Ovarian reserve in breast cancer: assessment with anti-Müllerian hormone.

Anti-Müllerian hormone (AMH) levels fall during chemotherapy. Treatment-induced amenorrhoea is a reversible phenomenon, but few data are available on long-term AMH changes in breast cancer. The aim of the study was to describe serum AMH levels before, during and in the long term after chemotherapy, and to show a potential AMH recovery. Between May 2010 and June 2011, we selected 134 women aged 18-43 years at the time of breast cancer diagnosis who received chemotherapy between 2005 and 2011, and had not undergone an oophorectomy or had previous cytotoxic treatment. The AMH levels were assessed before, during and 4 months to 5.5 years after the end of chemotherapy. During chemotherapy, AMH was undetectable in 69% of women. After chemotherapy, a significant increase in AMH was found, with an average magnitude of +1.2% per month (95% credibility interval: 0.7 to 1.6). Older age and 12 months of amenorrhoea were found to be associated with a lower AMH recovery rate, whereas baseline AMH and number of chemotherapy cycles were not. The process of AMH changes during and after chemotherapy is dynamic, and shows recovery after ovarian injury. Caution should be exercised in interpreting individual AMH assessment in this context.

Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism.

Among the pathogenic processes contributing to dopaminergic neuron (DN) death in Parkinson disease (PD), evidence points to non-cell-autonomous mechanisms, particularly chronic inflammation mounted by activated microglia. Yet little is known about endogenous regulatory processes that determine microglial actions in pathological states. We examined the role of glucocorticoid receptors (GRs), activated by glucocorticoids released in response to stress and known to regulate inflammation, in DN survival. Overall GR level was decreased in substantia nigra of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. GR changes, specifically in the microglia after MPTP treatment, revealed a rapid augmentation in the number of microglia displaying nuclear localization of GR. Mice with selective inactivation of the GR gene in macrophages/microglia (GR(LysMCre)) but not in DNs (GR(DATCre)) showed increased loss of DNs after MPTP intoxication. This DN loss in GR(LysMCre) mice was not prevented by corticosterone treatment, in contrast to the protection observed in control littermates. Moreover, absence of microglial GRs augmented microglial reactivity and led to their persistent activation. Analysis of inflammatory genes revealed an up-regulation of Toll-like receptors (TLRs) by MPTP treatment, particularly TLR9, the level of which was high in postmortem parkinsonian brains. The regulatory control of GR was reflected by higher expression of proinflammatory genes (e.g., TNF-α) with a concomitant decrease in anti-inflammatory genes (e.g., IL-1R2) in GR(LysMCre) mice. Indeed, in GR(LysMCre) mice, alterations in phosphorylated NF-κB levels indicated its protracted activation. Together, our data indicate that GR is important in curtailing microglial reactivity, and its deregulation in PD could lead to sustained inflammation-mediated DN injury.

Leptin is better than any other biological parameter for monitoring the efficacy of renutrition in hospitalized malnourished elderly patients.

OBJECTIVE: Despite malnutrition being a major problem in hospitalized elderly patients, there is a lack of studies focusing on the comparative value of biological parameters for monitoring renutrition. The aim of this study was to determine which biological parameter(s) could best monitor successful renutrition in hospitalized malnourished elderly patients. DESIGN: The objective of the study was to explore the impact of a 6-week renutrition process on anthropometric and biological parameters in elderly patients and to define the biological parameters associated with weight regain. PATIENTS: A total of 72 hospitalized malnourished elderly patients admitted to a hospital-based geriatric rehabilitation unit. MEASUREMENTS: Patients were evaluated at admission and at 6 weeks for anthropometric measurements of weight, sum of the four subcutaneous skinfold thicknesses, calf circumference and biological serum parameters including albumin, transthyretin, leptin, IGF-1, IGFBP-1 and IGFBP-3. Renutrition was considered successful if a patient gained at least 5% of body weight over 6 weeks. RESULTS: Leptin was the only biological parameter that increased at 6 weeks in successful renutrition. Leptin variations were not influenced by C-reactive protein variations, in contrast to transthyretin which can be modified by the inflammatory states frequently encountered in geriatric patients. CONCLUSIONS: Serum leptin is a more appropriate parameter than transthyretin for monitoring renutrition.

Assessment of theca cell function prior to controlled ovarian stimulation: the predictive value of serum basal/stimulated steroid levels.

BACKGROUND: Serum androgen levels correlate with ovarian sensitivity to follicle-stimulating hormone (FSH) but in practice, standard baseline serum testosterone (T) levels prior to in-vitro fertilization (IVF) may not be the most appropriate marker for determination. METHODS: Infertile women enrolled in an IVF programme were included in this study. Serum T and Delta4-androstenedione (A), and the androgen precursor 17-hydroxyprogesterone (17-OHP) were measured before and 24 h after a gonadotrophin-releasing hormone agonist stimulation test (GAST). An early follicular phase antral follicle count (AFC) was also performed. Patients were subsequently enrolled in a long gonadotrophin-releasing hormone agonist protocol with a standard FSH dose (150 IU) for 7 days to assess the association between androgen levels and ovarian responsiveness to FSH. RESULTS: The GAST elicited a significant increase in serum androgen levels that was well correlated with AFC. 17-OHP showed the greatest response to GAST and strongest correlation with AFC. The 17-OHP response to GAST differentiated patients with high ovarian reserve (OR) from those with low or normal OR as assessed by AFC, whereas only the estradiol response could differentiate those with low AFC. GAST-stimulated serum levels of 17-OHP were also correlated with ovarian response to FSH. Using receiver operating characteristic curve analysis, stimulated 17-OHP levels were predictive of the ovarian response to controlled ovarian stimulation, with similar power to that observed with AFC but lower power than with anti-Müllerian hormone. CONCLUSIONS: Serum androgen levels following GAST are correlated with AFC and ovarian response to FSH. Serum T is a less sensitive marker of theca cell function than 17-OHP.

Impaired glucose tolerance in patients with amyotrophic lateral sclerosis.

Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine potential association with parameters of lipid metabolism and clinical features. Glucose tolerance was assessed by the oral glucose tolerance test in 21 non-diabetic ALS patients and compared with 21 age- and sex-matched normal subjects. Lipids and lactate/pyruvate ratio, levels of pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and adipocytokines (leptin and adiponectin) were also measured in ALS patients. Mann-Whitney U-tests analysed continuous data and Fisher's exact tests assessed categorical data. Blood glucose determined 120 min after the glucose bolus was significantly higher in patients with ALS (7.41 mmol/l+/-1.68) compared to controls (6.05+/-1.44, p=0.006). ALS patients with impaired glucose tolerance (IGT) according to WHO criteria (n=7, 33%) were more likely to have elevated free fatty acids (FFA) levels compared to patients with normal glucose tolerance (0.77 nmol/l+/-0.30 vs. 0.57+/-0.19, p=0.04). IGT was not associated with disease duration or severity. In conclusion, patients with ALS show abnormal glucose tolerance that could be associated with increased FFA levels, a key determinant of insulin resistance. The origin of glucose homeostasis abnormalities in ALS may be multifactorial and deserves further investigation.

Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity.

In human obesity, white adipose tissue (WAT) is enriched in macrophages. How macrophage infiltration in WAT contributes to the complications of obesity is unknown. This study tested the hypothesis that recruitment of macrophages in omental WAT is associated with hepatic damage in obese patients. Paired biopsies of subcutaneous and omental WAT and a liver biopsy were collected during gastric surgery in 46 obese women and 9 obese men (BMI 47.9 +/- 0.93 kg/m(2)). The number of HAM56+ macrophages in WAT was quantified microscopically, and correlations with clinical and biological parameters and histological liver pathology were investigated. There were twice as many macrophages in omental as in subcutaneous WAT (P<0.0001). After adjustment for age, omental WAT macrophage infiltration was correlated to fasting glucose and insulin, quantitative insulin sensitivity check index, triglycerides, aspartate aminotransferase (AST), and gamma-glutamyltranspeptidase. We propose an easy equation to estimate the amount of macrophages in omental WAT. Increased macrophage accumulation specifically in omental WAT was associated with hepatic fibroinflammatory lesions (P=0.01). The best predictive model for the severity of hepatic damage includes adiponectinemia, AST, and omental WAT macrophages. These data suggest that the presence of macrophages in omental WAT participates in the cellular mechanisms favoring hepatic fibroinflammatory lesions in obese patients.

Weight loss reduces adipose tissue cathepsin S and its circulating levels in morbidly obese women.

CONTEXT: Human adipose tissue produces several adipokines, including the newly identified protein cathepsin S (CTSS), a cysteine protease involved in the pathogenesis of atherosclerosis. Obesity is characterized by high levels of CTSS in the circulation and in sc white adipose tissue (scWAT). OBJECTIVE: We investigated the effect of surgery-induced weight loss on circulating CTSS and its protein expression in scWAT. DESIGN: Fifty morbidly obese women before and 3 months after surgery and 10 healthy lean women were studied. We analyzed the relationships between circulating CTSS and clinical and biological parameters. Immunohistochemistry of the CTSS protein variations in scWAT was performed. RESULTS: Weight loss decreased by 42% (P < 0.0001) the circulating CTSS levels, which correlated with changes in body weight (P = 0.03). We observed a significant decrease in CTSS enzymatic activity by 25% after weight loss (P = 0.001). Adipose tissue CTSS content was reduced by 30% (P = 0.002) after surgery. The variations in CTSS expression in scWAT after surgery correlated with changes in circulating CTSS serum levels (P = 0.03). Most of the correlations between CTSS and clinical and biological parameters disappeared after adjustment for body mass index, emphasizing the strong link between CTSS and corpulence in humans. CONCLUSIONS: Changes in CTSS scWAT might contribute to serum variations in CTSS during weight loss. The decrease in CTSS concentrations in the circulation may contribute to vascular improvement in obese subjects after weight loss.

Serum amyloid A and obstructive sleep apnea syndrome before and after surgically-induced weight loss in morbidly obese subjects.

BACKGROUND: Serum amyloid A (SAA) is an inflammatory marker associated with cardiovascular disease (CVD) and found to be increased in obesity. Obstructive sleep apnea (OSA) syndrome, a frequent complication of obesity also associated with CVD risk, is improved after surgically-induced weight loss. To explore the potential role of SAA in the relation between OSA and CVD, we investigated relationships between changes in SAA concentrations and nocturnal respiratory events in obese subjects undergoing bariatric surgery. METHODS: We measured plasma SAA and used nocturnal respiratory polygraphy to assess the apneahypopnea index (AHI), the oxygen desaturation index (ODI) and the mean and lowest O(2) saturation (SaO(2) ) in 61 morbidly obese patients before either adjustable gastric banding or gastric bypass. For 35 subjects with OSA, the same data were obtained 1 year after the surgery. RESULTS: Before surgery, SAA concentrations were significantly higher in patients with severe OSA (56.2+/-6.4 microg/ml) compared to subjects with moderate OSA (22.9+/-3.2 microg/ml) or without OSA (16.2+/-2.2 microg/ml). Plasma SAA correlated positively with AHI and ODI, and negatively with mean and lowest SaO(2). After surgery, plasma SAA decreased significantly by 41.7%, and changes in plasma SAA correlated with variations in OSA parameters. In multivariate analyses, AHI was a predictor of plasma SAA, independent of BMI, both at baseline and during weight loss. CONCLUSION: The improvement of OSA after bariatric surgery is associated with a decrease in SAA, independent of the change in BMI. SAA may represent a marker of the improvement in CVD risk profile after surgically-induced weight loss in patients with OSA.

Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis.

The molecular mechanisms by which obesity increases the risk of cardiovascular diseases are poorly understood. The purpose of this study was to identify candidate biomarkers overexpressed in adipose tissue of obese subjects that could link expanded fat mass to atherosclerosis. We compared gene expression profile in subcutaneous adipose tissue (scWAT) of 28 obese and 11 lean subjects using microarray technology. This analysis identified 240 genes significantly overexpressed in scWAT of obese subjects. The genes were then ranked according to the correlation between gene expression and body mass index (BMI). In this list, the elastolytic cysteine protease cathepsin S was among the highly correlated genes. RT-PCR and Western blotting confirmed the increase in cathepsin S mRNA (P=0.006) and protein (P<0.05) in obese scWAT. The circulating concentrations of cathepsin S were also significantly higher in obese than in nonobese subjects (P<0.0001). Both cathepsin S mRNA in scWAT and circulating levels were positively correlated with BMI, body fat, and plasma triglyceride levels. In addition, we show that the proinflammatory factors, lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha increase cathepsin S secretion in human scWAT explants. This study identifies cathepsin S as a novel marker of adiposity. Since this enzyme has been implicated in the development of atherosclerotic lesions, we propose that cathepsin S represents a molecular link between obesity and atherosclerosis.

One-year changes in energy expenditure and serum leptin following adjustable gastric banding in obese women.

BACKGROUND: Weight loss is associated with a decrease in both energy expenditure and circulating leptin levels. Whether this holds true when the influence of body composition on energy expenditure and leptin is taken into account remains controversial. The aim of the study was to assess changes in resting metabolic rate (RMR) and serum leptin adjusted for body composition during surgically induced weight loss. METHODS: In 36 women (age 42.7+/-8.7 years; BMI 47.2+/-8.5 kg/m(2); mean+/-SD) undergoing laparoscopic adjustable gastric banding (LAGB) for morbid obesity, we measured RMR (by indirect calorimetry), body composition (by dual-energy X-ray absorptiometry) and serum leptin (by immunoradiometry), immediately before and 1 year after surgery. RESULTS: 1 year after LAGB, there were significant decreases in body weight (-23.7+/-11.6 kg, P<0.001), fat mass (FM: -20.9+/-11.3 kg, P<0.0001), lean body mass (LBM: -3+/-5.3 kg, P=0.005), RMR (-298+/-309 kcal/day, P<0.0001), serum leptin (-24.0+/-18.4 ng/ml, P<0.0001), RMR/LBM ratio (-3.9+/-5.8 kcal/kg LBM/day, P<0.01) and leptin/FM ratio (-0.21+/-0.29 ng/kg FM/ml, P<0.001). RMR values after surgery were correctly predicted by the regression equation relating RMR to LBM and FM at baseline, whereas this was not the case for serum leptin (in relation to FM). CONCLUSIONS: Changes in RMR 1 year after LAGB were explained by changes in body composition whereas changes in serum leptin were not. The data provide no evidence for a metabolic adaptation of RMR with weight loss, but suggest that serum leptin is decreased beyond expected values based on body composition, a factor that may favor weight regain after surgically induced weight loss.

Relationship between single nucleotide polymorphisms in leptin, IL6 and adiponectin genes and their circulating product in morbidly obese subjects before and after gastric banding surgery.

BACKGROUND: Certain adipose-produced signals are secreted in proportion to body fat mass and are involved in regulation of the energy metabolism of the whole body. Leptin, IL6 and adiponectin can be considered as adiposity signals. Several Single Nucleotide Polymorphisms (SNPs) in genes encoding for these molecules are known to influence their concentration in situations of stable weight. We hypothesized that polymorphism effects could be better detected in a situation of negative energy balance and that modified concentrations of adiposity signal genes could change the dynamics of weight gain in obese subjects. METHODS: 65 obese patients undergoing gastric banding surgery were genotyped for LEP+19A-->G, LEP-2548G-->C, IL6-174G-->C, APM1-11377C-->G and PM1-11391G-->A common SNPs. BMI and concentrations of leptin, IL6 and adiponectin were measured before surgery and after 1 year. RESULTS: All SNPs except IL6-174G-->C SNP were associated with modifications of the circulating concentrations of signals produced by adipose tissue at baseline. During weight loss, variant genotype carriers of LEP -2548 and +19 SNPs were characterized by a trend towards less decrease in circulating leptin. Weight loss was associated with an increase in IL6 concentration (16.9%+/-12.2) in the IL6-174 C/C genotype carriers, whereas the C/G or G/G genotypes carriers showed a decrease in IL6 (19.9%+/-5.2, P=0.001). CONCLUSION: We observed that the SNPs studied could modulate the concentration of adiposity signals not only at baseline but also during weight loss. Such variations may be sensed by the homeostatic feedback system that controls energy balance and may in turn contribute to some disturbances in weight regulation.

Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy.

OBJECTIVES: Adipocytokines, secreted by adipose tissue, may regulate fat metabolism, lipid and glucose homeostasis and insulin sensitivity. We analysed the relations between circulating concentrations of adiponectin, leptin, interleukin-6, tumor necrosis factor alpha and its soluble receptors sTNFR1 and R2, lipodystrophic phenotypes and metabolic alterations in patients under highly active antiretroviral therapy (HAART). METHODS: We studied 131 consecutive HIV-infected males under protease inhibitor (PI)-based HAART, with body mass index < 27 kg/m2 and C-reactive protein (CRP) < 10 mg/l. Patients were classified in four groups according to clinical examination: no lipodystrophy (NL), lipohypertrophy (LH), lipoatrophy (LA) and mixed lipodystrophy (ML). In addition to adipocytokines, we measured plasma fasting levels of triglycerides, cholesterol, cardiovascular risk markers (high-sensitivity CRP and apolipoproteins B/A1 ratio), fasted and 2 h post-glucose loading glycemia and insulinemia and calculated the quantitative insulin sensitivity check index. RESULTS: The patients were HIV-infected and PI-treated for a mean of 8.2 and 1.6 years respectively; 74% presented lipodystrophy, 38% altered glucose tolerance and 42% hypertriglyceridemia. Insulin sensitivity correlated positively with adiponectin and negatively with leptin and interleukin-6. Adiponectin, but not leptin, negatively correlated with all metabolic parameters. Insulin resistance, metabolic defects and cardiovascular risk markers were strongly negatively correlated with the adiponectin/leptin ratio (A/L), and positively with sTNFR1. LA patients had a longer duration of infection but ML patients presented the most severe metabolic alterations, insulin resistance and A/L decrease. CONCLUSIONS: These results suggest that adiponectin and the TNFalpha system are related to lipodystrophy, insulin resistance and metabolic alterations in patients under PI-based HAART. A/L and sTNFR1 could predict insulin sensitivity and potential cardiovascular risk in these patients.

Adiponectin gene expression in subcutaneous adipose tissue of obese women in response to short-term very low calorie diet and refeeding.

Adiponectin is an adipocyte-derived protein suggested to be involved in energy homeostasis and in lipid and glucose metabolism. Little is known regarding the consequence of acute changes in energy balance on adiponectin mRNA expression in human adipose tissue. Using a real-time RT-PCR assay, we investigated the effects of 2-d very low calorie diet (VLCD) and subsequent refeeding on adiponectin mRNA expression in sc adipose tissue of morbidly obese women. Basal adiponectin mRNA abundance of the obese women showed a wide distribution (2.6-14.3 mRNA/18S rRNA; coefficient of variation, 51.2%) and was significantly lower than that of lean controls (P < 0.001). In the obese group, the VLCD caused a 33% rise (P < 0.01) in the average level of mRNA, whereas refeeding caused a 32.8% fall (P < 0.05). In contrast, the change in leptin mRNA expression with either VLCD or refeeding was not statistically significant. The obese subjects who showed an acute adiponectin mRNA response to the changes in energy intake had a higher basal level of adiponectin mRNA (P = 0.02) and a borderline-significantly lower body mass index compared with the subjects who showed no or weak adiponectin mRNA response. Insulin sensitivity of the responder subgroup significantly increased by 89% (P = 0.008) after the VLCD, whereas insulin sensitivity of the nonresponder subgroup only increased by 24% (P = 1.56). This study indicates that adiponectin mRNA in sc adipose tissue can acutely respond to short-term energy changes in some obese subjects. Both the levels of adiposity and insulin sensitivity may contribute to the variation in adiponectin gene expression in response to acute energy changes.

Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction in the antiphospholipid syndrome: long-term outcome of 16 patients.

CONTEXT: Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction is a rare and life-threatening manifestation of the antiphospholipid syndrome (APLS). Data on the long-term outcome are scarce. OBJECTIVE: The aims of the present study were to analyze the long-term outcome related to APLS per se and to characterize the course of adrenal involvement. DESIGN: We conducted a retrospective study of patients with bilateral adrenal hemorrhage-adrenal infarction secondary to APLS seen in the Department of Internal Medicine of Pitié-Salpêtrière Hospital in Paris (France) between January 1990 and July 2010. RESULTS: Three patients died during the acute phase related to APLS manifestations. Sixteen patients (7 males; 9 females) were followed up during a median period of 3.5 years (range 0.3-28.1 years). Three episodes of recurrent thrombosis were noted. One patient died from cerebral hemorrhage 3 months after the onset of adrenal insufficiency. Repeated Synacthen tests showed complete absence of response in 8 of the 10 patients assessed; cortisol and aldosterone increased appropriately in one patient and to some extent in another one. Dehydroepiandrosterone levels and 24-hour urinary epinephrine levels remained abnormally low in all evaluated patients. Adrenal imaging performed more than 1 year after the initial event revealed completely atrophic glands in 9 of 11 patients. CONCLUSIONS: This particular subset of APLS patients who survive the acute phase has a rather favorable long-term outcome. Although adrenal dysfunction is generally irreversible, adrenocortical function may, at least partially, recover in rare cases. In this view, measurement of early morning cortisol during follow-up is indicated to detect these patients.

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia.

OBJECTIVE: Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility. DESIGN: Case/control study. METHODS: Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28 ± 3 days), were included. LH pulse patterns over 6 h were determined in patients and controls. RESULTS: No differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels. CONCLUSIONS: LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.

Impact of clinical, hormonal, radiological, and immunohistochemical studies on the diagnosis of postmenopausal hyperandrogenism.

OBJECTIVE: Evaluation of postmenopausal women with suspicion of androgen-secreting tumor. DESIGN AND PATIENTS: We retrospectively studied 22 postmenopausal women referred to our center for suspicion of androgen-secreting tumor. All patients had clinical, biological, and morphological evaluation. In absence of adrenal tumors, ovarian surgery was most often proposed and immunohistochemistry (IHC) studies were performed. RESULTS: Ovarian tumors were detected by ultrasound and/or magnetic resonance imaging in eight patients. Two adrenal androgen-secreting tumors were diagnosed by an adrenal computed tomography (CT) scan. The clinical presentation of the women with or without tumors was similar. Nevertheless, women with tumor exhibited significantly higher testosterone levels and lower basal FSH and LH levels than the other women (2.6±2.7 vs 0.9±0.9 ng/ml, P<0.05; 26.5±22.9 vs 66.5±26.0 IU/l, P<0.01; and 12.0±8.6 vs 24.1±8.9 IU/l, P<0.05 respectively). Based on a likelihood ratio test, patients with a tumor had 8.4 and 10.8 times higher risk of having a testosterone level ≥1.4 ng/ml or an FSH level ≤35 IU/l. Finally, IHC analysis with an anti-P450c17α antibody allowed the identification of an elevated number of ovarian androgen-producing cells in five patients in whom no tumor was found. CONCLUSIONS: Androgen-secreting tumors are clinically difficult to discriminate from other causes of postmenopausal hyperandrogenism. Testosterone and FSH were the two discriminative markers in a multivariate analysis. Ovarian and adrenal tumors were detected by imaging studies. However, ovarian non-tumoral causes of hyperandrogenism may be difficult to detect with conventional histology.

Children and adolescents with severe mental illness need vitamin D supplementation regardless of disease or treatment.

BACKGROUND: To protect against osteoporosis, keeping the vitamin D blood level (25[OH]D; VDBL) above 30 ng/mL is recommended. It is established that regular intake of vitamin D, calcium intake, and physical exercise contribute to maximizing bone mineral mass during childhood and adolescence. Recent articles suggest that patients with schizophrenia treated with antipsychotics have low VDBL and may have a higher risk of hip fractures in their later years than the general population. OBJECTIVES: To evaluate whether adolescent psychiatric inpatient VDBL is lower than the 30-ng/mL optimal threshold and to document low-VDBL risk factors. METHOD: We determined the VDBL of all consecutive inpatients from three adolescents units in 2009 (N = 136). Univariate analyses explored the influence on VDBL of (1) well-documented risk factors (e.g., age, gender, ethnic origin, body mass index, or season) and (2) suspected risk factors (e.g., disease type or antipsychotic treatment). RESULTS: All but six patients had a VDBL <30 ng/mL (mean [ ± SD]: 15.9 [ ± 8.4] ng/mL). VDBL was significantly lower for all patients during the first quarter of the year compared to the other three (all p < 0.01). VDBL was also lower for blacks/North Africans 12.8 (±7.0) than for Caucasians/Europeans 17.2 (±8.5): t = 2.62, p = 0.009. We found no differences between patients regarding disease category (K = 3.75, p = 0.154) or antipsychotic treatment (t = 0.127, df = 124, p = 0.89). CONCLUSION: VDBL in an adolescent population with severe mental illness is lower than current recommendations of optimal level for bone health regardless of treatment or disease type. Because adolescence is a period of bone construction and could represent a critical window of opportunity for maximizing bone mass, especially among patients with severe mental illness, we recommend vitamin D supplementation.

Resumption of ovarian function and pregnancies in 358 patients with premature ovarian failure.

CONTEXT: Resumption of ovarian activity and spontaneous pregnancies are described in patients with premature ovarian failure (POF), but there is a lack of data concerning the prevalence of and predictive factors for these phenomena. OBJECTIVE: The aim of the study was to determine both the prevalence of and predictive factors for spontaneous resumption of ovarian function in POF patients. DESIGN AND SETTING: A mixed retrospective and prospective study was performed at a referral center for reproductive endocrinology. PATIENTS: A total of 358 consecutive POF patients were followed from 1997 to 2010 in our center. MAIN OUTCOMES MEASURES: The cumulative incidence of resumption of ovarian function was determined, and predictive factors were identified by univariate and multivariate analysis. RESULTS: Of 358 patients with idiopathic POF, 86 (24%) patients presented features indicating resumption of ovarian function, and in 77 cases (88%) within 1 yr of diagnosis. Twenty-one spontaneous pregnancies (16 births, five miscarriages) occurred in 15 (4.4%) patients. Multivariate analysis (Cox model) showed that a familial history of POF, secondary amenorrhea, presence of follicles at ultrasound, and inhibin B and estradiol levels were significantly predictive of resumption of ovarian function (P < 0.01), whereas association with an autoimmune disease, anti-mullerian hormone level, the presence of follicles on biopsy, and/or genetic abnormalities did not appear predictive. We created a predictive score for resumption of ovarian function comprising age at diagnosis, presence of follicles at ultrasound, and inhibin B level. CONCLUSION: Intermittent ovarian activity in patients with POF is not a rare phenomenon. The predictive score described in this study may help us to identify POF patients most likely to recover intermittent ovarian function.

Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: In contrast to subfertility often reported in women suffering from the classical form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, fertility in nonclassical CAH (NC-CAH) has been rarely studied. Our objective was to evaluate fertility in NC-CAH women. MATERIAL AND METHODS: We studied 190 NC-CAH women (161 probands + 29 first degree relatives). Only 20 probands had consulted for infertility (12%), either alone or associated with hirsutism or menstrual cycle disorders. The diagnosis was established on post-ACTH 17-hydroxyprogesterone 10 ng/ml or greater and further characterized by CYP21A2 gene analysis. RESULTS: Ninety-five of the 190 women wanted pregnancy (aged 26.7 +/- 8.9 yr); 187 pregnancies occurred in 85 women, which resulted in 141 births in 82 of them. Ninety-nine pregnancies (52.9%) occurred before the diagnosis of NC-CAH (96 spontaneously and three with ovulation inducers) whereas 98 occurred after diagnosis (11 spontaneously and 77 with hydrocortisone treatment); 83% of pregnancies were obtained within 1 yr. The rate of miscarriages was 6.5% for pregnancies obtained with glucocorticoid treatment vs. 26.3% without. Two of the 141 infants (1.5%) were born with classical CAH. CONCLUSION: Subfertility is mild in NC-CAH. However, the rate of miscarriages is lower in pregnancies occurring with glucocorticoid treatment and argues for treating NC-CAH women wanting pregnancy. In addition, considering the high rate of heterozygotes for CYP21A2 mutations in the general population, it is essential to genotype the partner of patients with a severe mutation to predict the risk of classical CAH and offer genetic counseling.