Reconsideration of Surgical Indication for Prolactin-producing Pituitary Tumor Focusing on Visual Impairment.

Prolactin-producing pituitary tumor (PRLoma) is the most prevalent functional pituitary tumor. If the tumor becomes large, vision can be impaired. In contrast to other pituitary tumors, cabergoline (CAB) is extremely effective for PRLoma and has become the first-line treatment. In this study, we examined our experience with the pharmacological and surgical management of PRLomas with visual impairment (VI) to determine whether VI could be a surgical indication. Further, we discussed the function of surgery in situations where the gold standard of PRLoma treatment was CAB administration. Of the 159 patients with PRLomas (age, 13-77 [mean = 36.3] years; men, 29; women, 130) at Tokyo Women's Medical University Hospital from 2009 to 2021, 18 (age, 15-67 [mean = 35.8] years; men, 12; woman, 6) had VI (subjectively, 12; objectively, 6). They started CAB treatment immediately (maximum dose: 0.5 to 6 mg/week; average: 2.17 mg/week). VI improved in 16 patients (88.9%) but did not improve in 2 (11.1%) requiring surgeries. One of the two patients had a parenchymal tumor resistant to CAB, and the other had a cystic tumor due to intratumoral bleeding. Consequently, CAB is the first-line treatment for PRLomas with VI because of its significantly high rate of improvement. However, close and rigorous surveillance is necessary for cases resistant to CAB, and the correct decision is required regarding surgical interventions at proper timing and appropriate surgical approaches considering the purpose of surgery.

[Overcoming therapy resistance in prolactinomas: from perspectives to real clinical practice].

The main treatment option of prolactin-secreting pituitary adenomas is dopamine agonist therapy, which demonstrates prolactin level normalizing and reducing the size of an adenoma in the majority of cases. However, significant amount of patients - about 20% - poorly responds even to high doses of dopamine agonists that is explained by the resistance to therapy. The occurrence of pharmacodynamic characteristics is one of the causes responsible for the development of resistance to typical therapy. Clinical manifestations of persistent hyperprolactinemia are due to following pathological factors: hormonal hypersecretion and the mass-effect of pituitary adenoma. Prevention of irreversible changes is possible only with timely detection of resistance and determination of the optimal personalized treatment algorithm.We report a clinical case of dopamine-agonist resistant microprolactinoma. Patient's health stabilisation, normal level of prolactin and reduction in size of adenoma were achieved due to administration of combined treatment with tamoxifen and dopamine agonists. Hyperprolactinaemia occurring because of prolactin-secreting pituitary adenoma and associated adverse effects are significant problem, decreasing quality of life and demographics in general. This underlines the importance of figuring out causes and identifying predictors of the therapy resistance.The results of the study, illustrated by a clinical example, are presented in the present paper.

Prolactinoma in postmenopausal women: a systematic review.

IMPORTANCE: Prolactinomas occurring during the reproductive period exhibit a characteristic behavior. There are, however, gaps in the literature regarding the behavior of these tumors after menopause. OBJECTIVE: This study aimed to review and characterize the influence of menopause on prolactinoma behavior. EVIDENCE REVIEW: A systematic review of observational prospective or retrospective studies and clinical trials on prolactinomas was conducted in two situations: tumors diagnosed in the reproductive period (before menopause), with follow-up in the postmenopausal period, or prolactinomas diagnosed in the postmenopausal period, without language or date restrictions. Data extracted from the articles included patient and tumor characteristics (prolactinoma type, previous treatment, symptoms, and serum prolactin [PRL] levels). FINDINGS: This study included five studies comprising 180 participants. Prolactinomas diagnosed in women of reproductive age are treated with dopaminergic agonists (DAs), with indications of treatment withdrawal after menopause, exhibited stable tumor behavior and PRL levels. Considering the diagnosis during the postmenopausal period, macroprolactinomas were more prevalent and showed tumor shrinkage when DAs were used. Cabergoline, the most commonly used drug, lowers PRL levels and reduces symptoms associated with adenoma. CONCLUSIONS AND RELEVANCE: Microadenomas diagnosed before menopause can be followed up without treatment. Prolactinomas diagnosed after menopause are typically macroadenomas. Cabergoline remains the treatment of choice in the presence of clinical or compressive symptoms. We recommend at least one annual follow-up for such patients.

Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs.

BACKGROUND: The treatment of dopamine agonists (DA) resistant prolactinomas remains a formidable challenge, as the mechanism of resistance is still unclear, and there are currently no viable alternative drug therapies available. This study seeks to investigate the mechanism of DA resistance in prolactinomas and identify new potentially effective drugs. METHODS: To explore the mechanism of DA resistance in prolactinomas, this study conducted transcriptome sequencing analysis on 27 cases of DA-resistant prolactinomas and 10 cases of sensitive prolactinomas. In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an organoids model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo. RESULTS: The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified Genistein as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted apoptosis in pituitary tumor cells. Moreover, both the cell sequencing results and WB validation results of the drug-treated cells indicated that Genistein exerts its anti-tumor effect by inhibiting the FA pathway. In vivo, experiments also showed that Genistein can inhibit subcutaneous tumor formation. CONCLUSION: DA resistance in prolactinomas is associated with upregulation of the Focal Adhesion (FA) signaling pathway, and Genistein can exert its anti-tumor effect by inhibiting the expression of the FA pathway.

Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy.

Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSCmed cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.

Giant prolactinoma in Asian-Indians: A single-center experience from Western India.

PURPOSE: Giant prolactinomas (GP) are rare tumors accounting for 4.3% of prolactinomas, with paucity of literature from India. We aim to describe clinical, biochemical, radiological, and treatment outcomes in a large series of Asian-Indian patients with GP. METHODS: A single-center retrospective analysis of GPs (n=84), age-based (adults: 66 versus pediatric: 18) and gender-based (males: 64 versus females: 20) comparison was done. RESULTS: The mean age at presentation was 34.1±13years, and 64 (76.2%) were males. Males were younger at presentation (32.1±12.2 versus 40.1±13.8years, P: 0.01). The majority presented with mass-effect-related manifestations (visual disturbances: 91.6%, headache: 84.5%) and/or hypogonadism (98.7%). At baseline, largest tumor dimension was 5.3±1.0cm, and serum prolactin was 8343 (3865.5-12,306) ng/mL; most (94.6%) had gonadal axis involvement. Dopamine-agonist (DA) as first-line therapy (45/67, 67.2%) achieved normoprolactinemia (maximum cabergoline dose: 2.0±1.2mg/week) in 36/45 (80%) and tumor response (≥50% reduction) in 36/37 (97.3%) patients at the last follow-up (median duration: 33 [14.5-53.5]months). Notably, gonadal axis recovery was poor (6/30, 20%) despite normoprolactinemia post-DA monotherapy. At latest follow-up, secondary hypothyroidism (32.5% versus 82.6%, P: 0.001) and central hypocortisolism (5.6% versus 42.9%, P: 0.007) were less frequent in DA monotherapy (n=43) than in multimodal therapy group (n=23). The proportion of males (94.4% versus 71.2%, P: 0.04) was higher in the pediatric age group, with DA-induced (first-line) normoprolactinemia observed in 66.7% of them. CONCLUSION: GP has male predominance, DA as first-line therapy normalized prolactin in four-fifths of patients with better preservation of HPT and HPA axes in patients with DA monotherapy.

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

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

Prolactinomas Resistant to Dopamine Agonists: Pathophysiology and Treatment.

Prolactinomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Medical treatment with dopamine agonists (DA), mainly cabergoline, is considered the primary therapy for these patients. Prolactin normalization is achieved in 80-90% of prolactinomas treated with cabergoline. Patients resistant to the standard dose can escalate the dose of cabergoline up to the maximum tolerated dose. The expression of dopamine (D2) receptors and dopamine affinity is decreased in aggressive and resistant prolactinomas. Patients with aggressive and DA-resistant adenomas or with rare PRL-secreting carcinomas can be treated off-label with temozolomide (TMZ), a DNA alkylating agent. TMZ is effective in 40-50% of treated lactotroph tumors showing at least a partial response. However, patients tend to escape from the effect of TMZ after a limited time of response. Other therapeutic options include aromatase inhibitors, the somatostatin receptor ligand pasireotide, peptide receptor radionuclide therapy (PRRT), immune-checkpoint inhibitors, tyrosine-kinase inhibitors, or everolimus, the mammalian target of rapamycin inhibitor. These experimental treatments were effective in some patients carrying refractory prolactinomas showing usually partial tumor control. However, the number of treated patients with any of these new therapeutic options is very limited and treatment results are inconsistent, thus additional experience with more patients is required.

Anti-prolactin treatment alleviates lupus conditions by regulating the JAK2-STAT3 pathway.

OBJECTIVES: We previously revealed the role of prolactin (PRL) in antibody production and disease activity in patients with systemic lupus erythematosus. In this study, we sought to determine whether inhibition of PRL could improve lupus-like disease in MRL/lpr mice. METHODS: The expression levels of PRL in various cell types of lupus patients were measured by flow cytometry. The effects of anti-PRL on animal survival, renal histopathology, creatinine, proteinuria, anti-dsDNA antibody, cytokine production, splenomegaly and lymphadenopathy were assessed. The effect of anti-PRL on the Jak2-Stat3 signalling pathway was detected by western blotting. RESULTS: Prolactin was upregulated in B cells, neutrophils, CD4+ T cells, and monocytes isolated from patients with lupus. Furthermore, inhibition of PRL by anti-PRL treatment around the time of onset prolonged the survival of MRL/lpr mice, significantly reduced anti-dsDNA antibody production, and alleviated symptoms of lupus nephritis, splenomegaly, and lymphadenopathy. In addition, anti-PRL-treated mice showed a decrease in the levels of pathogenic cytokines such as IL-21 and IL-6. Furthermore, mechanistically, anti-PRL treatment significantly reduced the levels of p-Jak2 and p-Stat3 in MRL/lpr mice. CONCLUSIONS: In summary, these data suggest that PRL inhibition alleviates lupus-like disease in MRL/lpr mice by modulating the Jak2-Stat3 signalling cascade. More importantly, our results imply the potential of PRL inhibitors and may provide a novel therapeutic approach for lupus.

Incidental versus symptomatic nonfunctioning pituitary adenomas: Are they different?

BACKGROUND: Nonfunctioning pituitary adenomas (NFPAs) constitute one of the most common tumours in the sellar region and are often discovered only when associated with compressive symptoms. With the frequent use of brain imaging, there has been an increase in the prevalence of incidentally discovered NFPAs. AIM: We aim to determine the prevalence of incidental diagnosis with NPAs observed over a decade and compare the analytical, clinical and treatment differences between those who were diagnosed either incidentally or symptomatically. We also intend to evaluate the pathology differences between both groups. METHODS: We retrospectively analysed patients aged ≥18 years with an apparent NFPA, defined as a pituitary lesion compatible with pituitary adenoma which is not associated with the clinical or biochemical evidence of a hormone-secreting tumour. Inclusion criteria included normal prolactin level for lesions <9 mm or a prolactin level <100 ng/mL for lesions ≥10 mm in maximal tumour diameter. RESULTS: We included 119 patients [53.8% males; mean age: 56.8 years (SD = 16.7)]. Diagnosis was incidental in 47.1% of patients, and many patients had unappreciated signs and symptoms of pituitary disease. In the symptomatic and incidental groups, 66.7% and 41.1% of patients had hypopituitarism, respectively (p = .005). Only 20.4% of patients incidentally diagnosed had microadenoma (p = .060). Hypopituitarism was present in 18.8% of those patients with microadenomas. Most tumours were macroadenomas (87.4%). Half of those patients diagnosed incidentally were submitted to surgery, compared with 75.8% of those who were diagnosed symptomatically (p = .004). CONCLUSIONS: Nonfunctioning pituitary adenomas are commonly diagnosed incidentally, with many manifesting symptoms on examination. NFPAs incidentally diagnosed are more commonly macroadenomas and less frequently associated with hypopituitarism than symptomatic. Accordingly, if there was a greater level of knowledge and more suspicion about these pathologies, it might be possible to discover them earlier.

Innovative thiosemicarbazones that induce multi-modal mechanisms to down-regulate estrogen-, progesterone-, androgen- and prolactin-receptors in breast cancer.

The estrogen receptor-α (ER-α) is a key driver of breast cancer (BC) and the ER-antagonist, tamoxifen, is a central pillar of BC treatment. However, cross-talk between ER-α, other hormone and growth factor receptors enables development of de novo resistance to tamoxifen. Herein, we mechanistically dissect the activity of a new class of anti-cancer agents that inhibit multiple growth factor receptors and down-stream signaling for the treatment of ER-positive BC. Using RNA sequencing and comprehensive protein expression analysis, we examined the activity of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), on the expression and activation of hormone and growth factor receptors, co-factors, and key resistance pathways in ER-α-positive BC. DpC differentially regulated 106 estrogen-response genes, and this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namely ER, progesterone receptor (PR), androgen receptor (AR), and prolactin receptor (PRL-R). Mechanistic investigation demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-α, AR, PR, and PRL-R protein expression. DpC and Dp44mT also inhibited activation and down-stream signaling of the epidermal growth factor (EGF) family receptors, and expression of co-factors that promote ER-α transcriptional activity, including SRC3, NF-κB p65, and SP1. In vivo, DpC was highly tolerable and effectively inhibited ER-α-positive BC growth. Through bespoke, non-hormonal, multi-modal mechanisms, Dp44mT and DpC decrease the expression of PR, AR, PRL-R, and tyrosine kinases that act with ER-α to promote BC, constituting an innovative therapeutic approach.

Association between long-term use of prolactin-elevating antipsychotics in women and the risk of breast cancer: What are the clinical implications?

BACKGROUND: Some antipsychotic drugs elevate prolactin, and hyperprolactinaemia is associated with an increased risk of breast cancer. Women with schizophrenia have an increased incidence of breast cancer, but also multiple risk factors for the condition. METHOD: This paper will critically review recent epidemiological studies concerning antipsychotics and breast cancer from a psychiatric perspective. RESULTS: Two recent epidemiological studies have found an association between use of prolactin-elevating antipsychotics and breast cancer in women with schizophrenia and other psychotic disorders. Prolactin-elevating drugs include paliperidone, risperidone, amisulpride and haloperidol, whilst prolactin-sparing antipsychotics included aripiprazole, brexpiprazole, cariprazine and quetiapine. In the two studies, estimated increased risks of breast cancer were disconcertingly high (up to 62%), but a third recent study found only a weak dose-response association. There are extensive methodological complications in this research, including the extent to which studies measure other risk factors for breast cancer and disagreement about the extent of prolactin elevation by some antipsychotics. CONCLUSION: Although causation between prolactin elevating antipsychotics and breast cancer in women has not been demonstrated, recent epidemiological reports are worrying. For women on antipsychotics, informed consent should ideally include discussion of breast cancer concerns within the wider context of treatment benefits and risks.

Predicting psychotic relapse following randomised discontinuation of paliperidone in individuals with schizophrenia or schizoaffective disorder: an individual participant data analysis.

BACKGROUND: Predicting relapse for individuals with psychotic disorders is not well established, especially after discontinuation of antipsychotic treatment. We aimed to identify general prognostic factors of relapse for all participants (irrespective of treatment continuation or discontinuation) and specific predictors of relapse for treatment discontinuation, using machine learning. METHODS: For this individual participant data analysis, we searched the Yale University Open Data Access Project's database for placebo-controlled, randomised antipsychotic discontinuation trials with participants with schizophrenia or schizoaffective disorder (aged ≥18 years). We included studies in which participants were treated with any antipsychotic study drug and randomly assigned to continue the same antipsychotic drug or to discontinue it and receive placebo. We assessed 36 prespecified baseline variables at randomisation to predict time to relapse, using univariate and multivariate proportional hazard regression models (including multivariate treatment group by variable interactions) with machine learning to categorise the variables as general prognostic factors of relapse, specific predictors of relapse, or both. FINDINGS: We identified 414 trials, of which five trials with 700 participants (304 [43%] women and 396 [57%] men) were eligible for the continuation group and 692 participants (292 [42%] women and 400 [58%] men) were eligible for the discontinuation group (median age 37 [IQR 28-47] years for continuation group and 38 [28-47] years for discontinuation group). Out of the 36 baseline variables, general prognostic factors of increased risk of relapse for all participants were drug-positive urine; paranoid, disorganised, and undifferentiated types of schizophrenia (lower risk for schizoaffective disorder); psychiatric and neurological adverse events; higher severity of akathisia (ie, difficulty or inability to sit still); antipsychotic discontinuation; lower social performance; younger age; lower glomerular filtration rate; benzodiazepine comedication (lower risk for anti-epileptic comedication). Out of the 36 baseline variables, predictors of increased risk specifically after antipsychotic discontinuation were increased prolactin concentration, higher number of hospitalisations, and smoking. Both prognostic factors and predictors with increased risk after discontinuation were oral antipsychotic treatment (lower risk for long-acting injectables), higher last dosage of the antipsychotic study drug, shorter duration of antipsychotic treatment, and higher score on the Clinical Global Impression (CGI) severity scale The predictive performance (concordance index) for participants who were not used to train the model was 0·707 (chance level is 0·5). INTERPRETATION: Routinely available general prognostic factors of psychotic relapse and predictors specific for treatment discontinuation could be used to support personalised treatment. Abrupt discontinuation of higher dosages of oral antipsychotics, especially for individuals with recurring hospitalisations, higher scores on the CGI severity scale, and increased prolactin concentrations, should be avoided to reduce the risk of relapse. FUNDING: German Research Foundation and Berlin Institute of Health.

Prolactinoma - which patients react favorably to cabergoline medication?

Objective. Prolactinoma, as a common endocrine disorder and the most frequent type of pituitary tumor, acts primarily as a suppressor on the gonadal functions. It is generally successfully treated with dopamine agonists; however, treatment resistance still remains in an unneglectable ratio. In this study, we aimed to identify factors, which may play a role in the treatment response. Methods. Seventy-six patients with prolactinoma, who have been routinely followed between 2018 and 2022 in Istanbul Research and Educational Hospital Endocrinology Outpatient Clinic, were included into the study. Initial prolactin level, adenoma size, baseline weight, body mass index (BMI), glucose, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels were obtained from the patient's medical records. The patients were divided into two groups: treatment respondent and non-respondent (refractory) ones, according to treatment response in the duration as suggested by the guidelines. The treatment respondent and non-respondent groups were compared according to the initial and the 3rd month prolactin levels, adenoma size, weight, BMI, and metabolic values. Results. The initial tumor diameter was 15.27±10.62 mm in the refractory and 7.42±4.42 mm in the treatment respondent groups (p=0.01). The refractory group had higher prolactin baseline level 269.96±275.78 µg/l vs. 124.55±67.35 µg/l of the respondent group (p=0.01). The refractory group had higher the 3rd month prolactin level 50.97±52.55 µg/l vs. 29.70±27.31 µg/l of the respondent group (p=0.04). The refractory group had higher frequency of cystic/hemorrhagic adenoma (47.6%, n=11/21) (p=0.01), baseline pituitary failure (33.3%, n=7/21) (p=0.01), and baseline cavernous sinus invasion (25.8, n=5/21) (p=0.01). The treatment respondent group had lower initial body weight (69.54±17.51 kg vs. 83.29±16.21 kg) (p<0.01), and lower BMI (25.98±5.47 kg/m2 vs. 27.69±6.42 kg/m2) (p=0.02). Conclusions. In this study, initial tumor size, male gender, weight, BMI, the 3rd month prolactin level, initial pituitary deficiency, and cystic/hemorrhagic component in pituitary imaging in patients with prolactinoma were associated with a lower treatment response.

Epidemiological and clinical profiles of Saudi patients with hyperprolactinemia in a single tertiary care center.

BACKGROUND: Prolactin is a hormone of the pituitary gland whose main function is the production of milk. Hyperprolactinemia is defined as an increase in prolactin levels above 25 µg/L in women and 20 µg/L in men. Causes of hyperprolactinemia include pituitary tumors, especially prolactinomas. Hyperprolactinemia can manifest clinically with a variety of symptoms, including galactorrhea and menstrual irregularities in women and erectile dysfunction in men. There are limited data on the epidemiology of hyperprolactinemia in the Middle East region. OBJECTIVES: Description of the epidemiology and clinical features of hyperprolactinemia in a cohort from Saudi Arabia. DESIGN: Medical record review SETTING: Tertiary medical center in Riyadh PATIENTS AND METHODS: The study included adult patients with hyperprolactinemia in King Abdulaziz Medical City in Riyadh. The patients were treated in endocrinology clinics from 2015 to 2019. Patients of both sexes older than 14 years were enrolled in the study. Patients with insufficient follow-up were excluded. Data were collected on demographic characteristics, symptoms, prolactin level, cause of high prolactin level, and treatment. MAIN OUTCOME MEASURES: The frequency of different etiologies and symptoms in patients with hyperprolactinemia. SAMPLE SIZE: 295 patients RESULTS: The majority of patients with hyperprolactinemia were female 256 (86.8%). Hyperprolactinemia was diagnosed more frequently in patients in the age groups 21-30 years (42.6%) and 31-40 years (24.1%). The majority of the study population was obese or overweight: 136 (46.3%) and 74 (25.2%), respectively. Most of the cases were symptomatic (192, 65.1%). In women, the most common symptom was oligomenorrhea (35%). In men, infertility and erectile dysfunction were the most common clinical symptoms (50% and 44.7%, respectively). Idiopathic causes were the most common etiology (108, 36.6%), followed by pituitary adenomas (81, 27.5%). The majority of patients were treated (184,62.4%), with cabergoline being the most commonly used medication (173, 94.0%). CONCLUSION: The demographic and clinical presentations and causes of hyperprolactinemia in male and female Saudi patients were similar to that in studies in other populations. LIMITATIONS: Single-center retrospective chart review study. CONFLICT OF INTEREST: None.

Hyperprolactinemia in children and adolescents and longterm follow-up results of prolactinoma cases: a single-centre experience.

BACKGROUND: Hyperprolactinaemia refers to increased circulating prolactin and is divided into functional and pathological hyperprolactinaemia. Prolactinoma is the most common cause of severe hyperprolactinaemia. Prolactinomas are rare in children. Treatment outcomes and long-term follow-up data in children are insufficient. Dopamine agonists are the first step in the treatment of prolactinomas. There are no recommendations supported by a high level of evidence regarding the dose and duration of cabergoline treatment. METHODS: Patients with hyperprolactinaemia were evaluated for etiological, clinical, and follow-up characteristics. The case files of patients with high prolactin levels who were followed up in our clinic between 2001 and 2019 were reviewed retrospectively. RESULTS: 27 cases (20 female, 7 male) with hyperprolactinemia were detected. The median age of the cases was 15 years (0.3-17.4). Prolactinoma was detected in 40.7% of the cases (n=11). Among these cases, six were macroadenomas. The median prolactin level was 118 ng/mL (34-4340) in those with prolactinoma and 60 ng/mL (22-200) in the hyperprolactinaemia group (p=0.007). In the prolactinoma group, the median age at presentation in macroadenoma cases (13.8 years) was lower than in microadenoma cases (17 years) (p=0.06). There was a negative correlation between prolactin level and height SDS (r=-0.770, p=0.06). In all cases, the median initial cabergoline dose was 0.5 mg/week, and prolactin levels returned to normal within an average of 2.6±2.4 months. Cabergoline treatment achieved a 50% reduction in adenoma size in the first year of treatment without high doses. CONCLUSIONS: Prolactinoma consists of an important group among hyperplolactinemia in children. In our study, prolactinoma was detected in 40.7% of children with hyperplolactinemia, and children with prolonged use (over 4 years) tolerated cabergoline well and prolactin levels normalized without high doses. Follow-up is required for relapse after discontinuing the treatment.

Management of Granulomatous Lobular Mastitis and Risk Factors Associated with Recurrence.

BACKGROUND: Granulomatous lobular mastitis (GM), an inflammatory breast lesion with unknown etiology, is prone to recur. There is no global consensus on the optimal treatment at present. This study was conducted to show our step-by-step systemic procedure and discuss the recurrence risk factors of GM. METHODS: The medical record database was retrospectively searched for patients with GM treated in our hospital between January 2015 and September 2021. Patients were divided into non-recurrence group (group A) and recurrence group (group B). Demographic and clinical characteristics, treatment and follow-up were collected and analyzed. RESULTS: A total of 885 GM patients were included in our study, all of whom received step-by-step systemic management. The mean age was 33.2 ± 5.2 years. There were 760 (85.9%) patients in group A and 125 (14.1%) in group B. Univariate analysis showed that there was no statistically significant difference between the two groups in size of mass, pregnancy, hyperprolactinemia, bacterial cultures, erythema nodosum. Multivariate analysis showed that patients with purulent nipple discharge, skin lesion, bilateral disease and patients who need the combination of surgery and medication to achieve complete remission had higher risk of recurrence. CONCLUSIONS: We built a step-by-step systemic procedure for GM, and the recurrence rate was 14.1%. Prolactin level and microbiological results are important for the management of GM. Purulent nipple discharge, skin lesion, bilateral disease and patients who need the combination of surgery and medication to achieve complete remission are associated with GM recurrence. Prolonged maintenance therapy may secure a better prognosis.

ß-Catenin is reduced in membranes of human prolactinoma cells and it is inhibited by temozolomide in prolactin secreting tumor models.

INTRODUCTION: Prolactinomas are the most frequent pituitary tumor subtype. Despite most of them respond to medical treatment, a proportion are resistant and become a challenge in clinical management. Wnt/ß-Catenin pathway has been implicated in several cancers including pituitary tumors and other sellar region malignancies. Interestingly, Wnt/ß-Catenin inhibition augments the cytotoxicity of the chemotherapeutic agent Temozolomide (TMZ) in different cancers. TMZ is now being implemented as rescue therapy for aggressive pituitary adenoma treatment. However, the molecular mechanisms associated with TMZ action in pituitary tumors remain unclear. OBJECTIVES: Our aims in the present study were to evaluate differential ß-Catenin expression in human resistant prolactinomas and Wnt/ß-Catenin signaling activation and involvement in Prolactin (PRL) secreting experimental models treated with TMZ. RESULTS: We first evaluated by immunohistochemistry ß-Catenin localization in human resistant prolactinomas in which we demonstrated reduced membrane ß-Catenin in prolactinoma cells compared to normal pituitaries, independently of the Ki-67 proliferation indexes. In turn, in vivo 15 mg/kg of orally administered TMZ markedly reduced PRL production and increased prolactinoma cell apoptosis in mice bearing xenografted prolactinomas. Intratumoral ß-Catenin strongly correlated with Prl and Cyclin D1, and importantly, TMZ downregulated both ß-Catenin and Cyclin D1, supporting their significance in prolactinoma growth and as candidates of therapeutic targets. When tested in vitro, TMZ directly reduced MMQ cell viability, increased apoptosis and produced G2/M cell cycle arrest. Remarkably, ß-Catenin activation and VEGF secretion were inhibited by TMZ in vitro. CONCLUSIONS: We concluded that dopamine resistant prolactinomas undergo a ß-Catenin relocalization in relation to normal pituitaries and that TMZ restrains experimental prolactinoma tumorigenicity by reducing PRL production and ß-Catenin activation. Together, our findings contribute to the understanding of Wnt/ß-Catenin implication in prolactinoma maintenance and TMZ therapy, opening the opportunity of new treatment strategies for aggressive and resistant pituitary tumors.

Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. METHODS: This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI). RESULTS: The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037). CONCLUSIONS: Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

An aggressive lactotroph pituitary tumor in a young male: A pituitary carcinoma without metastasis.

This case report concerns a 31-year-old male with an aggressive pituitary tumor who presented initially with bitemporal hemianopsia and slightly elevated prolactin. On magnetic resonance imaging of the brain, there was a sellar mass with parasellar invasion to the lateral aspects of the internal carotid arteries, compressing the optic chiasm. On histopathological analysis, the diagnosis was made of a densely granulated lactotroph pituitary tumor with a Ki67 proliferation rate of 15%, a mitotic count of 6/10 high-power fields, and p53 positivity. Based on these features, the tumor was classified as a grade 2b tumor according to the Trouillas classification, and a more aggressive behavior of the tumor could be expected. In order to anticipate a future need for alternative drug treatments, the following analyses were undertaken: MGMT methylation (present) as well as the expression of estrogen receptor (negative), programmed-death ligand 1 (60 - 70% positive tumor cells), vascular endothelial growth factor-A and somatostatin receptor 2 (both positive). There was regrowth of residual tumor tissue, and the treatment consisted thus far of repeat surgery, cabergoline, pasireotide, and radiotherapy. Chemotherapy with temozolomide could not yet be initiated due to a concurrent infertility treatment. This case is unique because the tumor displays atypical characteristics, both in terms of morphology and behavior. It also illustrates how pathologists can play an important role in determining the diagnosis, prognosis, and possibilities for targeted therapy.