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Purpose of reviewThe mechanism of puberty initiation remains an enigma, despite extensive research in the field. Pulsatile pituitary gonadotropin secretion under the guidance of hypothalamic gonadotropin-releasing hormone (GnRH) constitutes a sine qua non for pubertal onset. In turn, the secretion of GnRH in the human hypothalamus is regulated by kisspeptin and its receptor as well as by permissive or opposing signals mediated by neurokinin B and dynorphin acting on their respective receptors. These three supra-GnRH regulators compose the Kisspeptin, Neurokinin B and Dynorhin neurons (KNDy) system, a key player in pubertal onset and progression.Recent findingsThe recent discovery that makorin ring finger protein 3 is also involved in puberty initiation provided further insights into the regulation of the KNDy pathway. In fact, the inhibitory (-amino butyric acid, neuropeptide Y, and RFamide-related peptide-3) and stimulatory signals (glutamate) acting upstream of KNDy called into question the role of makorin ring finger protein 3 as the gatekeeper of puberty. Meanwhile, the findings that neuroestradiol' produced locally and endocrine disruptors from the environment may influence GnRH secretion is intriguing. Finally, epigenetic mechanisms have been implicated in pubertal onset through recently discovered mechanisms.SummaryThe exact molecular machinery underlying puberty initiation in humans is under intensive investigation. In this review, we summarize research evidence in the field, while emphasizing the areas of uncertainty and underlining the impact of current information on the evolving theory regarding this fascinating phenomenon.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder with a significant psychological burden throughout the life course of affected women. Thus, use of mindful awareness may be beneficial as an adjunct to conventional medical management of women with PCOS. A randomized, controlled trial was conducted at the Evgenideion Hospital of the Athens University Medical School to explore the impact of an 8-week mindfulness stress management program on measures of depression, anxiety and stress as well as on the quality of life in reproductive age women with PCOS. The study was approved by the Research Ethics Committee. Twenty-three and 15 women with PCOS were randomly allocated to the intervention or control group, respectively. All participants were administered DASS21, PSS14, PCOSQ, Daily Life and General Life Satisfaction Questionnaires and provided three-timed daily samples of salivary cortisol, before and after the intervention. Intervention group participants were provided with the Credibility/Expectancy Questionnaire at the day of enrolment, to check for possible placebo effect on the outcome. Post-intervention, between-group results revealed statistically significant reductions in stress, depressive and anxiety symptoms, as well as in salivary cortisol concentrations, along with an increase in Life Satisfaction and Quality of Life scores in the intervention group only. There was no significant “placebo” effect on the outcome measures. Mindfulness techniques seem promising in ameliorating stress, anxiety, depression and the quality of life in women with PCOS and could be used as an adjunct method to the conventional management of these women.

BACKGROUND: Visceral adiposity index (VAI) is a novel gender-specific index based on waist circumference (WC), BMI, and lipid parameters. Although VAI does not actually estimate visceral adiposity, it accurately reflects visceral fat function and insulin resistance. This index has not been studied in children thus far. This study aims to fill this gap. METHODS: In a cohort of Saudi children and adolescents, anthropometric measurements and metabolic/hormonal profile were obtained. RESULTS: A total of 543 subjects, 292 of whom were boys, were included (mean age: 11.9 +/- 3.3 y; BMI: 19.8 +/- 5.6 kg/m(2)). In all subjects, VAI was inferior to BMI and WC regarding its correlations with adiponectin, leptin, insulin resistance (homeostasis model of assessment insulin resistance (HOMA-IR)), C-reactive protein (CRP) level, and systolic blood pressure, but it exhibited a stronger association with glucose in boys (r = 0.23; P < 0.01). In stepwise multivariate analyses, only BMI was consistent as an independent predictor of adiponectin, leptin, HOMA-IR, and CRP. VAI was the only index independently associated with glucose. CONCLUSION: Although VAI is related to glucose in children, it seems to be inferior to BMI in terms of association with insulin resistance, adipokines, and subclinical inflammation. Until specific studies can be performed in children, VAI should be extrapolated with caution in this age range.

Background Visceral Adiposity Index (VAI) is a gender-specific mathematical index estimated with the use of simple anthropometric (body mass index and waist circumference) and biochemical (triglycerides and high density lipoprotein cholesterol) parameters. Recent studies have shown that VAI reflects accurately the degree of visceral adiposity and insulin resistance. However, up to now, VAI has not been evaluated if it correlates with carbohydrate metabolism disorders, as well as with adipokine secretion from the fat mass. Methods In a cohort of 308 out of 414 adult Saudi subjects screened for the study, detailed personal medical history, anthropometrics and metabolic/hormonal profiles were obtained. Additionally, the circulating concentrations of several circulating adipokines, namely adiponectin, leptin, tumour necrosis factor-alpha (TNF-alpha) and resistin, were measured. Results Stepwise multivariate analysis showed that VAI was the sole determinant of adiponectin levels (R2 = 0.07, beta +/- SE: -0.25 +/- 0.05), while BMI and female gender predicted leptin levels (R2 = 0.26, 0.10 +/- 0.01 and 0.61 +/- 0.15, respectively). Furthermore, the presence of impaired fasting glucose (IFG)/diabetes was predicted only by age and VAI. Conclusions We report for the first time the direct relations of VAI with adipose tissue secretion, as well as with functional glycaemic disorders. Because VAI is estimated easily with data obtained in everyday practice, it could be used as an indirect index of adiponectin levels and the risk of impaired glucose metabolism.

Endocrine complications due to haemosiderosis are present in a significant number of patients with beta-thalassemia major (BTM) worldwide and often become barriers in their desire for parenthood. Thus, although spontaneous fertility can occur, the majority of females with BTM is infertile due to hypogonadotropic hypogonadism (HH) and need assisted reproductive techniques. Infertility in these women seems to be attributed to iron deposition and iron-induced oxidative stress (OS) in various endocrine organs, such as hypothalamus, pituitary, and female reproductive system, but also through the iron effect on other organs, such as liver and pancreas, contributing to the impaired metabolism of hormones and serum antioxidants. Nevertheless, the gonadal function of these patients is usually intact and fertility is usually retrievable. Meanwhile, a significant prooxidants/antioxidants imbalance with subsequent increased (OS) exists in patients with BTM, which is mainly caused by tissue injury due to overproduction of free radicals by secondary iron overload, but also due to alteration in serum trace elements and antioxidant enzymes. Not only using the appropriate antioxidants, essential trace elements, and minerals, but also regulating the advanced glycation end products, could probably reduce the extent of oxidative damage and related complications and retrieve BTM women’s infertility.

The levels of advanced glycation end products (AGEs) are increased under conditions of impaired glucose metabolism and/or oxidative stress, promoting insulin resistance and other endocrine abnormalities. AGEs play a major role in the pathogenesis of several diseases such as diabetes, atherosclerosis, polycystic ovary syndrome and Alzheimer’s disease, contributing to progressive ageing. Receptor-based clearance of AGEs by the receptor for AGE (RAGE) and/or the macrophage scavenger receptor A (SR-A) is considered as a main factor for the regulation of the concentration of AGEs under these conditions. This study aimed to investigate the expression of RAGE (AGER) and SR-A (MSR1) under high/low-dietary AGE conditions in vivo and their potential contribution to the metabolic and sex hormonal profile of female rats. Female Wistar rats were fed a low-AGE or high-AGE diet for 3 months. Serum samples were collected at baseline and at the completion of the 3-month period for the measurements of metabolic and hormonal parameters. Peripheral blood mononuclear cells (PBMCs) were isolated for the determination of the expression of RAGE and SR-A. The high-AGE diet-fed rats exhibited increased glucose, insulin and testosterone levels as well as decreased oestradiol and progesterone levels compared with the low-AGE diet-fed ones, thus indicating a metabolic and hormonal dysregulation attributed to high-AGE dietary exposure. The expression of RAGE was significantly down-regulated in the PBMCs of the high-AGE diet-fed rats (P=0.041), and it was correlated negatively with insulin and testosterone levels and positively with progesterone levels. The expression of SR-A was also decreased in the high-AGE diet-fed rats to marginal significance. Decreased monocytic expression of scavenger receptors such as RAGE and SR-A may result in a higher deposition of AGEs in peripheral endocrine tissues, thus promoting endocrine-related abnormalities and diseases.

Livadas S, Voutetakis A, Bourhis J-C, Maratou E, Dimitriadis G, Margeli A, Chandrinou H, Goussetis E, Papassotiriou I, Dacou-Voutetakis C. Severe hyperinsulinemia, decreased GLUT3 and GLUT4 expression, and increased retinol binding protein 4 in a patient with chronic graft-versus-host disease post bone marrow transplantation. ?Pediatr Transplantation 2011. (c) 2011 John Wiley & Sons A/S. Abstract: Hyperinsulinemia with or without DM2 is a frequent long-term sequela of BMT, especially following cGvHD. In this report, an extensive evaluation of a patient with cGvHD is described: glucose and insulin during OGTT, markers of inflammation, adiponectin and RBP4, body composition analysis, and the kinetics of GLUT3 and GLUT4 in circulating monocytes were evaluated. Hyperinsulinemia, associated with partial lipodystrophy, elevated RBP4, low adiponectin levels, and decreased expression of GLUT3 and GLUT4 were detected. The defects disclosed in this particular patient possibly explain, at least in part, the mechanisms underlying insulin resistance in patients undergoing BMT. It is not clear whether insulin resistance was caused by the drugs, the process itself, or the residual damage to the muscles and/or adipose tissue.

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a neurodegenerative disease with autosomal recessive inheritance with incomplete penetrance. DIDMOAD is a very rare disease with an estimated prevalence of 1 in 770,000 and it is believed to occur in 1 of 150 patients with juvenile-onset insulin-dependent diabetes mellitus. Additionally, WS may also present with different endocrine and metabolic abnormalities such as anterior and posterior pituitary gland dysfunction. This mini-review summarizes the variable presentation of WS and the need of screening for other metabolic and hormonal abnormalities, coexisting in this rare syndrome.

Objective: To investigate the effects of oral natural micronized P on hormonal and metabolic parameters in patients with polycystic ovary syndrome (PCOS) and to answer the clinical question whether induction of withdrawal bleeding is a necessity for the comparison of hormonal and metabolic data in subjects with PCOS. Design: Prospective clinical study. Setting: Academic medical center. Patient(s): Twenty-eight reproductive-aged women with PCOS. Main Outcome Measure(s): Blood sampling was collected at baseline, after 7 days of oral natural micronized P (200 mg) administration, and after withdrawal bleeding. At these three stages hormonal parameters and homeostasis assessment model (HOMA-IR) index were assessed in all patients. Result(s): Oral natural micronized P administration did not alter significantly insulin sensitivity index and androgen levels; however, LH was decreased when postbleeding values were compared to baseline. Nevertheless, after oral natural micronized P administration, P and 17 alpha-hydroxyprogesterone (17-OHP) concentrations were increased, and HOMA-IR was decreased, whereas androgens levels were not altered, in comparison with baseline. Conclusion(s): The induction of withdrawal bleeding, with this regimen, does not appear to be a necessity for the assessment of hormonal and metabolic profile in anovulatory women with PCOS. (Fertil Steril (R) 2010; 94: 242-6. (C) 2010 by American Society for Reproductive Medicine.)

Objective: Oocyte maturation process characterizes polycystic ovary syndrome (PCOS). The mechanisms of this abnormality leading to chronic anovulation are under investigation. Advanced glycosylated end products (AGEs). a marker of oxidative stress linked with oocyte Maturation are localized in granulosa cells and are increased in sera. in women with pCOS. The aim of this Study was to investigate the relationship, whether there is an association between the anti-mullerian hormone (AMH), a hormone produced by granulosa cells and AGEs in ovulatory and anovulatory PCOS (PCOS-Anov), its well as in non-PCOS anovulatory (Non-PCOS Anov) women. Design: Cross-sectional study. Methods: Data from sixty women with PCOS (37 anovulatory and 23 regularly ovulating) were compared with eleven Non-PCOS Anov women and 25 normal women. In each Subject biochemical, hormonal, and ultrasonographic parameters were Studied. Results: AMH values were statistically significantly higher in PCOS-Anov (7.63 +/- 3.12) in comparison with ovulatory PCOS (PCOS-Ov: 4.92 +/- 2.50), Non-PCOS Anov (3.66 +/- 1.4), and controls (4.02 +/- 1.27 ng/ml). AGEs demonstrated a similar pattern: 8.70 +/- 1.65 in PCOS-Anov, 7.43 +/- 1.79. PCOS-Ov, 5.21 +/- 0.09, Non-PCOS Anov, and 5.85 +/- 0.89 U/ml in controls (P < 0.005 for all comparison respectively). Follicle number was significantly higher in PCOS-Anov in comparison with other groups. A significant, positive correlation between AMH and AGEs was observed (r: 0.326, P < 0.01). and with the estimated AMH/AGEs ratio to follicle number (r: 0.42, P: 0.0001) and the presence of anovulation. Conclusions: These data suggest that an oxidative marker, AGEs. and AMH, may interact in the anovulatory mechanisms in women with PCOS.

Background: Pituitary enlargement, which can regress with time, has been described in a number of PROP1-deficient patients. We report a PROP1-deficient patient with a unique variation in pituitary size. Case Description: A 4-year-old boy was first examined in 1989 for short stature (- 2.3 standard deviation score). Growth hormone (GH) insufficiency was confirmed, and human GH (hGH) therapy was initiated and administered up to the age of 18.2 years. Levothyroxine was added 6 months after hGH initiation. Pituitary magnetic resonance imaging (MRI) obtained when the patient was 5 years old showed an enlarged pituitary gland, which grew larger by the age of 8.5 years and then regressed to normal size by the time the patient was 9.8 years old. MRI when the patient was 19 years old disclosed pituitary reenlargement, and another 3 years later indicated regression. On DNA analysis, the patient was found to be homozygous for the mutation 301-302 Delta GA of the PROP1 gene. When the patient was 18.8 years old and asymptomatic, an impaired cortisol response to glucagon was detected. Conclusions: Regression of the pituitary enlargement in PROP1-deficient patients does not seem to constitute an end stage with respect to pituitary pathology. Further changes in pituitary morphology and size can be expected; therefore, long-term followup with pituitary MRI is advised. Copyright (c) 2007 S. Karger AG, Basel.

Background: Thyroid volume (TV) varies between geographical regions. Thus, population-specific references for TV in regions with long-standing iodine sufficiency may be more accurate than a single international reference. Aim: The aim of the study was to determine TV and assess the prevalence of goiter and thyroid nodules in schoolchildren aged 5-18 years living in an iodine-replete area. Methods: Ultrasonography was used to assess TV and structure in 440 schoolchildren (200 boys and 240 girls) living in the Athens area. Urinary iodine excretion was also measured. Age, body surface area (BSA), body mass index (BMI), and Tanner stage were recorded. Results: TV was significantly correlated with age in boys (r = 0.779, p < 0.0005) and girls (r = 0.669, p < 0.0005), and with BSA in boys (r = 0.730, p < 0.0005) and girls (r = 0.623, p < 0.0005). TV increased with the progress of puberty in boys (Tanner stage I: 3.42 mL; Tanner stage II-V: 7.35 mL; p < 0.0005) and girls (Tanner stage I: 3.74 mL; Tanner stage II-V: 5.99 mL; p < 0.0005). We used the 97th percentile value as the upper limit and calculated the prevalence of goiter to be 3.2%. There was a weak correlation between TV and BMI standard deviation score only in boys (r = 0.166, p = 0.023). Boys in Tanner stage II-V had larger TV than girls had in the same pubertal stage (7.35mL vs. 5.99mL, p = 0.001); such a difference was not observed in Tanner stage I. The median urinary iodine was 307.83 mg I= g creatinine, indicating iodine sufficiency. There was a significant inverse correlation between TV and urinary iodine. In 5.1% of the studied subjects one or more nodules were observed, whereas in 4.1% of cases the nodules were accompanied by hypoechogenicity. Conclusions: In healthy Greek children living in an iodine-replete area, the main determinants of TV in both boys and girls were age, BSA, and pubertal stage. The prevalence of goiter was 3.2% and that of altered echostructure was 9.2%.