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The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH).A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay.Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities.This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.

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.

The aim was to assess the expression stability of three commonly used reference genes, namely, β-actin (ACTB), 18S ribosomal RNA (18S), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in placental tissue obtained from pregnant women with polycystic ovary syndrome (PCOS) and healthy controls.mRNA was isolated after delivery from the placentae of 10 PCOS and 10 control women with term, uncomplicated, singleton pregnancies. The expression of ACTB, 18S, and GAPDH was analyzed using real-time polymerase chain reaction (RT-PCR). Gene expression stability was evaluated with the RefFinder, GeNorm, Normfinder, BestKeeper, and Delta-Ct tools.ACTB was ranked as the most stably expressed gene, followed by 18S. The expression of GAPDH varied considerably in both studied groups, while it was increased in PCOS versus controls (5.3-fold, p 0.05).ACTB is an appropriate reference gene for placental gene expression studies in women with PCOS, whereas GAPDH is unfit for such a role, as its placental expression is increased in PCOS.

According to Greek mythology, the spring waters of Salmacis (or Salmakis) feminized the god Hermaphroditus (or Hermaphroditos) and transformed his nature from male to half-male and half-female. The mythical properties of these waters are described in the writings of authors and philosophers of the Hellenistic period. It is evident that the spring of Salmacis and lake actually existed (located in Halicarnassus, today Bodrum, Turkey) and are not the product of poetic imagination. Hence, it could be hypothesized that there were certain natural elements in the waters that had a feminizing effect on the male reproductive axis. We now know, in fact, that naturally occurring environmental agents, also known as endocrine disruptors, can affect the endocrine and reproductive function of both males and females. However, since most endocrine disruptors today are manmade products of the modern industrial lifestyle, the presence and effect of naturally occurring disruptors in times preceding the Industrial Revolution are not widely discussed. It is thus against this background that we seek to formulate a differential diagnosis of male feminization attributable to the effect of natural environmental factors in the form of endocrine disruptors that will have existed in environments round the globe since time immemorial. We conclude that if there had been an accumulation of the mycotoxin zearalenone (ZEA) in the waters of Salmacis, chronic exposure to the lake's water could have resulted in the phenotypic changes described in the Salmacis myth.

Although the suppressive action of synthetic steroids on the hypothalamus-pituitary-thyroid (HPT) axis is established, little is known regarding the effect of the administration of synthetic adrenocorticotropic hormone (ACTH).In the context of a randomized, open label, comparative study assessing the efficacy and safety of ACTH and betamethasone in the treatment of hospitalized patients with acute gout, we compared the effects of these agents on thyroid function tests.Serum TSH, total T4 and T3 and cortisol were measured before and at 24 and 48 h after a single intramuscular dose of synthetic ACTH (1 mg) or betamethasone (6 mg), in 38 hospitalized patients with acute gout and normal thyroid function.The final analysis included 32 patients, due to missing data. The ACTH and betamethasone groups did not differ regarding the mean age, gender, severity of gout attack, and baseline thyroid parameters. In the ACTH group TSH and T4 were significantly decreased at 24 and at 48 h compared to baseline, while T3 was decreased at 24 but not at 48 h. In the betamethasone group T3 remained stable; TSH and T4 decreased significantly from baseline levels at 24 h; at 48 h, TSH had returned to and T4 showed a partial rebound towards pre-treatment values.A single IM administration of 1 mg of synthetic ACTH has more profound and prolonged effects on the HPT axis, lasting for at least 48 h, compared to a single IM dose of 6 mg betamethasone.

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

The concept of metamorphosis (change of form, structure, or substance) is very frequently encountered in Ancient Greek and Roman literature. One of the most striking types of metamorphosis described in many myths is gender transformation, where a man becomes a woman or vice versa. Herein, we present a case of pubertal gender inversion, the marvelous story of the Cretan Leucippus, which not only inspired many ancient writers but also led to the development of a distinct, local, religious cult. A medical interpretation of the myth, whereby we attempt to establish a diagnosis for this case of heterosexual puberty, is also provided.

Previous studies have suggested that deletion of Foxo3a, FoxL2, PTEN, p27, and AMH leads to early exhaustion of the primordial follicle pool and premature ovarian insufficiency (POI) in transgenic mice. Our aim was to assess for the first time, to our knowledge, messenger RNA (mRNA) expression of these genes and AMHR2 in human ovarian tissue from women with POI. We hypothesized that these genes would be underexpressed in POI women compared with healthy controls. mRNA levels were evaluated by quantitative reverse transcription-polymerase chain reaction and real-time polymerase chain reaction in cortical ovarian tissue obtained by laparoscopy from Caucasian Greek women with POI (n = 5) and healthy women with normal menstruation (n = 6). Morphological analysis of the ovarian biopsies was also performed to assess the presence of primordial or other types of growing follicles. Ovarian tissue from POI patients showed lower Foxo3a, FoxL2, and p27 mRNA expression compared with controls (p = 0.017, p = 0.017, and p = 0.030, respectively). mRNA expression of AMH, PTEN, and AMHR2 was reduced in ovarian biopsies from POI patients as well. However, these differences were not statistically significant (p = 0.143, p = 0.247, and p = 0.662, respectively). Morphological analysis showed complete lack of follicular structures in all POI biopsies. Our findings suggest a possible role of Foxo3a, FoxL2, and p27 in the pathogenesis of human POI, which may prove to be of great diagnostic-therapeutic value. Further larger studies are needed to identify a similar pattern for AMH, PTEN, and AMHR2 and to investigate gene expression at a protein level.

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a rare disease with a wide spectrum of reproductive and non-reproductive clinical characteristics. Apart from the phenotypic heterogeneity, IGD is also highly genetically heterogeneous with >35 genes implicated in the disease. Despite this genetic heterogeneity, genetic enrichment in specific subpopulations has been described. We have previously described low prevalence of genetic variation in the Greek IGD cohort discovered with utilization of Sanger sequencing in 14 known IGD genes. Here, we describe the expansion of genetic screening in the largest IGD Greek cohort that has ever been studied with the usage of whole-exome sequencing, searching for rare sequencing variants (RSVs) in 37 known IGD genes. Even though Sanger sequencing detected genetic variation in 21/81 IGD patients in 7/14 IGD genes without any evidence of oligogenicity, whole exome sequencing (WES) revealed that 27/87 IGD patients carried a rare genetic change in a total of 15 genes with 4 IGD cases being oligogenic. Our findings suggest that next-generation sequencing (NGS) techniques can discover previously undetected variation, making them the standardized method for screening patients with rare and/or more common disorders.

During the Golden Age of the Roman Empire, Rome was transformed into a magnificent city where architecture, the arts, and commerce flourished. An inconceivable amount of wealth was accumulated by a handful of noble families, while the masses starved. In such a context, moral values inevitably decline, while sexual mores are liberalized and ever more veer towards salacity. This reality was elegantly illustrated in short, often sarcastic poems known as epigrams. Herein, we present a case of a woman with enigmatic appearance of the external genitalia, exhibiting unrestrained homosexual activity, as described in an epigram by Marcus Valerius Martialis (a contemporary poet who lived in the 1st century AD). Based on the information provided in the ancient text, we formulate a differential diagnosis and deduce that this woman was, in fact, a case of congenital adrenal hyperplasia (CAH). To our knowledge, this is the earliest literary description worldwide of a case of CAH as a cause of homosexuality and unquenchable lust.

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.

The concept of metamorphosis (change of form, structure, or substance) is very frequently encountered in Ancient Greek and Roman literature. One of the most striking types of metamorphosis described in many myths is gender transformation, where a man becomes a woman or vice versa. Herein, we present a case of pubertal gender inversion, the marvelous story of the Cretan Leucippus, which not only inspired many ancient writers but also led to the development of a distinct, local, religious cult. A medical interpretation of the myth, whereby we attempt to establish a diagnosis for this case of heterosexual puberty, is also provided.

The original version of this article, published 21 October 2019, unfortunately contained a mistake. The presentation of Fig. 1 was incorrect. The corrected figure is given below.

Over the past decade, considerable progress has been made in the field of pediatric endocrinology. However, there is still a long way to go regarding the exploration of novel avenues, such as epigenetics, the changing views on the pathophysiology and derived therapy of specific disorders, and the prevention of prevalent diseases. The next decade will hopefully bring the consolidation of most of those achievements and the development of new pathways for further progress.

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.

Over the past decades, research attention has increasingly been paid to the neurobiological component of sexual behavior. The aim of the present study was to investigate the correlation of estrogen receptor α (ERA) gene polymorphism (rs2234693-PvuII) (T→C substitution) and oxytocin receptor gene polymorphism (rs53576) (G→A substitution) with sexuality parameters of young, healthy women. One hundred thirty-three Greek heterosexual women, students in higher education institutions, 20–25 years of age, sexually active, with normal menstrual cycles (28–35 days), were recruited in the study. Exclusion criteria were chronic and/or major psychiatric diseases, use of oral contraceptive pills (OCs), polycystic ovary syndrome (PCOS), thyroid diseases as well as drugs that are implicated in hypothalamus–pituitary–gonadal axis. T allele (wildtype) of rs2234693 (PvuII) polymorphism of ERA gene was correlated with increased levels of arousal and lubrication, whereas A allele (polymorphic) of rs53576 (OXTR) polymorphism was correlated with increased arousal levels. The simultaneous presence of both T allele of rs2234693 (PvuII) and A allele of rs53576 (OXTR) polymorphisms (T + A group) was correlated with increased arousal, orgasm levels as well as female sexual function index full score. To our knowledge, this is the first study to investigate the interaction between ERA and OXTR with regard to sexual function in women. Female sexuality is a complex behavioral trait that encompasses both biological and psychological components. It seems that variability in female sexual response stems from genetic variability that characterizes endocrine, neurotransmitter and central nervous system influences.

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.

In Greek mythology, Melampus, son of Amythaon was a seer and healer. He became the ruler of Argos after curing the insanity of the daughters of Proetus, king of Tiryns. The daughters of Proetus were seized with manic madness, because they opposed the worship of Dionysus. They believed themselves to be cows and wandered in the wilderness. Their insanity manifested mainly as hypersexuality. Melampus chased the insane women through the woods, trapped them in a cave and healed them from madness with sacred baths and the use of an herb. The myth of Proetus’ daughters represents a very interesting medical case characterized by the acute onset of both psychiatric and dermatologic symptoms in several individuals simultaneously. In this paper, we try to explore whether Melampus, apart from being the healer, could also be the culprit of this "madness" by manipulating the use of several herbs.

Cases of sexual reassignment in Greco-Roman Antiquity, namely a pubertal female-to-male gender transformation, are described in the “paradoxical” literature. Textual evidence concerning a case of androgynism stored up by Phlegon of Tralles as an odd story of gender transformation during marriage is provided in the present study. Μedical interpretation of this case presents a contemporary differential diagnosis of heterosexual puberty in pseudohermaphrodites characterized by genital ambiguity.

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.

Cases of sexual reassignment in classical antiquity, namely a female-to-male gender change occurring after childhood, are described in the literature. Textual evidence concerning these cases of androgynism and their symbolism as well as a comprehensive scholar analysis is provided in the present study. Μedical interpretation of these cases covers the entire spectrum of differential diagnosis of heterosexual puberty in pseudohermaphrodites characterized by genital ambiguity.

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.

The polycystic ovary syndrome (PCOS) is a common and complex disease without a clear pattern of inheritance. Anti-Müllerian hormone (AMH) has an inhibitory effect on FSH-stimulated follicle growth. Serum AMH levels are higher in women with PCOS than in normo-ovulatory women. The elevated AMH levels may reflect abnormalities in AMH signaling.The purpose of this study was to evaluate the association of the anti-Müllerian hormone receptor 2 (AMHR2) -482 AG polymorphism (rs2002555) with the pathophysiology of PCOS.AMHR2 -482 AG polymorphism genotyping were performed in a large cohort of women with PCOS and in a healthy control group.A total of 858 Caucasian Greek women with PCOS and 309 healthy control women were studied.Genotyping and hormonal measurements were preformed.Hormone levels in women with PCOS were analyzed.The AMHR2 polymorphism was more common in women with PCOS than in control women (P = .026). Homozygous AMHR2 -482 AG gene polymorphisms (GG) were associated with decreased levels of LH (P = .003) and lower LH to FSH ratios (P = .01) in women with PCOS, as well as with lower prolactin levels (P = .004). No other associations related to AMHR2 -482 AG polymorphisms were observed in women with PCOS or control women.In this study, the role of the AMHR2 -482 AG gene polymorphism in the pathogenesis of PCOS was suggested by the association of the variant with PCOS risk. Thus, further research is needed to elucidate a possible association of the AMHR2 -482 AG gene polymorphism with AMH signaling and impaired ovarian function and its clinical significance in women with PCOS.

OBJECTIVE: To evaluate the effect of prolonged intensive aerobic exercise and acute energy deficit (180 km ultra-marathon race) on serum leptin, adiponectin, resistin and visfatin levels and their association and interaction with serum cortisol and insulin levels in highly trained ultra-endurance runners. DESIGN: The study included 17 highly trained ultra-endurance male athletes (mean age 51.29±6.84 years and body mass index (BMI) 23.51±1.90) participating in the 5th Olympian Race held in Greece on May 2010. Anthropometric values were assessed; serum cortisol, insulin, leptin, adiponectin, resistin and visfatin levels were measured at baseline, post-exercise and ∼20 hours after the end of the race. RESULTS: All hormonal values of the post-exercise and recovery status were corrected for plasma volume changes. The estimated energy deficit during the ultra-endurance event was about 5000 Kcal. At the end of the race serum resistin levels were elevated (p

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.

Individuals are becoming increasingly involved in physical activities, ranging from regular mild exercise to highly competitive performance requiring intensive and strenuous training. However, as the duration, frequency, and intensity of exercise increases, great concern and major reactions arouse regarding the deleterious effects of intensive physical activity on somatic growth, pubertal development, and biological maturation.

Exercise challenges homeostasis and establishes a new dynamic equilibrium. Elite Rhythmic Gymnasts (RG's) begin exercise at an early age, undergo physical and psychological stress, and adopt negative energy balance to retain a lean physique. The aim of the present study was to evaluate the effect of negative energy balance, acute and chronic exercise on salivary adiponectin, resistin and visfatin levels and their interaction with salivary cortisol, and insulin levels in elite RG's. This study is unique in character, as all variables were assessed on the field of competition. The study included 51 elite RG's participating in "Kalamata 2010 World Cup" in Kalamata, Greece on April 2010. Twenty-seven healthy age-matched girls were used as controls. Anthropometric values were assessed; baseline and post exercise salivary cortisol, insulin, adiponectin, resistin, and visfatin levels were measured. Comparisons regarding hormonal features between RG's and controls were adjusted for BMI and body fat percentage. Salivary adiponectin levels were higher (p0.05) and visfatin lower (p=0.094) in RG's compared with controls, while no significant changes were observed regarding salivary cortisol, insulin, and resistin levels. In elite RG's acute intensive anaerobic exercise led to increased salivary insulin levels (p0.001), reduced salivary adiponectin (p0.001) and visfatin levels (p0.05), and no changes in salivary resistin levels. Moreover, diurnal variation of salivary cortisol was lost. In elite RG's salivary adiponectin is upregulated and salivary visfatin is downregulated after chronic intensive exercise and negative energy balance, while both salivary adiponectin and visfatin levels are suppressed after short term intensive anaerobic exercise.

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.