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This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.This Consensus Statement, which is endorsed by the Pituitary Society, offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas.

Abstract Context Prolactinoma, the most common subtype of pituitary adenoma, is rare in children and adolescents. Clinical presentation and treatment outcomes of prolactinomas in this population have been evaluated insufficiently. Objective To summarize the clinical features, both medication and surgical outcomes of prolactinomas in children and adolescents in a large retrospective cohort from China. Methods A cohort of patients with prolactinomas aged ≤20 years at diagnosis between 2012 and 2021 in Peking Union Medical College Hospital were retrospectively analyzed. Results The cohort comprised 170 patients (115 females and 55 males, median age 16.6 years), with 20.0% (23/115) girls without menarche and 33.3% (18/54) boys in prepuberty. The median maximal diameter was 15.0 mm (61.2% macroadenomas and 4.6% giant adenomas), and the median baseline prolactin (PRL) level was 211.0 ng/mL. Larger sizes and higher PRL levels were observed in girls without menarche at diagnosis and in boys. Most girls presented with menstrual disturbance (86.7%), and boys were frequently bothered by headaches (42.6%), reduced height velocities (25.9%), and delayed puberty (18.2%). Dopamine agonists (DAs) were used as first-line treatment in 133 patients, and the resistance rate was 22.5% (25/111), independently associated with maximal tumor diameters (P = .035). Surgery was performed in 76 patients. Long-term surgical remission rates were 32.9% (25/76) overall, negatively associated with cavernous sinus invasion independently (P = .025), 59.4% (19/32) in noninvasive tumors (64.0% in 25 noninvasive macroadenomas), and 5.0% (1/20) in invasive tumors. Conclusion Pediatric prolactinomas exhibited more severe clinical characteristics in boys and in patients diagnosed during earlier stages of pubertal developments. Given the overall efficacy of PRL normalization by medication and considerable surgical remission rate in noninvasive tumors, DAs remain the first-line recommendation for prolactinomas in children and adolescents, while surgery might be viable for noninvasive tumors.

Abstract Objective To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics. Methods A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining. Results Tenacious tumor consistency (27.8% vs 9.8%, P < .001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P = .014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P = .043), and more surgical morbidities (19.4% vs 8.9%; P = .034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P = .001). Correlation analysis revealed a close correlation between collagen volume fraction and the cumulative dose of bromocriptine (BRC) in macroadenomas (r = 0.438, P < .001). Regarding endocrine outcomes, DA-pretreated microadenomas showed a lower proportion of initial remission compared with patients who underwent initial surgery (86.7% vs 100%, P = .047). Conclusion This study described increased surgical difficulty and inferior endocrine outcomes associated with tumor fibrosis secondary to presurgical BRC treatment in prolactinomas. Neurosurgeons should note that presurgical BRC treatment may render subsequent surgery more challenging.

Key Words: prolactinoma, fibrosis, surgery, bromocriptine, dopamine agonist

Leflunomide’s anti-tumor effects have been investigated in various types of tumors; however, its impact on pituitary adenoma, particularly prolactinoma, is unclear. Hence, the current study evaluates the effects of leflunomide on prolactinoma cells in vitro and in vivo and elucidates the potential underlying mechanism(s). Cell Counting Kit-8 results revealed that leflunomide inhibits the proliferation of rat pituitary tumor cell lines (GH3 and MMQ) in a concentration-dependent manner in vitro. However, combination therapy of cabergoline and leflunomide exerted stronger inhibitory effects than cabergoline in MMQ cells in vitro and in vivo. Transcriptomics and gene ontology (GO) analyses identified genes significantly enriched in apoptotic processes and programmed cell death. Protein–Protein Interaction (PPI) networks defined the roles of hub genes (Mdm2, Cdkn1a, Plk2, and Ccng1) in leflunomide-induced cell death. GO and pathway enrichment analyses showed that the combination drug-specific differentially expressed genes were associated with inhibiting protein translation, but were active in gene expression processes. Hence, the anti-proliferative effects of leflunomide on prolactinoma cell lines may be mediated through programmed cell death pathways. Importantly, combining cabergoline with leflunomide effectively enhances the toxic effect of cabergoline, suggesting a potential therapeutic role for leflunomide in drug-resistant prolactinoma.

Abstract Context Data are limited regarding prevalence, predictors, and mechanisms of persistent hypogonadotropic hypogonadism (HH) in males with a macroprolactinoma who achieve normoprolactinemia on dopamine-agonist therapy. None of the previous studies provide cutoffs to predict the achievement of eugonadism. Objective The objective of this work is to evaluate the prevalence of persistent HH and its determinants in men with a macroprolactinoma who achieve normoprolactinemia on cabergoline monotherapy. Design and Setting This retrospective study with prospective cross-sectional evaluation took place at a tertiary health care center. Patients Study participants included men with a macroprolactinoma and baseline HH who achieved normoprolactinemia on cabergoline monotherapy. Main Outcome Measures Outcome measures of this study included the prevalence of persistent HH and its predictors. Results Thirty participants (age, 38.3 ± 10.1 years) with baseline tumor size of 4.08 ± 1.48 cm and median (interquartile range) prolactin of 2871 ng/mL (range, 1665-8425 ng/mL) were included. Eight of 30 participants achieved eugonadism after a median follow-up of 3 years. Patients with persistent HH had suppression of the luteinizing hormone (LH)-testosterone axis with sparing of other anterior pituitary hormonal axes, including follicle-stimulating hormone-inhibin B. Baseline prolactin (1674 vs 4120 ng/mL; P = .008) and maximal tumor diameter (2.55 ± 0.36 vs 4.64 ± 1.32 cm; P = .003) were lower in patients who achieved eugonadism. Baseline maximal tumor diameter less than or equal to 3.2 cm (sensitivity: 75%, specificity: 63.6%) and serum prolactin less than or equal to 2098 ng/mL (sensitivity: 87.5%, specificity: 77.3%) best predicted reversal of HH. Conclusion Recovery of the LH-testosterone axis occurred in 26.7% of men with a macroprolactinoma who achieved normoprolactinemia on cabergoline monotherapy. Higher baseline tumor size and serum prolactin predict persistent HH. Our data favor chronic functional modification of the hypothalamic-pituitary-gonadal axis over gonadotroph damage as the cause of persistent HH.

Abstract Purpose To describe the clinical presentation and treatment outcomes in a nationwide cohort of patients with giant prolactinomas. Methods Register-based study of patients with giant prolactinomas [serum prolactin (PRL) > 1000 µg/L, tumor diameter ≥40 mm] identified in the Swedish Pituitary Register 1991-2018. Results Eighty-four patients [mean age 47 (SD ±16) years, 89% men] were included in the study. At diagnosis, the median PRL was 6305 µg/L (range 1450-253 000), the median tumor diameter was 47 mm (range 40-85), 84% of the patients had hypogonadotropic hypogonadism, and 71% visual field defects. All patients were treated with a dopamine agonist (DA) at some point. Twenty-three (27%) received 1 or more additional therapies, including surgery (n = 19), radiotherapy (n = 6), other medical treatments (n = 4), and chemotherapy (n = 2). Ki-67 was ≥10% in 4/14 tumors. At the last follow-up [median 9 years (interquartile range (IQR) 4-15)], the median PRL was 12 µg/L (IQR 4-126), and the median tumor diameter was 22 mm (IQR 3-40). Normalized PRL was achieved in 55%, significant tumor reduction in 69%, and combined response (normalized PRL and significant tumor reduction) in 43%. In the primary DA-treated patients (n = 79), the reduction in PRL or tumor size after the first year predicted the combined response at the last follow-up (P < .001 and P = .012, respectively). Conclusion DAs effectively reduced PRL and tumor size, but approximately 1 patient out of 4 needed multimodal treatment. Our results suggest that the response to DA after 1 year is useful for identifying patients who need more careful monitoring and, in some cases, additional treatment.

Abstract Context Treatment of hyperprolactinemia with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. Objective This study examines the efficacy and tolerability of the nonergot DA ropinirole for the long-term treatment of hyperprolactinemia. Methods Twelve hyperprolactinemic women were treated with ropinirole in a 6-month, open-label, dose-escalation trial; 7 of the 12 continued treatment in an extension study for up to 17 months. Ropinirole doses were uptitrated to achieve normal prolactin (PRL) levels, restore menses, and eliminate galactorrhea. Results Two of the 12 participants were DA naive; 6 of 12 were ergot DA intolerant; and 1 of 12 had known ergot DA resistance. Baseline PRL levels were 126.2 ± 41.4 ng/mL (SEM). Ropinirole was uptitrated from 0.125 to 0.25 mg/h to a median total daily dose (TDD) of 2 mg/d (1-4 mg/d [interquartile range]). PRL normalization was achieved in 50% of the participants (5 with microadenomas and 1 with idiopathic hyperprolactinemia) at a median effective TDD of 1 mg/d. Of the patients achieving PRL normalization, 83% were ergot DA intolerant. A persistent partial biochemical response (PRL reduction >50% from baseline) was achieved in 17% of the participants. During treatment, menses resumed in 67% of amenorrheic patients; galactorrhea resolved in 67%. Mild adverse effects were reported in 92% of participants; however, ropinirole was not discontinued because of intolerance even among the 50% of individuals with a prior history of ergot DA intolerance and resultant medication discontinuation. Conclusion These data demonstrate the efficacy and tolerability of ropinirole for the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia and suggest ropinirole may represent a novel therapeutic alternative for treating hyperprolactinemic disorders in patients with ergot DA intolerance.

Abstract Purpose Withdrawal of dopamine agonist (DA) therapy in patients with prolactinoma who are controlled by a small dose of medication is recommended by several guidelines. So far, the likelihood of reaching withdrawal conditions based on baseline characteristics remains uncertain. Methods We retrospectively examined early clinical, radiological, or biochemical features that may predict the likelihood of reaching withdrawal conditions in prolactinoma patients. Data were obtained in a single academic medical center in the United States from patients seen between 2000 and 2018. Using multiple logistic regression, we compared patients who reached withdrawal conditions with those who did not. Results Of 213 patients, 78 (36.6%) reached withdrawal conditions after at least 2 years of DA treatment. Initial maximal tumor diameter was significantly smaller in those who reached withdrawal conditions than in those who did not. Percent prolactin change at the first check from initiation of DA therapy and parasellar invasiveness were predictors of reaching withdrawal conditions. With constant independent variables, there was a 7% increase in odds for reaching withdrawal conditions for every 1% decrease in percent prolactin change at first check after DA therapy start (P = 0.0000). Parasellar invasion decreased the odds of reaching withdrawal conditions by 84% (P = 0.0000). Conclusions DA remains a potential life-long treatment modality for most prolactinoma patients. Patients with parasellar invasiveness and low prolactin percent change from baseline to first prolactin check are more likely to require long-term treatment.