EMAS position statement: Thyroid disease and menopause.

INTRODUCTION: Thyroid diseases are common in women in their late reproductive years; therefore, thyroid disease and menopause may co-exist. Both conditions may present with a wide range of symptoms, leading to diagnostic challenges and delayed diagnosis. Aim To construct the first European Menopause and Andropause Society (EMAS) statement on thyroid diseases and menopause. MATERIALS AND METHODS: Literature review and consensus of expert opinion (EMAS executive board members/experts on menopause and thyroid disease). SUMMARY RECOMMENDATIONS: This position paper highlights the diagnostic and therapeutic dilemmas in managing women with thyroid disease during the menopausal transition, aiming to increase healthcare professionals' awareness of thyroid disorders and menopause-related symptoms. Clinical decisions regarding the treatment of both conditions should be made with caution and attention to the specific characteristics of this age group while adopting a personalized patient approach. The latter must include the family history, involvement of the woman in the decision-making, and respect for her preferences, to achieve overall well-being.

Ketone Bodies in Diabetes Mellitus: Friend or Foe?

In glucose-deprived conditions, ketone bodies are produced by the liver mitochondria, through the catabolism of fatty acids, and are used peripherally, as an alternative energy source. Ketones are produced in the body under normal conditions, including during pregnancy and the neonatal period, when following a ketogenic diet (KD), fasting, or exercising. Additionally, ketone synthesis is also augmented under pathological conditions, including cases of diabetic ketoacidosis (DKA), alcoholism, and several metabolic disorders. Nonetheless, diet is the main regulator of total body ketone concentrations. The KDs are mimicking the fasting state, altering the default metabolism towards the use of ketones as the primary fuel source. Recently, KD has gained recognition as a medical nutrition therapy for a plethora of metabolic conditions, including obesity and diabetes mellitus (DM). The present review aims to discuss the role of ketones, KDs, ketonemia, and ketonuria in DM, presenting all the available new evidence in a comprehensive manner.

Diet Quality and Nutritional Risk Based on the FIGO Nutrition Checklist among Greek Pregnant Women: A Cross-Sectional Routine Antenatal Care Study.

The International Federation of Gynecology and Obstetrics (FIGO) nutrition checklist is a tool for everyday antenatal clinical practice, easy to use by most healthcare professionals, aiming to initiate a conversation regarding gestational weight gain (GWG) and nutrition and identify women who might require further assessment. The present cross-sectional study aimed to apply the FIGO nutrition checklist to pregnant women attending routine antenatal care and identify nutritional risk factors. Pregnant women (n = 200) were recruited from the outpatient pregnancy clinics of two hospitals in Thessaloniki and completed the checklist. The FIGO-diet quality score and the FIGO-nutritional risk score (NRS) were calculated. The results revealed that 99% of the women exhibited at least one nutritional risk factor based on the checklist. The median FIGO diet quality score of the sample was 4.0 (3.0-5.0), with 95% of the participants responding negatively to at least one question, indicating the need for improving diet quality. Improved diet quality was noted in cases of hyperemesis gravidarum and among those receiving vitamin D supplements. A large percentage of the participants (36%) exhibited five or more nutritional risk factors, as indicated by a total FIGO-NRS below 5. Women with low middle-upper arm circumference, indicative of protein-energy malnutrition (20.6% of the sample), exhibited more nutritional risk factors compared with the rest. On the other hand, being in the third trimester of pregnancy was associated with lower nutritional risk and, subsequently, better diet quality.

Microvascular and Endothelial Dysfunction in Prediabetes.

Prediabetes is a significant metabolic status since there is high potential for future progression of diabetes mellitus (DM). People with prediabetes are at increased risk of cardiovascular disease (CVD) and mortality. Endothelial and microvascular dysfunction is considered a key step towards the development and progression of CVD. Importantly, endothelial and microvascular dysfunction can be detected and monitored using non-invasive procedures in peripheral organs and tissues, including the retina, kidney, skin and skeletal muscle. Structural and functional alterations of the microvasculature have been consistently documented in the above microvascular beds in patients with diabetes mellitus. In contrast, such alterations remain understudied in prediabetes, but are currently receiving attention as markers of subclinical and future CVD. The aim of this review is to summarize available evidence regarding the presence of subclinical microvascular and endothelial dysfunction in prediabetes and their impact on cardiovascular risk.

Plasma Ceramide Concentrations in Full-Term Pregnancies Complicated with Gestational Diabetes Mellitus: A Case-Control Study.

Ceramides, a sphingolipid group that acts as a messenger in cellular differentiation, proliferation, apoptosis and senescence, have been associated with cardiovascular disease and type 2 diabetes. The evidence for an association between ceramides and gestational diabetes mellitus (GDM) is scarce. This case-control study aimed to compare women with GDM with healthy, pregnant women in terms of plasma ceramide concentrations at the time of delivery. Ninety-two pregnant women were included in this case-control study, 29 in the GDM group and 63 in the control group. All women were admitted to a tertiary academic hospital for a full-term delivery. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied for the quantification of four molecular ceramides, namely Cer d18:1/16:0 (Cer16:0), Cer d18:1/18:0 (Cer18:0), Cer d18:1/24:0 (Cer24:0) and Cer d18:1/24:1 (Cer24:1) in plasma samples. The raw chromatographic data obtained from the LC-MS/MS analysis were processed using Analyst SCIEX (AB Sciex Pte. Ltd., USA). In a univariate statistical analysis, Cer24:0 concentration was significantly lower in the GDM group compared with the control group (p = 0.01). The present study demonstrated lower Cer24:0 concentrations in pregnancies complicated by GDM. Further prospective studies are required to enhance the results of this study.

Seminal L-Carnitine In Infertile Oligoasthenoteratozoospermic Men with Varicocele.

Background: Few studies have investigated the relationship of seminal L-Carnitine (LC) with male infertility associated with varicocele. The purpose of this prospective cross-sectional study was to assess seminal plasma LC levels in infertile oligoathenoteratozoospermic (OAT) men with varicocele. Methods: Overall, 86 men were investigated. They were divided into infertile OAT men with varicocele (n=45), infertile OAT men without varicocele (n=21), and fertile men (n=20) as a control group. According to WHO guidelines, these men were subjected to history taking, clinical examination, and semen analysis. Seminal LC levels were evaluated by the colorimetric method. Statistical comparisons were done using Kruskal-Wallis and Mann-Whitney U tests and correlations were verified by the Pearson test. P-value<0.05 was set to be statistically significant. Results: The mean seminal plasma LC levels were significantly lower in infertile OAT men with varicocele (216.3±57.1 ng/ml) compared to infertile OAT men without varicocele (252.9±62.9 ng/ml, p=0.01), or fertile men (382.8±63.6 ng/ml, p=0.001). Besides, the mean seminal plasma LC level exhibited statistically significant decreases in infertile OAT men of varicocele grade III compared to varicocele grade II cases, and in infertile OAT men with bilateral varicocele compared with unilateral varicocele cases. Collectively, there was a statistically significant positive correlation between seminal LC levels with sperm concentration, motility, and normal morphology. Conclusion: Seminal LC levels are expressively reduced in infertile OAT men with varicocele and are influenced by an increase in varicocele grade and laterality.

Metabolic, Oxidative and Psychological Stress as Mediators of the Effect of COVID-19 on Male Infertility: A Literature Review.

Over 300 million patients with coronavirus disease 2019 (COVID-19) have been reported worldwide since the outbreak of the pandemic in Wuhan, Hubei Province, China. COVID-19 is induced by the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effect of SARS-CoV-2 infection on the male reproductive system is unclear. The aim of this review is to assess the effect of SARS-CoV-2 infection on male fertility and the impact of possible mediators, such as metabolic, oxidative and psychological stress. SARS-CoV-2 infection aggravates metabolic stress and directly or indirectly affects male fertility by reducing seminal health. In addition, SARS-CoV-2 infection leads to excessive production of reactive oxygen species (ROS) and increased psychological distress. These data suggest that SARS-CoV-2 infection reduces male fertility, possibly by means of metabolic, oxidative and psychological stress. Therefore, among other consequences, the possibility of COVID-19-induced male infertility should not be neglected.

Neurofibromatosis Type 1 Has a Wide Spectrum of Growth Hormone Excess.

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (<1 ng/mL) on oral glucose tolerance test (OGTT, n = 9) and frequent overnight sampling of GH levels (n = 6). Genetic testing was ascertained through targeted or whole-exome sequencing (n = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro NF1 variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of NF1 had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.

Exercise as a Therapeutic Intervention in Gestational Diabetes Mellitus.

Gestational Diabetes Mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Regular exercise is important for a healthy pregnancy and can lower the risk of developing GDM. For women with GDM, exercise is safe and can affect the pregnancy outcomes beneficially. A single exercise bout increases skeletal muscle glucose uptake, minimizing hyperglycemia. Regular exercise training promotes mitochondrial biogenesis, improves oxidative capacity, enhances insulin sensitivity and vascular function, and reduces systemic inflammation. Exercise may also aid in lowering the insulin dose in insulin-treated pregnant women. Despite these benefits, women with GDM are usually inactive or have poor participation in exercise training. Attractive individualized exercise programs that will increase adherence and result in optimal maternal and offspring benefits are needed. However, as women with GDM have a unique physiology, more attention is required during exercise prescription. This review (i) summarizes the cardiovascular and metabolic adaptations due to pregnancy and outlines the mechanisms through which exercise can improve glycemic control and overall health in insulin resistance states, (ii) presents the pathophysiological alterations induced by GDM that affect exercise responses, and (iii) highlights cardinal points of an exercise program for women with GDM.

Nonalcoholic fatty liver disease in males with low testosterone concentrations.

AIMS: There are limited clinical data on the association between serum testosterone concentrations and nonalcoholic fatty liver disease (NAFLD) in men. The main aim of this study was to evaluate the association between testosterone concentrations and NAFLD in adult men, in terms of noninvasive indices of NAFLD and hepatic fibrosis. METHODS: In this cross-sectional study, 98 men were recruited on an outpatient basis and were divided into low-testosterone (<12 nmol/l or <346 ng/dl, n = 37) or high-testosterone groups (≥12 nmol/l or ≥346 ng/dl, n = 61). Serum testosterone concentrations were measured by immuno-chemiluminescence. Hepatic steatosis index (HSI) and Triglyceride-to-HDL-C ratio (THR), as non-invasive indices of NAFLD, as well as AST-to-Platelet Ratio Index (APRI), fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), as non-invasive indices of hepatic fibrosis, were calculated based on standard formulas. RESULTS: Both the non-invasive indices of NAFLD (HSI and THR) were higher in low-testosterone compared with high-testosterone group (HSI: 47.5 ± 2.9 vs. 38.4 ± 1.0, p = 0.005; THR: 1.70 ± 0.16 vs. 0.98 ± 0.07, p < 0.001). On the contrary, none of the non-invasive indices of hepatic fibrosis was different between groups. HSI (p = 0.038), but not THR, remained inversely independently associated with serum testosterone, after adjustment for potential confounders, including sex hormone-binding globulin. CONCLUSIONS: Men with low testosterone concentrations have higher non-invasive indices of NAFLD (HSI and THR), but not of hepatic fibrosis (APRI, FIB-4, NFS), compared with counterparts of high testosterone concentrations. HSI was inversely and independently associated with testosterone concentrations.

The effect of underweight on female and male reproduction.

Chronic energy deficiency can impair the hypothalamic-pituitary-gonadal (HPG) axis and lead to hypothalamic anovulation in underweight women. This review presents the syndromes related to underweight status that are associated with infertility, summarizes the underlying mechanisms, and reviews the available treatment options. Eating disorders, such as anorexia nervosa (AN), constitute the most common cause of infertility in underweight women, who, in addition, experience miscarriages, and sexual dysfunction. The relative energy deficiency in sports (RED-S; former terminology: athlete's triad) involves menstrual dysfunction due to low energy availability, which results in anovulation. Moreover, lipodystrophies, malnutrition, starvation, systematic illnesses (malignancies, endocrinopathies, infectious diseases, advanced chronic diseases, neurologic illnesses), and the utilization of drugs can cause excessive weight loss. They may result in fertility problems due to the loss of adipose tissue and the subsequent hormonal disturbances. Each of these conditions requires multidisciplinary management. Nutritional counseling should target the restoration of energy balance by increasing intake and reducing output. Medical treatment, recommended only for patients who did not respond to standard treatment, may include antipsychotics, antidepressants, or leptin administration. Finally, psychiatric treatment is considered an integral part of the standard treatment.

The effect of excess body fat on female and male reproduction.

The dramatic increase in the prevalence of obesity coincides with a decline in reproductive health indices in both sexes. Energy excess mediates changes to the regulatory mechanisms of the reproductive system. Obese individuals exhibit increased estrogen concentrations, due to the overexpression of aromatase in the adipose tissue; via a negative feedback loop, men present with symptoms of hypogonadotropic hypogonadism. These hormonal changes, along with increased oxidative stress, lipotoxicity and disturbances in the concentrations of adipokines, directly affect the gonads, peripheral reproductive organs and the embryo. Clinical evidence is somewhat contradicting, with only some studies advocating worse semen parameters, increased incidence of erectile dysfunction, increased doses of ovulation induction medications, and worse live birth rates in assisted reproductive technology (ART) cycles in obese individuals compared with those of normal weight. Similar conclusions are drawn about patients with insulin resistance syndromes, namely polycystic ovary syndrome (PCOS). As far as treatment options are concerned, lifestyle changes, medical therapy and bariatric surgery may improve the reproductive outcome, although the evidence remains inconclusive. In this review, we summarize the evidence on the association of obesity and reproductive health on both the molecular and the clinical level, and the effect of weight-loss interventions on reproductive potential.

Non-coronary atherosclerotic cardiovascular disease in patients with familial hypercholesterolaemia.

Objective: Familial hypercholesterolaemia (FH) is a common autosomal dominant inherited disease, affecting 1 in 200-500 individuals worldwide. FH is characterized by elevated circulating low-density lipoprotein cholesterol (LDL-C) concentrations. Its association with increased risk of coronary heart disease (CHD) (>10-fold, compared with patients without FH) is well documented. However, the association between FH and non-CHD atherosclerotic cardiovascular disease (ASCVD) risk has been poorly documented.Methods: PubMed was searched for English language publications regarding the association between FH and carotid artery stenosis, stroke, peripheral artery disease (PAD; lower limbs and other arterial beds), aortic valve calcification (AoVC), aortic and renal artery disease, chronic kidney disease, atrial fibrillation and heart failure, from conception until 22 December 2019.Results: Despite the small number of available studies, as well as their characteristics (sample size, diagnostic criteria used, retrospective or cross-sectional design), there is evidence for a positive association between FH and stroke, PAD or AoVC. More data are needed for definitive conclusions regarding aortic and renal artery disease, chronic kidney disease, atrial fibrillation and heart failure. There is paucity of data with respect to homozygous FH. Increased lipoprotein (a) concentrations, often seen in FH patients, may also contribute to this non-CHD atherosclerotic process. A key question is whether statins or other LDL-C-lowering therapies, provide an additional reduction in the risk of these less-recognized vascular and non-vascular complications in FH patients.Conclusions: Heterozygous FH is associated with increased risk for stroke, PAD and AoVC. Clinicians should take these non-CHD ASCVD aspects into consideration for optimal management of FH patients.

Evidence for a manifold role of selenium in infertility.

This review aimed to assess the evidence from observational and interventional studies in humans and animals regarding the role of selenium (Se) in male and female infertility. As oxidative stress can seriously impair male, and possibly also female, reproductive functions, it can be speculated that the antioxidant properties of Se could constitute one of the pathways by which this element is involved in fertility. Specifically, there are strong indications that Se influences the growth, maturation, and replication of oocytes, though the precise mechanisms have not as yet been fully elucidated. Given that it is not clear at present which tissue sample (blood, serum, seminal plasma, sperm, or follicular fluid) renders the most accurate picture of Se concentration in terms of its role in reproduction, the data are still insufficient to recommend routine assessment of Se status in men and women seeking fertility. Nevertheless, the existing evidence, despite being of limited quantity and somewhat low quality, suggests that Se supplementation (< 200 µg/d) is possibly beneficial in men through its improvement of sperm motility. Well-designed, randomized control studies are needed to reveal the seemingly diverse protective/positive role of Se supplementation in men and women seeking fertility treatment.

Egg freezing and late motherhood.

Egg freezing was initially used as an intervention for iatrogenic ovarian insufficiency. Nowadays, it is not considered an experimental procedure, and it is increasingly popular among healthy women who wish to maintain their reproductive potential (fertility preservation). This review summarises the evidence on egg freezing technology, reproductive outcomes and long-term effects, as well as its psychological and socioeconomic implications. Egg freezing technology is advancing, with vitrification being the current method of choice, due to its effectiveness. The reproductive outcomes following egg freezing appear to be promising, though the strong negative association with maternal age has to be taken into consideration. Unfortunately, data on long-term outcomes are missing, raising safety issues. Egg freezing has several socioeconomic implications involving health risks, as well as financial and psychological factors.

Could Lipid Profile be Used as a Marker of Autonomous Cortisol Secretion in Patients with Adrenal Incidentalomas?

Adrenal incidentalomas (AIs) have been associated with an increased risk of metabolic syndrome and dyslipidemia, though evidence regarding the latter is limited. Lipid abnormalities in patients with AIs have been associated with subclinical hypercortisolism. The current study aims to test whether lipid profile in patients with AIs predicts "autonomous cortisol secretion" (ACS). Patients with AIs found on either computerized tomography (CT) or magnetic resonance imaging (MRI), were included in a prospective cohort study. All patients were followed up for at least three years. Alterations in their hormonal and lipid profiles were recorded. Ninety-four patients (69 women) harboring 111 AIs were included. There were no differences between patients with ACS and those without, with respect to their baseline lipid profile [total cholesterol, low-density-lipoprotein cholesterol (LDL-C), triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-HDL-C] and blood pressure (systolic and diastolic). Non-HDL-C concentrations decreased over time (Repeated Measures ANOVA, p=0.013), despite patients' body mass index (BMI) remaining unchanged. Logistic regression analysis revealed that the only predictor of ACS was the size of AIs, as calculated by CT or MRI. The current study demonstrated that lipid profile at baseline or during follow-up cannot predict ACS in patients with AIs. However, larger AIs may have a greater probability of ACS.

ThyPROgr: the Greek edition of the ThyPRO questionnaires for patients with benign thyroid diseases.

The thyroid-related patient-reported outcome measure ThyPRO is currently the most reliable and valid instrument for the measurement of thyroid-related quality of life. The objective of the current study was to translate the original (85 items) and short (39 items) versions of ThyPRO into the Greek language as well as to validate and culturally adapt ThyPRO among the Greek population. Translation of patient-reported outcomes was done according to standard methodology. Following the translation process, the Greek version of ThyPRO (ThyPROgr) was validated in consecutive patients with thyroid diseases who visited the outpatient clinics of the Department of Endocrinology, "Hippokration" General Hospital, Thessaloniki, Greece, between September and December 2016. To test cross-cultural validity, analysis of differential item functioning (DIF) between the original Danish and the new Greek version, using ordinal logistic regression, was applied. Cross-cultural validity of the Greek translation was evaluated for both versions of ThyPRO. The ThyPRO questionnaire was validated in 143 consecutive patients (131 women and 12 men) with thyroid diseases, with a mean age of 62 ± 6 (SD) years. In the 85-item ThyPRO, 17 instances of DIF were detected, most of which were minor, this accounting for the ~ 5% of the variation in scale score. Two instances of DIF among positively worded items were larger, with 8-10% of variance explained. For ThyPRO-39, five minor instances of DIF were found. As judged by the linguistic validation as well as the DIF analyses, ThyPROgr has good cross-cultural validity when compared with the original Danish version. The two versions of ThyPROgr can now be used to assess thyroid-specific quality of life in the Greek population.

Sexual Health During Postgraduate Training-European Survey Across Medical Specialties.

BACKGROUND: Sexual health problems are common. Therefore, training in sexual health is relevant for the clinical practice of trainees and early-career specialists in several specialties who deal with patients with sexual health problems. However, little is known about how sexual health training is provided across countries and specialties. AIM: To assess (i) sexual health training during postgraduate training programs in psychiatry, obstetrics and gynecology, urology, and endocrinology across Europe; (ii) the confidence of trainees and early-career specialists in dealing with patients with sexual health problems; and (iii) their need for further training in sexual health during postgraduate training programs. METHODS: The study was based on a collaboration among European societies of trainees in these 4 specialties. An online survey was developed and conducted from January 2015 through June 2016. MAIN OUTCOME MEASURES: Self-reported questionnaire. RESULTS: We collected 366 completed surveys from 40 countries. Sexual health training was considered an important or very important part of specialty training by 78.7% of participants. Overall, 62.3% of participants had not received any training in sexual health. Especially in obstetrics and gynecology, the large majority did not have training in sexual health (82.8%), followed by psychiatry (59.8%), urology (58.4%), and endocrinology (56.1%). There were statistically significant differences among specialties in the confidence of participants in managing patients with sexual health problems. In general, trainees and early-career specialists who had received sexual health training felt more confident in dealing with patients with gender dysphoria (P = .011), need for sexual therapy (P = .0004), paraphilic disorders (P = .0003), and sexual dysfunction (P = .0017). CONCLUSIONS: Trainees and early-career specialists found sexual health training important for their future medical practice; however, less than half received it during their postgraduate training. Participants felt more confident in managing patients with sexual health problems when sexual health training was included in the postgraduate training program. Kristufkova A, Pinto Da Costa M, Mintziori G, et al. Sexual Health During Postgraduate Training-European Survey Across Medical Specialties. Sex Med 2018;6:255-262.

In vitro fertilization/intracytoplasmic insemination and thyroid function: reviewing the evidence.

Recent findings, that specific G protein-coupled TSH receptors (TSHR) and the nuclear thyroid hormone receptors (THRs) are widely expressed in reproductive tissues, reveal the close links between hypothalamus-pituitary-thyroid and hypothalamus-pituitary-gonadal axes. It has been suggested that thyroid function as well as thyroid autoimmunity (TAI) have an impact on Assisted Reproduction Technology (ART) reproductive outcome. Lately, it became evident that ovarian stimulation (OS) may also have an impact on thyroid function. This narrative review describes the mutual interaction between thyroid function and OS, by reviewing the current evidence, assessing the pathophysiological links and arriving at practical recommendations.