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Atanaska Elenkova, Rabhat Shabani, Krassimir Kalinov, and Sabina Zacharieva

Background

In contrast to cabergoline, evidence-based information about a possible profibrotic effect of bromocriptine in prolactinoma patients is extremely limited.

Objective

To assess the prevalence of valvular lesions among patients on long-term bromocriptine or cabergoline therapy.

Design

Case–control study.

Methods

A transthoracic echocardiographic evaluation was performed in 334 subjects divided into four groups: 103 cabergoline treated, 55 bromocriptine treated, 74 naïve patients, and 102 controls.

Results

Clinically relevant valve regurgitations were equally prevalent in all investigated groups whereas subclinical valve fibrosis was significantly more frequent in both bromocriptine- and cabergoline-treated patients (40 vs 43.6 vs 21.6 vs 23.5%; P=0.004). The odds ratio (OR) for developing valvular fibrosis was 2.27 (95% CI 1.17–4.41; P=0.016) for cabergoline and 2.66 (95% CI 1.22–5.78; P=0.014) for bromocriptine groups compared with subjects not exposed to dopamine agonists (DAs). A significantly higher pulmonary arterial pressure corresponding to the longer treatment duration was observed among patients taking bromocriptine compared with cabergoline-treated subjects.

Conclusions

Long-term treatment with cabergoline and bromocriptine seems not to be associated with an increased risk of clinically significant valve disease but possible subclinical lesions should be expected. An echocardiographic examination is recommended at the beginning and periodically during therapy with DAs acting as full or partial agonists of 5-hydroxytrytamine 2B receptors (cabergoline and bromocriptine). Bromocriptine seems not to be a safe alternative for patients receiving cabergoline treatment who have preexisting or diagnosed abnormalities suggesting valvular, interstitial myocardial, or pulmonary fibrosis. Further studies are needed to investigate the possible impact of DA treatment on pulmonary arterial pressure.

Free access

Atanaska Elenkova, Iliana Atanassova, Georgi Kirilov, Vladimir Vasilev, Krassimir Kalinov, and Sabina Zacharieva

Background

Transforming growth factor β1 (TGFβ1) signaling pathway is crucial for both human fibrogenesis and tumorigenesis.

Objective

This study aimed to investigate the usefulness of TGFβ1 and matrix metalloproteinase 2 (MMP2) as potential circulating markers for fibrotic valvular heart disease (FVHD) and invasiveness as well as of Fetuin A as a marker for calcification in patients with prolactinomas.

Design

The study population consisted of 147 subjects divided into four groups: 30 dopamine agonist (DA)-treated prolactinoma patients with proven FVHD and three control groups with normal echocardiograms: 43 DA-treated patients, 26 naïve patients, and 48 healthy subjects.

Results

We observed significantly higher serum TGFβ1 levels in all three patient groups than in the healthy subjects (21.4±8.86 vs 19.1±9.03 vs 20.7±11.5 vs 15.8±7.2 ng/ml; P=0.032). Moreover, TGFβ1 levels were significantly higher in patients with macroprolactinomas and invasive prolactinomas than in those with microprolactinomas and noninvasive tumors respectively. In addition, a strong positive linear relationship between TGFβ1 levels and invasiveness score (ρ=0.924; P<0.001) and a moderate correlation between TGFβ1 levels and tumor volume (r=0.546; P<0.002) were observed in patients with invasive prolactinomas. By contrast, prolactin (PRL) levels exhibited a better correlation with tumor volume (r=0.721; P<0.001) than with invasiveness score (ρ=0.436; P<0.020). No significant difference was observed in Fetuin A levels between patients with FVHD and healthy controls. Results concerning MMP2 were unclear.

Conclusions

TGFβ1, MMP2, and Fetuin A are not reliable biomarkers for valvular fibrosis and calcification in DA-treated patients with prolactinomas, but TGFβ1 may represent a useful serum marker for tumor invasiveness. The simultaneous determination of TGFβ1 and PRL levels could improve the noninvasive assessment of prolactinoma behavior.

Free access

Maria A Tichomirowa, Anne Barlier, Adrian F Daly, Marie-Lise Jaffrain-Rea, Cristina Ronchi, Maria Yaneva, Jonathan D Urban, Patrick Petrossians, Atanaska Elenkova, Antoine Tabarin, Rachel Desailloud, Dominique Maiter, Thomas Schürmeyer, Renato Cozzi, Marily Theodoropoulou, Caroline Sievers, Ignacio Bernabeu, Luciana A Naves, Olivier Chabre, Carmen Fajardo Montañana, Vaclav Hana, Georges Halaby, Brigitte Delemer, José Ignacio Labarta Aizpún, Emmanuel Sonnet, Ángel Ferrandez Longás, Marie-Thérèse Hagelstein, Philippe Caron, Günter K Stalla, Vincent Bours, Sabina Zacharieva, Anna Spada, Thierry Brue, and Albert Beckers

Background

Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments.

Methods

We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age.

Results

Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas.

Conclusion

Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

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Martin Reincke, Adriana Albani, Guillaume Assie, Irina Bancos, Thierry Brue, Michael Buchfelder, Olivier Chabre, Filippo Ceccato, Andrea Daniele, Mario Detomas, Guido Di Dalmazi, Atanaska Elenkova, James Findling, Ashley B. Grossman, Celso E Gomez-Sanchez, Anthony P Heaney, Juergen Honegger, Niki Karavitaki, Andre Lacroix, Edward R Laws, Marco Losa, Masanori Murakami, John Newell-Price, Francesca Pecori Giraldi, Luis G. Pérez‐Rivas, Rosario Pivonello, William E Rainey, Silviu Sbiera, Jochen Schopohl, Constantine A Stratakis, Marily Theodoropoulou, Elisabeth F.C. van Rossum, Elena Valassi, Sabina Zacharieva, German Rubinstein, and Katrin Ritzel

BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson’s syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing’s disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28th, 2018.

RESULTS: Data covered definition and incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.