotrope cell size induced by estrogen treatment. Cell density was not affected by 7 days of IGF-I gene therapy. Estrogen had an inhibitory effect on thyrotrope cell density, whereas with RAd-IGF-I there was a nonsignificant trend towards restoration of cell density, without changes in cell size. RAd-IGF-I treatment decreased corticotrope cell size without changing cell density. Estrogen decreased gonadotrope cell size and density, which was reversed by RAd-IGF-I. We conclude that in estrogen-induced pituitary tumors, IGF-I gene therapy has inhibitory effects on the lactotrope, somatotrope and corticotrope populations, while reversing the effect of estrogen on gonadotropic cells. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Cystic prolactinomas are considered not amenable to dopamine agonist therapy. We present the results of dopamine agonist therapy in six patients with cystic prolactinomas. The inclusion criteria of patients were: (i) cystic macroadenomas with the cyst occupying more than 50% of the tumour volume; (ii) a serum prolactin value more than 150ng/mL. All patients were males with a mean age of 35years. The clinical presentations were erectile dysfunction in 66.6%, visual deficits in 50% and headache in 50% of patients. All patients were treated with bromocriptine only except one who was treated with both bromocriptine and cabergoline. The mean duration of follow up was 57.1months. At the final follow-up 50% of patients had hormonal cure, 50% had radiological cure and 50% had reduction in the size of the tumour. Hence, it is appropriate to consider dopamine agonist therapy in patients with cystic prolactinomas before considering surgery. [Copyright &y& Elsevier]

This review focusses on the epidemiology, diagnosis and treatment of prolactinomas. In particular, attention was given to recent data showing a high prevalence of these tumours in the general population, 3–5 times higher than previously reported. The diagnosis of hyperprolactinaemia has been simplified in recent years, and only prolactin (PRL) assay and magnetic resonance imaging of the sella are required. Nonetheless, macroprolactinaemia should be assessed in patients with hyperprolactinaemia in the absence of clinical symptoms of elevated PRL levels. The recent evidence that medical therapy with dopamine agonists should be continued lifelong has been confirmed by several studied. The patients achieving disappearance of the tumours and suppression of PRL levels during treatment are those showing the highest likelihood to have persistent remission of hyperprolactinaemia after treatment withdrawal. [Copyright &y& Elsevier]

Insulin-like growth factor-I (IGF-I) provides a physiologic feedback effect within the somatotropic axis. Gene therapy was implemented in young female Sprague-Dawley rats which received 2 pituitary stereotaxic injections of a control recombinant adenoviral vector expressing green fluorescent protein (RAd-GFP) or IGF-I (RAd-IGF-I). The animals were sacrificed 7 days after injection. Previously, on day –23, the experimental groups received subcutaneous implants of 17-β estradiol. Morphometric analysis revealed that the somatotrope cells in estrogen-treated rats without stereotaxic injections showed a significant (p < 0.01) increase in the cell size compared with intact controls (59.9 ± 1.1 vs. 42.9 ± 1.2 μm2) and had a significant (p < 0.05) decrease in cell density with respect to intact animals (10.5 ± 0.1 vs. 19.7 ± 1.7). The treatment of pituitary adenomas with RAd-IGF-I induced a significant (p < 0.05) decrease in cell size with respect to E2 + RAd-GFP (51.3 ± 0.3 vs. 58.9 ± 0.3 μm2) and no changes in cell density compared with RAd-GFP-injected animals (12.8 ± 1.7 vs. 10.5 ± 0.1). Serum growth hormone was higher (p < 0.01) in estrogen-treated animals versus controls (146.7 ± 6 vs. 73.9 ± 9 ng/ml). In rats carrying estrogen-induced adenomas, RAd-IGF-I injection induced a significant (p < 0.05) decrease in serum growth hormone compared to RAd-GFP-injected animals (107.5 ± 7 vs. 142.4 ± 9 ng/ml). IGF-I gene therapy appears to be an effective approach for the treatment of experimental somatomammotropic pituitary tumors and could be potentially useful as an adjuvant of conventional therapies. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Dopaminergic agonists are the treatment of choice for prolactinomas with bromocriptine being the primary agent used. There is a group of patients who are not responders to such therapy or have severe side effects (resistant or intolerant to bromocriptine, respectively). We undertook this study to evaluate the response to the administration of cabergoline in patients intolerant or resistant to bromocriptine. Methods: Twenty seven patients (25 females and 2 males) were recruited with prolactin-pituitary tumors, obtaining basal serum prolactin samples and again each month up to 3 months. We recorded signs associated with hyperprolactinemia and secondary effects of cabergoline. The initial dose was 0.25 mg twice weekly during the first week, with an increase to 0.5 mg twice weekly from the second week until the conclusion of the study. Statistical analysis included Shapiro-Wilk, Kruskal-Wallis and ANOVA tests. Results: Twenty two patients had microadenomas and five had macroadenomas. In the intolerant group (n = 11), the initial prolactin value of 61.45 ± 19.82 decreased by the third month to 4.94 ± 1.79 (p <0.024). In the resistant group (n = 16), basal prolactin values were 119.53 ± 11.52. In 15 of these patients, the prolactin value significantly decreased to 12.95 ± 3.66 ng/ ml (p <0.005) by the third month of treatment. In both groups the signs related to hyperprolactinemia significantly improved, with a low incidence of secondary effects due to cabergoline. Conclusions: Cabergoline is useful in most patients considered as intolerant or resistant to bromocriptine. [ABSTRACT FROM AUTHOR]

Although several genes and signalling pathways have been identified as important effectors in the development of pituitary tumours, our understanding of pituitary tumorigenesis remains incomplete and is the focus of much current research. Use of the mRNA differential display technique in prolactinomas from D2-receptor knockout mice and in stable GH3 cell line clones with enhanced tumorigenicity in vivo has led to the identification of two genes that are involved in the pathogenic process – BMP-4 and RSUME. Bone morphogenetic protein-4 (BMP-4) has been found to have a crucial role in prolactinoma development and also in signalling crosstalk with oestrogens. In contrast, BMP-4 has an inhibitory role in corticotrophinomas. RSUME (RWD-containing sumoylation enhancer) was identified from a transformed lactosomatotrophic cell line that had increased tumorigenic and angiogenic potential. Expression of RSUME was induced under hypoxic conditions and it has a potential role during vascularization. The differential expression and action of BMP-4 in prolactinomas and corticotrophinomas highlights the importance of studying a gene with contrasting actions in two cell lineages of the same organ in order to understand the pituitary transformation process. Both BMP-4 and RSUME may be interesting targets for inhibiting steps involved in pituitary tumorigenesis. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1−/TaqI B1−/HphI T−/NcoI T−] haplotype was found in 34.5% of patients normalizing PRL with 3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.The Pharmacogenomics Journal (2008) 8, 357–363; doi:10.1038/tpj.2008.1; published online 11 March 2008 [ABSTRACT FROM AUTHOR]

The molecular pathogenesis of prolactinomas has resisted elucidation; with the exception of a RAS mutation in a single aggressive prolactinoma, no mutational changes have been identified. In prolactinomas, a further obstacle has been the paucity of surgical specimens suitable for molecular analysis since prolactionomas are infrequently removed due to the availability and effectiveness of medical therapy. In the absence of mutational events, gene expression changes have been sought and detected. Using high-throughput analysis from a large bank of human pituitary adenomas, we examined these tumors according to their molecular profiles rather than traditional immunohistochemistry. We examined six prolactinomas and eight normal pituitary glands using oligonucleotide GeneChip microarrays, reverse transcription-real time quantitative polymerase chain reaction using 10 prolactinomas, and proteomic analysis to examine protein expression in four prolactinomas. Microarray analyses identified 726 unique genes that were statistically significantly different between prolactinomas and normal glands, whereas proteomic analysis identified four differently up-regulated and 19 down-regulated proteins. Several components of the Notch pathway were altered in prolactinomas, and there was an increased expression of the Pit-1 transcription factor, and the survival factor BAG1 but decreased E-cadherin and N-cadherin expression. Taken together, expression profiling and proteomic analyses have identified molecular features unique to prolactinomas that may contribute to their pathogenesis. In the current era of molecular medicine, these findings greatly enhance our understanding and supercede immunohistochemical diagnosis. [ABSTRACT FROM AUTHOR]

Background: Chronic administration of ethanol increases plasma prolactin levels and enhances estradiol’s mitogenic action on the lactotropes of the pituitary gland. The present study was conducted to determine the changes in the pituitary levels of G proteins during the tumor development following alcohol and ethanol treatments. Methods: Using ovariectomized Fischer-344 female rats, we have determined ethanol and estradiol actions at 2 and 4 weeks on pituitary weight and pituitary cell contents of prolactin, Gs. Gq11, Gi1, Gi2, and Gi3 proteins. Western blots were employed to measure protein contents. Results: Ethanol increased basal and estradiol-enhanced wet weight and the prolactin content in the pituitary in a time-dependent manner. Chronic exposure of estradiol increased the levels of Gs protein in the pituitary. Unlike estradiol, ethanol exposure did not show significant effect on the basal level of Gs protein, but moderately increased the estradiol-induced levels of this protein. Estradiol exposure enhanced Gq11 protein levels in the pituitary after 2 and 4 weeks, while ethanol treatment failed to alter these protein levels in the pituitary in control-treated or estradiol-treated ovariectomized rats. In the case of Gi1, estradiol but not ethanol increased the level of this protein at 4 weeks of treatment. However, estradiol and ethanol alone reduced the levels of both Gi2 and Gi3 proteins at 2 and 4 weeks of treatment. Ethanol also significantly reduced the estradiol-induced Gi2 levels at 4 weeks and Gi3 level at 2 and 4 weeks. Conclusions: These results confirm ethanol’s and estradiol’s growth-promoting and prolactin stimulating actions on lactotropes of the pituitary and further provide evidence that ethanol and estradiol may control lactotropic cell functions by altering expression of specific group of G proteins in the pituitary. [ABSTRACT FROM AUTHOR]

Background: Chronic administration of ethanol increases plasma prolactin levels and enhances estradiol’s mitogenic action on the lactotropes of the pituitary gland. The present study was conducted to determine whether ethanol’s lactotropic cell-proliferating action, like estradiol’s, is associated with alteration in the production of 3 peptides that regulate cell growth: transforming growth factor beta 1 (TGF-β1), TGF-β3 and basic fibroblast growth factor (bFGF). Methods: Using ovariectomized Fischer-344 female rats, we determined ethanol’s and estradiol’s actions on lactotropic cell proliferation and growth-regulatory peptide production and release in the pituitary gland during tumorigenesis. Results: Ethanol increased basal and estradiol-enhanced mitosis of lactotropes in the pituitary glands of ovariectomized rats. The level of growth-inhibitory TGF-β1 was reduced in the pituitary following ethanol and/or estradiol treatment for 2 and 4 weeks. In contrast, ethanol and estradiol alone as well as together increased levels of growth-stimulatory TGF-β3 and bFGF in the pituitary at 2 and 4 weeks. In primary cultures of pituitary cells, both ethanol and estradiol reduced TGF-β1 release and increased TGF-β3 and bFGF release at 24 hours. Ethanol’s effect on growth factor levels in the pituitary or growth factor release from the pituitary cells was less than that of estradiol. When ethanol and estradiol were applied together, their individual effects on these growth factors were amplified. Conclusions: These results confirm estradiol’s modulation of pituitary growth factor production and release, and provide evidence that ethanol, like estradiol, alters the production and secretion of growth-regulatory peptides controlling lactotropic cell proliferation. [ABSTRACT FROM AUTHOR]

Abstract: Suicide gene therapy has met limited success for the treatment of rat pituitary tumors. In order to determine the cause of primary pituitary tumor resistance to suicide gene therapy, we studied the transgene expression of an adenoviral (Ad.RSV.βgal.nls) and a herpes simplex virus-derived (tsK/β-gal) vector, both harboring the β-galactosidase reporter gene in rat prolactinomas. Rats carrying experimental prolactinomas received bilateral 1μl intrapituitary injections of either saline (saline group), 5×105 plaque-forming units (pfu) tsK/β-gal (HSV Group) or 5×105 pfu Ad.RSV.βgal.nls (RAd Group). Two or seven days later the tumors were examined. Macroscopic inspection of glands injected with either vector showed that the tissue expressing β-gal was concentrated at the ventral area around the site reached by the tip of the needle. Almost no transgene expression was observed in other sites. Cellularity and lactotrophic cell density was not affected by saline or virus injection. In the injected areas, apoptotic levels were (±S.E.M.): 9.3±0.5, 22.1±1.1 and 31.7±1.4%, for the saline, RAd and HSV groups, respectively. Serum prolactin and growth hormone levels were not affected by virus injection. We conclude that the low diffusibility of viral suspensions in the pituitary tissue may constitute a significant obstacle for achieving full remission of in situ pituitary tumors in rats. [Copyright &y& Elsevier]

Prolactinomas are the most frequent pituitary tumors. Treatment of infertility in such tumors usually is very successful. On the other hand, reports of pituitary tumor growth during pregnancy have been described since bromocriptine started to be used. Since then, dopamine agonists (DA) have been increasingly used as the first-choice treatment of prolactinomas, with surgery being reserved for resistance or persistent intolerance to DA or for special situations. More recently other DA, such as quinagolide and cabergoline have shown better tolerance than bromocriptine with similar or greater efficacy. Cabergoline is now the first choice drug but its use in pregnancy is still under evaluation. We followed 71 term pregnancies in women bearing microprolactinomas. Of the 22 patients with previous surgery, none presented symptoms of tumor growth. Of the 41 pregnant patients treated with bromocriptine alone, only one (2.4%) presented with headaches, which regressed with drug reintroduction. Fifty one term pregnancies in patients with macroprolactinomas were followed by us. Of those, 21 were in patients with previous surgery and none of them presented clinical evidence of tumor growth. On the other hand, of the 30 patients treated only with pre-gestational bromocriptine, 11 (37%) manifested complaints related to tumor growth. A non-hormonal contraceptive should be the use along with a DA drug until tumor shrinkage within sellar boundaries has been evidenced. After pregnancy has been confirmed, the DA can be withdrawn and the patient must be closely followed. If tumor expansion is suspected, confirmation can be made through MRI and by visual field testing. Reintroduction of bromocriptine in such cases can lead to tumor reduction and clinical improvement. Surgery can also be employed as treatment for symptomatic tumor growth in pregnancy. [ABSTRACT FROM AUTHOR]