Pathogenesis Of Prolactinomas Research Articles

Update in Pathogenesis, Diagnosis, and Therapy of Prolactinoma.

Simple SummaryThis review updates recent advances in the pathogenesis, diagnosis, and therapy of prolactinoma. Prolactinomas, comprising 30–50% of all pituitary neuroendocrine tumors, frequently occur in females aged 20 to 50 and cause hypogonadism and infertility. In typical cases, female patients exhibit galactorrhea and amenorrhea due to serum prolactin (PRL) elevation, and during pregnancy, they should be carefully treated. During diagnosis, other causes of hyperprolactinemia must be excluded, and an MRI is useful for detecting pituitary neuroendocrine tumors. For the treatment of prolactinoma, dopamine agonists are effective in decreasing PRL levels and shrinking tumor size in most patients. Surgical treatment is recommended for patients who are resistant or intolerant to dopamine agonists. This review also discusses giant and malignant prolactinomas, prolactinoma-associated pregnancy, and new therapeutic approaches.Prolactinomas comprise 30–50% of all pituitary neuroendocrine tumors, frequently occur in females aged 20 to 50, and cause hypogonadism and infertility. In typical cases, female patients exhibit galactorrhea and amenorrhea due to serum prolactin (PRL) elevation, and patients during pregnancy should be carefully treated. During diagnosis, other causes of hyperprolactinemia must be excluded, and an MRI is useful for detecting pituitary neuroendocrine tumors. For treating prolactinoma, dopamine agonists (DAs) are effective for decreasing PRL levels and shrinking tumor size in most patients. Some DA-resistant cases and the molecular mechanisms of resistance to a DA are partially clarified. The side effects of a DA include cardiac valve alterations and impulse control disorders. Although surgical therapies are invasive, recent analysis shows that long-term remission rates are higher than from medical therapies. The treatments for giant or malignant prolactinomas are challenging, and the combination of medication, surgery, and radiation therapy should be considered. Regarding pathogenesis, somatic SF3B1 mutations were recently identified even though molecular mechanisms in most cases of prolactinoma have not been elucidated. To understand the pathogenesis of prolactinomas, the development of new therapeutic approaches for treatment-resistant patients is expected. This review updates the recent advances in understanding the pathogenesis, diagnosis, and therapy of prolactinoma.

Inhibiting MAPK14 showed anti-prolactinoma effect

BackgroundThe specific underlying pathogenesis of prolactinoma has not been clarified yet, to the best of our knowledge. p38 mitogen-activated protein kinase (MAPK) signaling including p38α MAPK (MAPK14), p38β (MAPK11), p38γ (MAPK12) and p38δ (MAPK13) is associated with the development and progression of several types of cancer.MethodsImmunofluorescence analysis was performed on the prolactin (PRL) and MAPK14 expressions of pituitary gland in C57BL/6 mice and human prolactinoma specimen. In the present study, the role of MAPK14 in prolactinoma was determined using estradiol-induced mice and dopamine D2 receptor knockout (DRD2−/−) mice models in C57BL/6 wild-type (WT), MAPK14−/− and DRD2−/−MAPK14+/− mice. GH3 cells were transfected with different sets of MAPK14 small interfering RNA, which to study MAPK14 and PRL expression in GH3 cells.ResultsImmunofluorescence analysis showed that PRL and MAPK14 expression were colocalized and increased in the pituitary gland of mice and human prolactinoma specimen compared with the control specimen. It was shown that PRL and MAPK14 expression was colocalized and increased significantly in the pituitary gland of estradiol-injected prolactinoma mice compared with the control mice. Knockout of MAPK14 significantly inhibited tumor overgrowth, and PRL expression was decreased in estradiol-induced mice. Furthermore, MAPK14 knockout of DRD2−/−MAPK14+/− mice significantly reduced the overgrowth of pituitary gland and PRL production and secretion compared with DRD2−/− mice. MAPK14 knockout using siRNA inhibited PRL production in GH3 cells.ConclusionThese results suggest that MAPK14 serves a promoting role in the formation of prolactinoma, and highlights the potential of MAPK14 as a potential therapeutic target in the treatment of prolactinoma.

Somatic SF3B1 hotspot mutation in prolactinomas

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

Prolactinomas are increasingly viewed as a “problem of signal transduction.” Consequently, the identification of factors and signaling pathways that control lactotrope cell turnover is needed in order to encourage new therapeutic developments. We have previously shown that prolactin (PRL) acts as a proapoptotic and antiproliferative factor on lactotropes, maintaining anterior pituitary cell homeostasis, which contrasts with the classical antiapoptotic and/or proliferative actions exerted by PRL in most other target tissues. We aimed to investigate the PRLR-triggered signaling pathways mediating these nonclassical effects of PRL in the pituitary. Our results suggest that (i) the PRLR/Jak2/STAT5 pathway is constitutively active in GH3 cells and contributes to PRL-induced apoptosis by increasing the Bax/Bcl-2 ratio, (ii) PRL inhibits ERK1/2 and Akt phosphorylation, thereby contributing to its proapoptotic effect, and (iii) the PI3K/Akt pathway participates in the PRL-mediated control of lactotrope proliferation. We hypothesize that the alteration of PRL actions in lactotrope homeostasis due to the dysregulation of any of the mechanisms of actions described above may contribute to the pathogenesis of prolactinomas.

Relation among Aromatase P450 and Tumoral Growth in Human Prolactinomas.

The pituitary gland is part of hypothalamic-pituitary–gonadal axis, which controls development, reproduction, and aging in humans and animals. In addition, the pituitary gland is regulated mainly by hormones and neurotransmitters released from the hypothalamus and by systemic hormones secreted by target glands. Aromatase P450, the enzyme responsible for the catabolization of aromatizable androgens to estrogens, is expressed in different parts of body, including the pituitary gland. Moreover, aromatase P450 is involved in sexual dimorphism where alteration in the level of aromatase can initiate a number of diseases in both genders. On the other hand, the direct actions of estrogens, mainly estradiol, are well known for stimulating prolactin release. Numerous studies have shown that changes in the levels of estrogens, among other factors, have been implicated in the genesis and development of prolactinoma. The pituitary gland can produce estradiol locally in several types of endocrine cells, and it is possible that aromatase could be responsible for the maintenance of the population of lactotroph cells and the modulation of the action of central or peripheral regulators. Aromatase overexpression due to inappropriate gene regulation has clinical effects such as the pathogenesis of prolactinomas. The present study reports on the synthesis of pituitary aromatase, its regulation by gonadal steroids, and the physiological roles of aromatase on pituitary endocrine cells. The involvement of aromatase in the pathogenesis of pituitary tumors, mainly prolactinomas, through the auto-paracrine production of estradiol is reviewed.

Sex differences in the development of prolactinoma in mice overexpressing hCGβ: role of TGFβ1.

Female transgenic mice that overexpress the human chorionic gonadotrophin β subunit (hCGβ+) develop prolactinomas, whereas hCGβ+ males do not. The high levels of circulating hCG induce massive luteinization in the ovary of hCGβ+ females, and progesterone becomes the primary steroid hormone produced, but estradiol remains at physiological level. The involvement of high levels of progesterone in lactotroph proliferation is not clearly understood; hence, the pathogenesis of prolactinomas in hCGβ+ females remains unclear. TGFβ1 is an inhibitor of lactotroph function, and the reduced TGFβ1 activity found in prolactinomas has been proposed to be involved in tumor development. The aim of the present work was to study the role of TGFβ1 in the gender-specific development of prolactinomas in hCGβ+ mice. We compared the expression of different components of the pituitary TGFβ1 system in males and females in this model. We found reduced TGFβ1 levels, reduced expression of TGFβ1 target genes, TGFβ1 receptors, Ltbp1, Smad4 and Smad7 in hCGβ+ female pituitaries. However, no differences were found between the transgenic and wild-type male pituitaries. We postulate that decreased pituitary TGFβ1 activity in hCGβ+ females is involved in the development of prolactinomas. In fact, we demonstrated that an in vivo treatment carried out for increasing pituitary TGFβ1 activity, was successful in reducing the prolactinoma development, and the hyperprolactinemia in hCGβ+ females. Moreover, the stronger TGFβ1 system found in males could protect them from excessive lactotroph proliferation. Sex differences in the regulation of the pituitary TGFβ1 system could explain gender differences in the incidence of prolactinoma.

Microarray data analysis reveals differentially expressed genes in prolactinoma.

Gene expression profiles of prolactinomas were compared with those of normal pituitary glands to identify differentially expressed genes (DEGs). Protein-protein interaction (PPI) analysis and protein complex prediction were performed to reveal the cross-talk between these genes and molecular mechanisms underlying the disease. Microarray data were downloaded from Gene Expression Omnibus. DEGs were screened using GEO2R and false discovery rate (FDR) < 0.05 was set as the cut-off. Protein-protein interaction (PPI) network was constructed with information from STRING and significant KEGG pathways were unveiled. Protein complexes were predicted using ClusterONE from Cytoscape and then validated in terms of pathways, protein domain, cellular localization and literatures. A total of 1712 genes (1911 probes) were found to be differentially expressed in prolactinoma. Interactions were identified among 121 protein products. Nineteen significant pathways (FDR< 0.05) were acquired and pathways in cancer was the top one. Pathways linked to myeloid leukemia and tryptophan metabolism were also enriched in the DEGs. Four protein complexes were predicted and then validated. They were associated with focal adhesion, cytoskeleton, metabolism of tryptophan, arginine and proline as well as aldehyde dehydrogenases. They might play important roles in the pathogenesis of prolactinoma. In present study, not only DEGs were provided, but also PPIs and protein complexes were discussed. These findings promoted the knowledge about prolactinoma and provided novel candidate targets for the therapy development of prolactinoma. prolactinoma, differentially expressed genes, protein-protein interaction network, protein complex.

Nerve growth factor, D2 receptor isoforms, and pituitary tumors

Dopamine (DA), by interacting with D2 receptors (D2R), exerts two major effects in the anterior pituitary: It inhibits prolactin (PRL) secretion and controls lactotrope cell proliferation, playing a role during pituitary development and tumorigenesis. In 1982, it was first reported that the spontaneous development of prolactinomas in old female rats was associated with the loss of hypothalamic DA neurons and that young female rats with estrogen-induced prolactinomas had damaged tuberoinfundibular DA neurons [1]. More recently, the development of transgenic mice lacking either the DA transporter (DAT) or the D2R pointed to the crucial role of DA in the control of lactotrope cell proliferation and in the pathogenesis of prolactinomas. Ablation of DAT, which physiologically controls DA function by mediating its re-uptake into nerve terminals, leads to a generalized dopaminergic hypertone, including increased DA overflow to the anterior pituitary. As a result, these mice developed hypopituitarism due to a defect in the proliferation and migration of lactotrope and somatotrope cells [2]. In D2R knockout mice, on the other hand, the control of hypothalamic DA over pituitary function was lost due to the lack of D2R expression, resulting in proliferation of lactotrope cells and in the development of prolactinomas in the older animals [3]. Several mechanisms have been invoked to explain the effects of DA on lactotrope cell proliferation and differentiation. Among these, an important synergistic interaction between DA and intrapituitary growth factors has been demonstrated. In particular, nerve growth factor (NGF), which is expressed in lactotrope cells and is released under DA control, promotes proliferation and differentiation of lactotrope cells during pituitary development in vitro [4]. Moreover, NGF plays a crucial role in the pathogenesis of prolactinomas. The majority of these adenomas maintain most of the characteristics of lactotrope cells including the expression of D2R, an observation that led to the development of D2R agonists as the most effective pharmacological tool to lower plasma PRL levels and to reduce the tumor size. A small percentage of patients, however, are insensitive to this therapy due to decreased D2R expression and/or D2R signaling. Analysis of the NGF system in cell lines obtained from human prolactinomas revealed that tumors that are sensitive to bromocriptine express both the D2R and an autocrine loop mediated by NGF, while those that are insensitive to D2R agonists lack both D2R and NGF secretion [4]. Escape from NGF control thus results in the development of prolactinomas that are refractory to the DA therapy. Interestingly, exposure of these tumors to NGF resulted in their differentiation into a lactotrope-like phenotype that expresses the D2R and recovers sensitivity to subsequent administration of D2R agonists [4]. The D2R exists as two isoforms, the D2S and D2L, that are generated by alternative splicing from the same gene and have similar pharmacological and biochemical profiles despite the presence or the absence of a stretch of 29 amino acids in the third intracellular loop. The D2S and D2L isoforms are both expressed in the brain and the pituitary, with the D2L isoform as the most abundant, and were thought for a long time to share the same functions. However, the generation of transgenic mice over-expressing either isoforms in the pituitary made it possible to demonstrate that the D2S, but not the D2L receptor, inhibits lactotrope cell proliferation, leading to pituitary hypoplasia [5]. More recent data indicated that the D2S, but not the D2L isoform, mediates apoptosis of lactotrope C. Missale (&) Department of Biomedical Sciences and Biotechnologies, University of Brescia, Viale Europa 11, 25123 Brescia, Italy e-mail: cmissale@med.unibs.it

Expression of estrogen receptor α and growth factors in human prolactinoma and its correlation with clinical features and gender.

Many studies demonstrate that growth factors play an important role in the pathogenesis of prolactinoma induced by estrogen. The effects of estrogen are mainly mediated through its nuclear receptor (ERα); however, expression of ERα and growth factors in prolactinoma and healthy pituitary and their relationship remain obscure. To obtain new insights regarding the expression differences of these factors and their relationship and to investigate the correlation between gender and clinical features in patients with prolactinoma. A total of 21 human prolactinomas and 6 healthy human pituitaries were examined for mRNA expression of ERα, basic fibroblast growth factor (bFGF), transforming growth factor α (TGFα), TGFβ1, TGFβ3, and TGFβ receptor type II (TGFβRII) by means of real-time PCR. Patient clinical data was also analyzed. Both PRL level and tumor volume of the male patient group were higher than that of the female patient group. There was a significant correlation between PRL level and tumor volume in the total patient group. Expression of ERα, bFGF, TGFα, and TGFβ3 mRNA levels of the patient group were significantly different from that of the control group. A significant correlation between ERα mRNA levels and PRL levels, tumor volume, TGFβ1 mRNA levels in the total patient group were found. PRL level and tumor volume have a significant difference between genders in prolactinoma patients. ERα and some growth factors may be involved in the tumorigenesis of prolactinoma. ERα could potentially be an effective therapy target for treating prolactinoma.

Analysis of differential gene expression by fiber-optic BeadArray and pathway in prolactinomas

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.

Molecular pathogenesis of human prolactinomas identified by gene expression profiling, RT-qPCR, and proteomic analyses

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.

Advances in the Treatment of Prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.

Correlations between Expression of Estrogen and Androgen Receptors and the Clinical Characteristics of Prolactinoma

Objective: To study the correlations between estrogen receptor (ER) and androgen receptor (AR) and the clinical presentations of prolactinoma and investigate the effect of ER and AR expression on the pathogenesis of prolactinoma in sexual difference. Methods: The clinical data of 30 patients who had undergone transsphenoidal operations in Tongji Hospital from December 2000 to December 2001 were reviewed retrospectively. The clinical information included sex, age, serum-prolactin, size, tumor invasiveness, history of use of bromocriptine and frequency of recurrence. In 20 out of the 30 patients, the ER and AR expression was detected by using immunohistochemistry method. With help of Chi-square test, the relationship between ER, AR and the clinical presentations was analyzed. Results: The statistical values revealed that there was no significant correlation between the ER and AR expression levels with the clinical presentations such as sex, age, tumor size or tumor invasiveness among the 20 patients studied (P>0.05). Conclusion: The expression of ER or AR is not influenced by the clinical data of prolactinoma such as sex, age, tumor diameter or extent of tumor invasiveness. The tumor is more aggressive in males than in females. In maroadenoma or tumor with hyperprolactineamia (>200 ng/mL) simple surgical treatment can't successfully cure the prolactinoma. Post-operative bromocriptine therapy can't be determined by the sex of the patients, but is greatly related to the tumor size and serum-prolactin level before operation.

Prolactinomas in a large kindred with multiple endocrine neoplasia type 1: clinical features and inheritance pattern.

Multiple endocrine neoplasia type 1 (MEN 1) is associated with neoplasia and hyperfunction of the parathyroid and pituitary glands, pancreatic islet cells, and neuroendocrine cells of the gut. The inheritance pattern is autosomal dominant, and the underlying genetic defect is situated at chromosome 11q13. The MEN 1 gene behaves as a defective copy of a normally constitutive tumor suppressor gene. Development of the MEN 1 phenotype, however, is a multistep and multifactorial process. The Tasman 1 genealogy is the largest MEN 1 pedigree detected to date. Thus far, 90 related members with MEN 1 have been screened for evidence of prolactinoma. Prolactinomas were found in 18 patients (20%). Prolactinomas were not evenly distributed in the genealogy; in 2 branches of the overall genealogy prolactinomas were present in 50% or more of MEN 1-affected members. The familial distribution of prolactinomas in these branches was consistent with an autosomal dominant mode of inheritance. In the remainder of the pedigree, prolactinomas were uncommon and did not display this inheritance pattern. This pedigree represents one of the largest published MEN 1 genealogies in which the risk of developing prolactinoma follows an autosomal dominant pattern of transmission. It is the first to demonstrate an inheritance pattern for prolactinomas acting in addition to, yet distinct from, the inheritance of the underlying MEN 1 gene defect. These findings are consistent with the existence of an undefined second genetic defect involved in the pathogenesis of prolactinoma in MEN 1.

Role of defective dopaminergic inhibition of prolactin secretion in the pathogenesis of prolactinoma

Role of defective dopaminergic inhibition of prolactin secretion in the pathogenesis of prolactinoma

Role of defective dopaminergic inhibition of prolactin secretion in the pathogenesis of prolactinoma.

Prolactinomas pose an increasingly frequent therapeutic dilemma for the clinician. The neurosurgeon caring for the prolactinoma-bearing patient must stay abreast of the most current basic research concerning the pathogenesis of these often difficult tumors. A fascinating and dynamic line of research involves the possibility that prolactinomas arise secondary to a flaw in the normally inhibitory dopaminergic neurohypophyseal axis. The details of this hypothesis are presented, the current literature surrounding this topic is reviewed, and a brief synthesis of the available theoretical models of prolactinoma pathogenesis is provided.

Erythrocyte catechol-O-methyltransferase, platelet monoamine oxidase, and platelet phenol sulfotransferase activities in patients with prolactin-secreting pituitary adenomas.

Dopamine is metabolized by oxidative deamination catalyzed by monoamine oxidase, O-methylation catalyzed by catechol-O-methyltransferase, and sulfate conjugation catalyzed by phenol sulfotransferase. This study was performed to determine whether platelet monoamine oxidase, red blood cell catechol-O-methyltransferase and platelet phenol sulfotransferase enzymatic activities in patients with prolactinomas were quantitatively different from the same enzyme activities in blood samples from normal subjects. The mean enzyme activities in blood samples from 22 women with histologically proven prolactinomas were compared to the mean enzyme activities in blood samples from 32 normal women. The blood levels of these 3 enzymatic activities were not significantly different between the two groups (P greater than 0.4). If the regulation of these catecholamine-metabolizing enzyme activities in blood elements reflects the regulation of the enzymes in the hypothalamic-hypophyseal region, these results suggest that a defect in the regulation of dopamine-metabolizing enzymes is not associated with the pathogenesis of prolactinomas.