RARE DISEASE
Prolactinoma
Prolactinoma
Prolactinoma
Synonyms: Lactotroph adenoma, PRL-secreting pituitary adenoma, PRLoma, Pituitary lactotrophic adenoma, Prolactin-secreting pituitary adenoma
Synonyms: Lactotroph adenoma, PRL-secreting pituitary adenoma, PRLoma, Pituitary lactotrophic adenoma, Prolactin-secreting pituitary adenoma
Synonyms: Lactotroph adenoma, PRL-secreting pituitary adenoma, PRLoma, Pituitary lactotrophic adenoma, Prolactin-secreting pituitary adenoma
Drug discovery
0
drugs
With orphan designations
Overview
Prolactinomas are benign pituitary adenomas causing hyperprolactinemia, leading to hypogonadism, infertility, and mass effects (e.g., headaches, vision loss). They account for 40% of pituitary tumors [1][2][9]. Diagnosis combines serum prolactin measurement and MRI. First-line treatment involves dopamine agonists (cabergoline, bromocriptine), achieving normoprolactinemia in 80% of cases [3][6][18]. Surgery (transsphenoidal) or radiation is reserved for refractory or emergent cases [6][8][12].
Population
Therapies
Dopamine agonists: Cabergoline (preferred) or bromocriptine normalize prolactin and shrink tumors in 80–90% of cases [3][6][18].
Surgery: Indicated for drug resistance, intolerance, or vision-threatening macros (>10% of cases) [6][12][18].
Radiation/adjuvant therapy: For aggressive tumors refractory to prior treatments [6][12][13].
Categories: rare endocrine diseases, rare infertility disorders, rare neoplastic diseases
Research Papers
2,198 drug discovery papers about Prolactinoma, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,198 drug discovery papers about Prolactinoma, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Concurrent human epidermal growth factor receptor 2-positive breast cancer with axillary nodal metastasis in a patient with pituitary prolactinoma: a case report.
Managing high-risk human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) concurrent with a functioning pituitary adenoma is clinically challenging. Current oncological guidelines lack specific clinical consensus protocols regarding the simultaneous administration of intensive dual-HER2 targeted therapy, tyrosine kinase inhibitors (TKIs), and continuous dopamine agonists. A 56-year-old postmenopausal woman with a 5-year history of pituitary prolactinoma presented with a painless left breast mass over a 2-year duration. Her serum prolactin (PRL) was strictly pharmacologically controlled within the normal physiological range (8-15 ng/mL). Diagnostic breast magnetic resonance imaging (MRI) revealed a suspicious 3 mm × 5 mm spiculated nodule [Breast Imaging Reporting and Data System (BI-RADS) 4a]. She initially underwent an excisional biopsy which confirmed invasive carcinoma. Due to intraoperative sentinel lymph node positivity, the tumor's proximity to the nipple, and the patient's explicit refusal of breast conservation, she underwent a left modified radical mastectomy. Definitive surgery demonstrated a pathologically paradoxical finding: a minute 0.8 cm (pT1b) invasive ductal carcinoma accompanied by early axillary lymph node metastasis (pN1a, 2/27 positive nodes). The tumor exhibited high proliferative potential (Ki-67 40%) and parallel HER2 amplification (3+) in both the invasive and the high-grade ductal carcinoma in situ (DCIS) components. Adhering to a multidisciplinary plan while maintaining her cabergoline regimen uninterrupted, she received adjuvant chemotherapy, dual anti-HER2 blockade (trastuzumab and pertuzumab), and radiotherapy. She declined extended adjuvant neratinib due to gastrointestinal toxicity concerns. She remains completely disease-free at 36 months post-surgery with stable pituitary function. This case underscores the ongoing safety, feasibility, and practical compatibility of integrating dopamine agonists with intensive BC therapies. Furthermore, the paradoxical early lymphatic dissemination of a sub-centimeter primary tumor under physiological PRL levels suggests profound local crosstalk between HER2 and PRL receptor (PRLR) signaling. This necessitates vigilant management of even small, highly proliferative lesions in patients with concurrent endocrine comorbidities.
2026-08-13 | The Dutch Prolactinoma Cohort Studies: Cross-sectional Analysis of Females Focusing on the Patient's Perspective.
To assess the results of patient-reported outcome measures (PROMs) in a national cohort of females with a prolactinoma by disease activity. Females with prolactinoma included in the PRolaCT or ProlaC study were assessed cross-sectionally, comparing patients with active (prolactin above upper limit of normal (ULN)) and controlled (prolactin
2026-08-06 | Treatment of a Giant Prolactinoma with Bromocriptine Leads to Marked Improvement in Visual Field Defect
A 48-year-old male had blurred vision, narrowed visual field and headache over 6 months. He lost consciousness for which he was brought to the emergency department. Pertinent in the neurologic examination was bitemporal hemianopsia. The rest of the physical and neurological examination was normal. A pituitary mass causing optic chiasmal compression was then suspected.
2026-07-23 | Disentangling secretory ambiguity and the limitations of classical thresholds in defining prolactinomas.
Differentiating prolactinomas from non-functional pituitary adenomas (NFPAs) with stalk effect relies on biochemical thresholds that assume a linear relationship between tumor size and prolactin secretion. We applied a pathology-informed Prolactin Secretory Efficiency (PSE) framework to characterize diagnostic overlap between prolactinomas and NFPAs and evaluate the limitations of current prolactin thresholds. Retrospective study of 425 patients undergoing first-time surgery for pituitary adenomas: 115 pathology-confirmed lactotroph adenomas, 291 NFPAs, and 19 mammosomatotrophs. Patients with clinical or biochemical evidence of ACTH- or GH-secreting tumors were excluded. PSE was calculated as the serum prolactin-to-tumor volume ratio [Formula: see text]). Primary outcomes included PSE-based group separation and diagnostic accuracy of the 200 ng/mL threshold. While no NFPA exceeded 200 ng/mL, 42% of pathology-confirmed macroprolactinomas and 49% of macro-NFPAs fell within the diagnostic grey zone (ULN < prolactin < 200 ng/mL). PSE achieved superior group separation versus raw prolactin, yet a paradox emerged: high-efficiency stalk effect in some NFPAs produced PSE values exceeding those of low-efficiency macroprolactinomas. Rigid biochemical thresholds fail to capture the full spectrum of lactotroph adenoma biology. Significant secretory ambiguity exists for macroadenomas below 200 ng/mL, creating risk of misclassification. D2-agonist trials may serve as a low-risk diagnostic probe in this grey zone, ensuring low-efficiency prolactinomas receive appropriate first-line medical management.
2026-07-14 | Hyperprolactinaemia masked by the hook effect in a patient with a giant prolactinoma with growth hormone co-secretion.
We report a woman in her 50s with a giant co-secreting pituitary macroadenoma producing both prolactin and growth hormone. She presented with headache, proptosis, chemosis and secondary amenorrhoea since her 20s. Workup showed hyperprolactinaemia (251 μg/L; normal ≤23 μg/L). A brain MRI showed a giant mass at the base of the skull. Repeat prolactin assay after serum dilution showed marked hyperprolactinaemia (386 020 μg/L), consistent with a giant prolactin-secreting tumour. Additional tests established the presence of growth hormone excess. She was treated with cabergoline, leading to substantial clinical improvement and progressive decrease in tumour size and prolactin. Additionally, she was initially treated with lanreotide which was ineffective. She was switched to pegvisomant therapy, resulting in insulin-like growth factor I normalisation. This case emphasises the critical importance of recognising the hook effect artefact in patients with large sellar masses. Slow uptitration of dopamine agonist therapy is advisable in patients with large tumours to minimise the risks of cerebrospinal fluid leak, apoplexy and herniation.
proteins
2026-07-31 | Restoration of spermatogenesis in a male with prolactinoma-induced hypogonadotropic hypogonadism using follitropin delta and recombinant choriogonadotropin alfa: a case report.
Follitropin delta is a recombinant human follicle-stimulating hormone (FSH) produced in the human PER.C6 cell line, approved exclusively for controlled ovarian stimulation in women. Its unique glycosylation profile confers distinct pharmacokinetic advantages over Chinese hamster ovary-derived follitropin alfa. To date, no published report exists on the use of follitropin delta in males. The present case describes the first successful off-label use of follitropin delta in combination with recombinant choriogonadotropin alfa (hCG) to restore spermatogenesis in a male patient with prolactinoma-induced hypogonadotropic hypogonadism and exogenous testosterone-associated azoospermia. A 30-year-old male with a 6-cm pituitary prolactinoma diagnosed at age 18, managed with cabergoline, presented with azoospermia following 2 years of testosterone undecanoate replacement therapy. There was confirmed suppression of gonadotropins (luteinizing hormone 0.3 mIU/mL and FSH 0.3 mIU/mL) and prolactin of 100 ng/mL. Hormonal stimulation was initiated with follitropin delta 10 µg twice weekly and hCG alfa (~ 125 µg every 4-5 days), alongside continued cabergoline. After 4 months of therapy, semen analysis revealed sperm concentration of 3.5 million/mL (total sperm count 4.9 million/ejaculate). Testosterone levels normalized, with marked clinical improvement. This case provides the first evidence that follitropin delta can successfully replace conventional FSH preparations in male gonadotropin stimulation protocols. Spermatogenesis was restored within a favorable timeframe, enabling access to assisted reproductive technology (IVF/ICSI). Nevertheless, these findings are limited to a single case report and require confirmation in larger studies.
2025-08-14 | Hypogonadism in men with prolactinoma: Diagnosis, treatment, and management of persistent hypogonadism.
Prolactin-secreting adenomas comprise approximately 50 % of all clinically relevant pituitary adenomas. Most men with prolactinomas present with large and invasive tumors. Despite effective medical therapy with dopamine agonists and prolactin normalization, over 20 % of men with prolactinomas will remain with hypogonadism. There are two suggested mechanisms for hypogonadism: central suppression of the hypothalamic-pituitary-gonadal axis caused by elevated prolactin levels leading to inhibition of the kisspeptin neurons in the hypothalamus and loss of pulsatile luteinizing hormone secretion, and tumor mass effect with compression of the normal pituitary tissue and destruction of gonadotroph cells. Hypogonadism in men results in sexual dysfunction, low libido, anemia, fatigue, and infertility. Identification of patients who are likely to recover the damaged gonadal axis upon prolactin suppression is important. These are men that harbor smaller tumors, with higher testosterone levels at diagnosis, no visual field defects, and without impairment in the secretion of other pituitary hormones. Testosterone replacement should be offered to patients with lower chance of restoring normal function of the gonadal axis. However, most men will achieve spontaneous recovery of the hypothalamic-pituitary-gonadal axis within 12 months after prolactin normalization. For men with prolactinoma and hypogonadism persistence who wish to restore fertility, treatment with gonadotropins or with clomiphene citrate has been found to be safe and effective. In the present review, we propose an algorithm for the management of hypogonadism persistence in men with macroprolactinomas.
2023-03-02 | [Prolactin and its receptor: From animal models to pituitary pathophysiology].
Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by lactotroph cells of the anterior pituitary gland. The actions of prolactin are mediated by its transmembrane receptor, PRLR. The principal role attributed to PRL is to stimulate the proliferation and differentiation of the mammary cells required for lactation, but studies of animal models have assigned more than 300 separate actions to this hormone in various species. Hyperprolactinaemia is the prototypical pathological state associated with this hormone. Indeed, hyperprolactinaemia is the most common cause of amenorrhoea due to hypogonadotropic anovulation and is one of the most prevalent endocrine causes of infertility in women. In recent years, the study of conditional or complete Prlr -/- mouse models had improved the understanding concerning the regulation of gonadotroph and lactotroph axes. It is now demonstrated that prolactin exerts autocrine or paracrine actions on lactotroph cells in vivo. One of the major advances was to better understand, using mouse models, the impact of hyperprolactinemia on gonadotroph axis. It is now accepted that hypogonadotropic hypogonadism in patients with hyperprolactinemia is mediated by a decrease of hypothalamic kisspeptin secretion. Gonadotroph axis can be restored by intravenous administration of kisspeptin. However, the mechanisms of lactotroph tumorigenesis in Prlr -/- animals remain incompletely understood and transposable to the human species, since the only patient with biallelic PRLR loss-of-function mutation leading to complete prolactin resistance that has been described so far did not have pituitary adenoma visible on MRI. La prolactine et son récepteur : Des modèles animaux à la physiopathologie hypophysaire. La prolactine (PRL), hormone de la lactation par excellence, est majoritairement synthétisée et sécrétée par les cellules lactotropes de l’antéhypophyse. Ses actions sont médiées par le récepteur transmembranaire de la prolactine (PRLR). Alors que plus de 300 fonctions différentes ont été attribuées à cette hormone selon les espèces, son rôle chez l’Homme reste limité au développement de la glande mammaire et à l’allaitement. Les pathologies en lien avec la PRL sont essentiellement celles rencontrées en cas d’hypersécrétion de cette hormone. En effet, l’hyperprolactinémie entraîne l’altération du fonctionnement de l’axe gonadotrope chez l’homme comme chez la femme. Ainsi, l’hyperprolactinémie est une étiologie fréquente d’hypogonadisme hypogonadotrope acquis et l’une des principales causes d’anovulation et d’infertilité chez la femme. Ces dernières années, les études de modèles murins invalidés pour le PRLR, de manière globale ou conditionnelle dans l’hypophyse, ont permis d’apporter de nouveaux éléments dans la compréhension de la régulation des axes gonadotrope et lactotrope. Il est maintenant démontré que la prolactine exerce des actions autocrines ou paracrines sur les cellules lactotropes in vivo. Une des avancées majeures a été de mieux comprendre, à l’aide des modèles murins, l’impact de l’hyperprolactinémie sur l’axe gonadotrope. C’est ainsi qu’il a pu être établi que, comme chez les rongeurs, l’hypogonadisme hypogonadotrope chez les patientes atteintes d’hyperprolactinémie est médié par un déficit de sécrétion de kisspeptine hypothalamique, et que l’axe gonadotrope peut être restauré par l’administration intraveineuse de kisspeptine. Les mécanismes de tumorigenèse lactotrope des animaux Prlr −/− restent cependant incomplètement compris et transposables dans l’espèce humaine, puisque, jusqu’à présent, l’unique patiente porteuse d’une mutation bi-allélique perte de fonction du PRLR ayant fait l’objet d’une publication présentait une imagerie hypophysaire sans anomalie.
2023-01-13 | Prolactin receptor signaling: A novel target for cancer treatment - Exploring anti-PRLR signaling strategies
Prolactin (PRL) is a peptide hormone mainly secreted from the anterior pituitary gland. PRL is reported to play a role in pregnancy, mammary gland development, immune modulation, reproduction, and differentiation of islet cells. PRL binds to its receptor PRLR, which belongs to a superfamily of the class I cytokine receptor that has no intrinsic kinase activity. In canonical signaling, PRL binding to PRLR induces downstream signaling including JAK-STAT, AKT and MAPK pathways. This leads to increased cell proliferation, stemness, migration, apoptosis inhibition, and resistance to chemotherapy. PRL-signaling is upregulated in numerous hormone-dependent cancers including breast, prostate, ovarian, and endometrial cancer. However, more recently, the pathway has been reported to play a tumor-promoting role in other cancer types such as colon, pancreas, and hepatocellular cancers. Hence, the signaling pathway is an attractive target for drug development with blockade of the receptor being a potential therapeutic approach. Different strategies have been developed to target this receptor including modification of PRL peptides (Del1-9-G129R-hPRL, G129R-Prl), growth hormone receptor/prolactin receptor bispecific antibody antagonist, neutralizing antibody LFA102, an antibody-drug conjugate (ABBV-176) of the humanized antibody h16f (PR-1594804) and pyrrolobenzodiazepine dimer, a bispecific antibody targeting both PRLR and CD3, an in vivo half-life extended fusion protein containing PRLR antagonist PrlRA and albumin binding domain. There have also been attempts to discover and develop small molecular inhibitors targeting PRLR. Recently, using structure-based virtual screening, we identified a few antipsychotic drugs including penfluridol as a molecule that inhibits PRL-signaling to inhibit PDAC tumor progression. In this review, we will summarize the recent advances in the biology of this receptor in cancer and give an account of PRLR antagonist development for the treatment of cancer.
2022-10-14 | SFRP2 is a Novel Diagnostic Biomarker and Suppresses the Proliferation of Pituitary Adenoma
Pituitary adenoma (PA) constitutes one of the most common intracranial tumors. The present study was designed to identify potential diagnostic markers for PA. We used gene expression profiles (GEO: GSE26966 and GEO: GSE63357 datasets) derived from human PA and nontumor samples that were made freely accessible by the gene expression omnibus (GEO) datasets. Differentially expressed genes (DEGs) were screened between 14 normal specimens and 34 PA specimens by the use of the limma package of the R. The diagnostic genes were determined using a LASSO regression model and SVM-RFE analysis. SFRP2 expression in PA cells was analyzed using RT-PCR, and the effect of SFRP2 dysregulation on PA cell proliferation was measured using CCK-8 analysis. In this study, 361 DEGs were identified: 309 genes were downregulated and 52 genes were upregulated. The results of KEGG assays revealed that the 361 DEGs were mainly enriched in the PI3K-Akt signaling pathway, MAPK signaling pathway, growth hormone synthesis, secretion and action, and AGE-RAGE signaling pathway in diabetic complications. Results from the LASSO regression model and the SVM-RFE analysis indicated that LOC101060391 and SFRP2 were diagnostic genes. In contrast to normal tissue, the expressions of LOC101060391 and SFRP2 were much lower in PA samples. According to the ROC assays, high LOC101060391 and SFRP2 expression had an AUC value >0.9 for PA. Upregulation of SFRP2 distinctly inhibited the proliferative capacity of PA cells, as shown by CCK-8 analysis. Furthermore, knockdown of SFRP2 had an influence on cell growth in both the AtT-20 and HP75 cell lines. Taken together, our findings indicate that LOC101060391 and SFRP2 have diagnostic potential for PA. Furthermore, SFRP2 may be an antioncogene and a therapeutic target for PA.
antibodies
2026-01-19 | Long-term effect on bone mineral density of denosumab in the treatment of hyperpituitarism driven osteoporosis: an exploratory study.
Treatment of skeletal fragility in patients with pituitary diseases is challenging. Denosumab, an antiresorptive bone active drug, increased bone mineral density (BMD) and reduced incidence and risk of fractures in primary osteoporosis. This study aimed to evaluate the efficacy of denosumab in patients with pituitary disease-driven osteoporosis. This retrospective study investigated the frequency of fragility fractures (FF) and the percent BMD changes at 1-, 2-, 5-, and 10-years of treatment with denosumab, in patients with osteoporosis due to secreting pituitary adenoma. Seventeen patients were included: 5 patients (29.4%) were affected by hyperprolactinemia due to PRL-secreting pituitary adenoma (PAs), six patients (35.3%) were affected by acromegaly and six patients (35.3%) by Cushing's disease. Four patients carried prevalent-FF (23.5%). A single patient with acromegaly developed FF at 2 and at 5 years of treatment with denosumab. Femoral neck BMD increased in 11 patients (64.7%) at 1 year of treatment, in 9 patients (52.9%) at 2 years of treatment, in 8 patients (47.1%) at 5 years of treatment and in 2 patients (66.7%) at 10 years of treatment. Lumbar spine BMD improved in all patients at 1 year of treatment (100%), in 16 patients at 2 years of treatment (100%), in 11 patients at 5 years of treatment (100%), and in 2 patients at 10 years of treatment (66.7%). No drug related adverse events occurred. This study demonstrated for the first time that long-term treatment with denosumab is effective and safe in patients with osteoporosis due to secreting pituitary adenoma.
2025-10-29 | Immunohistochemical Comparison of Dopamine-2 Receptor Expression in Resistant and Non-Resistant Prolactinomas.
Background: Dopamine agonists (DAs) are first-line therapy for prolactin-secreting pituitary adenomas; however, a small proportion of tumors are resistant. Previous reports suggested that reduced D2R mRNA expression might cause resistance. This study aimed to determine if resistant prolactinomas express D2R protein. We also explored a role of estrogen receptor alpha (ERα) expression in DA resistance. Methods: We retrospectively selected 15 tumor specimens from 13 total patients (8 controls from 8 patients, 7 from 5 resistant patients) with resected lactotroph cell-type tumors. We reviewed age at diagnosis, tumor size, initial prolactin level, medical treatment, and reason for surgery. Immunohistochemistry was performed for D2R, prolactin, and ERα protein expression. Results: D2R expression was positive in seven of eight controls vs. two of seven in resistant tumors (p = 0.02). ERα expression did not significantly correlate with DA resistance. The two D2R expressing resistant tumors were ERα negative and both derived from a pre-pubertal female, supporting prior reports suggesting ERα may modulate DA therapy response. Conclusions: Our study introduces a reproducible method for assessing D2R protein expression in prolactinomas using commercially available D2R antibodies. Our findings align with current evidence indicating that lack of D2R expression, previously indicated by decreased mRNA levels, is common in DA-resistant prolactinomas and provide a basis for discontinuation of DA therapy to avoid potential harm to these patients.
2025-04-09 | An 18-year Odyssey: navigating the complex path of prolactinoma management: a case report
Abstract Background Prolactinomas are the most common type of pituitary adenomas, typically managed with dopamine agonists. However, some cases are refractory to standard therapies, posing significant clinical challenges. This case highlights the complexities of managing an aggressive macroprolactinoma resistant to conventional treatments and explores the use of immunotherapy as a novel intervention. Case presentation A 54-year-old male with a history of hypertension and type 2 diabetes mellitus presented with erectile dysfunction and low libido, leading to a diagnosis of prolactinoma. Over an 18-year period, he underwent multiple interventions, including cabergoline therapy, four transsphenoidal surgeries, radiation therapy, and various pharmacotherapies. Despite these, he had refractory disease with markedly elevated prolactin levels and tumor growth. In the final stages of the disease, pembrolizumab immunotherapy was attempted. Unfortunately, the patient’s condition continued to deteriorate, ultimately leading to hospice care and death at the age of 71. Conclusions This case underscores the challenges associated with managing refractory prolactinomas and highlights the need for innovative therapeutic strategies, including immunotherapy. Further research is essential to establish the role of emerging treatments in improving outcomes for patients with aggressive pituitary adenomas.
2024-09-14 | Therapeutical Usefulness of PD-1/PD-L1 Inhibitors in Aggressive or Metastatic Pituitary Tumours.
Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the therapeutic usefulness of anti-PD-1 drugs in patients with aggressive or metastatic PitNETs. Published cases and case series involving patients with PitNETs treated with PD-1/PD-L1 inhibitors were reviewed. Demographic data, clinical-pathological features, previous therapies, drug dosage and posology, and the best radiological and biochemical responses, as well as survival data, were evaluated. We identified 29 cases of aggressive (n = 13) or metastatic (n = 16) PitNETs treated with PD-1/PD-L1 inhibitors. The hypersecretion of adrenocorticotropic hormone (ACTH) was documented in eighteen cases (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to using ICIs. Overall, a positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen of twenty-nine cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 of the 17 functioning PitNET cases with available data (64.7%). The median survival of patients treated with ICIs was 13 months, with a maximum of 42 months in two ACTH-secreting tumours. Among 29 patients with PitNETs treated with PD-1/PD-L1 inhibitors, the positive radiological and biochemical response rates were 62.1% and 64.7%, respectively. Altogether, these data suggest a promising role of ICIs in patients with aggressive or metastatic PitNETs refractory to other treatment modalities.
2024-05-28 | Aggressive pituitary adenoma in the context of Lynch syndrome: a case report and literature review on this rare coincidence.
Lynch Syndrome (LS) is a cancer-predisposing condition resulting from hereditary mutation of DNA mismatch repair genes. Gastrointestinal, urogenital, and endometrial carcinomas are well-known to predominantly occur in LS patients. In contrast, there are only few reports on brain tumours in the context of LS and to date intracranial tumour manifestation appear to be rather coincidental. We present the case of a 56-year-old female developing aggressive lactotroph pituitary adenoma following a history of multiple Lynch-associated malignomas and having a confirmed MSH2 mutation. Furthermore, we performed a literature review via PubMed using the search terms 'Lynch Syndrome', 'HNPCC', 'MMR mutation' combined with 'intracranial tumour', 'sellar tumour', 'pituitary adenoma', or 'pituitary carcinoma', focusing on other reported cases and treatment regimens. A handful of studies have indicated an increased frequency of brain tumours in the context of LS, predominantly glioblastoma and less frequently low-grade glioma or other brain tumours. Based on our literature review, we summarized the known instances of pituitary adenoma in LS patients, including the present case. Furthermore, we reviewed the common recommendation of using temozolomide (TMZ) for treatment of aggressive pituitary adenoma or carcinoma and found strong indication that it might be insufficient in LS patients, while PD-1 blockade could be a promising treatment option. Combined with our case, there is a growing body of evidence that intracranial tumours and in particular those of the sellar region might be more prevalent in LS patients than previously assumed, due to their genetic profile substantially affecting viability and efficacy of treatment options. Clinical signs of aggressive tumour growth in combination with irresponsiveness to standard treatment in case of recurrence should lead to further diagnostic measures, because revelation of germline MMR mutations would call for an extended screening for other neoplastic manifestations and would markedly influence further treatment.
oligonucleotides
2023-05-17 | MicroRNA-137 inhibits pituitary prolactinoma proliferation by targeting AKT2.
Prolactinoma is the most common type of pituitary adenoma. Most prolactinoma need medical treatment, but some of them are aggressive and require surgery. In previous decades, some miRNAs have been manifested as oncogenes or tumor suppressors. Consequently, miRNAs' abnormal expression involves tumorigenesis, invasion, and metastasis of different types of tumors, including pituitary tumors. The current study aim to explore the aggressiveness-associated miRNAs in prolactinoma and underlying molecular mechanisms based on the bioinformatic analysis and fundamental experiment studies. GSE46294 miRNA expression profile from the Gene Expression Omnibus (GEO) database was downloaded. Differentially expressed miRNAs (DEMs) were filtered from this data. Subsequently, the target genes of downregulated miRNAs were analyzed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RT-qPCR, western blot, and CCK-8 assays were used to validate the effect of miR-137 on the proliferation of MMQ cells through AKT2. Finally, the binding site of rat miR-137 to AKT2 were predicted by Targetscan and Bibiserv database, and verified by double luciferase reporter assay. Twenty-four changed DEMs (fourteen upregulated and ten downregulated) were identified. Target genes of downregulated DEMs were classified into three groups by GO terms. KEGG pathway enrichment analysis revealed these target genes enriched in the PI3K-Akt pathway. We also confirmed that miR-137 can target AKT2 and inhibit the proliferation of MMQ cells induced by AKT2. MiR-137 suppressed prolactinomas' aggressive behavior by targeting AKT2.
2023-02-17 | Exosomal RNAs in the development and treatment of pituitary adenomas
Exosomes are small extracellular vesicles that carry various bioactive molecules including various RNAs that modulate the activities of recipient cells. It has drawn considerable attention as means of cell communication and drug delivery. Exosome plays important role in various tumors, but it is rarely summarized in pituitary adenoma (PA). PA is the second most common primary central nervous system tumor, and its recurrence and persistent postoperative hormone hypersecretion lead to compromised quality of life. How exactly exosomes impact tumor development and hormone secretion is important for the development of this tumor diagnosis and treatment. In this review, we discuss how exosomal RNAs impact PAs and their potential as future clinical therapies. In our literature review, first, we found that exosomal microRNA hsa-miR-1180-3p is a potential early biomarker for NFPAs. Since NFPAs are typically difficult to diagnose, this is an especially important finding. Second, exosomal protein transcripts are potential invasive biomarker, such as MMP1 , N-cadherin , CDK6 , RHOU , INSM1 , and RASSF10 . Third, exosomal contents such as hsa-miR-21-5p promote distant bone formation of GHPA patients. Fourth, tumor suppressors in the exosome constitute novel therapeutic application of exosome, including long noncoding RNA (lncRNA) H19, miR-149-5p, miR-99a-3p, and miR-423-5p. This review discusses the possible mechanisms of exosome and their contents in PA and promotes the use of exosomes in both clinical diagnosis and treatment of this tumor.
2022-03-21 | The SF3B1R625H mutation promotes prolactinoma tumor progression through aberrant splicing of DLG1.
Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and underlying molecular mechanisms remain largely unexplored. Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA. Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1R625H promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1R625H and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway. Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.
2021-06-29 | The long noncoding RNA-H19/miRNA-93a/ATG7 axis regulates the sensitivity of pituitary adenomas to dopamine agonists.
Dopamine agonists (DAs), such as cabergoline and bromocriptine, are the first-line clinical treatment for prolactinomas. Our previous study demonstrated that long noncoding RNA H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumor progression. However, the significance and mechanism of H19 in the DA treatment of prolactinomas are still unknown. In this study, we reported that H19 had a synergistic effect with DA treatment on prolactinomas in vitro and in vivo. Mechanistically, H19 promoted ATG7 expression in pituitary tumor cells by inhibiting miR-93a expression. In addition, a potential binding site between miR-93 and H19 was confirmed, and low expression of miR-93 was previously found in DA-resistant prolactinomas. Furthermore, we showed that miR-93a regulates ATG7 expression by targeting ATG7 mRNA. In conclusion, our study has identified the role of the H19-miR-93-ATG7 axis in DA treatment of prolactinomas, which may be a potential therapeutic target for human prolactinomas.
2021-04-29 | Expression and clinical significance of miR-193a-3p in invasive pituitary adenomas.
Our study aimed to investigate miR-193a-3p expression and its clinical significance in pituitary adenomas (PAs). Moreover, the correlation between miR-193a-3p expression and the invasiveness of PAs was explored. In this study, the relative expression levels of miR-193a-3p were detected via quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The correlations between miR-193a-3p and tumor size, clinical features, and prolactinomas postoperative prolactin (PRL) levels early remission were further analyzed. Compared with non-invasive PAs, there was a lower miR-193a-3p expression in invasive PAs. MiR-193a-3p expression had reverse relevance to tumor size. A higher risk of postoperative residual and recurrence was found in patients with downregulated miR-193a-3p. Prolactinomas patients with postoperative PRL levels early remission were at lower risk to relapse and patients with high-expression miR-193a-3p had a higher early remission rate, suggesting that miR-193a-3p was a significant prognostic factor for prolactinomas. MiR-193a-3p could have potential therapeutic value for invasive pituitary adenomas.
other
2025-09-04 | Identifying Hub Genes Associated with Sex Disparities in Prolactinomas.
Background: Male patients with prolactinomas exhibit greater invasiveness, resistance to dopamine agonists, making treatment more challenging. This study aims to explore the potential different genes contributing to sex disparities in prolactinomas. Materials and Methods: Weighted gene co-expression network analysis and differential expressed genes analysis were performed to identify sex-related hub genes. In addition, bioinformatics analyses were conducted to understand gene localization on chromosomes, gene regulatory networks, signaling pathways, and their relationship with immune function, which was verified in 21 human prolactinoma samples. Results: A total of 21 sex-related hub genes were identified. The hub genes in males included nine Y chromosome genes and six autosomal genes, while females had six specific genes. Further predictions using the NetworkAnalyst online tool suggested that transcription factors (REST, androgen receptor) and microRNAs (miR-27a-3p, miR-146a-5p) may be involved in regulating the above sex-related hub genes. CIBERSORT analysis revealed that prolactinomas in males showed significant infiltration of resting dendritic cells and naive CD4+ T cells. Correlation analysis between sex-related hub genes and immune checkpoint genes indicated that male hub genes were positively correlated with CD47 and CEACAM1, while showing a strong negative correlation with CD28, TNFSF14, and CD226. Finally, similar changes of gene expression in our surgical prolactinoma samples were confirmed by RT-qPCR. Conclusions: In prolactinomas, the male hub genes and female hub genes are identified by our bioinformatics analysis. Our findings suggest that KDM5D, PDCD1, ELOA3BP, XRRA1, and SIGLEC12 serve as potential biomarkers for male prolactinomas, while SOX3, DMGDH, and NPAS1 may serve as potential biomarkers for female prolactinoma, providing a theoretical basis for targeted therapy.
2025-01-17 | Determinants of cerebrospinal fluid leakage in a large cohort of macroprolactinomas.
Macroprolactinomas are the most frequent subtype of pituitary adenomas. Their treatment has been improved since the onset of dopamin agonists (DA). Nevertheless, DA can cause a cerebospinal fluid (CSF) leakage by shrinking the tumor and lead to a bacterial meningitis. This complication might have lethal consequences. We conducted an observational, retrospective study in the Pituitary Unit in Pitié Salpêtrière Hospital. A total of 171 patients with macroprolactinomas (larger diameter greater than 10mm) were included in the study. We compared patients who presented cerebrospinal rhinorrhea and/or meningitis, so-called complicated patients (C group), to patients who presented no complications during their follow-up, so-called uncomplicated patients (UC group): no occurrence of rhinorrhea, meningitis. Cerebrospinal fluid (CSF) leakage has been found in 5% of patients in our large cohort of macroprolactinoma. Determinants of CSF leakage seems to be : adenoma size with concomitant supra- and infrasellar extension, very high prolactin level (>1000µg/l), cabergoline treatment. Cerebrospinal rhinorrhea is a rare complication of macroprolactinomas, but potentially lethal because of meningitis risk. Anti-pneumococcal and anti-haemophilus vaccination appears to be appropriate in these patients at the time of introduction of DA, to prevent meningitis.
2022-07-27 | Disease Modeling of Pituitary Adenoma Using Human Pluripotent Stem Cells
Pituitary adenomas are characterized by abnormal growth in the pituitary gland. Surgical excision is the first-line treatment for functional (hormone-producing) pituitary adenomas, except for prolactin-producing adenomas; however, complete excision is technically challenging, and many patients require long-term medication after the treatment. In addition, the pathophysiology of pituitary adenomas, such as tumorigenesis, has not been fully understood. Pituitary adenoma pathophysiology has mainly been studied using animal models and animal tumor-derived cell lines. Nevertheless, experimental studies on human pituitary adenomas are difficult because of the significant differences among species and the lack of reliable cell lines. Recently, several methods have been established to differentiate pituitary cells from human pluripotent stem cells (hPSCs). The induced pituitary hormone-producing cells retain the physiological properties already lost in tumor-derived cell lines. Moreover, CRISPR/Cas9 systems have expedited the introduction of causative gene mutations in various malignant tumors into hPSCs. Therefore, hPSC-derived pituitary cells have great potential as a novel platform for studying the pathophysiology of human-specific pituitary adenomas and developing novel drugs. This review presents an overview of the recent progresses in hPSC applications for pituitary research, functional pituitary adenoma pathogenesis, and genome-editing techniques for introducing causative mutations. We also discuss future applications of hPSCs for studying pituitary adenomas.
2021-05-12 | Genomic and transcriptomic analysis of pituitary adenomas reveals the impacts of copy number variations on gene expression and clinical prognosis among prolactin-secreting subtype.
Pituitary adenomas (PAs) are slow growing and benign primary intracranial tumors that often cause occupying effects or endocrine symptoms. PAs can be classified into various subtypes according to hormone secretion. Although widespread transcriptional alterations that cause aberrant hormone secretion have been characterized, the impact of genomic variations on transcriptional alterations is unclear due to the rare occurrence of single-nucleotide variations in PA. In this study, we performed whole-genome sequencing (WGS) on 76 PA samples across three clinical subtypes (PRL-PAs; GH-PAs, and NFPAs); transcriptome sequencing (RNA-seq) of 54 samples across these subtypes was also conducted. Nine normal pituitary tissues were used as controls. Common and subtype-specific transcriptional alterations in PAs were identified. Strikingly, widespread genomic copy number amplifications were discovered for PRL-PAs, which are causally involved in transcriptomic changes in this subtype. Moreover, we found that the high copy number variations (CNVs) in PRL-PA cause increased prolactin production, drug resistance and proliferative capacity, potentially through key genes with copy number amplification and transcriptional activation, such as BCAT1. This study provides insight into how genomic CNVs affect the transcriptome and clinical outcomes of PRL-PA and sheds light on the development of potential therapeutics for aberrantly activated targets.
2017-10-23 | Case Report of a Prolactinoma in a Patient With a Novel MAX Mutation and Bilateral Pheochromocytomas
Pheochromocytomas are neuroendocrine tumors that can arise sporadically or be inherited as a familial disease, and they may occur in isolation or as part of a multitumor syndrome. Familial disease typically presents in younger patients with a higher risk of multifocality. Recently, the tumor suppressor MYC-associated factor X (MAX) gene has been implicated as a cause of familial isolated pheochromocytoma and paraganglioma. We describe a patient with a pituitary prolactinoma and bilateral pheochromocytomas who tested positive for a germline MAX mutation. Interestingly, the patient also had mild primary hyperparathyroidism that resolved upon resection of the pheochromocytomas despite the absence of parathyroid hormone staining in the tumors. To our knowledge, this case is the first report of prolactinoma in a patient with a MAX mutation, which suggests the possibility of germline MAX mutations also contributing to the development of prolactinomas.
small molecules
2026-08-13 | Concurrent human epidermal growth factor receptor 2-positive breast cancer with axillary nodal metastasis in a patient with pituitary prolactinoma: a case report.
Managing high-risk human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) concurrent with a functioning pituitary adenoma is clinically challenging. Current oncological guidelines lack specific clinical consensus protocols regarding the simultaneous administration of intensive dual-HER2 targeted therapy, tyrosine kinase inhibitors (TKIs), and continuous dopamine agonists. A 56-year-old postmenopausal woman with a 5-year history of pituitary prolactinoma presented with a painless left breast mass over a 2-year duration. Her serum prolactin (PRL) was strictly pharmacologically controlled within the normal physiological range (8-15 ng/mL). Diagnostic breast magnetic resonance imaging (MRI) revealed a suspicious 3 mm × 5 mm spiculated nodule [Breast Imaging Reporting and Data System (BI-RADS) 4a]. She initially underwent an excisional biopsy which confirmed invasive carcinoma. Due to intraoperative sentinel lymph node positivity, the tumor's proximity to the nipple, and the patient's explicit refusal of breast conservation, she underwent a left modified radical mastectomy. Definitive surgery demonstrated a pathologically paradoxical finding: a minute 0.8 cm (pT1b) invasive ductal carcinoma accompanied by early axillary lymph node metastasis (pN1a, 2/27 positive nodes). The tumor exhibited high proliferative potential (Ki-67 40%) and parallel HER2 amplification (3+) in both the invasive and the high-grade ductal carcinoma in situ (DCIS) components. Adhering to a multidisciplinary plan while maintaining her cabergoline regimen uninterrupted, she received adjuvant chemotherapy, dual anti-HER2 blockade (trastuzumab and pertuzumab), and radiotherapy. She declined extended adjuvant neratinib due to gastrointestinal toxicity concerns. She remains completely disease-free at 36 months post-surgery with stable pituitary function. This case underscores the ongoing safety, feasibility, and practical compatibility of integrating dopamine agonists with intensive BC therapies. Furthermore, the paradoxical early lymphatic dissemination of a sub-centimeter primary tumor under physiological PRL levels suggests profound local crosstalk between HER2 and PRL receptor (PRLR) signaling. This necessitates vigilant management of even small, highly proliferative lesions in patients with concurrent endocrine comorbidities.
2026-08-13 | The Dutch Prolactinoma Cohort Studies: Cross-sectional Analysis of Females Focusing on the Patient's Perspective.
To assess the results of patient-reported outcome measures (PROMs) in a national cohort of females with a prolactinoma by disease activity. Females with prolactinoma included in the PRolaCT or ProlaC study were assessed cross-sectionally, comparing patients with active (prolactin above upper limit of normal (ULN)) and controlled (prolactin
2026-08-06 | Treatment of a Giant Prolactinoma with Bromocriptine Leads to Marked Improvement in Visual Field Defect
A 48-year-old male had blurred vision, narrowed visual field and headache over 6 months. He lost consciousness for which he was brought to the emergency department. Pertinent in the neurologic examination was bitemporal hemianopsia. The rest of the physical and neurological examination was normal. A pituitary mass causing optic chiasmal compression was then suspected.
2026-07-23 | Disentangling secretory ambiguity and the limitations of classical thresholds in defining prolactinomas.
Differentiating prolactinomas from non-functional pituitary adenomas (NFPAs) with stalk effect relies on biochemical thresholds that assume a linear relationship between tumor size and prolactin secretion. We applied a pathology-informed Prolactin Secretory Efficiency (PSE) framework to characterize diagnostic overlap between prolactinomas and NFPAs and evaluate the limitations of current prolactin thresholds. Retrospective study of 425 patients undergoing first-time surgery for pituitary adenomas: 115 pathology-confirmed lactotroph adenomas, 291 NFPAs, and 19 mammosomatotrophs. Patients with clinical or biochemical evidence of ACTH- or GH-secreting tumors were excluded. PSE was calculated as the serum prolactin-to-tumor volume ratio [Formula: see text]). Primary outcomes included PSE-based group separation and diagnostic accuracy of the 200 ng/mL threshold. While no NFPA exceeded 200 ng/mL, 42% of pathology-confirmed macroprolactinomas and 49% of macro-NFPAs fell within the diagnostic grey zone (ULN < prolactin < 200 ng/mL). PSE achieved superior group separation versus raw prolactin, yet a paradox emerged: high-efficiency stalk effect in some NFPAs produced PSE values exceeding those of low-efficiency macroprolactinomas. Rigid biochemical thresholds fail to capture the full spectrum of lactotroph adenoma biology. Significant secretory ambiguity exists for macroadenomas below 200 ng/mL, creating risk of misclassification. D2-agonist trials may serve as a low-risk diagnostic probe in this grey zone, ensuring low-efficiency prolactinomas receive appropriate first-line medical management.
2026-07-14 | Hyperprolactinaemia masked by the hook effect in a patient with a giant prolactinoma with growth hormone co-secretion.
We report a woman in her 50s with a giant co-secreting pituitary macroadenoma producing both prolactin and growth hormone. She presented with headache, proptosis, chemosis and secondary amenorrhoea since her 20s. Workup showed hyperprolactinaemia (251 μg/L; normal ≤23 μg/L). A brain MRI showed a giant mass at the base of the skull. Repeat prolactin assay after serum dilution showed marked hyperprolactinaemia (386 020 μg/L), consistent with a giant prolactin-secreting tumour. Additional tests established the presence of growth hormone excess. She was treated with cabergoline, leading to substantial clinical improvement and progressive decrease in tumour size and prolactin. Additionally, she was initially treated with lanreotide which was ineffective. She was switched to pegvisomant therapy, resulting in insulin-like growth factor I normalisation. This case emphasises the critical importance of recognising the hook effect artefact in patients with large sellar masses. Slow uptitration of dopamine agonist therapy is advisable in patients with large tumours to minimise the risks of cerebrospinal fluid leak, apoplexy and herniation.
proteins
2026-07-31 | Restoration of spermatogenesis in a male with prolactinoma-induced hypogonadotropic hypogonadism using follitropin delta and recombinant choriogonadotropin alfa: a case report.
Follitropin delta is a recombinant human follicle-stimulating hormone (FSH) produced in the human PER.C6 cell line, approved exclusively for controlled ovarian stimulation in women. Its unique glycosylation profile confers distinct pharmacokinetic advantages over Chinese hamster ovary-derived follitropin alfa. To date, no published report exists on the use of follitropin delta in males. The present case describes the first successful off-label use of follitropin delta in combination with recombinant choriogonadotropin alfa (hCG) to restore spermatogenesis in a male patient with prolactinoma-induced hypogonadotropic hypogonadism and exogenous testosterone-associated azoospermia. A 30-year-old male with a 6-cm pituitary prolactinoma diagnosed at age 18, managed with cabergoline, presented with azoospermia following 2 years of testosterone undecanoate replacement therapy. There was confirmed suppression of gonadotropins (luteinizing hormone 0.3 mIU/mL and FSH 0.3 mIU/mL) and prolactin of 100 ng/mL. Hormonal stimulation was initiated with follitropin delta 10 µg twice weekly and hCG alfa (~ 125 µg every 4-5 days), alongside continued cabergoline. After 4 months of therapy, semen analysis revealed sperm concentration of 3.5 million/mL (total sperm count 4.9 million/ejaculate). Testosterone levels normalized, with marked clinical improvement. This case provides the first evidence that follitropin delta can successfully replace conventional FSH preparations in male gonadotropin stimulation protocols. Spermatogenesis was restored within a favorable timeframe, enabling access to assisted reproductive technology (IVF/ICSI). Nevertheless, these findings are limited to a single case report and require confirmation in larger studies.
2025-08-14 | Hypogonadism in men with prolactinoma: Diagnosis, treatment, and management of persistent hypogonadism.
Prolactin-secreting adenomas comprise approximately 50 % of all clinically relevant pituitary adenomas. Most men with prolactinomas present with large and invasive tumors. Despite effective medical therapy with dopamine agonists and prolactin normalization, over 20 % of men with prolactinomas will remain with hypogonadism. There are two suggested mechanisms for hypogonadism: central suppression of the hypothalamic-pituitary-gonadal axis caused by elevated prolactin levels leading to inhibition of the kisspeptin neurons in the hypothalamus and loss of pulsatile luteinizing hormone secretion, and tumor mass effect with compression of the normal pituitary tissue and destruction of gonadotroph cells. Hypogonadism in men results in sexual dysfunction, low libido, anemia, fatigue, and infertility. Identification of patients who are likely to recover the damaged gonadal axis upon prolactin suppression is important. These are men that harbor smaller tumors, with higher testosterone levels at diagnosis, no visual field defects, and without impairment in the secretion of other pituitary hormones. Testosterone replacement should be offered to patients with lower chance of restoring normal function of the gonadal axis. However, most men will achieve spontaneous recovery of the hypothalamic-pituitary-gonadal axis within 12 months after prolactin normalization. For men with prolactinoma and hypogonadism persistence who wish to restore fertility, treatment with gonadotropins or with clomiphene citrate has been found to be safe and effective. In the present review, we propose an algorithm for the management of hypogonadism persistence in men with macroprolactinomas.
2023-03-02 | [Prolactin and its receptor: From animal models to pituitary pathophysiology].
Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by lactotroph cells of the anterior pituitary gland. The actions of prolactin are mediated by its transmembrane receptor, PRLR. The principal role attributed to PRL is to stimulate the proliferation and differentiation of the mammary cells required for lactation, but studies of animal models have assigned more than 300 separate actions to this hormone in various species. Hyperprolactinaemia is the prototypical pathological state associated with this hormone. Indeed, hyperprolactinaemia is the most common cause of amenorrhoea due to hypogonadotropic anovulation and is one of the most prevalent endocrine causes of infertility in women. In recent years, the study of conditional or complete Prlr -/- mouse models had improved the understanding concerning the regulation of gonadotroph and lactotroph axes. It is now demonstrated that prolactin exerts autocrine or paracrine actions on lactotroph cells in vivo. One of the major advances was to better understand, using mouse models, the impact of hyperprolactinemia on gonadotroph axis. It is now accepted that hypogonadotropic hypogonadism in patients with hyperprolactinemia is mediated by a decrease of hypothalamic kisspeptin secretion. Gonadotroph axis can be restored by intravenous administration of kisspeptin. However, the mechanisms of lactotroph tumorigenesis in Prlr -/- animals remain incompletely understood and transposable to the human species, since the only patient with biallelic PRLR loss-of-function mutation leading to complete prolactin resistance that has been described so far did not have pituitary adenoma visible on MRI. La prolactine et son récepteur : Des modèles animaux à la physiopathologie hypophysaire. La prolactine (PRL), hormone de la lactation par excellence, est majoritairement synthétisée et sécrétée par les cellules lactotropes de l’antéhypophyse. Ses actions sont médiées par le récepteur transmembranaire de la prolactine (PRLR). Alors que plus de 300 fonctions différentes ont été attribuées à cette hormone selon les espèces, son rôle chez l’Homme reste limité au développement de la glande mammaire et à l’allaitement. Les pathologies en lien avec la PRL sont essentiellement celles rencontrées en cas d’hypersécrétion de cette hormone. En effet, l’hyperprolactinémie entraîne l’altération du fonctionnement de l’axe gonadotrope chez l’homme comme chez la femme. Ainsi, l’hyperprolactinémie est une étiologie fréquente d’hypogonadisme hypogonadotrope acquis et l’une des principales causes d’anovulation et d’infertilité chez la femme. Ces dernières années, les études de modèles murins invalidés pour le PRLR, de manière globale ou conditionnelle dans l’hypophyse, ont permis d’apporter de nouveaux éléments dans la compréhension de la régulation des axes gonadotrope et lactotrope. Il est maintenant démontré que la prolactine exerce des actions autocrines ou paracrines sur les cellules lactotropes in vivo. Une des avancées majeures a été de mieux comprendre, à l’aide des modèles murins, l’impact de l’hyperprolactinémie sur l’axe gonadotrope. C’est ainsi qu’il a pu être établi que, comme chez les rongeurs, l’hypogonadisme hypogonadotrope chez les patientes atteintes d’hyperprolactinémie est médié par un déficit de sécrétion de kisspeptine hypothalamique, et que l’axe gonadotrope peut être restauré par l’administration intraveineuse de kisspeptine. Les mécanismes de tumorigenèse lactotrope des animaux Prlr −/− restent cependant incomplètement compris et transposables dans l’espèce humaine, puisque, jusqu’à présent, l’unique patiente porteuse d’une mutation bi-allélique perte de fonction du PRLR ayant fait l’objet d’une publication présentait une imagerie hypophysaire sans anomalie.
2023-01-13 | Prolactin receptor signaling: A novel target for cancer treatment - Exploring anti-PRLR signaling strategies
Prolactin (PRL) is a peptide hormone mainly secreted from the anterior pituitary gland. PRL is reported to play a role in pregnancy, mammary gland development, immune modulation, reproduction, and differentiation of islet cells. PRL binds to its receptor PRLR, which belongs to a superfamily of the class I cytokine receptor that has no intrinsic kinase activity. In canonical signaling, PRL binding to PRLR induces downstream signaling including JAK-STAT, AKT and MAPK pathways. This leads to increased cell proliferation, stemness, migration, apoptosis inhibition, and resistance to chemotherapy. PRL-signaling is upregulated in numerous hormone-dependent cancers including breast, prostate, ovarian, and endometrial cancer. However, more recently, the pathway has been reported to play a tumor-promoting role in other cancer types such as colon, pancreas, and hepatocellular cancers. Hence, the signaling pathway is an attractive target for drug development with blockade of the receptor being a potential therapeutic approach. Different strategies have been developed to target this receptor including modification of PRL peptides (Del1-9-G129R-hPRL, G129R-Prl), growth hormone receptor/prolactin receptor bispecific antibody antagonist, neutralizing antibody LFA102, an antibody-drug conjugate (ABBV-176) of the humanized antibody h16f (PR-1594804) and pyrrolobenzodiazepine dimer, a bispecific antibody targeting both PRLR and CD3, an in vivo half-life extended fusion protein containing PRLR antagonist PrlRA and albumin binding domain. There have also been attempts to discover and develop small molecular inhibitors targeting PRLR. Recently, using structure-based virtual screening, we identified a few antipsychotic drugs including penfluridol as a molecule that inhibits PRL-signaling to inhibit PDAC tumor progression. In this review, we will summarize the recent advances in the biology of this receptor in cancer and give an account of PRLR antagonist development for the treatment of cancer.
2022-10-14 | SFRP2 is a Novel Diagnostic Biomarker and Suppresses the Proliferation of Pituitary Adenoma
Pituitary adenoma (PA) constitutes one of the most common intracranial tumors. The present study was designed to identify potential diagnostic markers for PA. We used gene expression profiles (GEO: GSE26966 and GEO: GSE63357 datasets) derived from human PA and nontumor samples that were made freely accessible by the gene expression omnibus (GEO) datasets. Differentially expressed genes (DEGs) were screened between 14 normal specimens and 34 PA specimens by the use of the limma package of the R. The diagnostic genes were determined using a LASSO regression model and SVM-RFE analysis. SFRP2 expression in PA cells was analyzed using RT-PCR, and the effect of SFRP2 dysregulation on PA cell proliferation was measured using CCK-8 analysis. In this study, 361 DEGs were identified: 309 genes were downregulated and 52 genes were upregulated. The results of KEGG assays revealed that the 361 DEGs were mainly enriched in the PI3K-Akt signaling pathway, MAPK signaling pathway, growth hormone synthesis, secretion and action, and AGE-RAGE signaling pathway in diabetic complications. Results from the LASSO regression model and the SVM-RFE analysis indicated that LOC101060391 and SFRP2 were diagnostic genes. In contrast to normal tissue, the expressions of LOC101060391 and SFRP2 were much lower in PA samples. According to the ROC assays, high LOC101060391 and SFRP2 expression had an AUC value >0.9 for PA. Upregulation of SFRP2 distinctly inhibited the proliferative capacity of PA cells, as shown by CCK-8 analysis. Furthermore, knockdown of SFRP2 had an influence on cell growth in both the AtT-20 and HP75 cell lines. Taken together, our findings indicate that LOC101060391 and SFRP2 have diagnostic potential for PA. Furthermore, SFRP2 may be an antioncogene and a therapeutic target for PA.
antibodies
2026-01-19 | Long-term effect on bone mineral density of denosumab in the treatment of hyperpituitarism driven osteoporosis: an exploratory study.
Treatment of skeletal fragility in patients with pituitary diseases is challenging. Denosumab, an antiresorptive bone active drug, increased bone mineral density (BMD) and reduced incidence and risk of fractures in primary osteoporosis. This study aimed to evaluate the efficacy of denosumab in patients with pituitary disease-driven osteoporosis. This retrospective study investigated the frequency of fragility fractures (FF) and the percent BMD changes at 1-, 2-, 5-, and 10-years of treatment with denosumab, in patients with osteoporosis due to secreting pituitary adenoma. Seventeen patients were included: 5 patients (29.4%) were affected by hyperprolactinemia due to PRL-secreting pituitary adenoma (PAs), six patients (35.3%) were affected by acromegaly and six patients (35.3%) by Cushing's disease. Four patients carried prevalent-FF (23.5%). A single patient with acromegaly developed FF at 2 and at 5 years of treatment with denosumab. Femoral neck BMD increased in 11 patients (64.7%) at 1 year of treatment, in 9 patients (52.9%) at 2 years of treatment, in 8 patients (47.1%) at 5 years of treatment and in 2 patients (66.7%) at 10 years of treatment. Lumbar spine BMD improved in all patients at 1 year of treatment (100%), in 16 patients at 2 years of treatment (100%), in 11 patients at 5 years of treatment (100%), and in 2 patients at 10 years of treatment (66.7%). No drug related adverse events occurred. This study demonstrated for the first time that long-term treatment with denosumab is effective and safe in patients with osteoporosis due to secreting pituitary adenoma.
2025-10-29 | Immunohistochemical Comparison of Dopamine-2 Receptor Expression in Resistant and Non-Resistant Prolactinomas.
Background: Dopamine agonists (DAs) are first-line therapy for prolactin-secreting pituitary adenomas; however, a small proportion of tumors are resistant. Previous reports suggested that reduced D2R mRNA expression might cause resistance. This study aimed to determine if resistant prolactinomas express D2R protein. We also explored a role of estrogen receptor alpha (ERα) expression in DA resistance. Methods: We retrospectively selected 15 tumor specimens from 13 total patients (8 controls from 8 patients, 7 from 5 resistant patients) with resected lactotroph cell-type tumors. We reviewed age at diagnosis, tumor size, initial prolactin level, medical treatment, and reason for surgery. Immunohistochemistry was performed for D2R, prolactin, and ERα protein expression. Results: D2R expression was positive in seven of eight controls vs. two of seven in resistant tumors (p = 0.02). ERα expression did not significantly correlate with DA resistance. The two D2R expressing resistant tumors were ERα negative and both derived from a pre-pubertal female, supporting prior reports suggesting ERα may modulate DA therapy response. Conclusions: Our study introduces a reproducible method for assessing D2R protein expression in prolactinomas using commercially available D2R antibodies. Our findings align with current evidence indicating that lack of D2R expression, previously indicated by decreased mRNA levels, is common in DA-resistant prolactinomas and provide a basis for discontinuation of DA therapy to avoid potential harm to these patients.
2025-04-09 | An 18-year Odyssey: navigating the complex path of prolactinoma management: a case report
Abstract Background Prolactinomas are the most common type of pituitary adenomas, typically managed with dopamine agonists. However, some cases are refractory to standard therapies, posing significant clinical challenges. This case highlights the complexities of managing an aggressive macroprolactinoma resistant to conventional treatments and explores the use of immunotherapy as a novel intervention. Case presentation A 54-year-old male with a history of hypertension and type 2 diabetes mellitus presented with erectile dysfunction and low libido, leading to a diagnosis of prolactinoma. Over an 18-year period, he underwent multiple interventions, including cabergoline therapy, four transsphenoidal surgeries, radiation therapy, and various pharmacotherapies. Despite these, he had refractory disease with markedly elevated prolactin levels and tumor growth. In the final stages of the disease, pembrolizumab immunotherapy was attempted. Unfortunately, the patient’s condition continued to deteriorate, ultimately leading to hospice care and death at the age of 71. Conclusions This case underscores the challenges associated with managing refractory prolactinomas and highlights the need for innovative therapeutic strategies, including immunotherapy. Further research is essential to establish the role of emerging treatments in improving outcomes for patients with aggressive pituitary adenomas.
2024-09-14 | Therapeutical Usefulness of PD-1/PD-L1 Inhibitors in Aggressive or Metastatic Pituitary Tumours.
Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the therapeutic usefulness of anti-PD-1 drugs in patients with aggressive or metastatic PitNETs. Published cases and case series involving patients with PitNETs treated with PD-1/PD-L1 inhibitors were reviewed. Demographic data, clinical-pathological features, previous therapies, drug dosage and posology, and the best radiological and biochemical responses, as well as survival data, were evaluated. We identified 29 cases of aggressive (n = 13) or metastatic (n = 16) PitNETs treated with PD-1/PD-L1 inhibitors. The hypersecretion of adrenocorticotropic hormone (ACTH) was documented in eighteen cases (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to using ICIs. Overall, a positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen of twenty-nine cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 of the 17 functioning PitNET cases with available data (64.7%). The median survival of patients treated with ICIs was 13 months, with a maximum of 42 months in two ACTH-secreting tumours. Among 29 patients with PitNETs treated with PD-1/PD-L1 inhibitors, the positive radiological and biochemical response rates were 62.1% and 64.7%, respectively. Altogether, these data suggest a promising role of ICIs in patients with aggressive or metastatic PitNETs refractory to other treatment modalities.
2024-05-28 | Aggressive pituitary adenoma in the context of Lynch syndrome: a case report and literature review on this rare coincidence.
Lynch Syndrome (LS) is a cancer-predisposing condition resulting from hereditary mutation of DNA mismatch repair genes. Gastrointestinal, urogenital, and endometrial carcinomas are well-known to predominantly occur in LS patients. In contrast, there are only few reports on brain tumours in the context of LS and to date intracranial tumour manifestation appear to be rather coincidental. We present the case of a 56-year-old female developing aggressive lactotroph pituitary adenoma following a history of multiple Lynch-associated malignomas and having a confirmed MSH2 mutation. Furthermore, we performed a literature review via PubMed using the search terms 'Lynch Syndrome', 'HNPCC', 'MMR mutation' combined with 'intracranial tumour', 'sellar tumour', 'pituitary adenoma', or 'pituitary carcinoma', focusing on other reported cases and treatment regimens. A handful of studies have indicated an increased frequency of brain tumours in the context of LS, predominantly glioblastoma and less frequently low-grade glioma or other brain tumours. Based on our literature review, we summarized the known instances of pituitary adenoma in LS patients, including the present case. Furthermore, we reviewed the common recommendation of using temozolomide (TMZ) for treatment of aggressive pituitary adenoma or carcinoma and found strong indication that it might be insufficient in LS patients, while PD-1 blockade could be a promising treatment option. Combined with our case, there is a growing body of evidence that intracranial tumours and in particular those of the sellar region might be more prevalent in LS patients than previously assumed, due to their genetic profile substantially affecting viability and efficacy of treatment options. Clinical signs of aggressive tumour growth in combination with irresponsiveness to standard treatment in case of recurrence should lead to further diagnostic measures, because revelation of germline MMR mutations would call for an extended screening for other neoplastic manifestations and would markedly influence further treatment.
oligonucleotides
2023-05-17 | MicroRNA-137 inhibits pituitary prolactinoma proliferation by targeting AKT2.
Prolactinoma is the most common type of pituitary adenoma. Most prolactinoma need medical treatment, but some of them are aggressive and require surgery. In previous decades, some miRNAs have been manifested as oncogenes or tumor suppressors. Consequently, miRNAs' abnormal expression involves tumorigenesis, invasion, and metastasis of different types of tumors, including pituitary tumors. The current study aim to explore the aggressiveness-associated miRNAs in prolactinoma and underlying molecular mechanisms based on the bioinformatic analysis and fundamental experiment studies. GSE46294 miRNA expression profile from the Gene Expression Omnibus (GEO) database was downloaded. Differentially expressed miRNAs (DEMs) were filtered from this data. Subsequently, the target genes of downregulated miRNAs were analyzed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RT-qPCR, western blot, and CCK-8 assays were used to validate the effect of miR-137 on the proliferation of MMQ cells through AKT2. Finally, the binding site of rat miR-137 to AKT2 were predicted by Targetscan and Bibiserv database, and verified by double luciferase reporter assay. Twenty-four changed DEMs (fourteen upregulated and ten downregulated) were identified. Target genes of downregulated DEMs were classified into three groups by GO terms. KEGG pathway enrichment analysis revealed these target genes enriched in the PI3K-Akt pathway. We also confirmed that miR-137 can target AKT2 and inhibit the proliferation of MMQ cells induced by AKT2. MiR-137 suppressed prolactinomas' aggressive behavior by targeting AKT2.
2023-02-17 | Exosomal RNAs in the development and treatment of pituitary adenomas
Exosomes are small extracellular vesicles that carry various bioactive molecules including various RNAs that modulate the activities of recipient cells. It has drawn considerable attention as means of cell communication and drug delivery. Exosome plays important role in various tumors, but it is rarely summarized in pituitary adenoma (PA). PA is the second most common primary central nervous system tumor, and its recurrence and persistent postoperative hormone hypersecretion lead to compromised quality of life. How exactly exosomes impact tumor development and hormone secretion is important for the development of this tumor diagnosis and treatment. In this review, we discuss how exosomal RNAs impact PAs and their potential as future clinical therapies. In our literature review, first, we found that exosomal microRNA hsa-miR-1180-3p is a potential early biomarker for NFPAs. Since NFPAs are typically difficult to diagnose, this is an especially important finding. Second, exosomal protein transcripts are potential invasive biomarker, such as MMP1 , N-cadherin , CDK6 , RHOU , INSM1 , and RASSF10 . Third, exosomal contents such as hsa-miR-21-5p promote distant bone formation of GHPA patients. Fourth, tumor suppressors in the exosome constitute novel therapeutic application of exosome, including long noncoding RNA (lncRNA) H19, miR-149-5p, miR-99a-3p, and miR-423-5p. This review discusses the possible mechanisms of exosome and their contents in PA and promotes the use of exosomes in both clinical diagnosis and treatment of this tumor.
2022-03-21 | The SF3B1R625H mutation promotes prolactinoma tumor progression through aberrant splicing of DLG1.
Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and underlying molecular mechanisms remain largely unexplored. Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA. Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1R625H promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1R625H and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway. Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.
2021-06-29 | The long noncoding RNA-H19/miRNA-93a/ATG7 axis regulates the sensitivity of pituitary adenomas to dopamine agonists.
Dopamine agonists (DAs), such as cabergoline and bromocriptine, are the first-line clinical treatment for prolactinomas. Our previous study demonstrated that long noncoding RNA H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumor progression. However, the significance and mechanism of H19 in the DA treatment of prolactinomas are still unknown. In this study, we reported that H19 had a synergistic effect with DA treatment on prolactinomas in vitro and in vivo. Mechanistically, H19 promoted ATG7 expression in pituitary tumor cells by inhibiting miR-93a expression. In addition, a potential binding site between miR-93 and H19 was confirmed, and low expression of miR-93 was previously found in DA-resistant prolactinomas. Furthermore, we showed that miR-93a regulates ATG7 expression by targeting ATG7 mRNA. In conclusion, our study has identified the role of the H19-miR-93-ATG7 axis in DA treatment of prolactinomas, which may be a potential therapeutic target for human prolactinomas.
2021-04-29 | Expression and clinical significance of miR-193a-3p in invasive pituitary adenomas.
Our study aimed to investigate miR-193a-3p expression and its clinical significance in pituitary adenomas (PAs). Moreover, the correlation between miR-193a-3p expression and the invasiveness of PAs was explored. In this study, the relative expression levels of miR-193a-3p were detected via quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The correlations between miR-193a-3p and tumor size, clinical features, and prolactinomas postoperative prolactin (PRL) levels early remission were further analyzed. Compared with non-invasive PAs, there was a lower miR-193a-3p expression in invasive PAs. MiR-193a-3p expression had reverse relevance to tumor size. A higher risk of postoperative residual and recurrence was found in patients with downregulated miR-193a-3p. Prolactinomas patients with postoperative PRL levels early remission were at lower risk to relapse and patients with high-expression miR-193a-3p had a higher early remission rate, suggesting that miR-193a-3p was a significant prognostic factor for prolactinomas. MiR-193a-3p could have potential therapeutic value for invasive pituitary adenomas.
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2025-09-04 | Identifying Hub Genes Associated with Sex Disparities in Prolactinomas.
Background: Male patients with prolactinomas exhibit greater invasiveness, resistance to dopamine agonists, making treatment more challenging. This study aims to explore the potential different genes contributing to sex disparities in prolactinomas. Materials and Methods: Weighted gene co-expression network analysis and differential expressed genes analysis were performed to identify sex-related hub genes. In addition, bioinformatics analyses were conducted to understand gene localization on chromosomes, gene regulatory networks, signaling pathways, and their relationship with immune function, which was verified in 21 human prolactinoma samples. Results: A total of 21 sex-related hub genes were identified. The hub genes in males included nine Y chromosome genes and six autosomal genes, while females had six specific genes. Further predictions using the NetworkAnalyst online tool suggested that transcription factors (REST, androgen receptor) and microRNAs (miR-27a-3p, miR-146a-5p) may be involved in regulating the above sex-related hub genes. CIBERSORT analysis revealed that prolactinomas in males showed significant infiltration of resting dendritic cells and naive CD4+ T cells. Correlation analysis between sex-related hub genes and immune checkpoint genes indicated that male hub genes were positively correlated with CD47 and CEACAM1, while showing a strong negative correlation with CD28, TNFSF14, and CD226. Finally, similar changes of gene expression in our surgical prolactinoma samples were confirmed by RT-qPCR. Conclusions: In prolactinomas, the male hub genes and female hub genes are identified by our bioinformatics analysis. Our findings suggest that KDM5D, PDCD1, ELOA3BP, XRRA1, and SIGLEC12 serve as potential biomarkers for male prolactinomas, while SOX3, DMGDH, and NPAS1 may serve as potential biomarkers for female prolactinoma, providing a theoretical basis for targeted therapy.
2025-01-17 | Determinants of cerebrospinal fluid leakage in a large cohort of macroprolactinomas.
Macroprolactinomas are the most frequent subtype of pituitary adenomas. Their treatment has been improved since the onset of dopamin agonists (DA). Nevertheless, DA can cause a cerebospinal fluid (CSF) leakage by shrinking the tumor and lead to a bacterial meningitis. This complication might have lethal consequences. We conducted an observational, retrospective study in the Pituitary Unit in Pitié Salpêtrière Hospital. A total of 171 patients with macroprolactinomas (larger diameter greater than 10mm) were included in the study. We compared patients who presented cerebrospinal rhinorrhea and/or meningitis, so-called complicated patients (C group), to patients who presented no complications during their follow-up, so-called uncomplicated patients (UC group): no occurrence of rhinorrhea, meningitis. Cerebrospinal fluid (CSF) leakage has been found in 5% of patients in our large cohort of macroprolactinoma. Determinants of CSF leakage seems to be : adenoma size with concomitant supra- and infrasellar extension, very high prolactin level (>1000µg/l), cabergoline treatment. Cerebrospinal rhinorrhea is a rare complication of macroprolactinomas, but potentially lethal because of meningitis risk. Anti-pneumococcal and anti-haemophilus vaccination appears to be appropriate in these patients at the time of introduction of DA, to prevent meningitis.
2022-07-27 | Disease Modeling of Pituitary Adenoma Using Human Pluripotent Stem Cells
Pituitary adenomas are characterized by abnormal growth in the pituitary gland. Surgical excision is the first-line treatment for functional (hormone-producing) pituitary adenomas, except for prolactin-producing adenomas; however, complete excision is technically challenging, and many patients require long-term medication after the treatment. In addition, the pathophysiology of pituitary adenomas, such as tumorigenesis, has not been fully understood. Pituitary adenoma pathophysiology has mainly been studied using animal models and animal tumor-derived cell lines. Nevertheless, experimental studies on human pituitary adenomas are difficult because of the significant differences among species and the lack of reliable cell lines. Recently, several methods have been established to differentiate pituitary cells from human pluripotent stem cells (hPSCs). The induced pituitary hormone-producing cells retain the physiological properties already lost in tumor-derived cell lines. Moreover, CRISPR/Cas9 systems have expedited the introduction of causative gene mutations in various malignant tumors into hPSCs. Therefore, hPSC-derived pituitary cells have great potential as a novel platform for studying the pathophysiology of human-specific pituitary adenomas and developing novel drugs. This review presents an overview of the recent progresses in hPSC applications for pituitary research, functional pituitary adenoma pathogenesis, and genome-editing techniques for introducing causative mutations. We also discuss future applications of hPSCs for studying pituitary adenomas.
2021-05-12 | Genomic and transcriptomic analysis of pituitary adenomas reveals the impacts of copy number variations on gene expression and clinical prognosis among prolactin-secreting subtype.
Pituitary adenomas (PAs) are slow growing and benign primary intracranial tumors that often cause occupying effects or endocrine symptoms. PAs can be classified into various subtypes according to hormone secretion. Although widespread transcriptional alterations that cause aberrant hormone secretion have been characterized, the impact of genomic variations on transcriptional alterations is unclear due to the rare occurrence of single-nucleotide variations in PA. In this study, we performed whole-genome sequencing (WGS) on 76 PA samples across three clinical subtypes (PRL-PAs; GH-PAs, and NFPAs); transcriptome sequencing (RNA-seq) of 54 samples across these subtypes was also conducted. Nine normal pituitary tissues were used as controls. Common and subtype-specific transcriptional alterations in PAs were identified. Strikingly, widespread genomic copy number amplifications were discovered for PRL-PAs, which are causally involved in transcriptomic changes in this subtype. Moreover, we found that the high copy number variations (CNVs) in PRL-PA cause increased prolactin production, drug resistance and proliferative capacity, potentially through key genes with copy number amplification and transcriptional activation, such as BCAT1. This study provides insight into how genomic CNVs affect the transcriptome and clinical outcomes of PRL-PA and sheds light on the development of potential therapeutics for aberrantly activated targets.
2017-10-23 | Case Report of a Prolactinoma in a Patient With a Novel MAX Mutation and Bilateral Pheochromocytomas
Pheochromocytomas are neuroendocrine tumors that can arise sporadically or be inherited as a familial disease, and they may occur in isolation or as part of a multitumor syndrome. Familial disease typically presents in younger patients with a higher risk of multifocality. Recently, the tumor suppressor MYC-associated factor X (MAX) gene has been implicated as a cause of familial isolated pheochromocytoma and paraganglioma. We describe a patient with a pituitary prolactinoma and bilateral pheochromocytomas who tested positive for a germline MAX mutation. Interestingly, the patient also had mild primary hyperparathyroidism that resolved upon resection of the pheochromocytomas despite the absence of parathyroid hormone staining in the tumors. To our knowledge, this case is the first report of prolactinoma in a patient with a MAX mutation, which suggests the possibility of germline MAX mutations also contributing to the development of prolactinomas.
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