Aromatase inhibitors as a therapeutic strategy for male prolactinoma resistant to dopamine agonists: a retrospective cohort study and literature review.

PURPOSE: To assess the effect of letrozole, an aromatase inhibitor (AI), in patients with resistant prolactinoma that presented an increase in serum prolactin (PRL) levels during testosterone replacement therapy (TRT). METHODS: A retrospective cohort study in a single tertiary care center. From March 2012 to July 2023, 53 male patients over 18 years with prolactinoma were followed in our Neuroendocrine Unit. Of those, 90.6% presented macroadenomas, 41% of them were resistant to cabergoline and 25% presented persistent hypogonadism to whom TRT was indicated. Among them, five presented a significant increase in PRL levels and AI was initiated. All five patients had resistant prolactinomas. One of them was excluded due to tumor aggressiveness and concomitant use of temozolomide during AI therapy. RESULTS: Four patients were included in the analysis, with a mean age of 28.5 (± 7.5) years, median prolactin of 1060 (600 to 6700) ng/mL and median of the largest tumor diameter of 3.6 (1.5 to 5) cm at the time of prolactinoma diagnosis. On TRT, all presented an increase in serum PRL levels (231 to 396%), with a subsequent decrease (61 to 93%) after adding AI. During AI treatment for a median time of 60.5 (21 to 120) months, tumor shrinkage was observed in two cases (-8 and -3 mm in the maximum diameter) and tumor stability in the other two. No major side effects occurred and AI was well tolerated. CONCLUSION: AI might be an option for men with resistant prolactinoma who have an increase in PRL levels on TRT. Nevertheless, prospective randomized clinical trials are needed to ensure efficacy and security for this approach.

Determination of the thermodynamic potentials of metallic glasses and their relation to the defect structure.

We performed calorimetric and shear modulus measurements on four bulk metallic glasses upon heating up to the temperature of the complete crystallization as well as in the fully crystallized state. On the basis of calorimetric experiments, we calculated the excess thermodynamic potentials with respect to the crystalline state-the enthalpy ΔH, entropy ΔSand Gibbs free energy ΔΦ-as functions of temperature. Using high-frequency shear modulus measurements we show that calorimetric determination of ΔH, ΔSand ΔΦ is consistent with the calculation of these potentials within the framework of the interstitialcy theory (IT) within a 15% uncertainty in the worst case for all MGs under investigation. It is concluded that the physical origin of the excess thermodynamic potentials in MGs can be related to a system of interstitial-type defects frozen-in from the liquid state upon melt quenching as suggested by the IT. The estimates of the defect formation enthalpyHfand entropySfshow thatHfscales with the shear modulus whileSfis quite large (10kBto 20kB), in line with the basic assumptions of the IT.

A Brazilian multicentre study evaluating pregnancies induced by cabergoline in patients harboring prolactinomas.

OBJECTIVE: To evaluate the maternal-fetal outcomes of CAB-induced pregnancies in patients with prolactinoma in a large cohort. METHODS: The prevalence of tumor growth, miscarriage, preterm, low birth weight, congenital malformations and impairment in neuropsychological development in children among women treated with CAB were assessed in a Brazilian multicentre retrospective observational study, RESULTS: We included 194 women with a mean age of 31 (17-45) years, 43.6% presenting microadenomas and 56.4% macroadenomas, at prolactinoma diagnosis. In 233 pregnancies, CAB was withdrawn in 89%, after pregnancy confirmation. Symptoms related to tumor growth occurred in 25 cases, more frequently in macroadenomas. The overall miscarriage rate was 11%, although higher in the subgroup of patients with CAB maintainance after pregnancy confirmation (38% vs. 7.5%). Amongst the live-birth deliveries, preterm occurred in 12%, low birth weight in 6% and congenital malformations in 4.3%. Neuropsychological development impairment was reported in 7% of cases. CONCLUSIONS: Our findings confirm previous results of safety in maternal and fetal outcomes in CAB-induced pregnancies; nevertheless, CAB maintenance after pregnancy confirmation was associated with higher miscarriage rate; result that must be further confirmed.

Interstitial clustering in metallic systems as a source for the formation of the icosahedral matrix and defects in the glassy state.

The paper presents molecular dynamics and -statics simulations of a prototypical mono-atomic metallic system (aluminum) and its defects in the crystalline and glassy states. It is shown that there is a thermodynamic driving force for the association of dumbbell interstitials in the crystalline lattice into clusters consisting of different amounts of defects. Clusters containing seven interstitials constitute perfect icosahedra. Within the general framework of the interstitialcy theory, melting of simple metallic crystals is intrinsically related to a rapid increase of the concentration of dumbbell interstitials, which remain identifiable structural units in the liquid state. Then, the glass produced by rapid melt quenching contains interstitial-type defects. The idea of the present work is to argue that the major structural feature of many metallic glasses-icosahedral ordering-originates from the clustering of interstitial-type defects frozen-in upon melt quenching. Separate defects and their small clusters represent the defect part of the glassy structure.

Cabergoline and prolactinomas: lack of association between DRD2 polymorphisms and response to treatment.

BACKGROUND: About 80% of prolactinomas respond to dopamine agonists (DA) with hormonal normalization and tumor shrinkage. Mechanisms of DA resistance include reduction of dopamine receptor subtype 2 (DRD2) expression, short and long isoform ratio and post-receptor mechanisms. It was suggested that polymorphisms in the gene encoding dopamine receptor subtype 2 gene (DRD2) could be associated with variable effectiveness of cabergoline (CAB). OBJECTIVE: To assess the influence of DRD2 polymorphisms in responsiveness of CAB treatment in patients with prolactinoma. STUDY DESIGN AND PATIENTS: Cross-sectional retrospective case-control study analyzing the frequency of five DRD2 polymorphisms in 148 patients with prolactinoma and 349 healthy subjects. The association of genetic variants and clinical characteristics with CAB responsiveness was performed in 118 patients (mean age at diagnosis 29 years; range 11-61 years) with hormonal evaluation. Patients with prolactin (PRL) normalization were considered as responders. RESULTS: No association in genotypes and allele proportions was found comparing patients and controls. On pharmacogenetic study, 118 patients on CAB were included and 20% were non-responders. No association was found between clinical characteristics (gender, age, PRL level and tumor size at diagnosis) and polymorphisms of DRD2 with CAB responsiveness. Otherwise, there was association between polymorphisms rs1076560 (allele A) and rs1800497 (allele T) and the presence of macroadenomas. CONCLUSION: No correlation was found between DRD2 polymorphisms and CAB responsiveness in patients with prolactinoma. More data are necessary in order to assess the influence of DRD2 genotyping on DA treatment response.

Pituitary autoimmune disease: nuances in clinical presentation.

Pituitary autoimmune disease is considered an autoimmune organ-specific disorder, characterized by a pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be secondary to systemic diseases or infections. Primary pituitary hypophysitis is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous), necrotizing and IgG4 plasmacytic, according to the histological findings. Concerning lymphocytic hypophysitis (LH), it is characterized by lymphocytic infiltration and can be subclassified according to the affected area on: lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis and lymphocytic panhypophysitis. LH had always been considered a rare disease. Nevertheless, with improved imaging techniques, especially magnetic resonance imaging (MRI), LH diagnosis has been increased. This disease usually affects young women during pregnancy or postpartum period with headache, visual impairment, ACTH deficiency and a homogenous sellar mass with thickening of pituitary stalk in MRI. Definitive diagnosis depends on histopathological evaluation; nevertheless, a presumptive diagnosis could be done in a typical case. As no specific autoantigen was identified in LH, there is no antipituitary antibody (APA) method available for helping diagnosis. However, APA used in some centers for research could support an autoimmune origin for some hypopituitarism previously named as idiopathic, confirming nuances in clinical presentation of pituitary autoimmune disease. Therapeutic approach should be based on the grade of suspicious and clinical manifestations of LH.

Diagnosis and management of hyperprolactinemia: results of a Brazilian multicenter study with 1234 patients.

OBJECTIVE: The aim of the study was to evaluate clinical and laboratorial features of 1234 patients with different etiologies of hyperprolactinemia, as well as the response of 388 patients with prolactinomas to dopamine agonists. DESIGN, SETTING, AND PATIENTS: A total of 1234 hyperprolactinemic patients from 10 Brazilian endocrine centers were enrolled in this retrospective study. MAIN OUTCOME MEASURE: PRL measurement, thyroid function tests, and screening for macroprolactin were conducted. RESULTS: Patients were subdivided as follows: 56.2% had prolactinomas, 14.5% drug-induced hyperprolactinemia, 9.3% macroprolactinemia, 6.6% non-functioning pituitary adenomas, 6.3% primary hypothyroidism, 3.6% idiopathic hyperprolactinemia, and 3.2% acromegaly. Clinical manifestations were similar irrespective of the etiology of the hyperprolactinemia. The highest PRL levels were observed in patients with prolactinomas but there was a great overlap in PRL values between all groups. However, PRL>500 ng/ml allowed a clear distinction between prolactinomas and the other etiologies. Cabergoline (CAB) was more effective than bromocriptine (BCR) in normalizing PRL levels (81.9% vs 67.1%, p<0.0001) and in inducing significant tumor shrinkage and complete disappearance of tumor mass. Drug resistance was observed in 10% of patients treated with CAB and in 18.4% of those that used BCR (p=0.0006). Side-effects and intolerance were also more common in BCR treated patients. CONCLUSION: Prolactinomas, drug induced hyperprolactinemia, and macroprolactinemia were the 3 most common causes of hyperprolactinemia. Although PRL levels could not reliably define the etiology of hyperprolactinemia, PRL values >500 ng/ml were exclusively seen in patients with prolactinomas. CAB was significantly more effective than BCR in terms of prolactin normalization, tumor shrinkage, and tolerability.

Physico-chemical and biological characterizations of two human prolactin analogs exhibiting controversial bioactivity, synthesized in Chinese hamster ovary (CHO) cells.

The synthesis, purification and characterization of G129R-hPRL and S179D-hPRL, the two better-studied antagonists of human prolactin (hPRL), is described. Both of these have been expressed for the first time, in their authentic form, by a stable CHO cell line, at secretion levels of 7.7 and 4.3 microg/10(6) cells/day, respectively. Previous studies had shown that these hPRL analogs, when produced in bacterial cytoplasm, consistently contained misfolded forms and multimers according to the specific denaturation, refolding and purification conditions. These versions also have an N-terminal extra methionine. An extensive physico-chemical characterization was carried out after a practical two-step purification process and included SDS-PAGE and Western blotting analysis, matrix-assisted laser-desorption ionization time-of-flight mass spectral (MALDI-TOF-MS) analysis, high-performance size-exclusion chromatography (HPSEC) and reversed-phase high-performance liquid chromatography (RP-HPLC). This last technique revealed a considerable difference in hydrophobicity due to a single amino acid substitution, with S179D-hPRL less (t(RR) = 0.85 +/- 0.010) and G129R-hPRL more (t(RR) = 1.10 +/- 0.013) hydrophobic than hPRL, where t(RR) is the relative retention time. The biological characterization was based on further refinement of a sensitive proliferation assay using the pro-B murine cell line (Ba/F3) transfected with the long form hPRL receptor cDNA such that the minimal detectable dose was 0.04 ng of hPRL/mL, the Ba/F3-LLP assay. On the basis of this assay, the relative residual agonistic activity of these two products, determined against a hPRL international standard in four independent assays, was 53 x 10(-3) for S179D-hPRL and 70 x 10(-5) for G129R-hPRL. We believe that the present synthesis and characterization could be extremely helpful for studies of these two proteins, which have been reported to antagonize tumor growth-promoting effects of hPRL in vivo in animal models of breast and prostate cancer.

Pitfalls in pituitary diagnosis: peculiarities of three cases.

Due to the increasing availability and sensitivity of diagnostic methods, biochemical and imaging abnormalities of pituitary function and anatomy are becoming more frequent. Hyperprolactinaemia was found in three women without any prolactin (PRL) related clinical features. All three patients had normal libido, regular menses with evidence of ovulation, no galactorrhoea, and normal FSH, LH, TSH and free T4 serum levels. Magnetic resonance imaging (MRI) of the sellar region showed images that were compatible with pituitary microadenomas in all three cases. Due to the discordance between laboratory and clinical features, we searched for the presence of PRL aggregates with high molecular weight and low biological activity (macroprolactinaemia). Initially, we screened with a polyethylene glycol precipitation method, and then confirmed the presence of macroprolactinaemia by chromatography. All three cases screened positive for the presence of macroprolactinaemia. MRI alterations, compatible with pituitary microadenomas, may be due to true microincidentalomas, normal anatomical variations or imaging artefacts. In conclusion, we have described the presence of double diagnostic pitfalls that might lead to unnecessary medical or surgical intervention.