Development Of Prolactinomas Research Articles

Pathogenesis, diagnosis and current treatment of prolactinoma: a review of the literature

ABSTRACT: Prolactinoma is a benign tumor of the pituitary gland that leads to the overproduction of prolactin. It is the most common type of pituitary adenoma, accounting for approximately 50% of all pituitary tumors. The clinical presentation of prolactinoma varies depending on the level of prolactin elevation and the size of the tumor. In women, common symptoms include galactorrhea, amenorrhea, and infertility. Men may present with hypogonadism, decreased libido, erectile dysfunction, and gynecomastia. Large prolactinomas, known as macroadenomas, can cause mass effects such as headaches, visual disturbances due to compression of the optic chiasm, and hypopituitarism due to pressure on surrounding pituitary tissue. Understanding the pathogenesis of prolactinoma is crucial for developing effective treatments and improving patient outcomes. The development of prolactinomas involves a complex interplay of genetic, hormonal, and cellular factors. Treatment of prolactinoma aims to normalize prolactin levels, reduce tumor size, and alleviate symptoms. The first-line therapy is dopamine agonists, such as cabergoline and bromocriptine, with surgery and radiotherapy reserved for refractory cases. Furthermore, chemotherapeutic agent - temozolomide may be a treatment of choice in aggressive or malignant prolactinomas. By understanding the underlying mechanisms and different treatment methods, healthcare providers can optimize the management and outcomes for patients with prolactinoma.

Menin, p27 and pAKT role in prolactinoma development

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Is prolactin receptor signaling a target in dopamine-resistant prolactinomas?

The hypothalamic neuroendocrine catecholamine dopamine regulates the lactotroph function, including prolactin (PRL) secretion, proliferation, and apoptosis. The treatment of PRL-secreting tumors, formerly known as prolactinomas, has relied mainly on this physiological characteristic, making dopamine agonists the first therapeutic alternative. Nevertheless, the group of patients that do not respond to this treatment has few therapeutical options. Prolactin is another physiological regulator of lactotroph function, acting as an autocrine/paracrine factor that controls PRL secretion and cellular turnover, inducing apoptosis and decreasing proliferation. Furthermore, the signaling pathways related to these effects, mainly JAK/STAT and PI3K/Akt, and MAPK, have been extensively studied in prolactinomas and other tumors as therapeutic targets. In the present work, the relationship between PRL pathophysiology and prolactinoma development is explored, aiming to comprehend the value of PRL and PRLR-associated pathways as exploratory fields alternative to dopamine-related approaches, which are worth physiological characteristics that might be impaired and can be potentially restored or upregulated to provide more options to the patients.

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 ERβ, 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 ERβ, TLR4, and PRL in these cells. Furthermore, the interaction between ERβ 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, ERβ 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 ERβ, and TLR4 is a potential therapeutic target for prolactinoma treatment.

Sex-specific Regulation of Prolactin Secretion by Pituitary Bradykinin Receptors.

Sex differences in the control of prolactin secretion are well documented. Sex-related differences in intrapituitary factors regulating lactotroph function have recently attracted attention. Sex differences in prolactinoma development are well documented in clinic, prolactinomas being more frequent in women but more aggressive in men, for poorly understood reasons. Kallikrein, the enzyme releasing kinins has been found in the pituitary, but there is no information on pituitary kinin receptors and their function. In the present work, we characterized pituitary bradykinin receptors (BRs) at the messenger RNA and protein levels in 2 mouse models of prolactinoma, Drd2 receptor gene inactivation and hCGβ gene overexpression, in both males and females, wild type or genomically altered. BR B2 (B2R) accounted for 97% or more of total pituitary BRs in both models, regardless of genotype, and was present in lactotrophs, somatotrophs, and gonadotrophs. Male pituitaries displayed higher level of B2R than females, regardless of genotype. Pituitary B2R gene expression was downregulated by estrogen in both males and females but only in females by dopamine. Activation of B1R or B2R by selective pharmacological agonists induced prolactin release in male pituitaries but inhibited prolactin secretion in female pituitaries. Increased B2R content was observed in pituitaries of mutated animals developing prolactinomas, compared to their respective wild-type controls. The present study documents a novel sex-related difference in the control of prolactin secretion and suggests that kinins are involved, through B2R activation, in lactotroph function and prolactinoma development.

Oophorectomy improves pituitary activin inhibitory function preventing lactotroph hyperplasia development.

Among pituitary adenomas, prolactinomas are the most frequently diagnosed (about 50%). Dopamine agonists are generally effective in the treatment of prolactinomas. However, a subset of about 25% of patients does not respond to these agents. The management of drug-resistant prolactinomas remains a challenge for endocrinologists and new inhibitory treatments are needed. Pituitary activins inhibit lactotroph function. Its expression and action were found reduced in animal models of lactotroph hyperplasia (female mice overexpressing the B subunit of the human chorionic gonadotrophin and female mice knockout for dopamine receptor type 2). In these models, an oophorectomy avoids prolactinoma development. Hormonal replacement with oestradiol and/or progesterone is not enough to reach the tumor size observed in transgenic females. We postulated that the loss of gonadal inhibins after an oophorectomy contributes to prevent hyperplasia development. Here, we demonstrated that an oophorectomy at 2 months age recovers the following in adulthood: (i) pituitary activin expression, (ii) activin receptor expression specifically in lactotroph population, (iii) activin biological activity in lactotrophs with a concomitant reduction of Pit-1 expression. To summarize, when an oophorectomy is performed, inhibins are lost and the inhibitory action of pituitary activins on lactotroph population is recovered, helping to prevent lactotroph hyperplasia development. These results emphasize the importance of the inhibitory action of activins on lactotroph function, positioning activins as a good therapeutic target for the treatment of resistant prolactinomas.

PBK/TOPK Inhibitor Suppresses the Progression of Prolactinomas.

BackgroundProlactinoma 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.MethodsDownloaded 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.ResultsA 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.ConclusionOur study of identification and functional validation of TOPK suggests that this candidate can be a promising molecular target for prolactinoma treatment.

Microglial NLRP3 inflammasome activation-mediated inflammation promotes prolactinoma development.

Prolactinomas have harmful effects on human health, and the pathogenesis is still unknown. Furthermore, 25% of prolactinoma patients do not respond to the therapy of dopamine receptor agonist in the clinic. Thus, it is important to reveal the pathogenesis and develop new therapeutic methods for prolactinomas. Herein, two animal models of prolactinomas, namely oestrogen-treated rats and transgenic D2 dopamine receptor-deficient mice, were used. PET/CT imaging detection showed that translocator protein-mediated microglia activation and inflammation significantly increased in the pituitary glands of prolactinomas rats. Messenger RNA microarrays were used to analyze and compare the differential gene and signal pathways of the pituitary glands between control and prolactinomas rats. Statistical results pertaining to gene enrichment showed that the innate immune response genes were upregulated in the pituitary glands of prolactinoma rats. This suggested that the innate immune response was activated. We analyzed the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome that is one of the most important members of the innate immune system in mammals and found that the expressions of NLRP3, Caspase-1, apoptosis-associated speck-like, interleukin 1B (IL1B) and IL18 proteins of pituitary glands in prolactinomas rats were increased considerably compared with those in control rats. This suggested the activation of the NLRP3 inflammasome during the emergence and evolution of prolactinomas. Immunohistochemistry results also confirmed that the NLRP3 expression was elevated in human prolactinoma tissues, and the microglia marker-ionised calcium binding adaptor molecule-1 was co-located with the NLRP3 protein in prolactinomas by immunofluorescence assay. Finally, compared with the WT mice, NLRP3-/- mice had smaller pituitary glands (weight/body weight) and diminished prolactin (PRL) expressions and secretions. These findings were associated with a reduction in the caspase-1 activation and maturation of IL1B. Furthermore, MCC950 decreased the PRL expression and secretion following the inhibition of NLRP3 inflammasome activation in GH3 cells stimulated with lipopolysaccharide and nigericin. And MCC950 inhibited the pituitary tumor overgrowth and PRL expression and secretion in prolactinoma rats. These data confirm that the microglial NLRP3 inflammasome activation upregulates the inflammatory cytokines IL1/IL18 in the pituitary glands and induces prolactinomas. Our findings showed that microglial NLRP3 inflammasome activation-mediated IL1B-related inflammation promoted the development of prolactinomas and identified the inflammasome as a new therapeutic target for prolactinomas.

Can Long-Standing GnRH Therapy Cause a Pituitary Prolactinoma?

Abstract Background: Pituitary adenoma (PA) is the most common cause of sellar masses and accounts for about 10% of all intracranial tumors. Several physiological, pathological, drugs, and rare causes like hypothyroidism can cause PA. We describe a case of long-standing treatment with GnRH analogues possibly contributing to development of PA. Clinical Case: An 86-year-old man with a history of prostate cancer (PC) treated with medical therapy, presented to the hospital with progressively worsening loss of vision in his right eye associated with low-grade headaches over the past few years. Fifteen years prior to presentation, the patient was diagnosed with Gleason 6 (3 + 3) localized PC. He had refused surgical intervention and hence was treated with flutamide, then leuprolide. Labs were significant for an elevated prolactin 34.2 ng/mL [n= 2.5 -17.4], low LH 0.7 mIU/mL [n=1.2-10.6], with normal FSH, TSH, ACTH, IGF, Cortisol, and PTH. CT head and MRI brain identified a 2.7cm x 2.6.3 cm X 1.7 cm mass in the suprasellar region involving the left cavernous sinus and right optic chiasm. These findings were consistent with a diagnosis of Prolactinoma. Patient refused surgery and hence was started on bromocriptine. The findings were suspected to be secondary to long-standing GnRH agonist therapy, and leuprolide was discontinued. DEXA scan confirmed osteoporosis with a T score of --2.5, which was treated with denosumab. Subsequently his vision improved. The patient continues to follow with endocrinology for the management of osteoporosis and prolactinoma. Conclusion: Primary hypothyroidism predisposes to PA due to loss of thyroxine feedback inhibition to hypothalamus with overproduction of TRH with hyperplasia of lactotrophs. We speculate that constant stimulation of the pituitary by GnRH analogues can also lead to enlargement of the anterior pituitary in a similar fashion, and can lead to the development of prolactinoma. LHRH agonists such as Leuprolide, as palliative treatment for advanced prostate cancer, causes desensitization of the anterior pituitary and decreases the production of LH and FSH, which ultimately leads to decreased testosterone in males. Although not standard of care for treatment of locally advance tumors, medical therapy was chosen in this patient’s case due to refusal of surgical intervention. He then developed a clinically significant pituitary adenoma years after the therapy. We suggest that constant stimulation of the pituitary by GnRH analogues can lead to enlargement of the anterior pituitary in a similar fashion, resulting in the development of the prolactinoma. Reference(1) Du J, Ji H, Jin J, Gao S, Yan X, Hu S. Pituitary adenoma secondary to primary hypothyroidism: Two case reports. Medicine (Baltimore). 2020;99(8). https://journals.lww.com/md-journal/Fulltext/2020/02210/Pituitary_adenoma_secondary_to_primary.47.aspx

Prolactinoma in a Male to Female Transgender Woman on Gender Affirming Hormone Therapy

Background: Estrogen promotes prolactin secretion and its role in prolactin secreting adenomas is still under investigation. The genesis and resolution of prolactinomas may be affected by gender affirming hormone therapy.Case Description: A 50 year old transgender female presented with new onset tunnel vision and extremity parathesias for one day. She had been taking oral estrogen for six years. Physical exam showed bilateral gynecomastia as well as galactorrhea. Her visual fields were intact by confrontation.Her brain MRI revealed a pituitary macroadenoma measuring 1.4cm x 1.3cm x 1.3cm. Laboratory studies showed prolactin 538 ng/mL (<20 ng/mL), IGF-1 89.0 (66-303 ng/ml). TSH 1.7 (0.4-4.7 mcIU/mL), Free T4 0.997 (0.58-1.76 ng/dL) and estradiol 103 pg/ml (N/A).She was treated with bromocriptine 5mg daily. Three months later galactorrhea had resolved, but gynecomastia was unchanged. The patient had a prolactin level of 3 ng/mL. Follow up brain MRI at one and three years showed no significant decrease in size of macroadenoma. Discussion: Despite this patient’s biochemical and symptomatic response to dopamine agonist therapy, her pituitary adenoma did not decrease in size over 3 years, which is a common occurrence with macroprolactinomas. However, her prolactin levels declined and her galactorrhea resolved with therapy. Research into the long term effects of gender transition therapy remains mainly in the realm of case reports and retrospective studies. Our review of the medical literature suggests that some transgender patients on estrogen therapy may have an increased risk of developing pituitary adenomas. However, guidelines have not yet been published and currently there are no recommendations for routine imaging or biochemical assessment during follow-up of these patients. While there are established reference ranges for prolactin levels for men, non-pregnant and pregnant women, no established reference ranges for prolactin levels are available for transgender women on gender affirming hormone therapy. Studies indicate that 76-86% of patients have a reduction in the size of their prolactinomas after dopamine agonist therapy. However, the same may not be true for transgender women on transfeminine hormone therapy with estrogen.Conclusion: Prolactinomas may commonly occur and be masked in transgender women on gender affirming hormone therapy due to the expected symptoms of gynecomastia, erectile dysfunction, and diminished libido from reduced testosterone levels. Estrogen promotes prolactin secretion by the pituitary gland and may have a role in development and expansion of prolactinomas. More research is needed in regards to the assessment and monitoring of the pituitary gland in transgender women on gender affirming hormone therapy with estrogen.

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens-An Insight From Translational Studies.

Estrogen signaling plays an important role in pituitary development and function. In sensitive rat or mice strains of both sexes, estrogen treatments promote lactotropic cell proliferation and induce the formation of pituitary adenomas (dominantly prolactin or growth-hormone-secreting ones). In male patients receiving estrogen, treatment does not necessarily result in pituitary hyperplasia, hyperprolactinemia or adenoma development. In this review, we comprehensively analyze the mechanisms of estrogen action upon their application in male animal models comparing it with available data in human subjects. Sex-specific molecular targets of estrogen action in lactotropic (PRL) cells are highlighted in the context of their proliferative and secretory activity. In addition, putative effects of estradiol on the cellular/tumor microenvironment and the contribution of postnatal pituitary progenitor/stem cells and transdifferentiation processes to prolactinoma development have been analyzed. Finally, estrogen-induced morphological and hormone-secreting changes in pituitary thyrotropic (TSH) and adrenocorticotropic (ACTH) cells are discussed, as well as the putative role of the thyroid and/or glucocorticoid hormones in prolactinoma development, based on the current scarce literature.

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas.

Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas.

GEOFFREY HARRIS AWARD 2019: Translational research in pituitary tumours.

Although effective treatment regimens (surgical resection, drug treatment with dopamine agonists or somatostatin analogues, radiotherapy) have been established for the therapy of most pituitary tumours, a considerable proportion of affected patients cannot completely cured due to incomplete resection or drug resistance. Moreover, even if hormone levels have been normalized, patients with hormone-secreting tumours still show persistent pathophysiological alterations in metabolic, cardiovascular or neuropsychiatric parameters and have an impaired quality of life. In this review reasons for the discrepancy between biochemical cure and incomplete recovery from tumour-associated comorbidities are discussed and the clinical management is delineated exemplarily for patients with acromegaly and Cushing's disease. In view of the development of additional treatment concepts for the treatment of pituitary adenomas we speculate about the relevance of RSUME as a potential target for the development of an anti-angiogenic therapy. Moreover, the role of BMP-4 which stimulates prolactinoma development through the Smad signalling cascade is described and its role as putative drug target for the treatment of prolactinomas is discussed. Regarding the well-known resistance of a part of somatotropinomas to somatostatin analogue treatment, recently identified mechanisms responsible for the drug resistance are summarized and ways to overcome them in future treatment concepts are presented. Concerning novel therapeutic options for patients with Cushing's disease the impact of retinoic acid, which is currently tested in clinical studies, is shown, and the action and putative therapeutic impact of silibinin to resolve glucocorticoid resistance in these patients is critically discussed.

RARE-05. ARE TRANSGENDER INDIVIDUALS STRONGLY PREDISPOSED TO DEVELOPMENT OF PROLACTINOMAS?

Abstract Transgender individuals usually receive long-term hormone treatment in the course of their sexual transition. Although the effects of this on possible development of neoplasia are largely unknown, very limited literature has suggested they may be predisposed to development of prolactinomas. We queried our databases to determine if we had encountered such cases at our tertiary care center for sellar region masses. Pathology databases from 2000–2019 were searched by the text word “transgender” to identify pituitary adenomas; cases were compared with all tissue specimens obtained from transgender persons. 2 pituitary adenomas were identified, out of approximately 1800+ sellar region masses at our institution during this same time period; neither were prolactinomas. The first occurred in a 71-year-old transgender male-to female who had undergone high-dose hormone therapy followed by orchiectomy 30 years prior; since that time various doses of estrogen had been received, most recently Premarin, .625 daily. Chronic hypertension associated with dizziness and vertigo prompted an endocrine workup which revealed an IGF-1 of 575 (normal &lt; 150 ng/ml). MRI disclosed a 10 X 7 X 13 mm. pituitary mass which proved to be a mixed somatotroph/ lactotroph adenoma. The second occurred in a 53-year-old transgender female-to-male who was being evaluated by an endocrinologist for hormone therapy for his transition when a slightly elevated prolactin level was discovered. MRI disclosed a 10 x 7 x 13 mm. pituitary mass. Transsphenoidal hypophysectomy showed a gonadotroph adenoma with patchy immunostaining for follicle stimulating hormone (FSH). In comparison, during this same time period, 60 other surgical specimens had been received, including 33 bilateral mastectomies, 15 hysterectomies, and 4 orchiectomies, almost all for gender transition purposes. Clinicians and pathologists may wish to be aware of the occurrence of pituitary adenomas in transgender individuals, although the incidence is quite low (2/1800 sellar region masses in our system).

Identification of a novel somatic mutation of POU6F2 by whole-genome sequencing in prolactinoma.

BackgroundPituitary adenomas (PAs) are one of the most common intracranial tumors; approximately half of PAs are prolactin (PRL)‐secreting PAs (prolactinomas). The genetic alterations prevalent in prolactinomas are unknown.MethodsHere, we present a patient with an extremely aggressive and giant prolactinoma accompanied by serious destruction of the surrounding bone mass. This patient exhibited resistance to dopaminergic drugs. Through whole‐genome sequencing, we identified two novel somatic mutations in the POU6F2 gene (NM_001166018.2: c. 839 C>T; NM_001166018.2: c. 875A>G).ResultsThis report is the first to identify these somatic mutations in the POU6F2 gene in a prolactinoma. We found that these two mutations obviously decreased the expression level of POU6F2. Inhibition of POU6F2 activity increased the cell proliferation and PRL secretion in rat pituitary cells, but proliferation and PRL secretion were decreased in cells with POU6F2 overexpression.Conclusions POU6F2 might play a crucial role in the development of prolactinomas and may be a promising target for developing new therapies against prolactinomas.

MPRs represent a novel target for PRL inhibition in experimental prolactinomas.

Membrane progesterone receptors are known to mediate rapid nongenomic progesterone effects in different cell types. Recent evidence revealed that mPRα is highly expressed in the rat pituitary, being primarily localized in lactotrophs, acting as an intermediary of P4-inhibitory actions on prolactin secretion. The role of mPRs in prolactinoma development remains unclear. We hypothesize that mPR agonists represent a novel tool for hyperprolactinemia treatment. To this end, pituitary expression of mPRs was studied in three animal models of prolactinoma. Expression of mPRs and nuclear receptor was significantly decreased in tumoral pituitaries compared to normal ones. However, the relative proportion of mPRα and mPRβ was highly increased in prolactinomas. Interestingly, the selective mPR agonist (Org OD 02-0) significantly inhibited PRL release in both normal and tumoral pituitary explants, displaying a more pronounced effect in tumoral tissues. As P4 also regulates PRL secretion indirectly, by acting on dopaminergic neurons, we studied mPR involvement in this effect. We found that the hypothalamus has a high expression of mPRs. Interestingly, both P4 and OrgOD 02-0 increased dopamine release in hypothalamus explants. Moreover, in an in vivo treatment, that allows both, pituitary and hypothalamus actions, the mPR agonist strongly reduced the hyperprolactinemia in transgenic females carrying prolactinoma. Finally, we also found and interesting gender difference: males express higher levels of pituitary mPRα/β, a sex that does not develop prolactinoma in these mice models. Taken together, these findings suggest mPRs activation could represent a novel tool for hyperprolactinemic patients, especially those that present resistance to dopaminergic drugs.

Ept7, a quantitative trait locus that controls estrogen-induced pituitary lactotroph hyperplasia in rat, is orthologous to a locus in humans that has been associated with numerous cancer types and common diseases.

Pituitary adenoma is a common intracranial neoplasm that is observed in approximately 10% of unselected individuals at autopsy. Prolactin-producing adenomas, i.e., prolactinomas, comprise approximately 50% of all pituitary adenomas and represent the most common class of pituitary tumor. Multiple observations suggest that estrogens may contribute to development of prolactinoma; however, direct evidence for a causal role of estrogens in prolactinoma etiology is lacking. Rat models of estrogen-induced prolactinoma have been utilized extensively to identify the factors, pathways and processes that are involved in pituitary tumor development. The objective of this study was to localize to high resolution Ept7 (Estrogen-induced pituitary tumor), a quantitative trait locus (QTL) that controls lactotroph responsiveness to estrogens and was mapped to rat chromosome 7 (RNO7) in an intercross between BN and ACI rats. Data presented and discussed herein localize the Ept7 causal variant(s) to a 1.91 Mb interval of RNO7 that contains two protein coding genes, A1bg and Myc, and Pvt1, which yields multiple non-protein coding transcripts of unknown function. The Ept7 orthologous region in humans is located at 8q24.21 and has been linked in genome wide association studies to risk of 8 distinct epithelial cancers, including breast, ovarian, and endometrial cancers; 3 distinct types of B cell lymphoma; multiple inflammatory and autoimmune diseases; and orofacial cleft defects. In addition, the Ept7 locus in humans has been associated with variation in normal hematologic and development phenotypes, including height. Functional characterization of Ept7 should ultimately enhance our understanding of the genetic etiology of prolactinoma and these other diseases.

P21Waf1/Cip1 and p27Kip1 are correlated with the development and invasion of prolactinoma.

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.

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 pituitary TGFβ1 system: The role of TGFβ1 in prolactinoma development.

Prolactinomas are the most frequent functioning pituitary adenomas, and sex differences in tumor size, behavior and incidence have been described. These differences have been associated with earlier diagnosis in woman, as well as with serum estradiol levels. Experimental models of prolactinomas in rodents also show a higher incidence in females, and recent findings suggest that gender differences in the transforming growth factor beta 1 (TGFβ1) system might be involved in the sex-specific development of prolactinomas in these models. The aim of this review is to summarize the literature supporting the important role of TGFβ1 as a local modulator of pituitary lactotroph function and to provide recent evidence for TGFβ1 involvement in the sex differences found in prolactinoma development in animal models.