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Adequate vitamin D levels are particularly important in pregnant women for both the maternal and neonatal health. Prior studies have shown a significantly high prevalence of vitamin D deficiency (VDD) among refugees. However, no study has addressed the prevalence of VDD in pregnant refugees and its effects on neonatal health. In this study, we examined the prevalence of VDD in refugee pregnant women living in Greece and compared our results with Greek pregnant inhabitants. Vitamin D deficiency was frequent in both groups but was significantly more common in refugees (92.2% vs 67.3% of Greek women, p=0.003) with 70.6% of refugees having severe hypovitaminosis D (

Background Even though polycystic ovary syndrome (PCOS) is a common reproductive disorder affecting young women, its impact on their sexual health is not well known. Aim To examine the different aspects of female sexuality in young women with PCOS and attempt to associate hormonal changes and ovulatory status with their sexual function. Methods Anthropometric characteristics, hormonal levels and sexual function based on the Female Sexual Function Index (FSFI) questionnaire were assessed in 76 young women with PCOS and 133 matched controls. Outcomes Sexual function is significantly impaired in young women with PCOS. RESULTS Women with PCOS demonstrated lower scores than controls in arousal (5.04 ± 1.19 vs 4.48 ± 1.44, P < .001), lubrication (5.29 ± 1.17 vs 4.69 ± 1.54, P < .001), orgasm (4.78 ± 1.40 vs 4.11 ± 1.61, P = .001), satisfaction (5.22 ± 1.10 vs 4.78 ± 1.31, P = .016), and total score of the FSFI (29.51 ± 5.83 vs 26.76 ± 6.81, P < .001), even after correction for BMI. When corrected for total testosterone, the domains of lubrication, satisfaction, and total score of FSFI remained significantly impaired in women with PCOS (P values .037, .024, & .044 respectively). In multivariate logistic regression analysis, after adjusting for the effect of BMI and hormone levels, dysfunction in orgasm, satisfaction and the total FSFI score were still 3–4 times more common in PCOS (adjusted OR [95% CI]: 3.54, P = .020; 2.96, P = .050; 3.87, P = .027). Even though no statistically significant differences were observed between women with ovulatory PCOS and controls, we detected statistically significant differences in all domains of sexual function apart from pain between controls and PCOS women with anovulation (desire P value .04, arousal P value Clinical Implications Women with PCOS have compromised sexual function, which is independent of their BMI and highly dependent on their ovulatory status. Strengths and Limitations This is the first study in women with PCOS that implicates anovulation as a risk factor for sexual impairment in PCOS. Further studies are needed to elucidate the mechanisms implicated and to examine the effect of PCOS therapy on the patients’ sexual function. CONCLUSION The adverse effect of PCOS status on the female sexual function is independent of BMI and only partially dependent on hormonal changes characterizing the syndrome. Anovulation appears to be the major determinant of sexual impairment among women with PCOS.

Importance Genitourinary syndrome of menopause (GSM) consists of genitourinary tract symptoms that occur due to physical changes caused by estrogen concentrations decline after menopause. Unlike menopausal symptoms, which subside with time, GSM symptoms persist throughout a woman's life. Objective This article aimed to systematically review the literature to investigate the prevalence of GSM and its treatment. Evidence review The search was conducted in the electronic databases PubMed, CENTRAL, and EMBASE until October 2020. Eligible for the systematic review were studies and surveys conducted via questionnaires or medical interviews evaluating the existence of GSM symptoms with or without gynecological examination in postmenopausal women or women >40 years of age. Findings After the application of predefined inclusion/exclusion criteria, 27 studies were included in the systematic review. The prevalence of GSM-related symptoms, such as vaginal dryness, irritation, itching, and dyspareunia, ranged from 13% to 87%. The use of GSM-specific treatment varied from 13% to 78%. Over-the-counter lubricants and moisturizers were the most popular therapeutic options (24.0%-85.5%), followed by low-dose vaginal estrogens (4.8%-35.0%). Vaginal health is not frequently discussed during doctor visits and awareness about the condition and the number of treatment options is low. Women are concerned about the long-term safety and side effects of hormonal treatment. The majority of women who suffer from genitourinary symptoms are dissatisfied by the treatment they have used. Conclusions and relevance GSM is a highly prevalent condition among women. Nevertheless, women are frequently not aware of its cause and its treatment options. The findings of this review underline the need for education of patients and healthcare professionals regarding GSM diagnosis and treatment options.

PURPOSE Teenage pregnancies have consistently been associated with preterm labor in a wide range of studies. Evidence regarding the incidence and potential complications of teenage pregnancies in Greece is at present scarce. The aim of this study was to evaluate the perinatal outcomes as well as the risk of perinatal and obstetric complications of teenage pregnancies. METHODS This retrospective study was conducted at the Department of Obstetrics and Gynecology of the University Hospital of Patras, Greece, and all data recorded concerned the year 2019 (January-December). We retrospectively reviewed 643 cases of singleton pregnancies divided into two groups, as follows: Group A included women of average maternal age (AMA) (20-34 years old), and Group B included teenagers, defined as women less than 20 years old. Data regarding demographic and pregnancy characteristics as well as obstetric and neonatal complications were collected. RESULTS Teenage pregnancies accounted for 6.7% of all deliveries. We detected significantly higher rates of preterm births (p = 0.025), primiparity (p

Diabetes mellitus type 2 (T2DM) is an emerging public health issue with high prevalence rates among older adults while fragility fractures constitute a significant public health burden with a great impact. Osteoporosis is the most important metabolic bone disease in patients with diabetes mellitus. Based on current evidence, individuals with T2DM are more vulnerable to fragility fractures than their non-diabetic counterparts, although until now, there aren’t any systematic reviews or meta-analyses concerning the impact of T2DM on the risk of fragility fractures in elderly patients. The aim of this study is to fill this gap in the current literature concerning this specific patient group. Literature in PubMed and Google Scholar was searched for relevant articles published up to January 2021. The keywords used were: elderly, diabetes mellitus type 2, and fragility fractures. Among the 180 articles retrieved, only four full-text articles were eligible and, finally, two studies (one population-based cohort study and one cross-sectional study) met the inclusion criteria for the review. Although we identified 15 records through the manual research, finally 17 records were included in the current review. The records retrieved from the manual research were 11 prospective cohort studies, two population-based studies, one prospective observational study, and one retrospective cohort study. The author's name, year of publication, country, type of study, and number of patients were reported. According to this systematic review, there is almost consensus about the increased prevalence of all kinds of fragility fractures and especially low-energy hip fractures among elderly patients with T2DM compared with their counterparts without T2DM while there is relative controversy concerning non-vertebral fractures. Vertebral fractures in the elderly with T2DM require further evaluation because the results from cohort studies are more conflicting. Finally, insulin usage can increase the possibility of fragility fractures and can even double this risk. Bone fragility should be recognized as a new complication of T2DM, especially in elderly patients, due to several additional aggravating factors such as senile osteoporosis, severe vitamin D deficiency, presence of many comorbidities, increased possibility of insulin usage, and the presence of diabetes-related complications (mainly neuropathy and retinopathy). Clinicians who treat these patients should be aware of the special diagnostic and therapeutic approaches concerning these patients.

Diabetes mellitus type 2 (T2DM) is an emerging public health issue with high prevalence among older adults (>60 years old). Taking into consideration the great increase in the elderly population (approximately 7.5 billion worldwide), we can easily understand the impact of this chronic disease and its complications. On the other hand, vitamin D deficiency (VDD) is also a serious public health problem with significant impacts and multiple health effects. The correlation between DM and VDD has been suggested and established from many observational studies, reviews, and meta-analyses. The literature in PubMed and Google Scholar was searched for relevant articles published up to October 2020. The keywords used were the following: vitamin D deficiency, elderly, and diabetes mellitus type 2. Among the 556 articles retrieved, 90 full texts were eligible and only 34 studies (12 retrospective studies, two prospective cohorts, three meta-analyses, seven cross-sectional studies, nine randomized control trials (RCTs), and one observational study) met the inclusion criteria for the review. The author's name, year of publication, country, type of study, and the number of patients were reported. According to this review there is adequate evidence to support the correlation between VDD and T2DM in the elderly. The results from the RCTs are more conflicting and more studies are needed to confirm the impact of vitamin D deficiency (VD) supplementation on metabolic and lipid profile, oxidative stress, and the complications of T2DM in older patients. VDD is clearly related with severe retinopathy, diabetic peripheral neuropathy, and poor cognition performance, while there is consensus about the beneficial effect of VD on peripheral artery disease, foot ulceration prevention, and wound healing. On the other hand, there is controversy about the effect of VD supplementation on cardiovascular adverse events, endothelial function, and estimated glomerular filtration rate (eGFR). Finally, the association of VDD with fragility fractures and depression in the elderly with T2DM is currently insufficiently studied and remains controversial.

Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X-linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as "overlap genes". Thus, some IGD genes play the role of the modifier genes or "second hits", providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations. The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also "milder" and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia, etc. Therefore, genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD.

GnRH (gonadotropin releasing hormone) is a crucial hormone for sexual development, puberty, and fertility, and its deficiency leads to hypogonadotropic hypogonadism (HH), which causes abnormal secondary sexual development and infertility. The combination of the lack of sense of smell, i.e., anosmia, and HH is a type of GnRH deficiency known as Kallmann syndrome, which affects both men and women. The impact of Kallmann syndrome can be very severe and causes a variety of psychological problems in patients. The aim of the present study was to investigate psychopathology, sexuality, and personality characteristics in patients with GnRH deficiency under hormonal replacement therapy. A total of 38 patients with GnRH deficiency aged 30.6 ± 10.44 years and 38 healthy matched for age individuals participated in the study and completed a series of questionnaires concerning sexual functioning, ego defense mechanisms, quality of life, personality characteristics, as well as anxiety and depression. After adjustment for anxiety and depression, no difference in sexuality parameters were reported between men with and without GnRH deficiency, while women with GnRH deficiency had significantly lower sexual desire compared to controls. Concerning quality of life, satisfaction with general health was significantly lower in patients compared to controls, even after adjusting for sex. Furthermore, patients with GnRH deficiency indicated markedly less anxiety and a trend for less depression compared to controls. Finally, defense styles, ego-strength, and hostility did not differ between GnRH deficiency patients and controls. Our study is the first to investigate psychological and sexual functioning impacts in patients with GnRH deficiency under hormonal replacement therapy. However, larger studies are needed so as to add further empirical evidence.

Isolated GnRH Deficiency (IGD) that is either displayed as Kallmann Syndrome (KS) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is a rare Mendelian disorder with wide clinical and genetic variability. Apart from the arrest of pubertal development, IGD is also characterized by a variety of non- reproductive features including unilateral renal agenesis (URA), midline defects, dental & ocular defects and many more. In this analysis we explored the role of unilateral renal agenesis, as a screening tool for detection of genetic changes associated with IGD. We performed detailed genetic screening with Sanger sequencing in 14 genes associated with Isolated GnRH Deficiency as well as screening of intragenic deletions in the gene of anosmin 1-ANOS1 with MLPA. No genetic variation was detected, suggestive of an alternative genetic cause for URA in these normosmic patients, highlighting the necessity of further genetic screening.

Low energy availability (LEA) may lead to menstrual disorders and low bone mineral density, predisposing to the female athlete triad. The primary aim of the present review was to systematically investigate the impact of chronic strenuous exercise on the energy status of professional female athletes compared to sedentary, recreationally active controls as concerns their menstrual status and bone mineral density (BMD). A secondary aim was evaluation of the combined prevalence of the components of the female athlete triad in athletes as compared to non-athletes. A systematic review was conducted from 2007 to February 2018. The inclusion and exclusion criteria of the studies were established in advance of the literature search according to the clinical inquiry and the study design. Four studies were included in this systematic review. The female athlete triad was more prevalent in professional athletes compared to non-athletes. The same results were obtained for both LEA and menstrual disorders. However, BMD and Z-scores showed high heterogeneity among the studies. Both female athletes and non-athletes are prone to LEA and subsequent menstrual disorders and low BMD or osteoporosis. Future studies are needed to examine energy availability in elite female athletes as well as in non-athletes.

Polycystic ovary syndrome (PCOS) affects 6-15% of women of reproductive age. Nonalcoholic fatty liver disease (NAFLD) affects 25-30% of the general population and its prevalence increases in parallel with the epidemics of obesity and type 2 diabetes mellitus. A growing body of evidence suggests that NAFLD and PCOS quite often co-exist. The aim of this article is to summarize and critically appraise the literature regarding: (1) the rates of co-existence of the two entities, (2) the possible pathophysiological links, (3) the proper diagnostic assessment and (4) the appropriate management of women with NAFLD and PCOS. Data from clinical studies and meta-analyses indicate a higher prevalence of NAFLD in women with PCOS ranging from 34% to 70% compared with 14% to 34% in healthy women. Inversely, women with NAFLD are more often diagnosed with PCOS. Insulin resistance (IR) and hyperandrogenism are two main potential pathophysiological links between the two entities. In this regard, IR seems to interplay with obesity and hyperandrogenism, thus affecting NAFLD and PCOS and being affected by them. Women with PCOS, particularly those with IR and/or hyperandrogenism, are suggested to be screened for NAFLD, while premenopausal women with NAFLD is suggested to be screened for PCOS. Lifestyle recommendations with a change in dietary habits, weight loss and exercise, constitute currently the cornerstone of the management of both NAFLD and PCOS. Insulin sensitizers maybe used for the treatment of these women, while there are limited promising data for the use of liraglutide.

In Ancient Greece, up to the Classical Era, hermaphrodites were considered as “monstrous” beings and therefore they were socially marginalized or treated with cruelty. As the centuries past by, tolerance towards these people gradually increased and they often found a place in society. In this manuscript, a case of a female prostitute of the Hellenistic Era with genital ambiguity is presented. Based on textual evidence, a contemporary differential diagnosis is conducted, leading to a possible diagnosis of partial androgen insensitivity syndrome.

STUDY QUESTION Is there a relationship between the genetic risk for polycystic ovary syndrome (PCOS) and genetic variants that influence timing of menopause? SUMMARY ANSWER The genetic risk score, which sums the contribution of variants at all menopause loci, was associated with PCOS. WHAT IS ALREADY KNOWN Ovarian parameters and anti-Mullerian hormone levels suggest that women with PCOS should have a later age at menopause. STUDY DESIGN, SIZE, DURATION The study was a case-control examination of genetic variants associated with age at menopause in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston recruited from 2003 to 2012. Replication was performed in women from Greece (cases, n = 884 and controls, n = 311). PARTICIPANTS/MATERIALS, SETTINGS, METHODS PCOS was defined by the National Institutes of Health criteria in Boston and Greece (n = 783), with additional subjects fulfilling the Rotterdam criteria (hyperandrogenism, polycystic ovary morphology and regular menses) in Greece (n = 101). Controls in Boston and Greece had regular menstrual cycles and no hyperandrogenism. Allele frequencies for variants previously associated with age at menopause were examined in PCOS cases and controls, along with the relationship to quantitative traits. MAIN RESULTS AND ROLE OF CHANCE The variant rs11668344-G was associated with decreased risk of PCOS (odds ratio: 0.77 [0.59-0.93]; P = 0.004). There was a strong relationship between the late menopause allele rs12294104-T and increased LH levels (β ± SE; 0.26 ± 0.06; P = 5.2 × 10(-5)) and the LH:FSH ratio (0.28 ± 0.06; P = 2.7 × 10(-6)). The minor allele at rs10852344-T was associated with smaller ovarian volume (-0.16 ± 0.05; P = 0.0012). A genetic risk score calculated from 16 independent variants associated with age at menopause was also associated with PCOS (P < 0.02), LH and the LH:FSH ratio (both P < 0.05). LIMITATIONS, REASONS FOR CAUTION The variant rs11668344 was not associated with PCOS in the Greek cohort, but results exhibited the same direction of effect as the Boston cohort. However, it is possible that the individual association was a false positive in the Boston cohort. WIDER IMPLICATIONS OF THE FINDINGS The study demonstrates that gene variants known to influence age at menopause are also associated with risk for PCOS. Further, our data suggest that the relationship between age at menopause and PCOS may be explained, at least in part, by effects on LH levels and follicle number. The data point to opposing influences of the genetic variants on both menopausal age and PCOS. STUDY FUNDING/COMPETING INTERESTS The project was supported by award number R01HD065029 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, award number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources and award 1-10-CT-57 from the American Diabetes Association. C.K.W. is a consultant for Takeda Pharmaceuticals. TRIAL REGISTRATION NUMBER NCT00166569.

Context: Puberty is a crucial period of dramatic hormonal changes, accelerated growth, attainment of reproductive capacity, and acquisition of peak bone mass. Participation in recreational physical activity is widely acknowledged to provide significant health benefits in this period. Conversely, intense training imposes several constraints, such as training stress and maintenance of very low body fat to maximize performance. Adolescent female athletes are therefore at risk of overtraining and/or poor dietary intake, which may have several consequences for endocrine function. The “adaptive” changes in the hypothalamic-pituitary-gonadal, -adrenal, and somatotropic axes and the secretory role of the adipose tissue are reviewed, as are their effects on growth, menstrual cycles, and bone mass acquisition. Design: A systematic search on Medline between 1990 and 2013 was conducted using the following terms: “intense training,” “physical activity,” or “exercise” combined with “hormone,” “endocrine,” and “girls,” “women,” or “elite female athletes.” All articles reporting on the endocrine changes related to intense training and their potential implications for growth, menstrual cycles, and bone mass acquisition were considered. Results and Conclusion: Young female athletes present a high prevalence of menstrual disorders, including delayed menarche, oligomenorrhea, and amenorrhea, characterized by a high degree of variability according to the type of sport. Exercise-related reproductive dysfunction may have consequences for growth velocity and peak bone mass acquisition. Recent findings highlight the endocrine role of adipose tissue and energy balance in the regulation of homeostasis and reproductive function. A better understanding of the mechanisms whereby intense training affects the endocrine system may orient research to develop innovative strategies (ie, based on nutritional or pharmacological approaches and individualized modalities of training and competition) to improve the medical care of these adolescents and protect their reproductive function.

Elite Rhythmic Gymnasts (RGs) constitute a unique metabolic model and they are prone to developing Anorexia Athletica. The aim of the present study was to evaluate the effect of training intensity on salivary adiponectin levels and assess a possible role of salivary adiponectin levels as a predictive factor of reproductive dysfunction and bone mass acquisition in elite RGs. The study included 80 elite female RGs participating in the World Rhythmic Gymnastics Championship tournament held in Montpellier, France on September 2011. Anthropometric values were assessed, training data and menstrual pattern were recorded, bone mass was measured with Broadband ultrasound attenuation (dB/Mhz) and baseline salivary adiponectin levels were determined. The athletes were classified as intensely and very intensely trained, considering the mean training intensity (40.84h/week). Moreover, considering their reproductive status, they were divided into RG's with normal menstruation, primary amenorrhea and oligomenorrhea. All comparisons were adjusted to age, BMI and body fat percentage differences. Very intensely trained RGs showed higher salivary adiponectin levels (p=0.05). Moreover, salivary adiponectin levels showed significant correlation with training intensity (r=0.409, p=0.003). On the other hand, no association of salivary adiponectin levels was documented with either reproductive function or bone mass acquisition. The results of the present study suggest that, in elite RGs, salivary adiponectin levels are associated with the intensity of training, possibly reflecting the deterioration of energy balance rather than the training stress. On the other hand, a predictive role of salivary adiponectin levels in reproductive dysfunction or bone mass acquisition could not be supported.

Regular physical activity during puberty improves bone mass acquisition. However, it is unknown whether extreme intense training has the same favorable effect on the skeleton.We evaluated the bone mass acquisition in a unique cohort of world-class rhythmic gymnasts.A total of 133 adolescent girls and young women with a mean age of 18.7 ± 2.7 (14.4-26.7) years participated in this study: 82 elite rhythmic gymnasts (RGs) and 51 controls (CONs).Anthropometric variables and body composition were assessed, and all participants completed questionnaires on their general medical, menstrual, and training histories. Broadband ultrasound attenuation (BUA in decibels per megahertz) was determined by quantitative ultrasound at the heel.RGs presented lower weight (-8.5%, P.001), body mass index (-11.7%, P.001), and body fat mass (-43%, P.001) and higher muscle mass (6.3%, P.01) and height (+2.8 cm, P.01). RGs presented an age of menarche significantly delayed compared with CONs (15.6 ± 1.6 vs 12.7 ± 1.7 years; P.001) and a high prevalence of menstrual disorders (64%). BUA values were higher in RGs vs CONs (68.6 ± 4.6 and 65.4 ± 3.3 dB/Mhz, respectively; P.001). This difference was exacerbated when BUA was adjusted for age and body weight. BUA values in RGs were not affected by menstrual or training status. Among RGs with menarche, BUA was higher (71.5 ± 4.1 and 67.9 ± 3.5 dB/Mhz) for delayed (14.4 ± 0.8 years) vs severely delayed (17.3 ± 1.4 years) menarcheal age. BUA was positively correlated with body weight and body mass index and tended to be correlated with age.Conversely to expectations for adolescents and young women with a high prevalence of menstrual disorders and/or delayed menarche, intense training in rhythmic gymnastics appeared to have a beneficial effect on the bone health of a weight-bearing site. This effect was nevertheless modulated by the age of menarche. The high mechanical loading generated by this activity may counterbalance the negative effect of menstrual disorders.

FGFR1 mutations have been identified in both Kallmann syndrome and normosmic HH (nIHH). To date, few mutations in the FGFR1 gene have been structurally or functionally characterized in vitro to identify molecular mechanisms that contribute to the disease pathogenesis. We attempted to define the in vitro functionality of two FGFR1 mutants (R254W and R254Q), resulting from two different amino acid substitutions of the same residue, and to correlate the in vitro findings to the patient phenotypes. Two unrelated GnRH deficient probands were found to harbor mutations in FGFR1 (R254W and R254Q). Mutant signaling activity and expression levels were evaluated in vitro and compared to a wild type (WT) receptor. Signaling activity was determined by a FGF2/FGFR1 dependent transcription reporter assay. Receptor total expression levels were assessed by Western blot and cell surface expression was measured by a radiolabeled antibody binding assay. The R254W maximal receptor signaling capacity was reduced by 45% (p

Giants are humanlike creatures of prodigious size and strength present in the myths and legends of many cultures. Cyclopes were a race of giants depicted in ancient Greek mythology and literature. Apart from their extraordinary stature, they were also characterised by the presence of one single eye, located in the centre of their forehead. One of them, Polyphemus, plays a central role in one of the most exiting episodes of Homer’s Odyssey. Besides, descriptions of cases of extremely tall individuals appear in the medical literature as early as in the 16 th century A.D. Post mortem evidence of pituitary tumors were identified in most of these cases, pointing towards acromegaly / gigantism as the most likely cause. More recent case reports on real life giants enriched with the use of radiographic imaging have yielded similar results and even familial cases have been identified. Today, pituitary adenomas over secreting growth hormone (GH) are recognised as the most common cause of acromegaly and advances have been made in understanding their aetiology and pathogenesis. Medical interpretation of the case of Cyclopes covers the differential diagnosis of familial tall stature concurrent with vision impairment in the form of bitemporal hemianopia. Combining textual evidence from Homer’s Odyssey with current scientific data has led us to the conclusion that gigantism in the context of Familial Isolated Pituitary Adenoma (FIPA) or X-linked acro-gigantism (X-LAG) due to mutations either in AIP or GPR101 is the possible culprit: a change in DNA sequence functioning as a link between myth and reality, proving not only that Cyclopes could have really existed, but also that giants are still living among us.

In the literature of the Roman Era, a case of macrosomia and genital ambiguity in a newborn is described. Textual evidence concerning this case of androgynism and its symbolism is provided in the present study. Medical interpretation of such cases covers the entire spectrum of differential diagnosis of macrosomia concurrent with genital ambiguity. Female pseudohermaphroditism may be excluded from the differential diagnosis, as the adrenal cortex physiology of the female fetus renders the concurrence of overgrowth and androgen excess unlikely. It will therefore have been a case of 46XY disorder of sexual differentiation due to either fetal overgrowth syndromes (Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes) or to mutations of the WT1 gene. Mutations of the WT1 gene are considered as the most probable diagnosis, resulting in genital ambiguity and macrosomia due to additional altered insulin-like growth factor I (IGF-I) and IGF-II action.

The aim of the present study was to evaluate the impact of obesity and insulin resistance on testosterone formation from androstenedione and its contribution to biochemical hyperandrogenemia in all different phenotypic subgroups of PCOS patients. The case-control study included 1087 PCOS women and 206 regularly menstruating, ovulatory controls. The main clinical measurements included anthropometric and basal hormonal characteristics and evaluation of hyperandrogenic and insulin resistance-related features. The results were the following: In PCOS women with biochemical hyperandrogenemia, obesity significantly lowers serum A levels and increases T to A ratio. These findings were not present in PCOS women with clinical hypeandrogenemia and in normal ovulatory controls.

OBJECTIVE: To highlight the recent developments in the field of menstrual function in sports and to provide an overview of our current understanding in regard to the pathophysiology, evaluation and management strategies of exercise-related reproductive dysfunction. DESIGN: A PUBMED search was carried out and all articles published from 1980 to 2010 with title words related to exercise, athletes, menstrual function and primary and secondary amenorrhea were reviewed. The review structure includes a pathophysiology overview, menstrual dysfunction among different athletic disciplines, clinical manifestations, evaluation and management strategies, with particular emphasis on recent data regarding the use of oral contraceptives and hormone replacement therapy. RESULTS AND CONCLUSION: Exercise-related reproductive dysfunction appears to be multifactorial in origin and remains a diagnosis of exclusion. Recent findings underscore the endocrine role of adipose tissue in the regulation of metabolism and reproduction, providing further data on our understanding of the pathophysiology of exerciserelated reproductive dysfunction. Clinical manifestations range from primary amenorrhea or delayed menarche to luteal phase deficiency, oligomenorrhea, anovulation and secondary amenorrhea. Amenorrhea constitutes the most serious clinical consequence and is associated with bone pathology. Early diagnosis, thorough evaluation and individualized management (ranging from diet and exercise, or behavior adjustments to pharmacologic treatment) should be achieved in order to preserve bone mass.

Bone mass (BM) and skeletal size are similar in prepubertal girls and boys and double between the onset of puberty and early adult life. Sex steroids are responsible for the maturation in human skeleton, as well as for the sexual dimorphism, observed after the onset of puberty. Physical activity in childhood is critical for maximizing bone growth and thus for preventing osteoporosis during older age. Therefore, it constitutes the most effective prevention strategy available. In athletes, high-impact loading activities have been shown to improve BM, whereas in sports requiring a lean somatotype (therefore leading to a negative energy balance), the delay in skeletal maturation and pubertal development predisposes athletes to osteopenia and osteoporosis. Although the early onset of training, the continuous intensive exercise and its long duration attenuate bone acquisition, the excess mechanical load to which these athletes are exposed from a young age exerts beneficial effects on bone formation that lead to a positive net-effect on BM.

Objective To evaluate basal metabolic rate (BMR) in women with PCOS and to determine its association with insulin resistance (IR). Design Prospective assessment of BMR in women with PCOS. Setting Outpatient clinic of the Division of Reproductive Endocrinology. Patient(s) The study included 91 Greek women with PCOS and biochemical hyperandrogenemia, with mean age 24.03 ± 0.55 years and mean body mass index (BMI) 26.67 ± 0.69 kg/m 2 , and 48 matched regularly menstruating women, with mean age 26.33 ± 0.93 years and mean BMI 23.35 ± 0.85 kg/m 2 , as control subjects. Intervention(s) Assessment of BMR by indirect calorimetry, IR by HOMA and QUICKI indices, fasting insulin, and fasting glucose/insulin ratio. Main Outcome Measure(s) Reduced BMR in PCOS with or without IR. Result(s) Adjusted BMR was 1,868 ± 41 kcal/day in the control group, 1,445.57 ± 76 in all PCOS women, 1,590 ± 130 in PCOS women without IR and 1,116 ± 106 in PCOS women with IR. Adjusted BMR showed a statistically significant difference between women with PCOS and control subjects, with lowest values in the group of PCOS women with IR, even after adjusting all groups for age and BMI. Conclusion(s) Women with PCOS, particularly those with IR, present a significantly decreased BMR.

To investigate the existence of ghrelin in seminal plasma and the levels of serum ghrelin in men with normospermia and dyspermia.Ninety-eight men were classified into three groups: Group 1, men with normospermia and proven fertility (n = 26); Group 2, men with idiopathic oligo-astheno-teratozoospermia (n = 62); and Group 3, men with idiopathic azoospermia (n = 10). Spermiograms and determination of ghrelin in serum and seminal plasma were performed in all men.Ghrelin was present in the seminal plasma of men from all groups at a concentration of 27%, 18% and 30% of the corresponding serum levels (mean +/- standard error: Group 1, 127.7 +/- 14.7 vs. 468.3 +/- 35.5 pmol/l, p = 0.003; Group 2, 117.0 +/- 10.1 vs. 637.0 +/- 29.3 pmol/l, p0.001; Group 3, 166.2 +/- 32.5 vs. 557.7 +/- 25.4 pmol/l, p = 0.068). When Group 1 men were compared with men from Groups 2 and 3 combined, there were no significant differences in serum (mean +/- standard error: 468.3 +/- 35.5 vs. 628.0 +/- 26.4 pmol/l, p = not significant) or seminal plasma ghrelin (mean +/- standard error: 127.7 +/- 14.7 vs. 123.9 +/- 9.9 pmol/l, p = not significant). In the total group of studied men (Groups 1 to 3), serum ghrelin was positively correlated with semen volume (r = 0.309, p = 0.037), whereas seminal plasma ghrelin was negatively correlated with age (r = -0.268, p = 0.008) and semen volume (r = -0.385, p0.000).Ghrelin is present in human seminal plasma at lower levels than in serum. There is no difference in seminal plasma ghrelin levels between men with normospermia and dyspermia.

Objective To correlate the presence of renal agenesis/dysgenesis to the prevalence of KAL1 gene defects in patients with sporadic Kallmann syndrome (KS). Design Prospective assessment of renal structure and DNA sequence analysis of the KAL1 gene. Setting Outpatient clinics of the divisions of endocrinology of university hospitals. Patient(s) Sixteen male patients with sporadic KS. Intervention(s) Assessment of renal structure by abdominal ultrasounds scans and DNA extraction, polymerase chain reaction amplification, and DNA sequence analysis of all 14 exons of the KAL1 gene. Main Outcome Measure(s) KAL 1 gene structure and presence of renal dysgenesis. Result(s) Renal dysgenesis was identified in only two of 16 KS patients. Genetic defects were found in only two patients with KS, that is, in those with the identified renal dysgenesis. The first gene defect was identified in a patient with associated right renal agenesis who had two point mutations in the KAL1 gene: the first was a G to A transition in exon 11, turning codon 514 encoding glutamic acid into lysine; and the second was a G to A transition in exon 13, turning codon 660 encoding alanine into threonine. The second gene defect was identified in a patient with ichthyosis, right renal agenesis, and mirror movements of the upper limbs (synkinesia) and comprised a deletion of exons 5–10 of the KAL1 gene and a complete deletion of the steroid sulphatase gene. Conclusion(s) The phenotype of renal agenesis/dysgenesis strongly indicates the existence of KAL1 gene defects in the genotype of patients with sporadic KS, providing evidence for the X-linked mode of inheritance and offering the opportunity for genetic counseling.

CASE PRESENTATION: A 36-year old man, operated on for cryptorchidism at the age of 8 years, was referred to the Outpatient Clinic of Reproductive Endocrinology for investigation of infertility. Clinical examination revealed ambiguous genitalia: penis 4–5 cm, testicular volume 2–3 ml, hypospadias, hypertrophic foreskin and scrotum bifida. Mild hypertension was confirmed. No skeletal malformations were detected. DESIGN: Hormonal and electrolytic determinations as well as semen analysis were conducted. PCR of the coding regions of 17-hydroxylase/17,20 lyase (P450c17) and of P450 oxidoreductase (POR) genes was also performed. RESULTS: Normal levels of electrolytes, low levels of androgens, high levels of gonadotropins and 17-hydroxyprogesterone as well as azoospermia were detected. Karyotype was shown to be 46,XY. Both hCG and ACTH stimulation significantly increased 17-hydroxyprogesterone with no increase in androgens. The diagnosis was congenital adrenal hyperplasia with apparent combined P450c17 and P450c21 deficiency due to mutations in the POR gene. Sequencing of the POR gene revealed: one deletion in exon 12 (Del 1696_1698delGTC >del531Valine) and one missense mutation in exon 7 (A259G) as well as two polymorphisms: rs1057868 (C/T A503V) and rs1057870 (G/A S572S) in exons 12 and 13, respectively. No nucleotide changes were detected in the 8 exons of P450c17. CONCLUSIONS: Molecular findings were consistent with the diagnosis of P450 oxidoreductase deficiency. Despite this severe deficiency, skeletal malformations simulating Antley-Bixler syndrome, which usually characterize the most severe forms, were not confirmed. This discrepancy could be attributed to the differential impact of a POR variant on each one of the P450 enzymes.

Introduction Disorders possibly associated with insulin resistance (IR) are hyperandrogenemia, hirsutism, irregular menstrual cycles, central obesity and polycystic ovarian syndrome (PCOS). It is known that PCOS is related to a high risk of endometrial hyperplasia after many years of estrogen stimulation from anovulation. Objectives The purpose of the study was to estimate the thickness of the endometrium in women with IR without a diagnosis of PCOS and in women with PCOS without IR. Study design Three groups of women included in the study: 15 women diagnosed as IR without PCOS, 16 women diagnosed as PCOS without IR and 20 women used as controls matched for age and body mass index (BMI) with the previous patients. Thickness of the endometrium was estimated in all cases with a transvaginal ultrasound in three consecutive measures during a cycle. Results The mean thickness of the endometrium was statistically higher in the PCOS group (11.1 mm), and in the IR group (9.6 mm), compared with the control group (6.2 mm) (F = 13.1, p Conclusions It is concluded that both in women diagnosed as having insulin resistance without PCOS, and in women with PCOS without insulin resistance, the ultrasonographically estimated thickness of the endometrium is relatively high and a closer follow-up of these women is required in order to detect those in risk to develop hyperplasia and/or atypia.

Objective: Kallmann's Syndrome is a heritable disorder characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. A common pathogenesis for KS and schizophrenia had been proposed based on shared pathologies of these two disorders, although no such clinical associations have ever been reported. Method: We report a 35 year old man with schizophrenia and Kallmann's Syndrome. The patient presented with signs and symptoms of hypogonadism, severe hyposmia and normal endocrine functions of the anterior pituitary. Hyposmia has been attributed to the absence of the olfactory bulbs and tracts and atrophy of the olfactory gyri, but normal olfactory mucosa. The patient presented with paranoid schizophrenia with persecutory delusions, auditory hallucinations, thought disorder, depersonalization, and gradual but marked global deterioration. Results: Psychiatric evaluation revealed an entirely different psychopathological and personality profile between the patient and the six other Kallmann patients studied. Cycle sequencing analysis revealed a normal sequence of all 14 exons of the KAL gene. In conclusion, based on the presented case, Kallmann's Syndrome and schizophrenia represent a rare clinical association rather than a syndrome with a common pathogenesis, which if present should be confined to the olfactory dysfunction.

Cerebellar ataxia has been described as being associated with hypogonadism for almost 100 years. In the majority of cases, hypogonadism is hypogonadotropic. The association of cerebellar ataxia with hypergonadotropic hypogonadism is a rare genetic disorder with a recessive mode of inheritance. Cerebellar ataxia and hypogonadism can also occur associated with a large spectrum of additional clinical manifestations, including mental retardation, sensorineural deafness, choroidal dystrophy, ectodermal dysplasia and short stature, and polyneuropathy. We report the case of a woman with early-onset spinocerebellar ataxia, primary amenorrhea due to hypergonadotropic hypogonadism, and late-onset sensorineural hearing loss. Additional family members from the father's side are affected with late-onset hearing loss, suggesting a dominant mode of inheritance.

The two traditional methods for the assessment of iodine deficiency in a given area are the estimation of urinary excretion of iodine, and the prevalence of goiter. In field studies, the estimation of urinary iodine excretion (UIE) in random urine specimens provides an adequate assessment of a population's iodine nutrition. The recommended method is the classic one, based on Sandell-Kolthoff reaction (Method A). Recently, a new semi-quantitative method has been introduced (rapid urinary iodide test [RUIT]). We performed a field study in a developing country (Azerbaijan) in order to compare the classic Method A to RUIT. The study included 942 schoolchildren, to whom UIE was estimated by RUIT. Comparing the two methods, (n = 260), the sensitivity of RUIT using as gold standard Method A, was 96% and the specificity was 61%. The correlation between median values UIE estimated by RUIT and by Method A was excellent (r = 0.98, p < 0.001). An agreement in iodine deficiency classification according to the World Health Organization-United Nations Children's Fund-International Council for the Control of Iodine-Deficiency Disorders (WHO-UNICEF-ICCIDD) between the two methods was observed in eight of nine areas. In conclusion, RUIT is a suitable method for UIE estimation in field studies of suspected iodine deficiency. The test is relatively inexpensive, easy to perform, and does not require sophisticated instruments.

OBJECTIVE: Adequate dietary iodine intake is necessary for normal thyroid gland function at all times, and most particularly during pregnancy. Increased iodine loss is cited, among other factors, as responsible for the increased iodine demand in this period. Our aim was to compare renal iodine excretion between women during all three pregnancy trimesters with that of their spouses and thereby to estimate the iodine intake in an a large sample of pregnant women in urban areas in Greece. DESIGN: Four hundred twenty-four healthy pregnant women were included prospectively (residents of Athens n=218, residents of Patras n=206). The spouses of 177 of these women following the same diet were also studied. Determinations included serum FT4, TSH and aTPO and urinary iodine excretion (UIE). RESULTS: No difference was found either in median UIE throughout pregnancy or between the UIE of the pregnant women and their spouses during the trimesters. Throughout pregnancy, mild iodine deficiency was noted and was classified as mild in 60%, moderate in 30% and severe in 10% of the women studied. Users of iodized salt had significantly higher median UIE compared with non-users. Serum FT4 levels decreased and TSH increased as pregnancy progressed. CONCLUSIONS: Our study indicates that renal iodine excretion is not increased during pregnancy. This finding needs to be confirmed by further investigation in other populations with different iodine intakes. Thus, increased iodine requirements in pregnancy are possibly due to extra-renal causes. The population of pregnant women in Greek urban areas is mildly-and often moderately and severely-iodopenic and needs to be treated accordingly.

To evaluate the impact of elevated serum Δ4A levels on the hormonal and metabolic features of the different phenotypes of PCOS. 1276 women with PCOS according to the Rotterdam criteria were included, in whom serum hormonal levels were determined. In PCOS women as a whole, as well as in patients presenting clinical and/or biochemical hyperandrogenemia (phenotypes I and II), Δ4A levels >3.8 ng/ml were positively related to LH, LH/FSH ratio, T, DHEAS, 17 OH progesterone and FAI and negatively related to T/Δ4A ratio. In the milder phenotype III, a positive correlation between Δ4A levels >3.8 ng/ml and T, DHEAS, 17 OH progesterone and FAI and a negative one between increased Δ4A and T/Δ4A ratio were reported. In the whole PCOS group with androstenedione >3.8 ng/ml, an increased ovarian volume was observed, while a greater mean follicular number was found only in phenotypes I and II. Increased serum Δ4A levels, which are associated with more severe PCOS phenotypes, possibly contribute to the worsening of PCOS features and therefore could be a valuable marker of biochemical hyperandrogenemia.

The goal of this study was to assess the prevalence of iodine deficiency (ID) in Azerbaijan after the discontinuation of an iodine prophylaxis program by assessing the prevalence of goiter, iodine intake, and thyroid function. The study included 942 schoolchildren (475 boys and 467 girls) ages 8-14 years, from 13 distinct regions. The survey included the following: (1) clinical evaluation; (2) assessment of thyroid volume both by ultrasound and by palpation; (3) determination of iodide in a morning urine specimen using the classic Sandel-Kolthoff reaction in 347 schoolchildren; (4) determinations of thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), thyroglobulin (Tg), and anti-thyroid peroxidase (TPO) in serum (n = 165) and TSH in whole blood spotted on filter paper (n = 942). The prevalence of goiter for the whole country was determined by ultrasound (US) to be 86% and by palpation 66%, reaching 100% in the mountainous regions of Caucasus. The median urinary iodine excretion (UIE) was 54 microg/L, reaching level of 26 and 39 microg/L in the Caucasus region. In conclusion, according to the World Health Organization (WHO) classification, Azerbaijan now has mild to moderate ID (median UIE, 54 microg/L) and in the mountainous regions with severe ID. The high prevalence of goiter and the low UIE emphasizes the need for urgent medical reintervention. An iodination program is now implemented by our team in the mountainous regions under the auspice of the government of Azerbaijan.

Iodine is an essential element for thyroid hormone synthesis. The thyroid gland has the capacity and holds the machinery to handle the iodine efficiently when the availability of iodine becomes scarce, as well as when iodine is available in excessive quantities. The latter situation is handled by the thyroid by acutely inhibiting the organification of iodine, the so-called acute Wolff-Chaikoff effect, by a mechanism not well understood 52 years after the original description. It is proposed that iodopeptide(s) are formed that temporarily inhibit thyroid peroxidase (TPO) mRNA and protein synthesis and, therefore, thyroglobulin iodinations. The Wolff-Chaikoff effect is an effective means of rejecting the large quantities of iodide and therefore preventing the thyroid from synthesizing large quantities of thyroid hormones. The acute Wolff-Chaikoff effect lasts for few a days and then, through the so-called "escape" phenomenon, the organification of intrathyroidal iodide resumes and the normal synthesis of thyroxine (T4) and triiodothyronine (T3) returns. This is achieved by decreasing the intrathyroidal inorganic iodine concentration by down regulation of the sodium iodine symporter (NIS) and therefore permits the TPO-H202 system to resume normal activity. However, in a few apparently normal individuals, in newborns and fetuses, in some patients with chronic systemic diseases, euthyroid patients with autoimmune thyroiditis, and Graves' disease patients previously treated with radioimmunoassay (RAI), surgery or antithyroid drugs, the escape from the inhibitory effect of large doses of iodides is not achieved and clinical or subclinical hypothyroidism ensues. Iodide-induced hypothyroidism has also been observed in patients with a history of postpartum thyroiditis, in euthyroid patients after a previous episode of subacute thyroiditis, and in patients treated with recombinant interferon-alpha who developed transient thyroid dysfunction during interferon-a treatment. The hypothyroidism is transient and thyroid function returns to normal in 2 to 3 weeks after iodide withdrawal, but transient T4 replacement therapy may be required in some patients. The patients who develop transient iodine-induced hypothyroidism must be followed long term thereafter because many will develop permanent primary hypothyroidism.

OBJECTIVE Children with β-thalassaemia major (β-thal) frequently have growth retardation in the presence of low serum IGF-I and a normal GH response to pharmacological stimulation suggesting that they have GH insensitivity (GHIS). This study was carried out to study the cause of their growth retardation. DESIGN We studied IGF-I and IGFBP-3 generation after exogenous GH administration for four days, in 15 prepubertal controls (C) and 41 prepubertal β-thal patients divided into three groups according to their growth status: (Group 1) 15 with normal growth (N-thal) (Group 2) 16 with decelerated growth (D-thal) and (Group 3) 10 with short stature (S-thal), in order to determine whether GHIS is the cause of their growth retardation. MEASUREMENTS IGF-I and IGFBP-3 were measured daily, before and for 4 days after daily administration of 0·1 IU/kg hGH, in 3 groups of prepubertal β-thal patients and normal controls. RESULTS N-thal and C had similar basal serum IGF-I (142 ± 52 and 196 ± 56 ng/ml, respectively) and IGFBP-3 concentrations (2·07 ± 0·49 and 2·66 ± 0·41 mg/l, respectively) as well as a similar percent increase of IGF-I (101 ± 23% and 104 ± 37%, respectively) and IGFBP-3 (52 ± 36%, and 38 ± 14%, respectively) during the generation tests. S-thal and D-thal had significantly lower basal IGF-I and IGFBP-3 concentrations (85 ± 42 and 101 ± 36 ng/ml; and 1·60 ± 0·49 and 1·79 ± 0·52 mg/l, respectively) as compared to N-thal and C (P

OBJECTIVE: Patients with beta-thalassemia frequently develop primary hypothyroidism and other endocrine disorders due to iron overload. We studied whether administration of excess iodide to patients with apparently normal thyroid function could uncover an underlying thyroid disease. DESIGN AND METHODS: Twenty-five patients, 10 prepubertal (mean age 11+/-3 years) and 15 adults (mean age 23+/-5 years) with normal thyroid hormone and TSH levels, a normal response of TSH to TRH and negative thyroid peroxidase antibodies received 20mg iodide three times daily for three weeks, and thyroid hormone and TSH levels were measured weekly during, and for three weeks after, iodide administration and every 3 months thereafter for the next 5 years. RESULTS: During iodide administration there was a significant decrease in thyroid hormone concentrations which remained within normal levels, and a significant increase in TSH concentrations which in 14 out of 25 (56%) patients reached the hypothyroid level. Baseline TSH values were higher in those patients who developed subclinical hypothyroidism (2.31+/-0.71mU/l vs 1. 34+/-0.64mU/l, P=0.0016). Subclinical hypothyroidism developed in 70% of prepubertal and in 47% of adult patients. Serum ferritin was elevated in all patients. Nine of the fourteen patients (64.3%) who developed subclinical hypothyroidism during iodide administration developed hypothyroidism during the 5-year follow-up compared with only one of the eleven patients with a normal response to iodide (P=0.004). CONCLUSIONS: Patients with beta-thalassemia should not be exposed to excess iodide due to increased sensitivity to its inhibitory effects on thyroid function. The susceptible individuals frequently develop permanent hypothyroidism in the following years.

Dear Sir, I am Neoklis A. Georgopoulos, from Department of Obstetrics and Gynaecology, Division of Reproductive Endocrinology, University of Patras Medical School, Greece. We present an early prepubertal diagnosis of Kallmann syndrome (KS) in a child with anosmia, renal agenesis and mirror movements. KS is a congenital defect characterized by the presence of hypogona-dotropic hypogonadism and anosmia or hyposmia 1. Besides hypogonadism and anosmia, the clinical phenotype is characterized by the presence of other associated features, including, among others, mirror movements (synkinesis), cleft palate and renal agenesis/dysgenesis. KS is a genetically heterogeneous disease showing X-linked, dominant or recessive autosomal, or oligogenic inheritance. The gene responsible for an X-linked mode of inheritance was identified in the short arm of the X chromosome (Xp22.3) and named KAL1 2. Mutations within the FGFR1 and the Prok2/ProkR2 genes have been implicated in the autosomal dominant and recessive inheritance forms, respectively. Certain non-reproductive features of KS might be linked to either KAL1 or FGFR1 gene defects. The mirror movements are present in approximately 80% of males with KAL1 mutations, but only in 10% of patients with FGFR1 gene defects. The frequency of KAL1 gene defects is estimated to be around 10% of all sporadic cases, whereas in the presence of associated renal agenesis/dysgenesis the frequency is as high as 89% 3, 4. To date, no case of KS and its associated renal agenesis caused by an FGFR1 mutation has been reported. The diagnosis of hypogonadotropic hypogonadism can be made in a male infant during the first 6 months of life on the basis of activation of the hypothalamic–pituitary–gonadotropic axis 5. Later, in childhood, the axis is suppressed and the definitive diagnosis of KS is therefore delayed until late adolescence, when the lack of pubertal development and the absence of secondary sex characteristics become obvious. The lack of pubertal development can cause considerable psychological damage to the young patient. We report on a child who was admitted to the Paediatric Clinic of Patras Medical School (Rio, Greece) at the age of 12 years for the evaluation of right renal agenesis. His height was 146.6 cm (25th percentile) and his weight was 38.8 kg (50th percentile). On clinical examination by a paediatric endocrinologist, his penis size was found to be normal for a prepubertal boy (length 5 cm, diameter 3.5 cm); his right testis was palpable in the scrotum, which was 2 cm in diameter, but his left testis was not palpable. The associated clinical features included an arched palate, mirror movements and anosmia. He was the only child in the family. As a detailed family history showed no evidence of hypogonadism, anosmia/hyposmia and/or delayed puberty in any relatives, the case was considered sporadic. Serum testosterone level was 8.46 ng dL-1, and there was no response of luteinizing hormone (LH) or follicle-stimulating hormone (FSH) to a gonadotropin-releasing hormone (GnRH) (100 μg) challenge (LH: < 0.01 mIU mL-1, FSH: 0.2 mIU mL-1). A detailed magnetic resonance imaging of the brain showed the absence of the olfactory bulbs and tracts and atrophy of the olfactory gyri. On the basis of the knowledge that KAL1 gene defects are highly probable in the presence of renal agenesis, we decided to sequence the KAL1 gene for a possible early clinical and genetic diagnosis of KS in our patient. We believed that the result of the genetic test would be worth considering, along with the fact that the patient had no clinical signs of hypogonadism. Sequence analysis of the KAL1 gene identified two genetic defects in the patient. The first mutation was a 259G to A transition in exon 1, turning codon 37 encoding glutamic acid into lysine (E37K), and the second an 835A to T transversion in exon 5, turning codon 235 encoding threonine into serine (T235S) (Figure 1). Neither mutation has been described earlier, and they are not identified in the sequence analysis of KAL1 gene in 53 normal men or in the two major public Single Nudeotide Polymorphism (SNP) databases, GenBank and Ensembl. Sequence analysis was carried out for the mother, because the KAL1 gene is located on the X chromosome that is passed on from the mother to the male proband. The mother was a heterozygote for exon 1 with a normal and mutant allele, but she was a wild-type homozygote for exon 5. Therefore, the mother transmitted the mutation in exon 1 to her son. The fact that the second mutation in her genome was absent suggested that the son had a de novo mutation in exon 5 (Figure 1). Figure 1 Electrochromatograms showing the two point mutations. (A) at 259 bp of exon 1 and (B) at 835 bp of exon 5 of KAL1 gene identified in the patient with Kallmann syndrome and renal aplasia and the heterozygotous status of his mother for (C) exon 1 and homozygotous ... The protein encoded by the KAL1 gene, named anosmin-1, is a glycoprotein of the extracellular matrix of unknown function. It has an amino terminus with a cysteine-rich domain, including a whey acidic protein-like four-disulphide core motif (WAP), four fibronectin type III domains (FnIII R1–R4) and a carboxyl-terminal histidine-rich domain. The E37K mutation is localized to the amino-terminal cysteine-rich domain of anosmin-1 and involves the non-conservative replacement of an acidic amino acid by a basic amino acid. The T235S mutation lies within the first R1 FNIII of the protein near a major cell adhesion site, which contains one of the predicted heparin sulphate binding sites of anosmin. A sequence-based prediction of the effects of these amino acid substitutions using the SIFT (Sorting Intolerant From Tolerant) software (http://blocks.fhcrc.org/sift/SIFT.html) revealed that the 259G to A transition (E37K) could affect protein function (with a score of 0.04), whereas the 835A to T transversion (T235S) was predicted to be tolerable. Indeed, with the latter mutation, at the protein level, the amino acid threonine was replaced by serine at position 235. Both amino acids are polar and they differ by only one methyl group (–CH3); therefore, the change was predicted to be tolerable. In contrast, the change from glutamic acid to lysine at position 37 replaces an acidic amino acid with a basic one, which might seriously affect protein function. To our knowledge, a genetic diagnosis of KS has never been reported during childhood. As our case was sporadic, any attempt to identify the genotype would have been extremely costly and time consuming. The KAL1 gene consists of 14 exons, and all reported causative mutations are scattered within the gene without any specific clustering. The finding of a right renal agenesis in a child with coexistent anosmia made sequencing the entire coding region of the KAL1 gene worthwhile, because the possibility of the identification of a causative mutation increased from 9% to 89%. It is therefore worthwhile to apply a genetic test only in the presence of associated non-reproductive clinical phenotypes in KS. Although a normal sequence in the KAL1 gene would not exclude KS, the finding of a causative mutation would further strengthen the diagnosis. Previously, an X-linked mode of inheritance dissociation of anosmia, delayed puberty and hypogonadotropic hypogonadism was reported in members of the same family 4, 6. In this study, the association of the right renal agenesis with anosmia strengthened the clinical diagnosis of KS, and it was further supported by the identification of the causative molecular defect. A normal clinical phenotype has not been reported in a case with KAL1 gene mutation. Through this letter, we wish to emphasise the im- portance of the presence of renal dysgenesis/agenesis and mirror movements as strong indicators for the presence of KAL1 gene mutations in patients with anosmia, even in childhood. Upon a prepubertal genetic diagnosis of the syndrome, the clinician can undertake therapeutic intervention for puberty induction at the age of 14 years, offering the patient a pubertal maturation that is similar to that of his teenage peers. As the correlations between genotypes and phenotypes cannot be predicted with certainty, treatment can be discontinued and the gonadotropic axis can be re-evaluated after puberty is reached. The documentation of the X-linked mode of inheritance could reassure these patients that the disease can only be transmitted as a recessive trait in their female offspring, and prenatal diagnosis could identify the presence of the causative mutation in the KAL1 gene in the male offspring of the next generation.

alpha(2beta) adrenoreceptor 301-303 deletion polymorphism does not influence basal metabolic rate, insulin resistance or weight gain in Greek women with polycystic ovary syndrome.

Study question Are PCOS risk variants identified in women of Han Chinese ethnicity also associated with risk of PCOS or the phenotypic features of PCOS in European women? Summary answer One variant, rs2268361-T, in the intron of FSHR was associated with PCOS and lower FSH levels, while another variant rs705702-G near the RAB5B and SUOX genes was associated with insulin and glucose levels after oral glucose testing in women with PCOS of European ethnicity. What is known already Three of the eleven variants associated with PCOS in the Han Chinese genome-wide association studies were also associated with PCOS in at least one European population when corrected for multiple testing (DENND1A, THADA and YAP1). However, additional replication is needed to establish the importance of these variants in European women and to determine the relationship to PCOS phenotypic traits. Study design, size, duration The study was a case-control examination in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston (Boston 1). Replication was performed in women from Greece (cases n = 884 and controls n = 311) and an additional cohort from Boston (Boston electronic medical record (EMR); n = 350 cases and n = 1258 controls). Participants/materials, settings, methods Women had PCOS defined by the National Institutes of Health criteria in Boston 1 and Greece (n = 783), with additional subjects fulfilling the Rotterdam criteria (hyperandrogenism, polycystic ovary morphology and regular menses) in Greece (n = 101). Controls in Boston and Greece had regular menstrual cycles and no hyperandrogenism. The second cohort from Boston was defined using the EMR and natural language processing. Allele frequencies for variants associated with PCOS in Han Chinese women were examined in PCOS cases and controls, along with the relationship to quantitative traits. Main results and the role of chance A variant rs2268361-T in an intron of FSHR was associated with PCOS (0.84 [0.76-0.93], OR [95% CI]; P = 0.002). The rs2268361-T was associated with lower FSH levels (-0.15 ± 0.05; P = 0.0029). A variant rs705702-G near RAB5B and SUOX was associated with insulin (-0.16 ± 0.05, P = 0.0029) and glucose levels (-0.20 ± 0.05, P = 0.0002) 120 min after an oral glucose test. Limitations, reasons for caution The study was large and contained replication cohorts, but was limited by a small number of controls in the Greek cohort and a small number of cases in the second Boston cohort. The second Boston group was identified using electronic medical record review, but was validated for the cardinal features of PCOS. Wider implications of the findings This study demonstrates a cross-ethnic PCOS risk locus in FSHR in women of European ancestry with PCOS. The variant may influence FSH receptor responsiveness as suggested by the associated change in FSH levels. The relationship between a variant near RAB5B and SUOX and glucose stimulated insulin and glucose levels suggests an influence of one of these genes on glucose tolerance, but the absence of a relationship with PCOS points to potential differences in the international PCOS patient populations. Study funding/competing interests The project was supported by Award Number R01HD065029 from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development, Award Number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources, award 1-10-CT-57 from the American Diabetes Association and the Partners Healthcare Center for Personalized Genetics Project Grant. C.K.W. is a consultant for Takeda Pharmaceuticals. Trial registration number NCT00166569.

Isolated GnRH deficiency is a heritable condition characterized by a functional deficit in GnRH secretion. Familial cases with different modes of inheritance have been described, and the gene responsible for the X-linked form (KAL-1) has been identified. However, sporadic cases with no documented family history of GnRH deficiency account for the majority of the affected patients. For this reason, we sought to determine the frequency with which KAL-1 gene mutations occur in patients with sporadic GnRH deficiency. Only 1 of 21 patients with sporadic GnRH deficiency was found to bear a defect in the KAL-1 gene (a deletion of 14 bases starting at codon 464). Three types of polymorphic single base substitutions with no apparent correlation with GnRH deficiency were also detected in several patients. In each of 3 different patients with an X-linked mode of inheritance, 3 genetic defects, 2 point mutations and a small intragenic deletion, were detected. These defects consist of a single base mutation introducing...

A 32-year-old primigravida with primary Addison's disease was followed up from the early stages of pregnancy to delivery and puerperium by a multidisciplinary medical board. Besides fetal surveillance, great attention was given to steroid replacement therapy in order to avoid complications. Vaginal labor resulted in the birth of a healthy neonate that performed well.

Objective To assess GH and insulin-like growth factor I (IGF-I) axis variability in hyperandrogenic adolescents with different sources of androgen excess and their relationship with insulin resistance. Design Baseline IGF-I, insulin-like growth factor binding protein-1 (IGFBP-1), IGFBP-3, GH response to the exercise-propranolol test, and insulin responses to a standard oral glucose tolerance test were compared among patients with functional ovarian hyperandrogenism, hyperandrogenic nonfunctional ovarian hyperandrogenism patients, and age-matched controls. Setting Outpatient clinic in a medical center. Patients Twenty-one adolescents with ovarian (group A) and 17 with nonovarian (group B) hyperandrogenism, and 20 controls. Results Serum IGF-I and poststimulated GH levels were similar among groups, whereas serum IGFBP-3 levels were significantly lower in group A than in controls. Mean serum insulin levels were significantly higher in patients than in controls, whereas 24% of patients had abnormal insulin responses to glucose and/or insulin sensitivity indexes. Serum IGFBP-3 levels correlated negatively with the free androgen index (free androgen index=T/sex hormone-binding globulin [SHBG]×100), whereas mean serum insulin levels correlated positively with the free androgen index and negatively with SHBG levels in all subjects. Conclusions Hyperinsulinemia is common in hyperandrogenic adolescents and correlates with the degree of hyperandrogenism and not with the androgen source. Hyperinsulinemia and decreased IGFBP-3 levels may enhance IGF-I bioavailability, which in turn may both decrease SHBG levels and increase androgen production.

The present study investigates the combined effect of diet, physical exercise and Orlistat for 24 weeks, on serum anti-Müllerian hormone (AMH) levels in overweight and obese women with polycystic ovary syndrome (PCOS) and in overweight and obese controls. Sixty-one (61) selected women with PCOS and 20 overweight and obese controls followed an energy-restricted diet, physical exercise plus Orlistat administration (120 mg, 3 times per day) for 24 weeks. At baseline, week 12 and week 24, serum levels of AMH, FSH, LH, PRL, androgens, sex hormone-binding globulin (SHBG), glucose, and insulin were measured and Free Androgen Index (FAI) and Insulin Resistance (IR) indices were calculated. In PCOS women, serum AMH levels increased after 12 and 24 weeks of treatment. After 12 weeks LH and SHBG were increased, while Testosterone decreased. After 12 and 24 weeks, FAI was decreased and all indices of IR were significantly improved. We concluded that in overweight and obese women with PCOS Orlistat administration, combined with diet and physical exercise, for 24 weeks, resulted in significant weight loss, improvement of hyperandrogenism and insulin sensitivity, and increased serum AMH levels.

Aromatase inhibitors (AIs) provide an alternative to tamoxifen as an adjuvant therapy for post-menopausal, hormone-receptor positive breast cancer patients. The aim of the present study was to evaluate the effect of PvuII and XbaI polymorphisms of the ERα gene at ΑΙs treatment's adverse effects in post-menopausal women with breast cancer. The study included 87 post-menopausal women with ER-positive breast cancer treated with AIs and 80 healthy controls. The overall presence of ERα polymorphisms in all women with breast cancer was not different from the healthy controls. Endometrial thickness under AIs treatment was reduced from (mean value ± SD) 6,404 ± 2,901 mm to 3,666 ± 1,4656 mm. Moreover, the AA XbaI genotype was associated with greater reduction in endometrial thickness during therapy with AIs (p = 0.005). The presence of the CC PvuII and the AA XbaI genotypes were associated with elevated LDL levels and elevated triglycerides. In conclusion, the results of the present study showed that the genotype of women with breast cancer under AIs treatment might influence treatment's adverse effects, as, the presence of the CC PvuII and the AA XbaI genotypes of the ERα were associated with elevated LDL and triglycerides serum levels, while the AA XbaI genotype was associated with a greater reduction in endometrial thickness.

Objective To investigate the effect of diet, physical exercise and sibutramine administration on serum anti-Mullerian hormone (AMH) levels, hormonal and metabolic parameters in overweight and obese patients with polycystic ovary syndrome (PCOS). Study design Prospective clinical study, in an outpatient clinic setting, of 76 overweight and obese women with PCOS. All patients were placed on a hypocaloric diet, physical exercise plus sibutramine (10 mg per day) for the first month and then on either a hypocaloric diet, physical exercise plus sibutramine (10 mg per day) or a hypocaloric diet and physical exercise for the subsequent 6 months. Serum AMH levels, body composition, hormonal and metabolic features and insulin sensitivity indices were evaluated at baseline and at 4 and 7 months of treatment. Results Body weight reduction was greater in the sibutramine group. Moreover, serum FSH and testosterone levels decreased, and SHBG, free androgen index and all indices of insulin resistance significantly improved at 4 and 7 months. Serum AMH levels decreased only in PCOS women who received sibutramine, at both 4 and 7 months of treatment. Conclusion A hypocaloric diet and a diet plus sibutramine both resulted in significant weight loss in overweight and obese women with PCOS. Patients who received sibutramine showed greater weight loss and improvement in hyperandrogenemia and insulin sensitivity after 7 months of treatment. Serum AMH levels significantly decreased at both 4 and 7 months of treatment only in PCOS women who received sibutramine, indicating a possible direct, gonadotropin independent effect of sibutramine on the ovarian production of AMH.

ObjectiveThe polycystic ovary syndrome (PCOS) is a common and complex disease with unclear pattern of inheritance, characterized by an androgen excess, while hyperinsulinemia and insulin resistance (IR) are common features of the syndrome. The angiotensin I converting enzyme (ACE) insertion (I)/deletion (D) gene polymorphism was proved to be involved in many pathophysiological conditions, including hypertension and IR.DesignThe purpose of this study was to evaluate the involvement of the ACE gene polymorphism in the pathogenesis of PCOS.MethodsIn a case–control association study involving 801 PCOS women and 266 healthy controls, hormonal determinations and ACE polymorphism genotyping were performed. The PCOS women were classified into three groups: Group A presented biochemical hyperandrogenism, combined with anovulation and polycystic ovarian morphology; Group B, clinical hyperandrogenism combined with anovulation and polycystic ovarian morphology; and Group C, chronic anovulation and polycystic ovarian morphology.ResultsA significant increase in the frequency of the DI genotype of the ACE polymorphism was detected in PCOS women as a whole (P=0.035), in PCOS Group A (P=0.039) and Group B (P=0.010), while there was no difference in Group C (P=0.939). Significant difference was also observed in hyperandrogenic PCOS women as a whole (Group A+B) (P=0.017). The II genotype was positively correlated with HOMA-IR and QUICKI and with fasting insulin and glucose/insulin ratio in these groups.ConclusionsThe association study of the ACE I/D polymorphism in PCOS women demonstrates an increase in the DI genotype incidence and an association of the II genotype with IR.

Hormonal determination in saliva offers several advantages. Peptides enter the salivary glands either by active transport mechanisms or are expressed and secreted by the salivary glands themselves. The collection of saliva is a noninvasive, easily repeatable and less stressful technique than blood withdrawal. The purpose of the present study was to introduce a method for measuring salivary resistin, visfatin and adiponectin levels and to evaluate their associations with serum levels. Resistin, visfatin and adiponectin levels were measured in serum and saliva of 50 healthy adult volunteers (17 male and 33 female) using commercial enzyme immunoassay kits for serum with minor modifications. The present study documented the determination of resistin and adiponectin levels in saliva and the significant correlation of salivary levels with serum levels (r=0.441, p

HLA-A, -B and -DR antigen distribution was studied in 49 girls with Turner Syndrome (TS), in 43 of their parents, as well as in 433 controls. No increased frequency of DR3, DR4 was found in our group. However, an increased frequency of HLA B 17 antigen was disclosed (18.3% in TS versus 6.4% in the controls, p

To assess the impact of metformin and of two different oral contraceptives (OCs) containing cyproterone acetate and drospirenone, on serum anti-Müllerian hormone (AMH) levels, in a cohort of women with polycystic ovary syndrome (PCOS) with hyperandrogenism.Prospective randomised study.Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki.Forty-five (45) women with PCOS diagnosed according to the criteria proposed in 1990 by the NIH.Women with PCOS were randomised into three groups, all treated for 6 months: Group A received an OC containing 35 μg ethinylestradiol plus 2 mg cyproterone acetate, Group B received an OC containing 30 μg ethinylestradiol plus 3 mg drospirenone and Group C received metformin 850 mg × 2. Main outcome measure(s). Anti-Müllerian hormone levels were measured by a specific ELISA.AMH was significantly decreased under treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate (p = 0.002 at 3 months and p0.001 at 6 months). Treatment with 30 μg ethinylestradiol plus 3 mg drospirenone, and treatment with metformin 850 mg × 2 did not significantly affect serum AMH levels. AMH was significantly decreased under OCs treatment compared to metformin 850 mg × 2 (p = 0.005).AMH serum levels were significantly decreased under treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, due to decrease in androgens and suppression of gonadotropins.