Changes in multi-modality management of acromegaly in a tertiary centre over 2 decades.

PURPOSE: Acromegaly is a rare disease associated with chronic multisystem complications. New therapeutic strategies have emerged in the last decades, combining pituitary transsphenoidal surgery (TSS), radiotherapy or radiosurgery (RXT) and medical treatments. METHODS: This retrospective monocentric study focused on presentation, management and outcome of acromegaly patients diagnosed between 2000 and 2020, still followed up in 2020, with a minimum follow-up of 1 year, and comparison of the first vs. second decade of the study. RESULTS: 275 patients were included, 50 diagnosed before 2010 and 225 after 2010. 95% of them had normal IGF-1 levels (with or without treatment) at the last follow-up. Transsphenoidal surgery was more successful after 2010 (75% vs. 54%; p < 0.01), while tumor characteristics remained the same over time. The time from first treatment to biochemical control was shorter after 2010 than before (8 vs. 16 months; p = 0.03). Since 2010, RT was used less frequently (10% vs. 32%; p < 0.01) but more rapidly after surgery (26 vs. 53 months; p = 0.03). In patients requiring anti-secretory drugs after TSS, the time from first therapy to biochemical control was shorter after 2010 (16 vs. 29 months; p < 0.01). Tumor size, tumor invasiveness, baseline IGF-1 levels and Trouillas classification were identified as predictors of remission. CONCLUSION: The vast majority of patients with acromegaly now have successful disease control with a multimodal approach. They reached biochemical control sooner in the most recent half of the study period. Future work should focus on those patients who are still uncontrolled and on the sequelae of the disease.

SFE-AFCE-SFMN 2022 Consensus on the management of thyroid nodules : Recommendations in thyroid cytology: from technique to interpretation.

The SFE-AFCE-SFMN 2022 consensus deals with the management of thyroid nodules, a condition that is a frequent reason for consultation in endocrinology. In more than 90% of cases, patients are euthyroid, with benign non-progressive nodules that do not warrant specific treatment. The clinician's objective is to detect malignant thyroid nodules at risk of recurrence and death, toxic nodules responsible for hyperthyroidism or compressive nodules warranting treatment. The diagnosis and treatment of thyroid nodules requires close collaboration between endocrinologists, nuclear medicine physicians and surgeons, but also involves other specialists. Therefore, this consensus statement was established jointly by 3 societies: the French Society of Endocrinology (SFE), French Association of Endocrine Surgery (AFCE) and French Society of Nuclear Medicine (SFMN); the various working groups included experts from other specialties (pathologists, radiologists, pediatricians, biologists, etc.). This section deals with the technique and interpretation of thyroid fine-needle aspiration biopsy (FNAB), a reference test for the analysis of thyroid nodules.

Meningiomas in patients with long-term exposition to progestins: Characteristics and outcome.

OBJECTIVE: The aim of this study was to describe progestin-associated meningiomas' characteristics, outcome and management. MATERIAL AND METHODS: We included 53 patients operated on and/or followed in the department for meningioma with progestin intake longer than one year and with recent drug discontinuation. RESULTS: Cyproterone acetate (CPA), nomegestrol acetate (NomA), and chlormadinone acetate (ChlA) were involved in most cases. Mean duration of progestin drugs intake was 17.5 years. Tumors were multiple in 66% of cases and were located in the anterior and the medial skull base in 71% of cases. Transitional subtype represented 16/25 tumors; 19 meningiomas were WHO grade I and 6 were grade II. The rate of transitional subtype and skull base location was significantly higher compared to matched operated meningioma general population. No difference was observed given WHO classification. But Ki67 proliferation index tends to be lower and 5/6 of the WHO grade II meningiomas were classified as WHO grade II because of brain invasion. Strong progesterone receptors expression was observed in most cases. After progestin discontinuation, a spontaneous visual recovery was observed in 6/10 patients. Under CPA (n=24) and ChlA/NomA (n=11), tumor volume decreased in 71% and 18% of patients, was stabilized in 25% and 64% of patients, and increased in 4% and 18% of patients, respectively. Volume outcome was related to meningioma location. CONCLUSIONS: Outcome at progestins discontinuation is favorable but different comparing CPA versus ChlA-NomA and comparing tumor location. Long-term follow-up is required. In most cases, simple observation is recommended and surgery should be avoided.

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform. AIMS: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD. DESIGN: On-line survey in endocrine centres throughout Europe. PATIENTS AND METHODS: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018. RESULTS: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved. CONCLUSION: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

Evaluation of an individualized education program in pituitary diseases: a pilot study.

INTRODUCTION: The low prevalence of pituitary diseases makes patient autonomy crucial, and self-management programs should be more common. OBJECTIVES: To assess the efficacy of an education program for patients with pituitary diseases in terms of patients' quality of life, satisfaction and goal attainment. DESIGN AND METHODS: Adult patients with pituitary disorders were recruited in a tertiary referral center and chose at least three of eight possible sessions on various topics, from disease management to psychosocial issues. Patients were included if they attended at least three sessions between 2012 and 2016 and completed the initial, final, and follow-up questionnaires. Data on quality of life (SF36), satisfaction and goal attainment were analyzed. RESULTS: Fifty-three patients were included (33 women; mean age, 53.5 years). There were a significant quality of life improvements in terms of physical and psychic limitation scores at the final assessment that persisted at follow-up evaluation. Most patients reached their objectives, especially those on sharing experiences and improving autonomy and self-confidence. More than half set new objectives at the end of the program, the most popular one being to reinforce their knowledge of their pituitary disease, its evolution and treatment (17.1% of patients). The mean overall satisfaction score was 3.75/4. At follow-up evaluation, patients reported improved self-management of pituitary disease (3.6/5) and improved self-efficacy (3.8/5). CONCLUSION: Individualizing the educational objectives of patients with pituitary disease improves the way they live with their disease. If confirmed in other cohorts, this approach could become the gold standard for education programs in rare endocrine diseases.

Acromegaly in Carney complex.

PURPOSE: Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by mucocutaneous pigmentation, cardiac, cutaneous myxomas and endocrine overactivity. It is generally caused by inactivating mutations in the PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) gene. Acromegaly is an infrequent manifestation of CNC, reportedly diagnosed in 10% of patients. METHODS: We here report the case of a patient who was concomitantly diagnosed with Carney complex, due to a new mutation in PRKAR1A ((NM_002734.3:c.80_83del, p.(Ile27Lysfs*101 in exon 2), and acromegaly. In parallel, we conducted an extensive review of published case reports of acromegaly in the setting of CNC. RESULTS: The 43-year-old patient was diagnosed with an acromegaly due to a GH-secreting pituitary microadenoma resistant to somatostatin analogs. He underwent transsphenoidal surgery in our tertiary referral center, which found a pure GH-secreting adenoma. In the literature, we identified 57 cases (24 men, 33 women) of acromegaly in CNC patients. The median age at diagnosis was 28.8 ± 12 year and there were 6 cases of gigantism. Acromegaly revealed CNC in only 4 patients. 24 patients had a microadenoma and two carried pituitary hyperplasia and/or multiple adenomas, suggesting that CNC may result in a higher proportion of microadenoma as compared to non-CNC acromegaly. CONCLUSIONS: Although it rarely reveals CNC, acromegaly is diagnosed at a younger age in this setting, with a higher proportion of microadenomas.

French Endocrine Society Guidance on endocrine side effects of immunotherapy.

The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPIs). However, the use of ICPI has a risk of side effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, and we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side effects in oncology using 'common terminology criteria for adverse events' (CTCAE) and the difficulties in applying this to endocrine side effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side effects (high-dose corticosteroids, contraindicated in ICPI for example) and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high-dose glucocorticoid intake.

Pre-surgical medical treatment, a major prognostic factor for long-term remission in acromegaly.

PURPOSE: To determine whether pre-surgical medical treatment (PSMT) using long-acting Somatostatin analogues in acromegaly may improve long-term surgical outcome and to determine decision making criteria. METHODS: This retrospective study included 110 consecutive patients newly diagnosed with acromegaly, who underwent surgery in a reference center (Marseille, France). The mean long-term follow-up period was 51.4 ± 36.5 (median 39.4) months. Sixty-four patients received PSMT during 3-18 (median 5) months before pituitary surgery. Remission was defined at early (3 months) evaluation and at last follow-up by GH nadir after oral glucose tolerance test < 0.4 µg/L and normal IGF-1. RESULTS: Pretreated and non-pretreated groups were comparable for the main confounding factors except for higher IGF-1 at diagnosis in PSMT patients. Remission rates were significantly different in pretreated or not pretreated groups (61.1% vs. 36.6%, respectively at long-term evaluation). In multivariate analysis, PSMT was significantly linked to 3 months (p < 0.01) and long-term remission (p < 0.01). Duration of PSMT was not significantly different in cured or non-cured patients, at both evaluation times. PSMT appeared to be more beneficial for patients with an invasive tumor. No patient with a tumor greater than 18 mm or mean GH level exceeding 35 ng/mL at diagnosis was cured by surgery alone (vs. 8 and 9 patients in the pretreated group, respectively). Patients with PSMT showed more transient mild hyponatremia after surgery. CONCLUSIONS: PSMT significantly improved short and long-term remission in patients with acromegaly, independent of its duration, especially in invasive adenomas.

A threshold value in Shear Wave elastography to rule out malignant thyroid nodules: a reality?

OBJECTIVES: To evaluate the ability of a threshold value in ShearWave™ elastography to rule out malignant thyroid nodules while studying its pertinence in association with morphological signs. EQUIPMENT AND METHODS: 148 patients (110 women and 38 men; 52.5 y.o. 15.8) referred for surgery of thyroid nodules underwent standard ultrasound as well as elastography. Characteristics of the morphological signs and maximum elastographic index were calculated in relation to histology. Association of morphological signs alone and then of elastography was also evaluated. One hundred and fifty one nodules were studied on a double-blind basis. RESULTS: 297 nodules were studied. Thirty-five cancers were detected (11.6%). Elastographic index was higher in malignant nodules (115 kPa 60.4) than in benign nodules (41 kPa 25.8) (p<0.001, Student's t-test). Cut off value of 66 kPa was the best to discriminate malignant nodules with a sensitivity of 80% (CI 95%, 62.5; 90.9) and a specificity of 90.5% (CI 95%, 86.1; 93.6) (p=0.0001). Association of elastography and morphological ultrasound signs presented a sensitivity of 97% (CI 95%, 83.3; 99.8) and a negative predictive value of 99.5% (CI 95%, 95.6; 99.9). Interobserver reproducibility proved to be excellent with an interclass correlation of 0.97 (CI 95%, 0.96; 0.98) (p<0.001). CONCLUSION: The 66 kPa threshold in Shear Wave elastography is the best ultrasound sign to rule out malignant thyroid nodules. The method is simple, quantitative, reproducible and usable in the study of nodules larger than 3 cm. Progress must still be made in the study of calcified nodules and follicular tumors.

What is the contribution of elastography to thyroid nodules evaluation?

The determination of elasticity index by elastography has been recently proposed in the evaluation of thyroid nodules, since malignancy is correlated with stiffness of the nodules. The aim of this report is to give an overview on different techniques and results reported by eleven groups active on the field. Advantages and limitations of elastography are also discussed. In our opinion, further studies, preferentially multicentric, are necessary before being able to conclude about the place of elastography in thyroid nodules evaluation, versus fine-needle aspiration cytology (FNAC), the gold standard. Indeed, elastography could reduce FNAC or at least allow to select nodule's (or nodular zone's) for aspirations.

Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms.

BACKGROUND: Pituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause. OBJECTIVES: i) To compare subgroups with or without extra-pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS. Study design We analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes. RESULTS: PSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS. CONCLUSION: PSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for <5% of cases and were found in consanguineous or familial cases.

Does first-line surgery still have its place in the treatment of acromegaly?

Transsphenoidal surgery is currently the first-line treatment of acromegaly. Remission is observed in 80 to 90% microadenomas, 50 to 60% non-invasive macroadenomas, and less than 20% invasive macroadenomas. Predictive factors include age, maximal size of the adenoma, cavernous sinus invasion, initial hormone levels and neurosurgeon's experience. Complications are rare, with about 5% definitive diabetes insipidus and 10% of new anterior pituitary hormone deficits. Somatostatin agonist pretreatment can be proposed as it decreases tumor volume in about 25% cases and might reduce the rate of immediate postsurgical complications; however, there is no obvious difference in surgical remission rate whether patients are pretreated or not. Debulking surgery can also be proposed in very large macroadenomas incompletely controlled by somatostatin agonists or resistant to medical treatment, as it was shown to facilitate somatostatin agonist efficacy in more than 50% cases.

A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism.

CONTEXT: LHX4 is a LIM homeodomain transcription factor involved in pituitary ontogenesis. Only a few heterozygous LHX4 mutations have been reported to be responsible for congenital pituitary hormone deficiency. SUBJECTS AND METHODS: A total of 136 patients with congenital hypopituitarism associated with malformations of brain structures, pituitary stalk, or posterior pituitary gland was screened for LHX4 mutations. RESULTS: Three novel allelic variants that cause predicted changes in the protein sequence of LHX4 (2.3%) were found (p.Thr99fs, p.Thr90Met, and p.Gly370Ser). On the basis of functional studies, p.Thr99fs mutation was responsible for the patients' phenotype, whereas p.Thr90Met and p.Gly370Ser were likely polymorphisms. Patients bearing the heterozygous p.Thr99fs mutation had variable phenotypes: two brothers presented somato-lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the mutation induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. We also identified prolactin and GH promoters as potential target genes of LHX4 and found that the p.Thr99fs mutant was also unable to transactivate these promoters. CONCLUSIONS: The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities.

[Clinical and genetic aspects of combined pituitary hormone deficiencies]. / Déficit hypophysaire combiné multiple : aspects cliniques et génétiques.

DEFINITION: Congenital hypopituitarism is characterized by multiple pituitary hormone deficiency, including somatotroph, thyrotroph, lactotroph, corticotroph or gonadotroph deficiencies, due to mutations of pituitary transcription factors involved in pituitary ontogenesis. INCIDENCE: Congenital hypopituitarism is rare compared with the high incidence of hypopituitarism induced by pituitary adenomas, transsphenoidal surgery or radiotherapy. The incidence of congenital hypopituitarism is estimated to be between 1:3000 and 1:4000 births. CLINICAL SIGNS: Clinical presentation is variable, depending on the type and severity of deficiencies and on the age at diagnosis. If untreated, main symptoms include short stature, cognitive alterations or delayed puberty. DIAGNOSIS: A diagnosis of combined pituitary hormone deficiency (CPHD) must be suspected when evident causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism...) have been ruled out. Clinical, biological and radiological work-up is very important to better determine which transcription factor should be screened. Confirmation is provided by direct sequencing of the transcription factor genes. AETIOLOGY: Congenital hypopituitarism is due to mutations of several genes encoding pituitary transcription factors. Phenotype varies with the factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph and sometimes corticotroph deficiencies; pituitary hyper and hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph and gonadotroph deficiencies, limited head and neck rotation) and LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities). MANAGEMENT: An appropriate replacement of hormone deficiencies is required. Strict follow-up is necessary because patients develop new deficiencies (for example late onset corticotroph deficiency in patients with PROP1 mutations). GENETIC COUNSELLING: Type of transmission varies with the factor and the mutation involved (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal or recessive for POU1F1 and HESX1). PROGNOSIS: It is equivalent to patients without pituitary deficiencies if treatment is started immediately when diagnosis is confirmed, and if a specialized follow-up is performed.