Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man.

Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss-of-function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/-; Pou1f1+/dw double heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked the development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for the activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.

Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.

Osilodrostat in Cushing's disease: The risk of delayed adrenal insufficiency should be carefully monitored.

Antisecretory data shows a highly effective and prolonged blockade of cortisol secretion with osilodrostat. The drawback is the occurrence of adrenal insufficiency (AI) in roughly a quarter of treated patients. In this short manuscript, we report three cases of atypical adrenal insufficiency with osilodrostat.

Prolactin immunoassay: does the high-dose hook effect still exist?

PURPOSE: Measurement of prolactin in clinical laboratories is an important component in the management of patients with pituitary adenoma. Prolactin measurement is known to be sensitive to the high-dose hook effect, in the presence of extremely high prolactin concentrations. This interference is referred to in most recent articles discussing prolactin assays and the management of prolactin-secreting pituitary adenomas. The objective of our study was to evaluate if the high-dose hook effect remains relevant in current practice, when using currently available assays. METHODS: Serum from a patient with a giant macroprolactinoma was assayed using all of the available prolactin assays in France in 2020, using native serum and after dilution. Technical inserts from assays were reviewed to assess the information on analytical principles, numbers of steps, and any reference to high dose hook effect. RESULTS: Fourteen assay kits were studied by 16 laboratories; all were two-site immunometric assays, mostly using one step (11/14). Results obtained after dilution varied from 17,900 µg/L to 86,900 µg/L depending on the assay used. One tested assay was sensitive to the high-dose hook effect leading to a falsely lower prolactin concentration when measuring native serum (150 µg/L compared to 17,900 µg/L after dilution). CONCLUSION: The high-dose hook effect still exists in a very small minority of prolactin assays. The evolution of assay methods may lead to new assays that remain sensitive to this effect in the future. We therefore advise that the hook effect should still be mentioned in prolactin assay recommendations.

Fully endoscopic endonasal approach for the treatment of intrasellar arachnoid cysts.

PURPOSE: To report our experience of endoscopic endonasal obliteration of symptomatic sellar arachnoid cyst (SAC). METHODS: From 2002 to 2019, we retrospectively reported the data of 17 cases of SAC operated in Timone University Hospital, Marseille, France. Preoperative clinical findings were collected including main symptoms, visual function and endocrinological assessment. Surgical procedure was homogeneous and consisted in endonasal fully endoscopic surgical obliteration of the cyst cavity with fat graft. Post-operative outcomes, complication and follow-up was reported. RESULTS: Visual disorders and/or headaches were the main symptoms. Our technique provided improvement for 83.3% of the patients suffering from visual disturbance and for 87.5% of those suffering from headaches. We reported 2 cases of cerebrospinal fluid (CSF) leakage (11.8%), but no meningitis. One case of definitive diabetes insipidus occurred and one case of postoperative syndrome of inappropriate antidiuretic hormone secretion was temporary. There was one case of recurrence reported. The mean follow-up was 39 months. CONCLUSION: Patients with symptomatic SAC can be treated successfully by endoscopic endonasal obliteration of the cyst. This simple technique offers true benefits for the patients without craniotomy, but the complication rate remains high especially with the risk of CSF leakage. Special attention to skull base opening and closing could reduce this risk.

Patient-reported outcomes in patients with acromegaly treated with pegvisomant in the ACROSTUDY extension: A real-world experience.

PURPOSE: To report the effects of pegvisomant (PEGV) treatment on patient-reported outcomes in acromegaly patients. METHODS: We conducted an extension study of an open-label, multinational, non-interventional study (ACROSTUDY) evaluating the long-term safety and efficacy of PEGV for acromegaly in routine clinical practice. Enrolled patients were rollover patients from ACROSTUDY, or treatment naïve/semi-naïve (NSN; no PEGV within 6 months of enrollment). Exploratory efficacy endpoints were changes in symptoms with the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and quality of life with the Acromegaly Quality of Life questionnaire (AcroQoL) analyzed by controlled or uncontrolled IGF-I levels. Results were analyzed in all patients, in NSN patient subgroup, and by diabetes status. RESULTS: A total of 544 patients with acromegaly were enrolled, including 434 rollover subjects from ACROSTUDY and 110 NSN patients. Mean PEGV treatment duration was 7.8 years (range, 0-19.6 years). Overall, the majority of PASQ scores improved over time, but there was no significant difference between IGF-I controlled or uncontrolled groups. In the NSN subgroup, most PASQ and AcroQoL scores remained similar to baseline up to 1 year, regardless of IGF-I control. Patients with diabetes reported better PASQ scores over time with PEGV treatment, regardless of IGF-I control. IGF-I normalization increased from 10% of patients at baseline to more than 78% at year 10, with a mean daily PEGV dose of 18.7 mg. CONCLUSIONS: Overall, patients treated with PEGV had small improvements in PASQ. While IGF-I normalization increased with PEGV treatment, IGF-I control had no effects on PASQ and AcroQoL scores.

Levoketoconazole in the treatment of patients with endogenous Cushing's syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS).

PURPOSE: The efficacy of levoketoconazole for endogenous Cushing's syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. METHODS: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14-19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. RESULTS: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: - 54.5% (95% CI - 75.7, - 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). CONCLUSIONS: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing's syndrome. No new risks of levoketoconazole treatment were identified.

Women's perceptions of femininity after craniopharyngioma: a qualitative study.

BACKGROUND: Previous quantitative studies have shown a reduced quality of life in patients treated for craniopharyngioma (CP). However, few have assessed their sexual quality of life and other issues related to patient intimacy have not yet been addressed. Standardized questionnaires limit the approach to sexuality and the exploration of patient experiences. A qualitative study, which allows in-depth analysis, may represent an interesting approach to explore intimacy in women with a history of CP. OBJECTIVE: To assess the impact of a CP history on femininity and relationships in women. DESIGN AND PATIENTS: A qualitative study with semi-structured interviews was conducted with 15 adult women treated for CP during childhood, adolescence or at childbearing age up to 40 years of age. Interviews were audio recorded, anonymized and transcribed literally. Data analysis was carried out with an inductive approach according to the grounded theory method. RESULTS: Three main themes were identified: (a) apparent changes leading to altered self-perception that may impact on femininity and generate lower self-esteem; (b) managing the hidden disabilities of the disease inducing a need for permanent control; and (c) building parenthood and couple relationships: coping with sexual dysfunction and infertility. CONCLUSIONS: Our study highlighted alterations in self-perception and femininity due to body change and disability resulting from CP treatment, impacting both couple and social relationships. Interviewing women who underwent CP surgery at different ages highlighted specific needs and different expectations of medical professionals which emphasize the importance of offering both global and personalized care.

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort.

CONTEXT: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism. AIMS: To describe main phenotype patterns and their evolution through life. DESIGN: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. RESULTS: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. CONCLUSION: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

Characterization of the ability of a, second-generation SST-DA chimeric molecule, TBR-065, to suppress GH secretion from human GH-secreting adenoma cells.

CONTEXT: Somatostatin (SST) and dopamine (DA) inhibit growth hormone (GH) secretion and proliferation of GH-secreting pituitary adenomas (GHomas) through binding to SSTR2 and D2R receptors. Chimeric SST-DA compounds (Dopastatins) display increased potency in inhibiting GH secretion, as compared with individual SST or DA analogs (alone or combined). OBJECTIVE: To assess the efficacy of a second-generation dopastatin, TBR-065, in suppressing GH secretion from human GH- and GH/prolactin(PRL)-omas. DESIGN: We compared the ability of TBR-065 to inhibit GH secretion from primary cultures of human GH- or GH/PRLoma cells to that of the first generation dopastatin, TBR-760 (formerly BIM-23A760), octreotide (OCT) and cabergoline (CAB), the later either alone or combined. We investigated whether there was any impact of BIM-133, the metabolite of TBR-065, on the ability of TBR-065 to inhibit GH in these cultures. METHODS: 17 GH- and GH/PRLomas were included in this study. Inhibition of GH secretion by TBR-065, TBR-760, OCT and CAB (0.1 pM to 0.1 µM) was assessed over a period of 8 h. RESULTS: All tumors expressed SSTR2 and D2R mRNAs. GH suppression was higher with TBR-065 as compared with TBR-760 (Emax = 57 ± 5.6% vs. 41.1 ± 12.5%, respectively, p < 0.001) or with OCT + CAB (Emax = 56.8 ± 7.2% vs. 44.4 ± 9.4%, p < 0.001). BIM-133 did not have any impact on the activity of TBR-065. CONCLUSION: TBR-065 has significantly improved efficacy in suppressing GH secretion as compared to current available therapies and may represent a new promising option for the treatment of acromegaly.

Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients.

OBJECTIVE: Familial hypocalciuric hypercalcaemia type 1 (FHH1), related to heterozygous loss-of-function mutations of the calcium-sensing receptor gene, is the main differential diagnosis for primary hyperparathyroidism. The aim of our study was to describe clinical characteristics of adult patients living in France with a genetically confirmed FHH1. DESIGN AND PATIENTS: This observational, retrospective, multicentre study included 77 adults, followed up in 32 clinical departments in France, with a genetic FHH1 diagnosis between 2001 and 2012. RESULTS: Hypercalcaemia was diagnosed at a median age of 53 years [IQR: 38-61]. The diagnosis was made after clinical manifestations, routine analysis or familial screening in 56, 34 and 10% of cases, respectively, (n = 58; data not available for 19 patients). Chondrocalcinosis was present in 11/51 patients (22%), bone fractures in 8/56 (14%) and renal colic in 6/55 (11%). The median serum calcium was 2.74 mmol/L [IQR: 2.63-2.86 mmol/L], the median plasma parathyroid hormone level was 4.9 pmol/L [3.1-7.1], and the median 24-hour urinary calcium excretion was 2.8 mmol/24 hours [IQR: 1.9-4.0]. Osteoporosis (dual X-ray absorptiometry) or kidney stones (renal ultrasonography) were found in 6/38 patients (16%) and 9/32 patients (28%), respectively. Fourteen patients (18%) underwent parathyroid surgery; parathyroid adenoma was found in three patients (21%) and parathyroid hyperplasia in nine patients (64%). No correlation between genotype and phenotype was established. CONCLUSION: This large cohort study demonstrates that FHH1 clinical characteristics can be atypical in 33 patients (43%). Clinicians should be aware of this rare differential diagnosis in order to adopt an appropriate treatment strategy.

Parasellar Meningiomas.

Parasellar spaces remain particularly singular, comprising the most important neurovascular structures such as the internal carotid artery and optic, oculomotor, and trigeminal nerves. Meningiomas are one of the most frequent tumors arising from parasellar spaces. In this location, meningiomas remain mostly benign tumors with WHO grade I and a meningothelial subtype. Progestin intake should be investigated and leads mostly to conservative strategies. In the case of benign nonsymptomatic tumors, observation should be proposed. Tumor growth will lead to the proposition of surgery or radiosurgery. In the case of an uncertain diagnosis and an aggressive pattern, a precise diagnosis is required. For cavernous sinus and Meckel's cave lesions, complete removal is rarely considered, leading to the proposition of an endoscopic endonasal or transcranial biopsy. Optic nerve decompression could also be proposed via these approaches. A case-by-case discussion about the best approach is recommended. A transcranial approach remains necessary for tumor removal in most cases. Vascular injury could lead to severe complications. Cerebrospinal fluid leakage, meningitis, venous sacrifice, visual impairment, and cranial nerve palsies are more frequent complications. Pituitary dysfunctions are rare in preoperative assessment and in postoperative follow-up but should be assessed in the case of meningiomas located close to the pituitary axis. Long-term follow-up is required given the frequent incomplete tumor removal and the risk of delayed recurrence. Radiosurgery is relevant for small and well-limited meningiomas or intra-cavernous sinus postoperative residue, whereas radiation therapy and proton beam therapy are indicated for large, extended, nonoperable meningiomas. The place of the peptide receptor radionuclide therapyneeds to be defined. Targeted therapy should be considered in rare, recurrent, and aggressive parasellar meningiomas.

Surgical indications for pituitary tumors during pregnancy: a literature review.

PURPOSE: Surgical indications for pituitary tumors during pregnancy are rare, and are derived from a balance between expected benefits, particularly for maternal benefits, and anesthetic/surgical risks. METHODS: A literature review was performed to define the optimal surgical indications for pituitary adenomas (PA) and other pituitary tumors during pregnancy. RESULTS: Main benefits are expected in case of critical visual impairment and/or life-threatening endocrine disturbances. Multidisciplinary patient management is systematically required although nonobstetric surgery presents a reasonable risk during pregnancy. The risks of congenital malformation during the first trimester and those of premature birth during the third trimester make the second trimester the optimal period for surgery. In prolactin-secreting, nonsecreting, GH- and TSH-secreting PAs, transsphenoidal surgery (TS) is recommended in cases involving severe visual impairment, characterized by severe visual field deficit, visual acuity impairment, and abnormal optical coherence tomography findings, and when no other medical alternatives are possible and/or sufficient. Uncontrolled and severe Cushing's disease (CD) during pregnancy increases both maternal and fetal morbimortality, thus justifying TS or sometimes dopamine agonist therapy as a safer alternative. Finally, metyrapone, ketoconazole, or bilateral adrenalectomy could be recommended in certain cases after the failure of medical therapies and/or TS. Surgery is also required for suprasellar meningiomas, craniopharyngiomas, and pituitary cysts in the case of severe visual deficit. CONCLUSION: Surgical indications for pituitary tumors are rare during pregnancy; therefore, surgery should be avoided when possible. Further, the second trimester should be considered as the optimal surgical period. Severe visual disturbance and uncontrolled CD are the main surgical indications during pregnancy.

The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodeling.

The anterior and intermediate lobes of the pituitary gland derive from the surface ectoderm. They provide a simple system to assess mechanisms of developmental identity established by tissue determinants. Each lobe contains a lineage expressing the hormone precursor pro-opiomelanocortin (POMC): the corticotropes and melanotropes. The T-box transcription factor Tpit controls terminal differentiation of both lineages. We now report on the unique role of Pax7 as a selector of intermediate lobe and melanotrope identity. Inactivation of the Pax7 gene results in loss of melanotrope gene expression and derepression of corticotrope genes. Pax7 acts by remodeling chromatin and allowing Tpit binding to a new subset of enhancers for activation of melanotrope-specific genes. Thus, the selector function of Pax7 is exerted through pioneer transcription factor activity. Genome-wide, the Pax7 pioneer activity is preferentially associated with composite binding sites that include paired and homeodomain motifs. Pax7 expression is conserved in human and dog melanotropes and defines two subtypes of pituitary adenomas causing Cushing's disease. In summary, expression of Pax7 provides a unique tissue identity to the pituitary intermediate lobe that alters Tpit-driven differentiation through pioneer and classical transcription factor activities.

LARGE ADRENAL INCIDENTALOMAS REQUIRE A DEDICATED DIAGNOSTIC PROCEDURE.

Objective: The management of large nonsecreting adrenal tumors (at least 4 cm) is still a matter of debate as it is unclear whether imaging, especially 18F-fluorodeoxyglucose (FDG), can be used to characterize their potential malignancy. Moreover, the risk of new hypersecretion in nonoperated tumors is uncertain. Our aim was to better characterize these large adrenal incidentalomas. Methods: Patients followed in our center for a nonsecreting large (at least 4 cm) adrenal incidentaloma, with an initial computed tomography (CT) and 18F-FDG positron emission tomography (PET) CT, were retrospectively included. Patients who were not operated after initial diagnosis had to be followed with clinical, biological, and imaging evaluations for at least 3 years or until delayed surgery. Results: Eighty-one patients were included in the study: 44 patients (54.3%) had initial surgery while 37 were followed, including 21 (25.9%) who were operated after a mean of 19 months. Among the 65 operated patients, 13 (20%) had a malignant lesion (3 with metastasis, and 10 with adrenocortical carcinoma). Unenhanced CT <10 showed 85.6% sensitivity and 78.8% specificity; all had a 18F-FDG uptake ratio >1.5. Among the 24 patients who were followed for at least 3 years, 5 (20.8%) finally presented hypercortisolism (4 subclinical). Conclusion: As expected, large adrenal tumors are at a higher risk of malignancy. The combination of unenhanced CT <10 and 18F-FDG PET ratio <1.5 prove to be reassuring and might lead to a close follow-up rather than immediate surgery. Hormonal follow-up should be focused on the risk of hypercortisolism. Abbreviations: CI = confidence interval; CT = Computed Tomography; ENSAT = European Network for the Study of Adrenal Tumors; ESE = European Society of Endocrinology; FDG = fluorodeoxyglucose; HU = Hounsfield units; PET = positron emission tomography; ROI = regions of interest; SUV = standard uptake value.

Quantitative 18F-DOPA PET/CT in pheochromocytoma: the relationship between tumor secretion and its biochemical phenotype.

INTRODUCTION: 18F-FDOPA illustrates the properties of uptake and storage of catecholamines in pheochromocytomas (PHEOs). Until now, the relationship between 18F-FDOPA quantitative parameters and a PHEO secretory profile has not been specifically evaluated. MATERIALS AND METHODS: Fifty-six patients (56% females, median age: 47.5 yrs) with non-metastatic PHEO, evaluated by 18F-FDOPA PET/CT, were included in this retrospective study. Forty-five patients had negative genetic testing (80.4%); five patients (8.9%) had RET, two patients (3.6%) had SDHB, two had SDHD (3.6%), one patient (1.8%) had NF1, and one patient had a VHL (1.8%) mutation. Correlation between 18F-FDOPA metabolic parameters (tumor SUVmax, tumor SUVmean, tumor SUVmax/liver SUVmax, MTV 42%, total lesion uptake), urinary metanephrines (MNs), and plasma chromogranin A (CgA) were evaluated. RESULTS: All patients had positive 18F-FDOPA PET/CT. On univariate analysis, there was a strong correlation between all metabolic parameters and urinary MNs and plasma chromogranin A (CgA). The highest correlations were observed between total lesion (TL) uptake and the value of urinary MNs regardless of their nature (p = 8.10-15 and r = 0.80) and between MTV 42% and plasma CgA levels (p = 2.10-9, r = 0.74). On multivariate analysis, the correlation of uptake parameters and CgA levels did not persist further due to the relation of CgA and tumor diameter. A correlation between TL uptake and the normetanephrine/metanephrine ratio (NMN/MN) was also found, a finding that was in accordance with in vitro studies, which were found to have a higher catecholamine content in epinephrine producing PHEOs. CONCLUSION: This retrospective study shows a correlation between 18F-FDOPA uptake, especially using TL uptake, urinary MNs, and a PHEO biochemical phenotype. This illustrates that beyond its localization value, 18F-FDOPA PET further enables PHEO characterization at a specific metabolic level.

Gamma Knife radiosurgery for hypothalamic hamartoma preserves endocrine functions.

Gamma Knife radiosurgery (GK) is an effective treatment for hypothalamic hamartoma. No precise data are available on the risk of endocrine side effects of this treatment. In this study, 34 patients with hypothalamic hamartoma (HH) were followed prospectively at the Department of Endocrinology, La Timone Hospital, Marseille, France, for a mean follow-up of >2 years (mean ± standard deviation [SD] 3.6 ± 2 years). Initial pre- and post-GK radiosurgery evaluations were performed, including weight, body mass index (BMI), and a complete endocrinological workup. At diagnosis, eight patients presented with central precocious puberty at a mean age of 5.4 ± 2.4 years. At the time of GK (mean age 18.2 ± 11.1 years), two patients previously treated with surgery presented with luteinizing hormone/follicle-stimulating hormone (LH/FSH) deficiency. After GK, only one patient presented with a new thyrotropin-stimulating hormone (TSH) deficiency, 2 years after the procedure. The other pituitary axes remained normal in all but two patients (who had LH/FSH deficiency prior to GK). There was no significant difference between pre- and post-GK mean BMI (26.9 vs. 25.1 kg/m2 , p = 0.59). To conclude, in this group of 34 patients, GK did not induce major endocrinologic side effects reported with all the other surgical techniques in the literature. It is, thus, a safe and effective procedure in the treatment of hypothalamic hamartoma.

Development of ACRODAT®, a new software medical device to assess disease activity in patients with acromegaly.

PURPOSE: Despite availability of multimodal treatment options for acromegaly, achievement of long-term disease control is suboptimal in a significant number of patients. Furthermore, disease control as defined by biochemical normalization may not always show concordance with disease-related symptoms or patient's perceived quality of life. We developed and validated a tool to measure disease activity in acromegaly to support decision-making in clinical practice. METHODS: An international expert panel (n = 10) convened to define the most critical indicators of disease activity. Patient scenarios were constructed based on these chosen parameters. Subsequently, a panel of 21 renowned endocrinologists at pituitary centers (Europe and Canada) categorized each scenario as stable, mild, or significant disease activity in an online validation study. RESULTS: From expert opinion, five parameters emerged as the best overall indicators to evaluate disease activity: insulin-like growth factor I (IGF-I) level, tumor status, presence of comorbidities (cardiovascular disease, diabetes, sleep apnea), symptoms, and health-related quality of life. In the validation study, IGF-I and tumor status became the predominant parameters selected for classification of patients with moderate or severe disease activity. If IGF-I level was ≤1.2x upper limit of normal and tumor size not significantly increased, the remaining three parameters contributed to the decision in a compensatory manner. CONCLUSION: The validation study underlined IGF-I and tumor status for routine clinical decision-making, whereas patient-oriented outcome measures received less medical attention. An Acromegaly Disease Activity Tool (ACRODAT) is in development that might assist clinicians towards a more holistic approach to patient management in acromegaly.

Successful IVF pregnancy despite inadequate ovarian steroidogenesis due to congenital lipoid adrenal hyperplasia (CLAH): a case report.

Steroidogenic acute regulatory protein (StAR) mutations are the most frequent aetiologies of congenital lipoid adrenal hyperplasia (CLAH). Phenotypes may vary, and puberty may be absent in affected individuals. To date, only two pregnancies have been described in 46,XX CLAH patients with StAR mutations; these patients exhibited ovarian steroidogenesis along with spontaneous puberty and menarche and normal menses. The patient described here presented with CLAH caused by the homozygous (unreported, 1 bp) deletion c.719del in the StAR gene, which was diagnosed after acute adrenal insufficiency when the patient was 10 days old. The patient did not undergo spontaneous puberty, so puberty was induced by HRT when the patient was 13 years old. At the age of 25 years, the patient was referred to our reproductive unit because she desired to conceive. An initial cycle of clomiphene, stimulation produced follicular growth with two mature follicles measuring 18 and 15 mm, respectively, but the plasma oestradiol levels remained low (18 pg/ml) and the endometrium was thin (3 mm). Pregnancy was finally achieved after ovarian stimulation, IVF and transfer of frozen-thawed embryos after endometrial preparation with HRT. A normal female child was delivered following a 40 weeks' uneventful pregnancy. We therefore report the first IVF pregnancy achieved in a 46,XX CLAH patient homozygous for a StAR mutation, with inadequate ovarian steroidogenesis and no spontaneous puberty.

Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome.

STUDY QUESTION: What are the prevalence and the outcomes of spontaneous pregnancies (SP) in a large cohort of French women with Turner syndrome (TS)? SUMMARY ANSWER: Amongst 480 women with TS, 27 women (5.6%) had a total of 52 SP, with 30 full-term deliveries for 18 women. WHAT IS KNOWN ALREADY: Primary ovarian insufficiency is a classic feature of TS. So far, few studies have evaluated the rate of SP in these patients. STUDY DESIGN, SIZE, DURATION: The French Ministry of Health set up a National Reference Centre for Rare Growth Disorders (CRMERC), including TS. We studied a cohort of adult TS patients from seven endocrine units (Saint-Antoine, Pitié-Salpêtrière, Bicêtre, Lyon, Marseille, Brest, Reims Hospitals) belonging to this centre, between January 1999 and January 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 480 adult patients with TS were included. The patients' clinical characteristics, karyotypes and reproductive histories had been collected, after informed consent, in a web database called CEMARA. Our reference population was issued from a database belonging to the French Health Ministry, collecting pregnancy outcomes in the French general population. In order to find predictive characteristics of SP, TS with spontaneous pregnancies were compared with non-pregnant TS patients from our cohort. MAIN RESULTS AND THE ROLE OF CHANCE: There were 27 patients (5.6%) who had a total of 52 SP. The two predictive factors which correlated with occurrence of a SP were spontaneous menarche and mosaic karyotype. The median delay to conception was 6 months (range 0-84). Miscarriage occurred in 16 pregnancies, 30.8% versus 15% in the general French population (P < 0.01). The remaining pregnancy outcomes were legal abortion (n = 2), medical interruption (n = 3), intrauterine fetal death (n = 1) and delivery at term (n = 30). Caesarean section rates were higher than in the general population, respectively 46.7% versus 21% (P < 0.001). Pregnancy-induced hypertensive disorders (PHDs) occurred in four cases (13.3%), including two cases of mild pre-eclampsia (6.7%). Neither aortic root dilatation nor aortic dissection were observed. The median birthweight was 3030 g (range 2020-3460). Two cases of TS were identified in the 17 daughters issued from this cohort. LIMITATIONS, REASONS FOR CAUTION: It would have been interesting to evaluate AMH levels and SP occurrence, as a predictive factor. Unfortunately, hormonal measurements were missing for some patients. Prospective studies are necessary to display prognostic values of AMH for SP and thus better target fertility preservation programmes in TS patients. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that pregnancy outcomes in SPs are more favourable than those after oocyte donation in TS patients. However, the risk of fetal chromosomal abnormalities remains high. Our study will be useful in order to give patients with TS, their families, paediatricians and physicians involved in reproduction, better counselling concerning their fertility. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by the Association pour la recherche Claude Bernard, Paris France All authors claim no competing interests. TRIAL REGISTRATION NUMBER: NA.