Dopamine agonists are usually very effective in the treatment of prolactinomas. Nonetheless, a subset of individuals does not respond satisfactorily to these agents, and this resistance is ...characterized by failure to achieve normoprolactinemia and a 30% or more reduction in maximal tumor diameter (in the case of macroprolactinoma) under maximally tolerated doses. The overall prevalence of dopamine agonist resistance is 20-30% for bromocriptine (BRC) and around 10% for cabergoline (CAB). The 2 main predictive factors are male gender and tumor invasiveness. The management of drug-resistant prolactinomas includes several options. Any BRC-resistant patient should be switched to CAB which will normalize prolactin in 80% of patients. As long as adverse effects do not develop, dose escalation of CAB is reasonable, with the expectation that subsequent dose reduction will be possible. Echocardiographic monitoring is advised in such patients because of the potential association with cardiac valvular fibrosis. Also, maintaining maximal CAB doses at 3.5 mg/week may lead to progressive hormonal control in a significant proportion of patients. Complete resistance to CAB is infrequent. In a study of 122 patients with a macroprolactinoma, only 7 (6%) could not achieve control despite maximal CAB doses for > 12 months. A large resistant prolactinoma is also an indication for transsphenoidal neurosurgery, aiming at a debulking which may improve postoperative medical control. For patients who harbor aggressive prolactinomas, radiotherapy may be considered. However, normal prolactinemia will eventually occur in only one-third of patients after many years. Finally, temozolomide may be a therapeutic option in malignant/aggressive prolactinomas.
Prevalence and incidence of prolactinomas are approximately 50 per 100,000 and 3–5 new cases/100,000/year. The pathophysiological mechanism of hyperprolactinemia-induced gonadotropic failure involves ...kisspeptin neurons. Prolactinomas in males are larger, more invasive and less sensitive to dopamine agonists (DAs). Macroprolactin, responsible for pseudohyperprolactinemia is a frequent pitfall of prolactin assay.
DAs still represent the primary therapy for most prolactinomas, but neurosurgery has regained interest, due to progress in surgical techniques and a high success rate in microprolactinoma, as well as to some underestimated side effects of long-term DA treatment, such as impulse control disorders or impaired quality of life. Recent data show that the suspected effects of DAs on cardiac valves in patients with prolactinomas are reassuring. Finally, temozolomide has emerged as a valuable treatment for rare cases of aggressive and malignant prolactinomas that do not respond to all other conventional treatments.
Giant prolactinomas are rare tumours, representing only 2–3% of all prolactin (PRL)-secreting tumours and raising special diagnostic and therapeutic challenges. Based on several considerations ...developed in this review, their definition should be restricted to pituitary adenomas with a diameter of 40 mm or more, significant extrasellar extension, very high PRL concentrations (usually above 1000 μg/l) and no concomitant GH or ACTH secretion. Giant prolactinomas are much more frequent in young to middle-aged men than in women, with a male to female ratio of about 9:1. Endocrine symptoms are often present but overlooked for a long period of time, and diagnosis is eventually made when neurologic complications arise from massive extension into the surrounding structures, leading to cranial nerve palsies, hydrocephalus, temporal epilepsy or exophthalmos. PRL concentrations are usually in the range of 1000–100 000 μg/l, but may be underestimated by the so-called ‘high-dose hook effect’. As in every prolactinoma, dopamine agonists are the first-line treatment allowing rapid alleviation of neurologic symptoms in the majority of the cases, a significant reduction in tumour size in three-fourths of the patients and PRL normalization in 60–70%. These extensive tumours are usually not completely resectable and neurosurgery has significant morbidity and mortality. It should therefore be restricted to acute complications such as apoplexy or leakage of cerebrospinal fluid (often induced by medical treatment) or to patients with insufficient tumoural response or progression. Irradiation and temozolomide are useful adjuvant therapies in a subset of patients with aggressive/invasive tumours, which are not controlled despite combined medical and surgical treatments. Because of these various challenges, we advocate a multidisciplinary management of these giant tumours in expert centres.
Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition. We previously demonstrated that administration of Akkermansia muciniphila to ...mice prevents the development of obesity and associated complications. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.
SUMMARY
Background
Glucose sensors, such as FreeStyle® Libre, are innovative medical devices developed for diabetes patients as a replacement for classic glucose meters, ensuring continuous glucose ...monitoring without the disadvantage of regular skin finger pricks.
Objectives
To report several cases of allergic contact dermatitis caused by FreeStyle® Libre, and to report on isobornyl acrylate as a culprit allergen.
Patients and Methods
Fifteen patients presented with allergic contact dermatitis caused by FreeStyle® Libre. All but 1 were patch tested with a baseline series, and with pieces and/or ultrasonic bath extracts of (the adhesive part of) the glucose sensor. Isobornyl acrylate was patch tested, in various concentrations and vehicles, in 13 patients. Gas chromatography–mass spectrometry (GC‐MS) of the sensors was performed.
Results
All patients reacted to the adhesive part of the sensor, and 12 patients were shown to be sensitized to isobornyl acrylate. Simultaneous reactions to other allergens were rarely observed. GC‐MS showed the presence of isobornyl acrylate in the sensors.
Conclusions
Cases of allergic contact dermatitis caused by FreeStyle® Libre are increasingly being observed, and isobornyl acrylate is a relevant culprit allergen. Cross‐reactivity to other acrylates was infrequently observed, but other, hitherto unidentified, contact allergens may still be present in the device.
Introduction Additional robust criteria to predict early postoperative recurrence of non-functioning pituitary macroadenomas (NFMAs) are needed. Recently, a new classification of pituitary tumors has ...been proposed, which is based on both radiological and histological criteria and allows the grading into 5 groups of different potential aggressiveness. The aim of this study was to use this classification to further characterize predictive factors of recurrence in an independent series of NFMA. Cases and methods 120 patients operated for a NFMA were analyzed retrospectively. For each of them, the invasion of the cavernous and/or sphenoidal sinuses by the tumor was studied on the preoperative MRI and the proliferative character was based on precise histological and immunohistological examination. Results 26% (n = 31) of the adenomas were proliferative and 57% (n = 68) were invasive. The invasive lesions were larger (P < 0.001) and their removal was complete in only 82% of the cases. The distribution of NFMAs was as follows: 32% grade 1a, 11% (proliferative) grade 1b, 42% (invasive) grade 2a and 15% (proliferative and invasive) grade 2b. Their probability of recurrence at 5 years was 20, 39, 44 and 66%, respectively. A young age, the atypical character and the presence of postoperative residual tumor were all independent risk factors of recurrence (P < 0.025). Discussion The new clinicopathological classification proves to be very useful in predicting the risk of recurrence of non-functioning pituitary macroadenomas after a first surgery. In particular, grade 2b lesions showed an overall likelihood of recurrence that was 8.6 times greater than those of grade 1a.
Objectives: Central hypothyroidism (CeH) is a rare form of hypothyroidism characterized by insufficient thyroid stimulation due to disturbed pituitary and/or hypothalamic functioning. Due to its ...origin and the whole clinical context, CeH represents a challenging condition in clinical practice as it is characterized by suboptimal accuracy of clinical and biochemical parameters for diagnosis and management. Since no expert consensus or guidance for this condition is currently available, a task force of experts received the commitment from the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. Study Design: The task force started to work in February 2017 and after a careful selection of appropriate references (cohort studies, case reports, expert opinions), a preliminary presentation and live discussion during the 2017 ETA meeting, and several revision rounds, has prepared a list of recommendations to support the diagnosis and management of patients with CeH. Results: Due to the particular challenges of this rare condition in the different ages, the target users of this guidance are pediatric and adult endocrinologists. Experts agreed on the need to recognize and treat overt CeH at all ages, whereas treatment of milder forms may be dispensable in the elderly (> 75 years). Conclusions: Despite the lack of randomized controlled clinical trials, the experts provide 34 recommendations supported by variable levels of strength that should improve the quality of life of the affected patients and reduce the metabolic and hormonal consequences of inadequate management.
Summary
Acromegaly is frequently associated with alterations of glucose metabolism but factors predisposing these patients to exhibit impaired glucose tolerance or overt diabetes at diagnosis are ...poorly understood. This study included 148 patients with newly diagnosed acromegaly (80 men; mean age: 45 ± 20 year). All patients underwent an oral glucose tolerance test (OGTT), unless already treated for diabetes. Insulin sensitivity (S) and β-cell function (B) were also evaluated by homeostasis model assessment (HOMA). Normal glucose tolerance (NGT) was observed in 67 patients (46 %), impaired fasting glycaemia (IFG) or glucose tolerance (IGT) were found in 39 (26 %), and diabetes mellitus (DM) in 42 (28 %). NGT patients were 10 years younger than patients with abnormal glucose metabolism (
p
< 0.001) and diabetic patients had a higher BMI (
p
< 0.05). While HOMA-S was similar, HOMA-B was reduced in the IFG/IGT group (
p
< 0.05) and further in the DM group (
p
< 0.001). IGF-I z-score was higher in IFG/IGT (5.2 ± 1.4) and DM patients (5.4 ± 1.3) than in NGT patients (4.4 ± 1.3;
p
< 0.05), but fasting and post-OGTT GH levels were not different between groups. In multivariate analyses, family history of diabetes and IGF-I were associated with hyperglycaemia, BMI and IGF-I predicted insulin resistance, and age was inversely correlated with β-cell function. Impaired glucose metabolism is present in more than 50 % of patients at diagnosis of acromegaly, and is associated with an older age, a higher BMI, a family history of diabetes and a higher IGF-I z-score, but not with fasting or post-OGTT GH levels.
ContextMacroprolactinomas poorly responsive to dopamine-agonists are often more aggressive and are usually termed ‘resistant’ but this clinical concept has always been defined empirically.ObjectiveTo ...define resistance to cabergoline (CAB) on the basis of a dose–response relationship established in a large series of macroprolactinoma patients and to assess the influence of gender and tumor invasiveness on the response to treatment.DesignRetrospective study.MethodsOne hundred and twenty-two patients (72 women and 50 men) primarily treated with CAB for at least 1 year were included. Main outcome measures were serum prolactin (PRL) and tumor size.ResultsNormalization of PRL was obtained in 115 out of the 122 patients (94%). The majority of patients (96/115, 83%) were controlled with a CAB dose ≤1.5 mg/week. Most of the other patients (19/26) had only a partial resistance, responding to a further increase of the CAB dose. Beyond the dose of 3.5 mg/week, there was no clear advantage in further increasing the dose instead of continuing the treatment at the same dose. Most tumors (98/119 assessable cases, 82%) showed a significant shrinkage during CAB treatment. It was more likely to occur in cases of PRL normalization. Both cavernous sinus invasion and male gender were significantly and independently associated with partial or complete resistance to treatment.ConclusionsMost macroprolactinomas primarily treated with CAB are adequately controlled with doses ≤1.5 mg/week. About 20% of patients, mainly men and/or those with invasive tumors will require a higher dose of CAB. We suggest defining such patients as resistant to CAB.
Objectives
Nonfunctionning pituitary macroadenomas (NFPMA) are benign tumors that cause symptoms of mass effects including hypopituitarism. Their primary treatment is transsphenoidal surgery. We ...aimed to determine the outcome of pituitary hormone deficits after surgical treatment of NFPMA and to identify factors predicting hormonal recovery.
Design
We retrospectively included 246 patients with NFPMA diagnosed and operated in one of the two participating centers. All hormonal axes were evaluated except growth hormone (GH). Postoperative improvement of pituitary endocrine function was considered if at least one hormonal deficit had recovered and a lower total number of deficits was observed 1 year after surgery.
Results
80% (
n
= 197) of patients had one or more pituitary deficits and 28% had complete anterior hypopituitarism. Besides GH, the gonadotropic and thyrotropic axes were the most commonly affected (68% and 62%, respectively). The number of hypopituitary patients dropped significantly to 61% at 1 year (
p
< 0.001) and a significant improvement was observed for all hormonal axes, except central diabetes insipidus. Among patients with preoperative hypopituitarism, 88/175 (50%) showed improved pituitary function at 1 year. Both hyperprolactinemia at diagnosis and a lower tumor diameter independently predicted favorable endocrine outcome.
Conclusions
Hypopituitarism is present in 80% of patients with NFPMA and nearly half of them will benefit from sustained improvement after surgery. Hyperprolactinaemia at diagnosis and lower tumor dimensions are associated with favorable endocrine prognosis. This supports the option of early surgery in NFPMA patients with pituitary deficits independent of the presence of visual disturbances.
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