Fractionated Stereotactic Radiation Therapy for Pituitary Adenomas: An alternative escalating protocol of hypofractionated stereotactic radiotherapy delivering 35Gy in 5 fractions.

PURPOSE: Evaluate efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) for patients treated for pituitary adenoma (PA) with an alternative HSRT escalating protocol delivering 35Gy in 5 fractions. MATERIAL AND METHODS: From June 2007 to March 2017, 29 patients with pituitary adenoma were treated in Antoine Lacassagne Cancer Centre with an alternative HSRT protocol. Prescribed dose was 35Gy in 5 fractions of 7Gy. Radiographic responses were assessed by annual MRI. Hormone blood samples were evaluated each year after HSRT. RESULTS: A total of 29 patients aged between 23 and 86 years (median 54 years) were included. Twelve patients received HSRT for recurrent cases and 12 received postoperative adjuvant HSRT, 5 patients did not have surgery. After a median follow-up period of 47 months local control rate was 96%. One patient presented an out-field tumor regrowth 73 months after HSRT. The majority of PA were endocrine-active (18 patients, 62%). After HSRT, 8 patients (44%) presented complete response on initial secretion, 4 patients (23%) presented partial response on initial secretion. Four patients (14%) presented grade 2 or more acute radiation toxicities. One grade 4 visual disorder was observed for one patient. CONCLUSIONS: HSRT delivering 35Gy in 5 fractions represents a feasible treatment and shows promising results to reduce hormonal overproduction and to improve local control in PA.

Iodine status has no impact on thyroid function in early healthy pregnancy.

Aim. To assess the impact of iodine status in early pregnancy on thyroid function. Methods. Women >18 years old seen at their first prenatal consult before 12 weeks of amenorrhea and without personal thyroid history were proposed thyroid screening and were eligible if they had strictly normal thyroid tests (fT4 > 10th percentile, TSH < 2.5 mUI/L, negative anti-TPO antibodies). Evaluation included thyroid ultrasound, extensive thyroid tests, and ioduria (UIE). Results. 110 women (27.5 y, 8 weeks of amenorrhea, smoking status: 28% current smokers) were enrolled. Results are expressed as medians. UIE was 116 µg/L. 66.3% of women had iodine deficiency (ID) defined as UIE < 150. FT4 was 14.35 pmol/L; TSH 1.18 mUI/L; fT3 5 pmol/L; thyroglobulin 17.4 ng/mL; rT3 0.27 ng/mL; thyroid volume: 9.4 ml. UIE did not correlate with any thyroid tests, but correlated negatively with thyroid volume. UIE and all thyroid tests, except fT3, correlated strongly with ßhCG. Smoking correlated with higher thyroid volume and thyroglobulin and with lower rT3. Conclusions. In pregnant women selected for normal thyroid function, mild ID is present in 66% during the 1st trimester. The absence of correlation between UIE and thyroid tests at that stage contrasts with the impact of ßhCG and, to a lesser degree, maternal smoking.

Vascular placental abnormalities and newborn death in a pregnant diabetic woman with familial partial lipodystrophy type 3: a possible role for peroxisome proliferator-activated receptor γ.

The peroxisome proliferator-activated receptor protein gamma (PPARγ), a nuclear receptor involved in adipocyte differentiation, energy homoeostasis and fat storage, can lead, in rare cases of coding mutations, to familial partial lipodystrophy type 3 (FPLD3) with severe insulin resistance. PPARγ is also highly expressed in the syncytiotrophoblast and extravillous cytotrophoblast cells. It has a key role in trophoblast invasion, as shown by studies in vitro, but its precise role during placentation remains to be elucidated, and fetomaternal outcomes of FPLD3 pregnancies also need to be assessed. This report is of a novel missense heterozygous mutation of PPARγ identified during pregnancy in a young diabetic woman who, at 3weeks of amenorrhoea, prematurely delivered a baby who died 24 h later. Histopathological analysis revealed important vascular placental abnormalities. The presence of the PPARγ mutation in placental tissues in the absence of fetal malformations and maternal hypertension suggests that FPLP3 pregnancies may be at high-risk, especially if the fetus has inherited the mutation. It also supports a physiological role for PPARγ during placentation.

[Post-menopausal ovarian hyperthecosis]. / Hyperthécose ovarienne post-ménopausique.

Ovarian hyperthecosis is infrequent but it represents the first cause of post-menopausal hyperandrogenia. Pathophysiology of ovarian hyperthecosis remains poorly understood but the metabolic syndrome observed in most patients suggests that insulin resistance associated with high, postmenopausal LH levels, might play a role as in polycystic ovarian syndrome. We report here four patients who presented post-menopausal hyperandrogenia. Although high, tumoral, plasma testosterone levels, lack of focused radiological lesions except enlarged ovaries, associated to the metabolic syndrome, suggested ovarian hyperthecosis. Bilateral annexectomy allowed histological confirmation of hyperthecosis showing specific luteinized stromal cells and led to the complete suppression of the inappropriate androgen secretion.

Universal two-step screening strategy for gestational diabetes has weak relevance in French Mediterranean women: should we simplify the screening strategy for gestational diabetes in France?

AIM: Currently, there is no international consensus for gestational diabetes mellitus (GDM) diagnosis. This is a report of our experience of GDM screening according to the 1996 French guidelines. METHODS: For 5 years, all pregnant women followed at our hospital (n=11,545) were prospectively screened for GDM between weeks 24 and 28 of pregnancy with a two-step strategy: the O'Sullivan test (OS) with a threshold at 130 mg/dL, followed by a 100-g OGTT if positive. GDM was diagnosed according to Carpenter and Coustan criteria. RESULTS: Prevalence of GDM was 4.26% [344/1451 of patients with an OS of 130-199 mg/dL (12.1%); and 148 patients with an OS greater than 200 mg/dL]. The false-positive rate for the OS was 76.8%. Compared with 140 mg/dL, a threshold of 130 mg/dL caused 401 additional negative OGTTs in 90% of cases. In 80.7% GDM patients, fasting glucose was less than 95 mg/dL. The time lag between OS and OGTT was 3 weeks (1-84 days). Risk factors associated with GDM were maternal age, preconception overweight and obesity, parity, personal history of GDM or macrosomia, and familial history of obesity (P<0.05), but not diabetes. Also, 20% of GDM patients had no risk factors, whereas they were present in 75% of patients without GDM. CONCLUSION: In our population, a two-step screening strategy for GDM was neither relevant nor efficient. It could be simplified with a single-step definitive screening strategy using a 75-g OGTT, as used in the HAPO study, and as recommended by the IADPSG and the recent French Expert Consensus. At present, there are still no evidence-based arguments to help in deciding between selective or universal screening for GDM.

Klinefelter's syndrome and bone mineral density: is osteoporosis a constant feature?

OBJECTIVES: Data on bone mineral density (BMD) in Klinefelter syndrome (KS) are scarce and contradictory. The aim of the present study was to investigate BMD in patients with KS and in healthy controls with special attention to gonadal status. MATERIAL AND METHODS: We investigated 26 patients with KS (30±9 yr) who had never been treated with testosterone. Thirty-nine age-matched healthy males served as controls. We assessed BMD by performing dual energy X-ray absorptiometry and measured serum hormone levels, including total testosterone (T), free testosterone, estradiol (E2), leptin. The estrogen to androgen ratio (E2/T) was used as an indirect measure for aromatase activity. RESULTS: No difference was found in BMD at femoral neck (1.06 ± 0.16 vs 1.04 ± 0.14 g/cm²), or at lumbar spine (1.00 ± 0.09 vs 1.03 ± 0.11) between patients and controls. Two patients and one control were classified as osteoporotic (T-score ≤ -2.5). Compared with controls, patients had lower levels of T and free testosterone, similar E2 levels, and increased E2/T (P < 0.05). In KS patients, leptin was significantly higher and correlated positively with E2/T (r = 0.484, P = 0.02). E2/T correlated with femoral neck BMD (r = 0.566, p = 0.02), T and free T correlated with lumbar spine BMD (r = 0.433, P = 0.05 and r = 0.534, P = 0.05). CONCLUSION: Osteoporosis is not a constant feature in young patients with KS, even without testosterone substitution. The aromatisation of T into E2, related to adiposity, may contribute to the achievement and maintenance of normal BMD in some KS patients.

[Relevance of gestational diabetes mellitus screening and comparison of selective with universal strategies]. / Intérêt du dépistage du diabète gestationnel et comparaison des stratégies ciblée et systématique.

OBJECTIVES: To assess the relevance of gestational diabetes mellitus (GDM) screening policy and to compare selective with universal screening. METHODS: Systematic review of all French and English languages publications in Medline and Cochrane Databases, published since 1990. RESULTS: Maternal hyperglycemia is associated with increased maternal and neonatal complications. The 75 g OGTT (Oral Glucose Tolerance Test) is a valid and reliable test for GDM diagnosis. Treatment of GDM reduces perinatal complications. Selective screening allows to limit false positive rate and to concentrate medical resources. Nevertheless, screening might be more difficult to perform and lead to miss up to 45% of GDM cases. Universal screening offers higher sensitivity but leads to more therapeutic interventions whose benefit and cost/efficiency ratio need to be estimated in low risk women. CONCLUSION: The benefits of GDM screening and treatment have only been proven for women with GDM risk factors. Their relevance in women without risk factor remains controversial.

Relevance of gestational diabetes mellitus screening and comparison of selective with universal strategies.

OBJECTIVES: To assess the relevance of gestational diabetes mellitus (GDM) screening policies and to compare selective with universal screening. METHODS: Systematic review of all French and English language publications in the Medline and Cochrane Databases, published since 1990. RESULTS: Maternal hyperglycaemia is associated with increased maternal and neonatal complications. The 75g OGTT (Oral Glucose Tolerance Test) is a valid and reliable test for GDM diagnosis. Treatment of GDM reduces perinatal complications. Selective screening helps limit false positive rates and concentrate medical resources. Nevertheless, screening could be more difficult and lead to missing up to 45% of GDM cases. Universal screening offers higher sensitivity but leads to more therapeutic interventions whose benefit and cost/effectiveness ratio need to be estimated in low risk women. CONCLUSION: The benefits of GDM screening and treatment have only been proven for women with GDM risk factors. Their relevance in women without risk factor remains controversial.

Birth defects observed with maternal carbimazole treatment: Six cases reported to Nice's Pharmacovigilance Center.

GOALS: To report cases of embryopathy occurring following first trimester exposure to anti-thyroid drugs. METHODS: Retrospective screening of the database of our Pharmacovigilance Center from 1987 to date. RESULTS: We report six cases of embryopathy, all following carbimazole exposure during the first trimester: two cases of abdominal wall defect, including one associated with facial dysmorphia; one case of digestive malformation (patent omphalomesenteric duct); two cases of aplasia cutis including one with facial dysmorphism; one case of bilateral choanal atresia with aorta coarctation associated with poorly controlled insulin dependent diabetes. Four out of five patients were euthyroid with treatment during the first trimester. We found a context suggesting genetic predisposition to congenital malformation in three cases: two cases of parental cleft lip/palate, one case of consanguinity. Outcome was favorable in all cases. CONCLUSIONS: We want to raise awareness about the potential teratogenicity of carbimazole, probably on a predisposed genetic background. We suggest better reporting of congenital anomalies in children of women with Graves'disease, with or without in utero exposure to anti-thyroid drugs. In light of current literature, propylthiouracil should be the first line treatment for hyperthyroid women wishing a pregnancy.

Lethal acute demyelinization with encephalo-myelitis as a complication of cured Cushing's disease.

Cushing's disease is usually associated with higher mortality rate, especially from cardiovascular causes. Development or exacerbation of autoimmune or inflammatory diseases is known to occur in patients with hypercortisolism after cure. We report for the first time a 34-year old woman with a psychiatric background, who developed four months after the surgical cure of Cushing's disease an acute disseminated encephalomyelitis (ADEM) presenting initially as a psychiatric illness. We hypothesize that the recent correction of hypercortisolism triggered ADEM and that the atypical presentation, responsible for diagnosis delay, led to the death of this patient.

Use of insulin glargine throughout pregnancy in 102 women with type 1 diabetes.

AIM: The aim of this study was to examine the safety of insulin glargine during pregnancy in women with type 1 diabetes mellitus (T1DM). METHODS: This retrospective multicentre study involved women with T1DM treated with insulin glargine before conception and throughout pregnancy. The main investigated parameters were HbA(1c) during the first and third trimesters, major congenital malformations, and perinatal mortality and complications. RESULTS: For the 102 women with T1DM in the study, HbA(1c) during the first and third trimesters was 6.7+/-1.2% (95% CI 6.4-6.9%) and 6.2+/-0.9% (95% CI 6.0-6.4%), respectively. Two congenital malformations (2%) were reported, and one stillbirth (1%) occurred at week 35 of gestation. The rate of preterm delivery was 23%. The mean birth weight was 3381+/-595 g (95% CI 3255-3506 g), and the proportion of large-for-gestational-age infants was 30%. CONCLUSION: Insulin glargine use throughout pregnancy does not appear to be associated with an increased rate of severe congenital malformations.

Polycystic ovary syndrome (PCOS).

1. The Rotterdam classification should be used to define PCOS in the event of: menstrual cycle anomalies; amenorrhoea, oligomenorrhoea or long cycles, clinical and/or biochemical hyperandrogenism and ultrasound appearance of polycystic ovaries. 2. The presence of two of these three criteria is sufficient once all other diagnoses have been ruled out. 3. Diagnosis of hirsutism should not be based on the Ferriman-Gallway score. 4. The ultrasound definition of PCOS contains precise criteria that must be included in the report: presence of at least 12 follicles in each ovary measuring 2-9 mm in diameter, and/or increase in ovary size>10 ml. 5. Screening for elevated plasma LH no longer necessary. Testing for GnRH serves no purpose. 6. Routine screening for metabolic abnormalities should be carried out systematically based on weight, height and BMI, waist circumference, blood pressure and laboratory parameters: plasma glucose, triglycerides, HDL cholesterol. 7. In the case of obesity (BMI>30 kg/m(2)), oral glucose tolerance testing (OGTT) is recommended where fasting serum glucose is normal. 8. Clomiphene citrate (CC) remains the first-line therapy for ovulation induction. In patients with BMI>30, it should be preceded by improvement of metabolic status through appropriate lifestyle modifications.

[Iodine status and thyroid function of 330 pregnant women from Nice area assessed during the second part of pregnancy]. / Statut iodé et fonction thyroïdienne chez 330 femmes de la région niçoise évaluées en deuxième partie de grossesse.

BACKGROUND: Iodine deficiency (ID) is still common in Western Europe and its prevention remains a challenge, particularly during pregnancy. METHODS: We studied 330 pregnant women in the third trimester of pregnancy for ioduria (UIE) and thyroid tests (TSH, fT4). We collected information on personal history of thyroid disease and treatment with thyroid hormones or iodinated pregnancy tablets. RESULTS AND DISCUSSION: Median UIE was 64 microg/l, reflecting inadequate iodine intake in our population. According to the UIE threshold used for diagnosis (100 to 150 microg/l), ID was present in 74.3% to 85.8% of women; 5.4% had excessive iodine intake, including one taking iodine fortified tablets. Only 8.8% had adequate intake, suggesting that current strategies to eradicate ID are inefficient in our country. Among the 22 women taking iodine supplements, only three had adequate UIE and four had UIE below the detection level, which could suggest either poor compliance or insufficient supplementation. Median fT4 was 12.3pmol/l (8-20.1) and TSH 1.93mUI/l (0.24-6.57). We used different thresholds proposed in the literature to diagnose: hypothyroxinemia: 41.2% were less than 12pmol/l, 10% less than 10.3pmol/l and 1.8% less than 9pmol/l (lower limit of our reference range); subclinical hypothyroidism: 26.3% had TSH greater than 2.5 or 3.9% greater than 4mUI/L, 1.2 to 13% had combined low fT4 (<9pmol/l or <12pmol/) and higher TSH (>2.5mUI/l). There was no correlation between UIE and thyroid tests, nor maternal predicting factors for ID. CONCLUSION: ID is common in our population. The wide range of hypothyroxinemia and subclinical hypothyroidism prevalence should also trigger reflection of diagnostic thresholds and therapeutic intervention.

Unilateral testicular tumour associated to congenital adrenal hyperplasia: Failure of specific tumoral molecular markers to discriminate between adrenal rest and leydigioma.

Testicular adrenal rest tumours are frequently associated with congenital adrenal hyperplasia (CAH). These ACTH-dependent tumours cannot be easily distinguished histologically from Leydig-cell tumours. We report the case of a 30-year-old man who was explored for infertility, azoospermia and unilateral testicular tumour. High levels of 17-OH progesterone and ACTH, low cortisol and undetectable gonadotropins levels, associated to bilateral adrenal hyperplasia, led to the diagnosis of CAH by 21-OH deficiency with a composite heterozygoty. The testicular tumour was first considered as adrenal rest. However, histological analysis of this unilateral painful tumour showed a steroid-hormone-secreting cell proliferation with atypical and frequent mitosis. To discriminate between a benign adrenal rest tumour and a possible malignant leydigioma, tumoral expression of specific gene products was analyzed by RT-PCR. No 11-beta-hydroxylase nor ACTH receptor mRNAs could be found in the tumour, which did not behave like usual adrenal rest cells. For this unilateral testicular tumour, the lack of adrenal-specific markers associated with a high rate of mitosis and pleiomorphism supported a leydigian origin with malignant potential. However, lack of tumoral LH-R mRNA expression and a tumour-free 3-year follow-up led us to retain the diagnosis of adrenal rest tumour with loss of adrenal gene expression and progressive autonomous behaviour.

Auto-immune cerebellar ataxia with anti-GAD antibodies accompanied by de novo late-onset type 1 diabetes mellitus.

UNLABELLED: Autoantibodies to glutamic acid decarboxylase (GAD-Ab) have been described in stiff-man syndrome, type 1 diabetes mellitus and in patients with auto-immune polyglandular failure. In addition, a few patients with progressive cerebellar ataxia show high titres of GAD-Ab, suggesting an auto-immune origin. AIM: This is a report of a patient presenting with cerebellar ataxia associated to late-onset type 1 diabetes and polyendocrine auto-immunity. CASE REPORT: A 47-year-old woman with a past medical history of vitiligo and Graves' disease presented with late-onset type 1 diabetes. For two years, she had complained of progressive gait instability and oscillopsia. Neurological examination revealed multidirectional, horizontal rotatory fixation and gaze nystagmus, gait ataxia and mild limb ataxia in the left upper arm. METHODS: Imaging studies, electrophysiological studies, routine biological and detailed immunological screening as well as a study of cerebrospinal fluid (CSF) were performed. RESULTS: Brain magnetic resonance imaging showed cerebellar atrophy. Routine biological screening was normal. Immunological screening showed positivity for numerous antibodies (Ab), including GAD-Ab, thyroid peroxidase-Ab, thyroglobulin-Ab, 21-hydroxylase (adrenal)-Ab, gastric parietal cell-Ab and GM1 ganglioside IgG-Ab. CSF was normal, with no oligoclonal bands detected. GAD-Ab were positive in CSF, suggesting an auto-immune origin of the cerebellar ataxia. Treatment with intravenous immunoglobulin led to a slight improvement in nystagmus and gait instability. CONCLUSION: Auto-immune cerebellar ataxia related to GAD-Ab is a rare condition that typically affects women with late-onset type 1 diabetes or other auto-immune disorders, including auto-immune polyendocrinopathy. Immunomodulatory treatment may be effective.

Adrenal tuberculosis after a pheochromocytoma: a misleading tumoral presentation.

Adrenal gland involvement could account for 6% of active tuberculosis. The diagnosis of this extrapulmonary form of tuberculosis is difficult, especially when presenting as unilateral adrenal tumor. This report describes an unusual case of adrenal tuberculosis presenting as a tumor occurring shortly after surgical removal of an adrenal pheochromocytoma located in the opposite gland, in a 63-year-old woman with a previous history of breast cancer. At initial presentation, the patient suffered from symptomatic paroxysmal hypertension. A pheochromocytoma in the left adrenal was diagnosed and resected. One year later, while physical examination and biological parameters were unremarkable, an enhanced adrenal computed tomography (CT) scan showed a right adrenal mass mimicking the CT features of the resected pheochromocytoma. A peripheral tissular rim delineating a central hypodensity characterized this tumor. Magnetic resonance imaging (MRI) showed the same findings on gadolinium-enhanced T1-weighted slices, while the mass was not seen on T2-weighted images. No tumoral signal loss was observed on out of phase images when using the in phase-out of phase T1-weighted sequence. Because of the tumoral evolution and the uncertainty of the nature of that lesion, the patient underwent a second adrenalectomy. Definitive diagnosis was provided by culture of tissue sample, which resulted in the identification of Mycobacterium tuberculosis. In an era of tuberculosis resurgence, this unusual case underscores the necessity of keeping in mind adrenal tuberculosis as a possible differential diagnosis in adrenal tumors of uncertainty nature. It stresses the importance of culture of biopsy tumor, whenever feasible, to avoid unnecessary operations. In the near future, interferon-gamma assay could be a valuable means to recognize extrapulmonary forms of tuberculosis.

Combination of apolipoprotein E2 and lipoprotein lipase heterozygosity causes severe hypertriglyceridemia during pregnancy.

Pregnancy is a physiological condition where plasma triglyceride levels are moderately increased. This results from raised synthesis of very-low-density lipoproteins (VLDL) in response to elevated estrogen levels. The occurrence of marked hypertriglyceridemia (HTG) is rare and may result from combination of heterozygote mutation in the lipoprotein lipase (LPL) gene and apolipoprotein E2 isoform, as reported in this case. This observation illustrates the interaction between genetic and environmental factors, since pregnancy may disclose a silent LPL deficiency. The risk of acute pancreatitis threatens both the mother and fetus lives. Early recognition of severe HTG and appropriate management are essential for a successful pregnancy outcome.

[Pregnancy in type 1 diabetes: insulin pump versus intensified conventional therapy]. / Grossesse et diabète de type 1: pompe à insuline versus traitement intensifié conventionnel.

OBJECTIVES: To evaluate and compare the outcome of pregnancies in women with type 1 diabetes treated with continuous subcutaneous insulin pump or multiple insulin injections. PATIENTS AND METHODS: Thirty-three patients treated with pump, 23 with multiple injections. Were mainly investigated: glycemic control (HbA1C), fetal outcome (congenital malformations, preterm delivery, perinatal mortality), rates of gestational hypertension and cesarean section. RESULTS: HbA1C (1st, 2nd and 3rd trimester) with pump was not significantly different from that obtained with multiple injections (respectively, 7.5 +/- 1.24 vs 7.6 +/- 1.4; 6.34 +/- 0.6 vs 6.6 +/- 0.8; 6.6 +/- 0.7 vs 6.4 +/- 0.7). Fetal prognosis was also similar. The occurrence of gestational hypertension was linked to diabetic complications [OR 5,7, IC95% 1.24-25, p = 0.0025]. The rate of cesarean section (70% in women treated with pump) was influenced by diabetes duration. In planned pregnancy, independently of therapeutic device, HbA1C during organogenesis was better (6.9% +/- 0.78 vs 8.51 +/- 1.3, p < 0.0001) with no perinatal death and no major congenital malformation. DISCUSSION AND CONCLUSION: Fetal prognosis is not overall significantly different with insulin pump compared with intensified conventional therapy. The initiation of insulin pump therapy should not be systematic. Instead, the benefits risks ratio must be assessed resulting in a tailored prescription according to individual needs. This therapeutic choice should be discussed before conception, as planned pregnancy is a main prognostic factor. Diabetes duration and complications remain key factors for the prognosis.

Pregnancy in women with type 2 diabetes: an uncertain prognosis.

The increasing prevalence of type 2 diabetes in women of childbearing age leads to an increasing number of pregnant women with type 2 diabetes. Pregnancy complicated by type 2 diabetes is a high-risk pregnancy, associated with birth defects and high perinatal mortality to the same extent as in type 1 diabetes. Until now, most attention was directed toward women with type 1 diabetes. Recent data stresses the urgent need to develop better screening and efficient care strategies in women with type 2 diabetes, who also display many risk factors for adverse fetal outcome. Family physicians, diabetologists and gynaecologists must be aware of this growing concern. Improvement of pregnancy planning, adequate metabolic control from conception to delivery and a multi-disciplinary team approach to care should improve fetal and maternal outcomes. Furthermore, diabetes screening in high-risk women prior to pregnancy is warranted.