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Andreas Ebbehoj, Per Løgstrup Poulsen, and Esben Søndergaard

Open access

Renato Cozzi, Maria Rosaria Ambrosio, Roberto Attanasio, Claudia Battista, Alessandro Bozzao, Marco Caputo, Enrica Ciccarelli, Laura De Marinis, Ernesto De Menis, Marco Faustini-Fustini, Franco Grimaldi, Andrea Lania, Giovanni Lasio, Francesco Logoluso, Marco Losa, Pietro Maffei, Davide Milani, Maurizio Poggi, Michele Zini, Laurence Katznelson, Anton Luger, and Catalina Poiana

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts.

The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology.

In the last century prolactinomas represented the paradigm of pituitary tumors for whom the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

Restricted access

Frederic Castinetti, Philippe Caron, Isabelle Raingeard, Vincent Amodru, Frederique Albarel, Isabelle Morange, Philippe Chanson, Julie Calvo, Thomas Graillon, Karine Baumstarck, Henry Dufour, Jean Regis, and Thierry Brue


Persistent growth hormone hypersecretion can be observed in roughly 50% of patients operated for somatotroph adenomas, requiring additional treatments. Despite its proven antisecretory efficacy, the use of Gamma Knife radiosurgery (GK) is limited probably due to the lack of data on long-term side effects, including potential cognitive consequences.


The LATe Effects of Radiosurgery in Acromegaly study was a cross-sectional exposed/unexposed non-randomized study. The primary objective was to determine the long-term neurocognitive effects of GK focusing on memory, executive functions, and calculation ability. Exposed patients had been treated by GK for acromegaly at least 5 years before inclusion. Unexposed patients (paired for age) had to be cured or controlled at last follow-up without any radiation technique. Patients of both groups were cured or controlled at the last follow-up.


Sixty-four patients were evaluated (27 exposed and 37 unexposed). Mean follow-up after GK was 13 ± 6 years (including 24 patients followed for at least 10 years). While up to 23.8% of the patients of the whole cohort presented at least one abnormal cognitive test, we did not observe any significant difference in neurocognitive function between both groups. During the follow-up, 11 patients presented at least one new pituitary deficiency (P  = 0.009 for thyroid-stimulating hormone deficiency with a higher rate in exposed patients), two presented a stroke (1 in each group), and one presented a meningioma (12 years after GK).


While GK exposes patients to a well-known risk of pituitary deficiency, it does not seem to induce long-term cognitive consequences in patients treated for acromegaly.

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Steinunn Arnardóttir, Jacob Järås, Pia Burman, Katarina Berinder, Per Dahlqvist, Eva Marie Erfurth, Charlotte Höybye, Karin Larsson, Oskar Ragnarsson, Bertil Ekman, and Britt Edén Engström

Objective: To describe treatment and long-term outcomes of patients with acromegaly from all health-care regions in Sweden.

Design and Methods: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991-2011. The latest clinical follow-up date was December, 2012, while mortality data were collected for 28.5 years until June, 2019.

Results: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy and 39% medical treatment. At the 5- and 10-year follow-ups, IGF-I levels were within the reference range in 69% and 78% of patients, respectively. In linear regression the proportion of patients with biochemical control including adjuvant therapy at 10 year follow-up increased over time with 1.23 % per year. The SMR (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed 1991-2000, SMR 1.06 (0.85-1.33) or 2001-2011, SMR 0.87 (0.61-1.24). In contrast, non- controlled patients at the latest follow up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively.

Conclusions: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.

Open access

Alexandra Dietz de Loos, Geranne Jiskoot, Annemerle Beerthuizen, Jan Busschbach, and Joop Laven


Women with polycystic ovary syndrome (PCOS) have an increased risk of metabolic syndrome (MetS). Both PCOS and MetS are associated with excess weight.


To examine the effect of a three-component lifestyle intervention (LSI) with or without short message service (SMS+ or SMS−, respectively) on the prevalence and severity of MetS and metabolic parameters, compared to care as usual (CAU).


Randomized controlled trial.


Women diagnosed with PCOS and a BMI >25 kg/m2 (n = 183) were either assigned to a 1-year three-component (cognitive behavioural therapy, diet, and exercise) LSI, with or without SMS support, or to CAU which provided weight-loss advice only. Main outcome measures included changes in the prevalence of MetS, the continuous MetS severity z-score (cMetS z-score), metabolic parameters, and the impact of weight loss.


After 1 year, the decrease in the cMetS z-score was greater in the SMS+ group than the CAU group (−0.39, P  = 0.015). The prevalence of MetS changed with −21.6% (P  = 0.037), −16.5% (P  = 0.190), and +7.0% (P  = 0.509) in both LSI groups and CAU group, respectively. A post hoc analysis for both LSI groups combined vs CAU resulted in a MetS difference of −25.9% (P  = 0.046). Moreover, weight loss per se resulted in significantly favourable effects on all metabolic parameters.


This three-component LSI was more successful in improving metabolic health compared to CAU. Therefore, we recommend this intervention to women with PCOS and excess weight, provided that a clinically relevant weight loss is being pursued.

Open access

Charlotte J. Green, Thomas Marjot, John Walsby-Tickle, Catriona Charlton, Thomas Cornfield, Felix Westcott, Katherine E Pinnick, Ahmad Moolla, Jonathan M Hazlehurst, James McCullagh, Jeremy W Tomlinson, and Leanne Hodson


Metformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with NAFLD. Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL) and fatty acid (FA) oxidation in vivo in humans.

Design and Methods:

Metabolic investigations, using stable-isotope tracers, were performed in 10 insulin-resistant, overweight/obese human participants with NAFLD who were treatment naïve before and after 12-weeks of metformin treatment. The effect of metformin on markers of subcutaneous adipose tissue FA metabolism and function, along with the plasma metabolome were investigated.


Twelve weeks treatment with metformin resulted in a significant reduction in body weight and improved insulin sensitivity, but IHTG content and FA oxidation remained unchanged. Metformin treatment was associated with a significant decrease in VLDL-triglyceride (TG) concentrations and a significant increase in the relative contribution of DNL-derived FAs to VLDL-TG. There were subtle and relatively few changes in subcutaneous adipose tissue FA metabolism and the plasma metabolome with metformin treatment.


We demonstrate the mechanisms of action of metformin whereby it improves insulin sensitivity and promotes weight loss, without improvement in IHTG; these observations are partly, explained through increased hepatic DNL and a lack of change in fatty acid oxidation.

Open access

Lucie Canaff, Vito Guarnieri, Yoojung Kim, Betty Y.L. Wong, Alexis Nolin-Lapalme, David E. C. Cole, Salvatore Minisola, Cristina Eller-Vainicher, Filomena Cetani, Andrea Repaci, Daniela Turchetti, Sabrina Corbetta, Alfredo Scillitani, and David Goltzman


Objective: Our aim was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism, and in Familial Isolated Hyperparathyroidism (FIHP) without and with a parathyroid carcinoma.

Design: We characterized two families with hypoparathyroidism, and nineteen with FIHP in which we examined the mechanism of action of GCM2 variants.

Methods: Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses.

Results: A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pulldown assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA.

Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S), heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain (CCID) were identified in affected individuals of three of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitro transcriptional activity, including increased stimulation of the PTH promoter.

Conclusions: We provide evidence that 2 novel GCM2 R67C inactivating mutations with inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.

Free access

Alexander A Leung, Janice L Pasieka, Hossein Sadrzadeh, and Gregory A Kline

Restricted access

David J Handelsman, Reena Desai, Ann J Conway, Nandini Shankara-Narayana, Bronwyn Ga Stuckey, Warrick J Inder, Mathis Grossmann, Bu Beng Yeap, David Jesudason, Lam P Ly, Karen Bracken, and Gary Allen Wittert

Context: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known.

Objective: To investigate rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections.

Methods: Men (n=303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo(P)-controlled randomized clinical trial of TU treatment were recruited for a further 12 months while remaining blinded to treatment. Sex steroids (T, DHT, E2, E1) by LCMS, LH, FSH and SHBG by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire (PDQ), International Index of Erectile Function (IIEF), SF-12) were measured at entry (three months after last injection) and 6, 12, 18, 24, 40 and 52 weeks later.

Results: In the nested cohort of TU-treated men, serum T was initially higher but declined to 12 weeks remaining stable thereafter with serum T and SHBG 11% and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carryover higher scores in T-treated men, but after weeks 18 showed no difference between T and P treated men. Initially fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since last injection.

Conclusions: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

Open access

Y S Elhassan, B Altieri, S Berhane, D Cosentini, A Calabrese, M Haissaguerre, D Kastelan, M C B V Fragoso, J Bertherat, A Al Ghuzlan, H Haak, M Boudina, L Canu, P Loli, M Sherlock, O Kimpel, M Laganà, A J Sitch, M Kroiss, W Arlt, M Terzolo, A Berruti, J J Deeks, R Libé, M Fassnacht, C L Ronchi, and the ENSAT


Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC.


This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy.


The S-GRAS score was calculated as a sum of the following points: tumour stage (1–2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0–9% = 0; 10–19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0–1, 2–3, 4–5, and 6–9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell’s Concordance index (C-index) and Royston–Sauerbrei’s R2D statistic.


We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0–9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4–5.


The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).