Endocrine disorders in Woodhouse-Sakati syndrome: a systematic review of the literature.

First described in 1983, Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive genetic disorder that leads to a spectrum of hypogonadal symptoms in adolescence. The responsible gene, DCAF17 located on chromosome 2q31.1, was discovered in 2008 and to date nine mutations have been reported in the literature. The aim of the study was to review WSS descriptively in the light of new case reports with focus on endocrine features. Phenotypic description of three patients (two females, one male) with WSS followed in the Endocrinology Department of the University Hospital of Nancy, France, and exhaustive review of the literature using the PUBMED database were performed. Of 72 patients from 29 families with documented WSS who were identified, 39 had undergone genetic testing. WSS was invariably associated with hypogonadism, decreased IGF1 and frontotemporal alopecia starting in childhood. In addition to this triad, some patients exhibited intellectual disabilities of varying severity (87 %), bilateral deafness (76 %), cervicofacial dystonia and limb pain (42 % of cases, rising to 89 % after 25 years) and diabetes (66 %, rising to 96 % after 25 years). The pathophysiology of WSS remains unclear.

Effects of lean and fat mass on bone mineral density and arterial stiffness in elderly men.

SUMMARY: The role of body composition on arterial stiffness and osteoporosis remains unclear, especially in the elderly male population. Our results indicate that elderly men with high lean mass and low fat mass exhibit the best arterial and bone profile with the lowest arterial stiffness and the highest bone mineral density. INTRODUCTION: The aim of this study was to evaluate the influence of fat and lean mass on both arterial stiffness and bone mass density (BMD) in elderly men. METHODS: This study was performed in 169 French males over 60 years old. Aortic stiffness was assessed by carotid/femoral pulse wave velocity (PWV). BMD and body composition were determined with a dual-energy X-ray absorptiometry device in the lumbar spine L1-L4, femoral neck, and total body. RESULTS: Lean mass was positively correlated with the three T scores accounting for 11.6%, 26.6%, and 12.2% of the variability in the lumbar spine L1-L4, femoral neck, and total body BMD T scores, respectively. Fat mass had no effect on BMD. However, fat mass was positively correlated with aortic PWV, accounting for 9.8% of its variability. Lean mass was not a determinant of PWV. Hypertension, diabetes, and dyslipidemia were associated with higher PWV but had no effect on BMD. CONCLUSIONS: In males from a general population over 60 years of age, bone and arterial aging are differently influenced by lean and fat mass. Our results indicate that elderly men with high lean mass and low fat mass exhibit the best arterial and bone profile with the lowest arterial stiffness and the highest BMD.

Assessment of determinants for osteoporosis in elderly men.

SUMMARY: The aim of this cross-sectional study was to determine and quantify some determinants associated to low bone mineral density (BMD) in elderly men. This study showed that ageing, a lower body mass index (BMI), a higher blood level of C-terminal cross-linking telopeptides of type I collagen (CTX-1), family history of osteoporosis, and/or fracture and prior fracture were associated with bone mineral density. INTRODUCTION: Our aims were to identify some determinants associated to low bone mineral density in men and to develop a simple algorithm to predict osteoporosis. METHODS: A sample of 1,004 men aged 60 years and older was recruited. Biometrical, serological, clinical, and lifestyle determinants were collected. Univariate, multivariate, and logistic regression analyses were performed. Receiver operating characteristic analysis was used to assess the discriminant performance of the algorithm. RESULTS: In the multiple regression analysis, only age, BMI, CTX-1, and family history of osteoporosis and/or fracture were able to predict the femoral neck T-score. When running the procedure with the total hip T-score, prior fracture also appeared to be significant. With the lumbar spine T-score, only age, BMI, and CTX-1 were retained. The best algorithm was based on age, BMI, family history, and CTX-1. A cut-off point of 0.25 yielded a sensibility of 78%, a specificity of 59% with an area under the curve of 0.73 in the development and validation cohorts. CONCLUSION: Ageing, a lower BMI, higher CTX-1, family history, and prior fracture were associated with T-score. Our algorithm is a simple approach to identify men at risk for osteoporosis.

Bone metastases from differentiated thyroid carcinoma.

The presence of distant metastases from differentiated thyroid carcinoma decreases the 10-year survival of patients by 50%. Bone metastases represent a frequent complication especially of follicular thyroid cancer and severely reduce the quality of life causing pain, fractures, and spinal cord compression. Diagnosis is established by correlating clinical suspicion with imaging. Imaging is essential to detect, localize, and assess the extension of the lesions and should be used in conjunction with clinical evidence. Bone metastases are typically associated with elevated markers of bone turnover, but these markers have not been evaluated in differentiated thyroid cancer. Skeletal and whole-body magnetic resonance imaging and fusion 2-deoxy-2-[18F]fluoro-D-glucose whole-body positron emission tomography/computed tomography (PET/CT) are the best anatomic and functional imaging techniques available in specialized centers. For well-differentiated lesions, iodine-PET scan combined (124)I-PET/CT is the newest imaging development and (131)I is the first line of treatment. Bisphosphonates reduce the complications rate and pain, alone or in combination with radioiodine, radionuclides, or external beam radiotherapy and should be employed. Surgery and novel minimally invasive consolidation techniques demand an appropriate patient selection for best results on a multimodal approach. Basic research on interactions between tumor cells and bone microenvironment are identifying potential novel targets for future more effective therapeutic interventions for less differentiated tumors.

A comparison of the effect of alendronate and risedronate on bone mineral density in postmenopausal women with osteoporosis: 24-month results from FACTS-International.

OBJECTIVES: To compare alendronate 70 mg once weekly (OW) with risedronate 35 mg OW with respect to change in bone mineral density (BMD), biochemical markers and upper gastrointestinal (UGI) tolerability over 24 months. METHODS: This was a 12-month extension to the Fosamax Actonel Comparison Trial international study (FACTS). Postmenopausal women with osteoporosis randomly assigned to either alendronate 70 mg OW or risedronate 35 mg OW for the 12-month base study continued taking the same double-blind study medication. Efficacy measurements were BMD at the hip trochanter, lumbar spine, total hip, and femoral neck and levels of four bone turnover markers at 24 months. The primary hypothesis was that alendronate would produce a greater mean per cent increase from baseline in hip trochanter BMD at 24 months. RESULTS: Trochanter BMD increased significantly from baseline to month 24 in both groups, with a significantly larger increase with alendronate: adjusted mean treatment difference of 1.50% (95% confidence interval: 0.74%, 2.26%; p < 0.001). Similar results were seen at all BMD sites. Significant geometric mean per cent decreases (p < 0.001) from baseline were seen for all four bone turnover markers in both groups, with significantly larger decreases (p < 0.001) with alendronate: adjusted mean treatment differences ranged from 8.9% to 25.3%. No significant differences were seen in incidence of UGI or other adverse events. CONCLUSIONS: Alendronate 70 mg OW yielded significantly greater BMD gains and larger decreases in bone turnover marker levels than risedronate 35 mg OW over 24 months, with no difference in UGI tolerability.

Frailty, osteoporosis and hip fracture: causes, consequences and therapeutic perspectives.

OBJECTIVE: The aim of this review of the literature is to report the factors which both contribute to the frailty syndrome and increase hip fracture risk in the elderly. This work is the fruit of common reflection by geriatricians, endocrinologists, gynecologists and rheumatologists, and seeks to stress the importance of detection and management of the various components of frailty in elderly subjects who are followed and treated for osteoporosis. It also sets out to heighten awareness of the need for management of osteoporosis in the frail elderly. DESIGN: The current literature on frailty and its links with hip fracture was reviewed and discussed by the group. RESULTS: The factors and mechanisms which are common to both osteoporosis and frailty (falls, weight loss, sarcopenia, low physical activity, cognitive decline, depression, hormones such as testosterone, estrogens, insulin-like growth factor-I (IGF-I), growth hormone (GH), vitamin D and pro-inflammatory cytokines) were identified. The obstacles to access to diagnosis and treatment of osteoporosis in the frail elderly population and common therapeutic pathways for osteoporosis and frailty were discussed. CONCLUSION: Future research including frail subjects would improve our understanding of how management of frailty can can contribute to lower the incidence of fractures. In parallel, more systematic management of osteoporosis should reduce the risk of becoming frail in the elderly population.

MRI follow-up is unnecessary in patients with macroprolactinomas and long-term normal prolactin levels on dopamine agonist treatment.

OBJECTIVE: Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA. PATIENTS AND METHODS: We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained. RESULTS: In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 ± 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline. CONCLUSION: No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas.

[Evaluation of theoretical teaching of the French diploma of medical gynecology]. / Enseignement théorique du Diplôme d'études spécialisées de gynécologie médicale en France: évaluation nationale.

OBJECTIVES: As far as the reform of the "Diplômes d'études spécialisées" (DES) is approaching, a first national evaluation of the Medical Gynecology diploma was necessary. The objective was to evaluate the practices of the theoretical teaching with the whole students, by receiving their opinions and their wishes of changing, and by proposing some improving measures. PATIENTS AND METHODS: The self-evaluation form made by members of the Association of residents (AIGM) and the Teacher's College (CNEGM) was submitted to the students during the national teaching session of June 2014. RESULTS: Fifty-six results were gathered among 145 students enrolled at the DES (38.6 %). Twelve half days of national theoretical training are yearly scheduled. The accordance of the national theoretical training to the level of the students was assessed on average at 7.8 (VAS from 0 to 10). The scientific and pedagogical skills of the speakers are evaluated at 8.9 and 7.8. The theoretical training of the diploma was considered as satisfying for 76.6 % of the respondents. DISCUSSION AND CONCLUSION: Despite a globally satisfying evaluation, some points can be improved in the organization of the diploma. The introduction of courses about establishment, medical acts and imaging, the implementation of gradual progress teaching, the development of hands-on training and practical works, reciprocal evaluation of the students and the teachings/teachers, should be set up.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Serum parathormone profile during surgical treatment of hyperfunctioning parathyroid adenoma: a multicompartmental model.

Patterns of intact parathyroid hormone (iPTH) elimination and subsequent recovery of parathyroid function were studied in seven patients undergoing surgical removal of solitary hyperfunctioning parathyroid adenoma. Using a sensitive two-site immunoradiometric assay, iPTH levels were measured pre, peri-, and postoperatively. Blood samples were taken at very early and at late stages, including 3, 6, 9, and 15 minutes and 48, 72, and 96 h after adenomectomy. A biexponential formula was calculated to fit the decreasing values of iPTH in all patients. The PTH half-life in the early phase was 1.4 +/- 1.1 minutes (95% confidence limits). The PTH half-life in the second phase was 64.45 +/- 32.19 minutes (95% confidence limits). A third phase is represented by a slow, linear increase in plasma iPTH values as a result of the recovery of healthy suppressed parathyroid glands. The extrapolation to baseline of the later phase shows that the recovery of normal parathyroid function begins as soon as 240 minutes after adenomectomy and is independent of the decrease in PTH of adenomatous origin. All individual results were consistent with this model. Five patients had iPTH values below 5 pg/ml, one had 15 pg/ml, and the last had 27 pg/ml 5 h after parathyroid adenomectomy. The recovery of the hormonal activity of the remaining glands occurred rapidly. By the postoperative hour 24 the mean serum iPTH concentration was 12.28 +/- 8.07 pg/ml. The intraoperative serum iPTH concentration offers a model to assess both recovery of hormonal secretion from functionally suppressed parathyroid glands and disappearance of parathyroid hormone.

Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma.

Vascular endothelial growth factor (VEGF) is a potent stimulator of endothelial cell proliferation. It has been implicated in tumor growth of human thyroid carcinomas. Using the VEGF immunohistochemistry staining score, we correlated the level of VEGF expression with the metastatic spread of 19 cases of thyroid papillary carcinoma. The VEGF immunostaining score, ranging from 0-9, was determined as the multiplication of a percentage of labeled thyrocytes score (0, no labeling; 1, <30%; 2, 31--60%; 3, >61% of labeled thyrocytes) and an intensity score (0, no staining; 1, weak; 2, mild; 3, strong staining). The mean score +/- SD was 5.74 +/- 2.59 for all carcinomas. The mean score for metastatic papillary carcinoma was 8.25 +/- 1.13 vs. 3.91 +/- 1.5 for nonmetastatic papillary cancers (P < 0.001). By discriminant analysis, we found a threshold value of 6.0, with a sensitivity of 100% and a specificity of 87.5%. There were no statistical differences between metastatic and nonmetastatic carcinomas when age, tumor size, or thyroglobulin levels were considered. The VEGF immunostaining score seems to be a helpful marker for metastasis spread in differentiated thyroid cancers. An increased production of VEGF could assess an aggressive disease and be the hallmark of a trend to produce metastasis. We propose the VEGF immunostaining score as a marker for the prognosis in differentiated thyroid cancers. A value of 6 or more, should be considered as at high risk for metastasis threat, prompting the physician to institute a tight follow up of the patient.

Vascular endothelial growth factor gene and protein: strong expression in thyroiditis and thyroid carcinoma.

Angiogenesis is implicated in several pathological conditions, such as inflammation and tumor growth. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a potent stimulator of endothelial cell proliferation in vitro and in vivo. The present work aimed to compare VEGF expression in human normal thyroid glands, thyroiditis tissue and thyroid carcinomas using immunohistochemistry and in situ hybridization (ISH). Both chronic lymphocytic thyroiditis and differentiated thyroid carcinomas were found to strongly express VEGF mRNA and encode larger amounts of VEGF than normal thyroid tissue as attested by a VEGF immunostaining score. In addition, tumor samples from patients with metastases showed a higher immunostaining score than their non-metastatic counterparts (P<0.05). Carcinomas with the greatest contents of VEGF mRNA and VEGF protein had the most intense mitogenic activity. Special focus on endothelial cells showed intense mitogenic activity in neoplastic tissues in contrast to the total quiescence of endothelial cells in non-tumoral tissues. An intense VEGF production by differentiated thyroid carcinoma, attested either by a higher immunostaining score or a strong VEGF mRNA expression using ISH, could be a promising marker of tumor aggressiveness and may also be useful as a predictor of metastatic potential.

Lead poisoning secondary to hyperthyroidism: report of two cases.

With long-term exposure to lead, lead accumulates in bone, where it is stored for years. These quiescent lead stores are mobilised when increased bone turnover occurs, and latent lead toxicity may then become symptomatic. Although Graves' disease is a common cause of increased bone turnover, to date hyperthyroidism has been implicated in lead poisoning only twice. We describe herein two cases of hyperthyroidism, one caused by toxic multinodular thyroid enlargement, the second by Graves' disease, leading to lead poisoning. Treatment of hyperthyroidism with radioactive iodine cured both hyperthyroidism and lead poisoning and no chelating agent therapy was necessary. Lead poisoning is an important environmental health problem, and physicians must be aware of the endocrine disorders such as hyperthyroidism and hyperparathyroidism that increase bone turnover, favouring lead mobilisation. Atypical symptoms should draw the physician's attention to the possibility of lead poisoning, particularly in workers with occupational exposure to lead and in areas where lead poisoning is endemic.

Successful pregnancy and birth after sequential cotreatment with growth hormone and gonadotropins in a woman with panhypopituitarism: a new treatment protocol.

OBJECTIVE: To report a successful pregnancy in a woman with panhypopituitarism who received 3 months of pretreatment with growth hormone (GH) before ovulation induction. Prior attempts at ovulation induction had failed for this patient. DESIGN: Case report. SETTING: Department of Endocrinology. PATIENT(S): A 32-year-old woman with panhypopituitarism and secondary infertility. INTERVENTION(S): GH (1 IU/day) alone for 3 months; during the next cycle, 1 IU/day of GH; 3 ampules of hMG per day during days 1-21; 1 ampule of hCG on day 21. GH was discontinued on day 35 when a pregnancy test was positive. MAIN OUTCOME MEASURE(S): Pregnancy and delivery. RESULTS: Pregnancy and birth of a normal child after a single ovulation stimulation using GH and gonadotropins. CONCLUSION(S): This case report suggests interest in a new protocol for follicular stimulation in women with hypopituitarism who are responding poorly to gonadotropin therapy.

Osteogenic anaplastic carcinoma of the thyroid.

An unusual osteogenic anaplastic carcinoma of the thyroid developed in a 68-year-old man and showed follicular and osteosarcomatous components. Seven months after surgery and 70 mCi 131I treatment, a local tumor recurrence was found and showed an intense uptake of 99mTc-MDP on the bone scan. After a second operation, pathologic and immunostaining analysis revealed no more thyroid carcinoma but only osteosarcomatous cells. Chemotherapy was ineffective and the patient died with diffuse pulmonary metastases 26 months after the diagnosis. The importance of osteogenic sarcomatous differentiation is proven by the bone scan. Osteosarcoma of the thyroid is a rare but well known tumor. Usually these tumors do not contain any cells originating from the thyroid epithelium and only comprise sarcomatous components. Ten cases of undifferentiated carcinoma of thyroid origin with osteogenic component have been reported. These tumors have been recently included in undifferentiated carcinomas in the second edition of the WHO classification. The evolution and pathologic findings favor the hypothesis of a transdifferentiation of the thyroid cell into osteogenic cells.

Effect on osteoarthritis of spa therapy at Bourbonne-les-Bains.

OBJECTIVES: Several studies suggest a beneficial overall effect of spa therapy in chronic musculoskeletal diseases. The present open controlled study investigated the effects of spa therapy at Bourbonne-Les-Bains, France, in patients with hip or knee osteoarthritis or low back pain. PATIENTS AND METHODS: In 1998, 102 men and women older than 50 years were included in the study. All had low back pain or lower limb osteoarthritis, and none had contraindications to spa therapy. Quality of life was assessed three times at intervals of 4 weeks, twice before and once immediately after 3 weeks of spa therapy, using the Duke Health Profile (five dimensions and five dysfunctions). RESULTS: Mean age was 66.4 years, and 67% of the patients were women. Quality of life was markedly decreased as compared to the population at large (1996, CFES). The two pretreatment evaluations produced similar quality-of-life scores. Spa therapy was associated with significant improvements in overall quality of life (P=0.004), self-esteem (P=0.009), and pain (P=0.01). CONCLUSION: These findings support those of other studies conducted in France and in other European countries. They indicate that patients report meaningful improvements in their quality of life after spa therapy.

Scanning electron microscopy (SEM) of the human thyroid gland: a technical improvement for follicular cell observation.

SEM is a valuable tool for the examination of hollow organ free surfaces. It has been used in a few studies of human thyroid. The cell surface observation is usually limited by the presence of colloid in the follicular lumen. A technique of direct removal of the colloid has been previously proposed. It gives good morphological results. But this method needs preliminary fixation and critical point drying of thyroid samples. Antigenic properties of tissue blocks are then unsuitable for further staining. We describe a fast and easy technique for colloid removal by washing thyroid samples in a saline solution. Colloid is correctly removed from the tissue block surface prior to fixation. Apical cells are left undamaged. The exposure of thyroid blocks to ultrasound did not improve colloid removal. A post-fixative chemical drying in hexamethyldisilazane shortens processing time. We have studied the efficiency of this technique on 24 human thyroid samples obtained by surgery (normal tissue, Grave's disease, heteromultinodular goiter, toxic solitary adenoma). All specimens were observed by SEM and transmission electron microscopy in order to assess the good preservation of cell surface details. This easy technique could be used as a routine process.

[Inappropriate antidiuretic hormone secretion by hematoma of the caudate nucleus]. / Sécrétion inappropriée d'hormone anti-diurétique (SIADH) par hématome du noyau caudé.

The authors report the favorable evolution of one case of inappropriate antidiuretic hormone secretion after a cerebral hemorrhage limited to the caudate nucleus. The limitation of the lesions explains the transient desinhibition of ADH producing centers.

[Severe hyponatremia disclosing adenohypophyseal insufficiency with empty sella syndrome]. / Hyponatrémie sévère révélatrice d'une insuffisance anté-hypophysaire avec selle turcique vide.

We report a case of extremely severe hyponatraemia which led to the discovery of anterior hypophysis insufficiency associated with empty sella turcica in a dysimmune context. This type of hyponatraemia is consecutive to corticotropic and thyreo-tropic hormones deficiency and to inappropriate secretion of arginine vasopressin. These endocrine abnormalities are of suprapituitary origin. They can be explained by a hypothalamo-hypophyseal dysregulation of little known mechanism, or by a lesion of the hypothalamus.

[Value of ketoconazole in the treatment of Cushing disease]. / Intérêt du kétoconazole dans le traitement de la maladie de Cushing.

Ketoconazole has been successfully used in short-term treatment of Cushing's syndrome. We treated 4 patients who had Cushing's disease with ketoconazole administered during 5 to 18 months. Two of them are still controlled after 15 months of treatment and 7 months after treatment was withdrawn. In the other two patients, treatment was ineffective primarily and after 5 months. Our data confirm the usefulness of ketoconazole in the treatment of Cushing's disease, but they also show that primary resistance and tachyphylaxis in long-term treatment may occur, as previously reported.