Visual morbidity in macroprolactinoma: A retrospective cohort study.

OBJECTIVE: The management of visual field damage in patients with macroprolactinomas is a major therapeutic challenge. We aimed to study the visual morbidity associated with macroprolactinoma and its outcomes following medical and surgical treatment. We aimed to identify predictors of visual recovery. METHODS: We retrospectively reviewed patient's data including clinical presentation, serial pituitary magnetic resonance imaging, laboratory tests, visual symptoms and neuro-ophthalmologic examination, visual field tests and optical coherence tomography tests. The main outcome was complete visual field recovery. Descriptive analyses were conducted. Predictors of visual recovery were investigated. PATIENTS: The study cohort included 150 patients with macroprolactinoma [median follow-up, 6.0 years (interquartile range (IQR) 2.9-10.6)]. RESULTS: At diagnosis, visual field defects were evident in 40 patients (26.7%). At the end of follow-up, 24 out of 39 available visual field tests (61.5%) exhibited complete recovery. Patients that achieved complete visual recovery had smaller macroadenomas at diagnosis [30.5 mm (15.0-80.0) vs. 42.0 mm (30.0-85.0), p < .01], lower baseline serum prolactin levels [1414 mcg/L (489-3586) vs. 4119 mcg/L (2715-6315), p < .01], lower rates of central hypogonadism (78.3% vs. 93.3%, p = .05) and central hypothyroidism (20.8% vs. 53.3%, p = .04), lower rates of compressive optic neuropathy (35.3% vs. 87.5%, p = .02) and a better visual acuity (better than 6/8 in both eyes, 93.7% vs. 28.6%, p < .01). CONCLUSIONS: In our cohort of 150 patients with macroprolactinoma, 40 patients (26.7%) presented with visual field defects, of which 61.5% achieved complete visual recovery with treatment. Patients that achieved complete visual recovery presented with smaller macroadenomas, lower serum prolactin levels, lower rates of central hypogonadism and central hypothyroidism, lower rates of compressive optic neuropathy and better visual acuity.

Curcumin affects autophagy of prolactinoma cells by upregulating miR-206 to exert antitumor effects.

We explored the effects of curcumin on the aberrant biological behaviors of prolactinoma cells and the downstream pathways through which curcumin exerts its antitumor effects. We used quantitative reverse transcription-polymerase chain reaction assays to measure miR-206 expression levels in peripheral blood samples from patients with prolactinoma before and after curcumin treatment. We also investigated the proliferation level, viability, and invasion ability of groups of cells treated with different concentrations of curcumin using 3-(4,5)-dimethylthiahiazo (-z-y1)-3-di-phenytetrazoliumromide (MTT) assays, cell cloning assays, and Transwell assays, respectively. Furthermore, we determined the levels of autophagy-related proteins and protein kinase B/mammalian target of the rapamycin (Akt/mTOR) signaling pathway-related proteins in each group of treated cells by western blot. Curcumin treatment upregulated miR-206 expression levels in the peripheral blood of patients with prolactinoma and in GH3 cells. Knockdown of miR-206 expression enhanced the proliferation and invasive ability of GH3 cells, while curcumin treatment effectively inhibited the aberrant biological behavior of GH3 cells enhanced by miR-206 knockdown. miR-206 knockdown also activated the Akt/mTOR signaling pathway and inhibited autophagy in GH3 cells, and these changes were effectively reversed by curcumin treatment. Thus, curcumin inhibited the Akt/mTOR signaling pathway and promoted cell autophagy by miR-206 upregulation, resulting in antitumor effects that inhibited prolactinoma cell proliferation and invasion.

Paradoxical effect of dopamine-agonists on IGF-1 in patients with prolactinoma: the role of weight.

PURPOSE: An increase of IGF-1 has been reported during therapy with dopamine agonists (DA) for prolactinomas; in such cases a correct diagnosis is pivotal to avoid an unnecessary reduction or withdrawal of DA, which are needed to maintain normal prolactin levels. This study was aimed to measure IGF-1 levels, at baseline and during follow-up, in a cohort of patients with prolactinoma, treated with cabergoline, stratified by body mass index. METHODS: We retrospectively enrolled 35 patients (15 F/20 M; age m ± SD, years: 43.4 ± 13.7) with prolactinoma (21 microadenomas and 14 macroadenomas) who were followed-up at the Endocrinology Unit, in Siena, and with available pituitary hormone assessment at baseline and during follow-up (m ± SD, years: 2.74 ± 0.55). RESULTS: IGF-1 increased in the whole cohort, but remaining within normal range, except two patients, in whom acromegaly was ruled out with oral glucose tolerance test. After dividing patients by weight, this trend was confirmed only in subjects with overweight and obesity (OV/OB) (p = 0.04). Interestingly, the reduction of prolactin levels was significantly greater in the OV/OB compared to normal-weight patients (median decrease of 97.5% versus 88.2%, p = 0.04). CONCLUSIONS: Since DA and normalization of prolactin are known to improve insulin sensitivity, we speculated they have favored the increase of IGF-1 in OV/OB. Our results should be confirmed and the hypothesis proven by further studies.

Network pharmacology analysis and molecular mechanism of paeoniflorin and its metabolite in prolactinoma cells.

Prolactinoma was the most common functional pituitary neuroendocrine tumor tissue type, which was caused by excessive proliferation of pituitary prolactin (PRL) cells. Drug therapy of dopamine receptor agonists was generally considered as the prior treatment for prolactinoma patients. However, there were still prolactinoma patients who were resistant to dopamine agonists. Studies have been reported that paeoniflorin can inhibit the secretion of PRL in prolactinoma cells lacking dopamine D2 receptor (D2R) expression, and paeoniflorin can be metabolized into albiflorin by intestinal flora in rats. The effect of albiflorin on prolactinoma has not been reported yet. In this study, network pharmacology was used to analyze the mechanism of paeoniflorin and its metabolite albiflorin as multi-target therapy for prolactinoma, and the experimental verification was carried out. In order to clarify the complex relationship among paeoniflorin, albiflorin and prolactinoma, we constructed a component-target-disease network, and further constructed interaction network, MMP9, EGFR, FGF2, FGFR1 and LGALS3 were screened as the core targets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that paeoniflorin and albiflorin may be involved in various pathways in the treatment of prolactinoma, included relaxin signaling pathway and PI3K-Akt signaling pathway. Molecular docking analysis showed that paeoniflorin and albiflorin had good binding activity with MMP9. Western blotting results showed that paeoniflorin and albiflorin could significantly reduce the expression of MMP9, and ELISA results showed that paeoniflorin and albiflorin could significantly reduce the concentration of PRL in GH3 cells, and the reduce degree of albiflorin was stronger than paeoniflorin at 50 µM, which indicated that albiflorin might be a potential drug to treat prolactinoma, which can regulate prolactinoma through MMP9 and reduce the concentration of PRL. Our study provided a new therapeutic strategy for prolactinoma.

Prolactin-secreting tumors, dopamine agonists and pregnancy: a longitudinal experience of a tertiary neuroendocrine center.

PURPOSE: Prolactin (PRL)-secreting tumours are associated with infertility and can be reverted by dopamine agonist (DA) therapy. The suspension of DA is recommended once pregnancy is established, as all DAs cross the placenta. The aim of the study was to evaluate the rate of maternal-foetal complications in women treated with cabergoline (CAB) or bromocriptine (BRM) for prolactinoma during gestation and the effect of pregnancy on prolactinoma progression. METHODS: This was a retrospective observational study involving 43 women affected by prolactinoma who became pregnant during therapy with CAB or BRM for a total of 58 pregnancies. For each patient, medical records were analysed by integrating the data with outpatient or telephone interview. RESULTS: At the time of conception, 18 women were in the BRM group, while 40 were in CAB group. No differences were found in obstetric or neonatal outcomes between the two groups. There was a significant difference (p = 0.046) in child complications reported in maternal interview found exclusively in the CAB group. No further confounding factors were detected. Disease remission rate after the first pregnancy was 42.9% and the main predictor was a lower PRL nadir before pregnancy (p = 0.023). No difference was detected between the two groups in terms of tumor remission. Breastfeeding did not modify the outcome. CONCLUSION: Foetal exposure to DAs during the first weeks of embryogenesis is not associated with a greater risk of complications. The transient and mild developmental disorders recorded resolved spontaneously and the prevalence was substantially overlapping with that observed in the general population.

Recovery from hypogonadism in men with prolactinoma treated with dopamine agonists.

PURPOSE: In men with prolactinoma treated with dopamine agonists (DA), the extent, timeline, and predictive factors of gonadotropic axis recovery are still unclear. METHODS: We analyzed data of 97 men with a prolactinoma treated with DA (77/97 macroprolactinomas). We excluded patients with primary hypogonadism, surgery < 12 months after DA initiation, and patients with tumors < 5 mm or prolactin < 45 µg/l at diagnosis. RESULTS: Among the 97 patients, 12 had normal total testosterone (NT group) and 85 had low testosterone at diagnosis (LT group). In the NT group, testosterone rose from a mean of 13.5 nmol/l to 17.1nmol/l at 6 months (n = 11; p < 0.05) then remained stable at 12 months (n = 8). In the LT group, testosterone rose from a mean of 5.2 nmol/l to 9.6 nmol/l at 6 months (n = 66; p < 0.001) and further to 13.1nmol/l at 12 months (n = 40; p < 0.001) then remained stable. Recovery from hypogonadism occurred in 43%, 50%, and 54% of patients at 6, 12 and 24 months, respectively (61%, 69 and 69% if prolactin was normal). Factors independently associated with persistent hypogonadism at 12 months were at baseline the presence of visual field deficit and lower testosterone levels, while the most significant independent predictor of persistent hypogonadism at one year was a testosterone level < 7.4 nmol/l at 6 months, with 91% sensitivity and 94% specificity. CONCLUSION: Testosterone levels recover in a small majority of men with prolactinoma mostly during the first year of DA treatment. However, testosterone replacement could be considered earlier in patients with large and compressive tumors, and in whom testosterone remains below 7.4 nmol/l after 6 months of DA treatment.

Quality of life in Prolactinoma: A systematic review.

BACKGROUND: Prolactinomas are common tumours that significantly reduce quality-of-life (QOL) due to sellar mass effect, secondary hypogonadism, and the peripheral effects of prolactin. Understanding the factors that influence QOL would provide insights into therapeutic targets to optimise patient outcomes and improve wellbeing in prolactinoma. METHODS: A systematic review was performed in accordance with the PRISMA statement. Studies that reported patient QoL using validated metrics were included. Bias and methodological rigour were assessed using the MINORS criteria. RESULTS: A total of 18 studies were identified studies were available for review, comprising 877 patients. Most were small cross-sectional studies at high risk of bias. Prolactinoma exhibit worse QOL than healthy controls, particularly mental and psychosocial wellbeing. QOL is also worse than patients with non-functional adenomas, but better than those with Cushing's disease and acromegaly. QOL correlates with prolactin levels, and approaches population baseline with prolonged biochemical control. Dopamine agonists and surgery both improve overall QOL, however improvements are more rapid with surgery. CONCLUSION: Poor quality of life in prolactinoma is multifactorial, related to biochemical control, side effects of therapy, and sellar mass effect. Targeting persistent symptoms, reducing healthcare costs, and reducing side-effects of therapy are avenues to improving QOL in patients with prolactinoma.

Impulse control disorders in patients with dopamine agonist-treated pituitary adenomas: a cross-sectional multicenter study.

BACKGROUND: Impulse control disorders (ICDs) have been described as underrecognized side effects of dopamine agonists (DAs) in neurological disorders but are not sufficiently understood in endocrine conditions. OBJECTIVE: To identify the prevalence of DAs induced ICDs and determine potential risk factors related to these disorders in patients with prolactinoma and non-function pituitary adenomas (NFPAs). METHODS: This is a cross-sectional multicenter study involving 200 patients with prolactinoma and NFPAs, who received follow-ups in tertiary referral centers. DA-induced ICDs were assessed using ICD questionnaires modified from prior studies. RESULT: At least one ICD was reported by 52% of participants, among whom 28.5% mentioned compulsive shopping, 24.5% punding, and 24.5% hypersexuality. Furthermore, 33% of the patients reported the presence of one type of ICD behavior, while 12% specified two and 7% had three types of such behavior. The multivariable logistic regression showed that the significant risk factors of ICD were younger age (adjusted odds ratio [AOR]: 0.92, 95% confidence interval [CI]: 0.88-0.97, p 0.001), being single (AOR: 0.15, 95%CI: 0.03-0.84, p 0.03), and a positive history of psychiatric illness (AOR: 7.67, 95% CI: 1.37-42.97, p 0.021). CONCLUSION: ICDs with a broad range of psychiatric symptoms are common in individuals with DA-treated prolactinoma and NFPAs. Endocrinologists should be aware of this potential side effect, particularly in patients with a personal history of psychiatric disorder.

Pituitary apoplexy: a comprehensive analysis of 93 cases across functioning and non-functioning pituitary adenomas from a single-center.

INTRODUCTION: Pituitary apoplexy (PA) is a rare clinical syndrome due to acute/subacute pituitary hemorrhage and/or infarction; data on PA in functioning pituitary adenoma (FPA) is scarce. METHODS: A retrospective record-review of details of PA in non-functioning (NFPA) and FPA managed at tertiary endocrine center. RESULTS: 93 patients [56 males; 33.3% FPA: 5 acromegaly, 14 prolactinoma, and 12 Cushing's Disease (CD)] diagnosed with PA were included. Median age was 40 years, with younger age of presentation in FPA. Type A (acute) [49.5%] and headache (78.5%) were the commonest presentations, with PA being the initial manifestation in 98.4% of NFPA. Median (range) Pituitary Apoplexy Score (PAS) was 2 (0-8). Median tumor diameter was 2.5 cm, with larger tumors in FPA (3.2 cm vs. 2.3 cm). 29 (46.7%) NFPA-PA and 14 (45.2%) FPA-PA patients [71% prolactinoma, 33% in CD, and none in acromegaly] were conservatively managed. In the NFPA cohort, those managed surgically had significantly higher PAS (4 vs. 1) and larger tumor size (2.6 vs. 1.8 cm); however, both arms had comparable recovery of neuro-visual, radiological, and hormonal outcomes. In FPA cohort, CD and acromegaly required definitive treatment, whereas prolactinomas were effectively managed (clinical and biochemical recovery) with oral cabergoline and glucocorticoids. Matching PAS cohorts (to overcome allocation bias for management approach) in macroadenomas (excluding prolactinoma) showed comparable neuro-deficit and hormonal recovery between surgical and conservative approaches. CONCLUSION: PA in FPA has distinct features and management issues. Carefully selected patients (PAS guided) in NFPA with PA for conservative management have comparable outcomes to surgery.

Clinical use of [18F]fluoro-ethyl-L-tyrosine PET co-registered with MRI for localizing prolactinoma remnants.

PURPOSE: To assess the utility of [18F]fluoroethyl-L-tyrosine PET co-registered with magnetic resonance imaging ([18F]FET-PET/MRICR) in patients with difficult-to-localize prolactinoma to inform clinical decision-making and (surgical) treatment planning. METHODS: Retrospective cohort study of 17 consecutive patients with prolactinoma undergoing [18F]FET-PET/MRICR between October 2020 and September 2022 for either (1) additional information in case of difficult-to-visualize remnants after prior transsphenoidal surgery (TSS), or pharmacological treatment, or (2) radiological diagnosis in absence of a (clear) adenoma on diagnostic/post-treatment conventional MRI. RESULTS: [18F]FET-PET/MRICR identified a lesion in 14/17 patients, yet failed to identify active lesions in 2 patients with negative conventional MRI despite prolactin > 7.5 times upper limit of normal. [18F]FET-PET/MRICR results were inconclusive in 1 patient due to diffuse tracer uptake 10 weeks post-surgery. [18F]FET-PET/MRICR was completely concordant with a suspected lesion on conventional MRI in 10/17 patients, and partially concordant in 3/17 patients. New foci were identified in 4/17 patients. The [18F]FET-PET/MRICR conclusions influenced clinical shared decision-making in 15/17 patients, of whom 7 patients underwent TSS and 8 refrained from TSS. One patient underwent TSS despite negative [18F]FET-PET/MRICR, and one patient underwent additional imaging. Intraoperative findings corresponded with [18F]FET-PET/MRICR in 5/8 patients, and immunohistochemistry was positive in 5/8 patients. The treatment goal was achieved in 7/8 patients, and remission was achieved in 5/7 patients in whom total resection was considered feasible. CONCLUSION: [18F]FET-PET/MRICR can be of added value in the preoperative decision-making process for selected patients with difficult-to-localize prolactinoma (remnants), or patients lacking a substrate on conventional MRI.

Surveillance Imaging Strategies for Pituitary Adenomas: When, How Frequent, and When to Stop.

OBJECTIVE: To describe a practical approach of when and how often to perform imaging, and when to stop imaging pituitary adenomas (PAs). METHODS: A literature review was carried out and recommendations provided are derived largely from personal experience. RESULTS: Magnetic resonance imaging is the mainstay imaging modality of choice in the assessment, treatment planning, and follow-up of PAs. These adenomas are discovered incidentally during imaging for a variety of unrelated conditions, because of clinical symptoms related to mass effects on the adjacent structures, or during workup for functional alterations of the adenoma. Imaging is also used in the preoperative and postoperative phases of assessment of PAs, for surgical and radiotherapy planning, for postoperative surveillance to assess for adenoma stability and detection of adenoma recurrence, and for surveillance to monitor for adenoma growth in unoperated PAs. Currently, because there are no evidence-based consensus recommendations, the optimal strategy for surveillance imaging of PAs is not clearly established. Younger age, initial adenoma size, extrasellar extension, mass effect, cavernous sinus invasion, functional status, histopathologic characteristics, cost considerations, imaging accessibility, patient preference, and patient contraindications (eg, implanted metallic devices and patient claustrophobia) are all important factors that influence the strategy for surveillance imaging. CONCLUSIONS: This review provides a practical approach of performing surveillance imaging strategies for PAs that should be individualized based on clinical presentation, history, adenoma morphology on imaging, and histopathologic characteristics.

Bromocriptine sensitivity in bromocriptine-induced drug-resistant prolactinomas is restored by inhibiting FGF19/FGFR4/PRL.

PURPOSE: At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological treatments, such as bromocriptine (BRC) and cabergoline (CAB), are important treatments for prolactinomas, but drug resistance is an urgent problem that needs to be addressed. Therefore, exploring the mechanism of drug resistance in prolactinomas is beneficial for clinical treatment. METHODS: In our research, BRC-induced drug-resistant cells were established. Previous RNA sequencing data and an online database were used for preliminary screening of resistance-related genes. Cell survival was determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence and Co-immunoprecipitation (Co-IP) were used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination was evaluated in drug-resistant cells and xenograft tumors in nude mice. RESULTS: Consistent with the preliminary results of RNA sequencing and database screening, fibroblast growth factor 19 (FGF19) expression was elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibited increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. After confirming that FGF19 binds to FGFR4 in prolactinoma cells, we found that FGF19/FGFR4 regulated prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. Regarding the effect of targeting FGF19/FGFR4 on BRC efficacy, FISO and BRC synergistically inhibited the growth of tumor cells, promoted apoptosis and reduced PRL levels. CONCLUSION: Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.

Investigating the relationship between cognitive impairment and brain white matter tracts using diffusion tensor imaging in patients with prolactinoma.

BACKGROUND: Cognitive impairment is known to occur in patients with prolactinoma, but the underlying mechanism is unclear. OBJECTIVE: To evaluate cognitive function in patients with prolactinoma and to investigate the basis of possible cognitive impairment in brain white matter changes using diffusion tensor imaging (DTI). METHODS: 37 consecutive patients with prolactinoma and 37 healthy controls of similar age, sex, and education were enrolled in the study. Hormone levels were determined in all participants, comprehensive neuropsychological testing was performed, and DTI was used to reconstruct and evaluate white matter tracts. RESULTS: In patients with prolactinoma, short- and long-term visual and verbal memory, attention, concentration, and executive and language functions were impaired compared to the healthy group. When comparing the DTI results, lower fractional anisotropy (FA) values were found in the patients' right uncinate fasciculus (R-UF), indicating neuronal damage. After applying the Bonferroni correction, the two groups had no significant difference in 42 tracts (p > 0.0012 for all). A positive correlation was found between poor FA scores on the R-UF and low scores on long-term memory, category and letter fluency tests. In addition, patients with hypoprolactinemia had the worst short-term memory scores, while normoprolactinemia had the best scores. Also, the poorer R-UF FA values were found in the patients with hypoprolactinemia and the highest in those with normoprolactinemia. CONCLUSION: This study is the first to investigate reasons for cognitive dysfunction in patients with prolactinoma by DTI. No significant structural changes were found in brain tracts of patients with prolactinoma. Still, there may be a link between potential damage in the R-UF and cognitive dysfunction, and further research is needed. In addition, the results showed that the development of hypoprolactinemia is associated with cognitive dysfunction and emphasized that overtreatment should be avoided.

Nonalcoholic Fatty Liver Disease, Bone and Muscle Quality in Prolactinoma: A Pilot Study.

OBJECTIVE: Hyperprolactinemia has negative impacts on metabolism and musculoskeletal health. In this study, individuals with active prolactinoma were evaluated for nonalcoholic fatty liver disease (NAFLD) and musculoskeletal health, which are underemphasized in the literature. METHODS: Twelve active prolactinoma patients and twelve healthy controls matched by age, gender, and BMI were included. Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) was used to evaluate hepatic steatosis and magnetic resonance elastography (MRE) to evaluate liver stiffness measurement (LSM). Abdominal muscle mass, and vertebral MRI-PDFF was also evaluated with MRI. Body compositions were evaluated by dual energy X-ray absorptiometry (DXA). The skeletal muscle quality (SMQ) was classified as normal, low and weak by using "handgrip strength/appendicular skeletal muscle mass (HGS/ASM)" ratio based on the cut-off values previously stated in the literature. RESULTS: Prolactin, HbA1c and CRP levels were higher in prolactinoma patients (p<0.001, p=0.033 and p=0.035, respectively). The median MRI-PDFF and MRE-LSM were 3.0% (2.01-15.20) and 2.22 kPa (2.0-2.5) in the prolactinoma group and 2.5% (1.65-10.00) and 2.19 kPa (1.92-2.54) in the control group, respectively and similiar between groups. In prolactinoma patients, liver MRI-PDFF showed a positive and strong correlation with the duration of disease and traditional risk factors for NAFLD. Total, vertebral and pelvic bone mineral density was similar between groups, while vertebral MRI-PDFF tended to be higher in prolactinoma patients (p=0.075). Muscle mass and strength parameters were similar between groups, but HGS/ASM tended to be higher in prolactinoma patients (p=0.057). Muscle mass was low in 33.3% of prolactinoma patients and 66.6 of controls. According to SMQ, all prolactinoma patients had normal SMQ, whereas 66.6% of the controls had normal SMQ. CONCLUSION: Prolactinoma patients demonstrated similar liver MRI-PDFF and MRE-LSM to controls despite their impaired metabolic profile and lower gonadal hormone levels. Hyperprolactinemia may improve muscle quality in prolactinoma patients despite hypogonadism.

A multicenter study of clinical outcomes and volumetric trends in suspected microprolactinomas.

The diagnosis of pituitary microprolactinomas is often obscured by relatively low levels of elevated prolactin compared to macroprolactinomas. This may lead to varying patterns of medical therapy versus observation. We sought to correlate prolactin levels in suspected microprolactinomas with tumor volumes and clinical outcomes. This was a multicenter retrospective study of patients with pituitary microadenomas with baseline prolactin levels > 18ng/ml for males and > 30ng/ml for females. A linear-mixed model was used to depict changes in tumor volume over time. There were 65 patients with a mean tumor volume of 95.9mm3 and mean prolactin level of 59.4ng/ml. There were significantly higher prolactin levels in patients with tumors above the mean volume versus below (74.0 versus 53.4ng/ml, p = 0.027). 26 patients were observed, 31 were treated with anti-dopaminergic therapy, and 8 had surgery. There were significantly greater baseline prolactin levels for patients who were treated surgically (mean 86.4ng/ml) than those treated medically (mean 61.7 g/ml) or observed (mean 48.5ng/ml) (p = 0.02). Among the 26 patients who were surveilled, 13 patients demonstrated spontaneous tumor shrinkage, 12 remained stable, and 1 patient's tumor grew but was lost to follow-up. Linear mixed modeling demonstrated a statistically significant rate of tumor shrinkage over time of 3.67mm3/year (p = 0.03). When analyzing patients who were observed versus those requiring surgery after initially being surveilled, there were significantly greater baseline PRL/volume ratios in surgical patients versus those observed (8.1 ng/ml/mm3 versus 2.4 ng/ml/mm3, p = 0.025). Suspected microprolactinomas may demonstrate more convincingly elevated prolactin levels when measuring over 95.9mm3. Tumors with baseline prolactin levels over 50ng/ml may be more inclined to undergo medical treatment. In tumors with levels below 50ng/ml, it may be reasonable to undergo surveillance as these tumors tend to spontaneously shrink over time. In tumors that are surveilled, an elevated baseline PRL/volume ratio of > 8 ng/ml/mm3 may be indicate serial tumor growth that may necessitate medical and/or surgical intervention.

Characteristics and outcomes of men with erectile dysfunction as the presenting symptom due to a lactotroph adenoma.

PURPOSE: Erectile dysfunction (ED) is frequently underreported in men suffering from prolactinomas and can be challenging to manage. Both dopamine agonists (DAs) and transsphenoidal surgery (TSS) correct hyperprolactinemia and restore gonadal function. However, there is scarce data regarding their effectiveness in correcting ED over the long term. METHODS: This study is a retrospective single-center comparative cohort study analyzing men diagnosed with prolactinomas, both with and without confirmed erectile dysfunction (ED) at diagnosis. Independent risk factors for persistent ED over the long term were examined using multivariate logistic regression. RESULTS: Among the 39 men with lactotroph adenomas, ED was one of the presenting symptoms in 22 (56%). The mean age at diagnosis was 45 ± 12 years. Surgery was the primary treatment in 6 (27%) ED patients and 8 (47%) non-ED patients. After a mean follow-up of 74 ± 48 months, remission from hyperprolactinemia was achieved in the majority (76%) of men: 71% in the non-ED cohort and 81% in the ED group (p = 0.70), regardless of the primary treatment strategy (surgical 84% versus medical 72%, p = 0.46). Long-term remission of ED was noted in 16 (73%) patients. Interestingly, high baseline BMI levels emerged as potential risk factors for persistent ED over the long term (OR 1.4, 95%CI 1.0-1.9; p = 0.04), while neither the initial adenoma size nor the primary treatment strategy (i.e., TSS vs. DAs) reached statistical significance. CONCLUSIONS: Correcting hyperprolactinemia and its associated hypogonadism significantly improves ED in the majority of men with prolactinomas over the long term, regardless of the primary treatment strategy employed. In addition to addressing endocrine deficiencies, the early initiation of weight control programs may be considered for men with lactotroph adenomas and ED. Although our study suggests an association between BMI and the risk of persistent ED, further research is needed to establish any causal relationships.

Preoperative treatment with dopamine agonist therapy influences surgical outcome in prolactinoma: a retrospective single-center on 159 patients.

INTRODUCTION: Prolactinoma account to the most common pituitary adenomas and current therapy regime constitutes of dopamine agonist therapy (DA) and surgery in selected cases [17]. Due to tumor fibrosis induced by previous DA therapy, surgical removal can be challenging though. Therefore, this study investigates how preoperative DA usage influences perioperative treatment and surgical outcome in prolactinoma and aims to ascertain whether a specific subgroup of prolactinoma patients could derive greater benefit from exclusive surgical intervention. METHODS: We retrospectively analyzed n = 159 surgically treated and histologically confirmed prolactinomas in the sella region from 2013-2022 in our institution. Clinical, radiological and surgical features were analyzed. Univariate and multivariate analyses were performed. RESULTS: Out of total of 159 prolactinoma patients, 83.6% received previous treatment with DA followed by surgery, while only 16.4% received exclusive surgery. Both groups presented similar initial tumor volumes (1.9cm3 vs. 1.5cm3, p = 0.59) and equal preoperative prolactin levels (PRL) (199.7 µg/l vs. 191.0 µg/l, p = 0.44). Surgical procedures took significantly longer when patients received prior DA treatment (79 min. vs. 70 min., p = 0.0479). Six months after surgery, pretreated patients revealed significantly higher PRL compared to non-treated (107 g/l vs. 8.64 µg/, p = 0.0009). Additionally, untreated microprolactinoma presented a remission of 100%, whereas pretreated exhibited a remission rate of 88.75%. CONCLUSION: The current study demonstrates that prior DA treatment is associated with significantly longer surgeries, higher recurrence rates and lower rates of normalization of PRL levels after surgery, particularly in microprolactinomas and support the latest recommendations of the Pituitary Society's Consensus Statement 2023, which favors the option of surgery alone as first-line therapy for microprolactinomas.

An Overview of Cardiovascular Risk in Pituitary Disorders.

Cardiovascular comorbidities owing to hormonal excess or deficiency are the main cause of mortality in patients with pituitary disorders. In patients with Cushing's Disease, there is an increased prevalence of cardiovascular diseases and/or risk factors including visceral obesity, insulin resistance, atherosclerosis, arterial hypertension, dyslipidaemia, hypercoagulability as well as structural and functional changes in the heart, like cardiac hypertrophy and left ventricle (LV) dysfunction. Notably, these demonstrate limited reversibility even after remission. Furthermore, patients with acromegaly may manifest insulin resistance but also structural and functional heart changes, also known as "acromegalic cardiomyopathy". Patients with prolactinomas demonstrate an aggravation of metabolic parameters, obesity, dysregulation of glucose and lipid metabolism as well as endothelial dysfunction. Hypopituitarism and conventional hormonal replacement therapy may also contribute to an unhealthy metabolic status, which promotes atherosclerosis and may lead to premature mortality. This review discusses the literature on cardiovascular risk in patients with pituitary disorders to increase physician awareness regarding this aspect of management in patients with pituitary disorders.

Feasibility of Early Surgical Treatment for Adolescent Patients with Prolactinoma: A Case Report and Literature Review.

Background and Objectives: Prolactinomas are the most common pituitary adenomas, comprising 30-50% of such tumors. These adenomas cause hyperprolactinemia, leading to decreased fertility, reduced energy and libido, and galactorrhea. Diagnosing and treating prolactinomas in adolescents present unique challenges, as symptoms may be confused with age-related developmental variations. This case report explores the outcomes of early surgical intervention in an adolescent with a prolactinoma. Materials and Methods: A 14-year-old female presented delayed menarche and absent pubertal development. Initial evaluation revealed hyperprolactinemia (228.37 ng/mL) with normal estradiol levels. Initial management through observation was adopted, but persistent amenorrhea and severe headaches prompted further investigation. Magnetic resonance imaging revealed a cystic pituitary mass with apoplexy. Due to concerns regarding delayed puberty and the need for rapid normalization of prolactin levels, the patient underwent transsphenoidal surgery. Results: After operation, prolactin levels normalized, menarche occurred within three months, and secondary sexual characteristics developed within eight months. Pathology confirmed a pituitary adenoma with a high Ki-67 index (15%). Conclusions: Early surgical intervention for prolactinomas in adolescents can achieve successful biochemical remission and resolution of endocrine symptoms. Adolescents, particularly those with a high Ki-67 index and potential resistance to dopamine agonists, may benefit from prompt surgical management, resulting in improved clinical outcomes and complete tumor resection.

THE PLACE OF SURGERY IN THE MANAGEMENT OF PROLACTIN SECRETING ADENOMAS.

Introduction: Surgery has lost a lot of ground as the main therapy of most prolactinomas as it is clear from the current guidelines in most prolactin secreting adenomas, even in the setting of optic compression. However, we believe that surgery is still an important part in the treatment of this type of adenomas. This study is aimed to define what is the role of pituitary surgery in the current setup of prolactinoma management. Material and methods: In this retrospective, single-center study we analyzed 12 consecutive patients who underwent primary endoscopic transsphenoidal surgery for prolactinomas, between 2013 and 2022. Surgical indication, previous dopamine agonist (DA) treatment, remission rates, surgical complications, pituitary function and imagistic appearance are presented. Results: Of the 12 patients included, 4 had giant PRL and 8 macroadenomas, while 9 of them had previous DA treatment. The main surgical indication was pituitary apoplexy in 5 patients followed by CSF leak after DA treatment, 3 cases, and DA resistance in 3 cases. The main surgical complications were transitory diabetes insipidus in 7 cases. Normalization of prolactin levels was achieved in 2 patients. Conclusions: Surgical intervention should be strongly considered in all patients with neurologic symptoms referable to the lesion, resistance to medical therapy, other treatment failure or with complications after DA treatment. The endoscopic endonasal surgery offers good surgical outcomes with low rates of surgical complications and should remain an open option for specific cases.